1

Chapter 1: Oxygen-Directed Hydroboration

1.1 The Versatility of Organoboranes

Organoboron species are among the most versatile functionalities in synthetic

chemistry. Aliphatic and alkenyl boranes can be oxidized to alcohols and carbonyl

groups, respectively.1 Aliphatic boranes can also be converted to amines

2 and are well

known for undergoing one-carbon homologation chemistry, allowing for installation of

formyl groups, esters, and nitriles.3-5

Transition metal catalysis greatly expands the

utiltity of organoboron chemistry. Palladium catalysis enables Suzuki cross-coupling

reactions with both aryl/vinyl6 and alkyl

7,8 coupling partners as well as with carbon

monoxide,9,10

while rhodium catalyzes addition of vinyl boranes to aldehydes.11-13

Trifuoroborate salts are more robust than other organoboron species, as they resist

oxidation upon exposure to air and even by dimethyldioxirane (DMDO), enabling

R

BXn

OH

RNHBn

R

R

NaOOHBCl3 , BnN

3

Rh0 , R

'CHO

OH

R'

Pd0, CO,

ROH

R

CO2R

R

BXnO

Pd0,

X

R

LiCCl2OMe

R

O

H

R

N ClCH2CN

DMDO

Scheme 1A: The Synthetic Transformations of Organoborons

1A1

1A2

1A3

1A4

1A5

1A6

1A7

1A8

2

oxidation of olefins in the presence of boron.14

What makes all of these boron species

even more attractive as synthetic intermediates is that they are all conveniently accessible

by hydroboration.

1.2 The Limitation of Steric and Electronic Influence on Intermolecular

Hydroboration Regioselectivity

Hydroboration is crucial for the synthesis of organoboranes, and involves the

syn-addition of a boron-hydrogen bond across a carbon-carbon multiple bond in a four-

membered transition state such as 1B2b.15

Intermolecular hydroboration of simple

olefins is controlled by the steric environment of the olefin in concert with its electronic

properties to provide anti-Markovnikov selectivity. The steric component of

regioselectivity reflects the smaller bulk of hydride compared to a BR2 moiety (R= alkyl

or H). Therefore, a borane (HBR2) preferentially approaches an olefin with boron at the

3

less hindered carbon. Electronic effects supplement the steric preference. The dipole of

a borane B-H bond provides the hydrogen with negative character and the boron with

positive character. The four-membered transition state features the hydride of the borane

forming a bond with the more substituted carbon, which favors having partial positive

character relative to the less substituted carbon.16

(Scheme 1B). The combination of

steric and electronic effects leads to excellent selectivity (19:1) with terminal olefins even

when R=H. Good selectivity is also achieved with trisubstituted olefins (98:2) and

2,2-disubstituted olefins (99:1). However, achieving regioselective hydroboration of a

1,2-disubstituted olefin remains an unresolved issue in the hydroboration literature. The

following chapter presents the reports in the literature that discuss the possibility of

affecting regio- and stereoselectivity by directing hydroboration with oxygen-containing

functionalities.

1.3 Mechanistic Proposals of Brown (Dissociative) and Pasto (Associative)

It has been proposed that intermolecular hydroboration can occur via either a

dissociative pathway or an associative pathway. The work of H. C. Brown et al. supports

a mechanism requiring that an uncomplexed trivalent borane be generated via

dissociation from either its dimer 1C1 or a Lewis-base complex 1C2, in order to react

with an olefin (Scheme 1C).17-20

There are several kinetic studies that report the

observation of first order (in dimer) and three-halves order (1/2 order in dimer) kinetics

for reactions of 9-BBN dimer with fast reacting and slow reacting olefins,

respectively.17-19

Another study using disiamylborane provides similar kinetic evidence

that dialkylboranes participate in hydroborations via a dissociative pathway.20

4

HB

HB

R

R

R

R

BH R

RLB

BHR

RLB

THF

BR2

Scheme 1C: Brown's Dissociation Pathway for Hydroboration17-20

BR2

BR2

1C1

1C2

1C3 1C4

1C5

1C5

H BR2

1C5

Compared to monoborane (BH3), dialkylboranes are much easier reagents with

which to conduct kinetic studies. This is due to the fact that BH3 reacts with alkenes to

form multiple alkylborane species RXBH(3-X), rendering kinetic data unclear. Despite this

setback, Brown initiated Lewis base concentration studies involving dimethylsulfide-

borane (Me2S·BH3; BMS) and triethylamine-borane (Et3N·BH3).21

A qualitative rate

reduction was observed upon increasing the concentration of excess Me2S and Et3N in

the reactions of their corresponding borane complex with 1-octene. This led Brown to

propose a dissociative mechanism for BH3, as a rate reduction under such conditions

would not be expected if an associative mechanism were in effect.

Pasto has published an alternative associative hydroboration mechanism,

proposing that THF remains complexed to boron while an olefin complexes to the boron

atom of THF·BH3 1D1 and undergoes hydroboration (Scheme 1D).22, 23

This mechanism

is supported by kinetic studies conducted with 2-methyl-2-butene and 1D1. In addition to

the observation of second order kinetics, first order in both olefin and borane, Pasto also

reports an entropy value of -27 ± 1 eu.22

The kinetic data support a mechanistic pathway

in which 1D1 is directly attacked by an olefin and the entropy value indicates that this

attack does not result in the displacement of THF. The mechanism has been supported by

5

several theoretical studies,24,25

including work by Schleyer, which supports ethylene

complexation to R2O·BH3 occurring in a SN2-like fashion.26

Scheme 1D: Pasto's Associative Mechanism for Hydroboration22,23

O B

H

H

H O B

H

H H

O B

H

H H

O B

H

H

1D1 1D2 1D3 1D4

1.4 Defining Oxygen-Directed Hydroboration

In order to discuss oxygen-directed hydroboration (ODHB), one must first

establish what is meant by „directed reaction‟. Whenever the incorporation of an oxygen

atom into a substrate affects the reactivity or selectivity of a transformation, one can

argue that the change is due to some form of oxygen direction. This is regardless of

whether the effect is due to the steric environment of oxygen or to an inductive or

resonance polarization effect the oxygen might impose upon the substrate.

For example, Brown refers to “directive effects in the hydroboration of substituted

styrenes” in a study reporting the effects of a methoxy group on regioselectivity

(Equation 1).27

Due to the planar structure of the fully conjugated system that separates

oxygen from the alkene-borane complex in the transition state with five bonds, these

6

results are due to the electronic perturbation placed on the substrate by remote oxygen.

“Directive Effects” is also the terminology used by Brown to describe the inductive

effects that chloride and tosylate groups have on the regioselectivity of a proximal

terminal alkene (Equation 2).28

For the purposes of providing a perspective on literature accounts of ODHB in the

following chapter, the definition of a directed reaction to be used will be that of Hoveyda,

Evans, and Fu:29

“Preassociation of the reacting partners either through hydrogen

bonding, covalent, or Lewis acid-base union is followed by the maintenance of this

interaction during the ensuing chemical transformation.” This is not to indicate that all

reports of ODHB to be discussed share(d) the same definition, but to establish a point of

reference for the discussion herein.

1.5 Oxygen Directed Hydroboration in the Literature

1.5i Ether Directed Hydroboration

Narutis et al. have recognized contrasting results in hydroboration studies

conducted by Gassman and Brown.30

Brown has reported that norbornene 1E5 provides

>99:1 exo-selectivity upon hydroboration/oxidation, while increasing steric bulk at C-7

via incorporation of a methyl group syn to the alkene (1E6) leads to 22:78 exo:endo

selectivity (Scheme 1E).31

However, Gassman has reported that 7,7-dimethoxy-

norbornene 1E1 undergoes hydroboration with THF·BH3 to provide a 78:22 exo/endo

mixture of alcohol 1E2 upon oxidative workup.32

This selectivity does not correspond

with Brown‟s steric argument. Narutis attributes the contrast of the 7,7-dimethoxy-

norbornene result to the formation of ether-borane complex 1E3 but a proposed

mechanistic pathway is not specified.30

7

Methyl ethers have also been reported as affecting the regioselectivity of the

hydroboration of E- and Z-methoxy-ene-ynes.33

Zweifel et al. have reported that treating

Z-methoxy-ene-ynes 1F1 and 1F5 with dicyclohexylborane (chex2BH) in THF leads to

preferential delivery of the boron to the alkyne carbon proximal to the methoxy group.

On the other hand, treating the corresponding E-substrates 1F4 and 1F8 under the same

conditions results in an increased preference for boron delivery to the distal alkyne

carbon. The authors rationalize the change in regioselectivities by invoking a transition

state 1F9, which illustrates the Z-methyl ether maintaining an interaction with chex2BH

while the B-H bond is added across the carbon-carbon triple bond (Scheme 1F). It should

be noted that the olefin geometry equilibrates to trans under the oxidation conditions,

after the hydroboration events.

8

H

OMe

H

H

OMe

H

Si

MeO

H

H

MeO

H

H

Si

1.chex2BH

THF2. NaOOH

MeO

H

H

O MeO

H

H O

MeO

H

H

O MeO

H

H O

MeO

H

H

Si

O

MeO

H

H

O

Si

MeO

H

H

Si

O

H

MeO

H

RBH

96 : 4

65 : 35

56 : 44

1 : 99

R' R'

Scheme 1F: Anomalous Hydroboration Results on Methoxy Ene-Ynes

1F1 1F2 1F3

1F4 1F2 1F3

1F5 1F6 1F7

MeO

H

H

O

Si

1F6 1F71F8

1F9

1.chex2BH

THF2. NaOOH

1.chex2BH

THF2. NaOOH

1.chex2BH

THF2. NaOOH

Results reported by Suzuki serve as evidence against ether complexation to a

hindered dialkylborane in an intramolecular hydroboration. In pursuit of avencolide,

Suzuki observed unexpectedly low anti-Markovnikov regioselectivity upon

hydroboration (THF·BH3)/oxidation (NaOOH) of a monosubstituted olefin 1G1. The

expected terminal alcohol 1G3 was isolated in 39% yield while the regioisomeric

secondary alcohol 1G4 was isolated in 31% yield. The authors attributed this unusual

result to a six-membered transition state 1G2. Interestingly, using a hindered

dialkylborane (chex)2BH exclusively provides the expected terminal alcohol in 86% yield

9

after oxidative workup. The steric bulk of the dialkylborane is believed to be responsible

for making the corresponding 1G2-like complex unfavorable, thus providing the

regioselectivity one would expect from intermolecular hydroboration. Jung et al. have

also discussed the possibility of benzyl ether-directed hydroboration with 5-benzyloxy-2-

heptene 1G5, which provides a 65:35 regioselectivity in favor of the 3,5-disubstituted

product 1G6 upon hydroboration with THF·BH3 followed by oxidative workup (Equation

3). ODHB was dismissed because no diastereoselectivity was observed.34

OBn OBn OBnOH

OH

THF·BH3

NaOOH

(3)

65 : 351G5 1G6 1G7

10

1.5ii Acetate Directed Hydroboration

There is one example of acetate-directed hydroboration proposed in the literature.

In the pursuit of epiallogibberic acid, House and Melillo treated the tetracyclic acetoxy

olefin 1H1 with disiamylborane, generating cis-diol 1H3 after oxidative workup.35

The

authors propose that the disiamylborane is “solvated” by the acetoxy group of the

substrate, which provides the diastereo- and regioselectivity (Scheme 1H). Jung et. al

have reported that hydroboration of 5-acetoxy-2-heptene 1H4 provides 3,5-diol 1H5 with

75:25 regioselectivity after oxidative workup (Equation 4), but ODHB was dismissed in

their report because no diastereoselectivity was observed.34

OAc OH OHOH

OH

THF·BH3

NaOOH

(4)

75 : 251H4 1H5 1H6

1.5iii Alcohol Directed Hydroboration

Several diastereoselective hydroboration results have been attributed to alcohol

direction. Results reported by Bryson in the pursuit of helenalin are the most intriguing.36

Unsaturated alcohol 1I1 was treated with either THF·BH3 or thexylborane (ThxBH2),

generating respective 1:7 and 1:11 ratios of diastereomeric diols 1I3 and 1I4. On the

other hand, treating unsaturated iodide 1I5 with THF·BH3 generates a 4:1 ratio of

11

diastereomers 1I6 and 1I7. This reversal of diastereoselectivity was attributed to an

intermediate monoalkoxyborane that reacts via the bridged bicyclic transition state 1I2.

The proposal of an intramolecular hydroboration via a thexylalkoxyborane is supported

by the work of Cha et al., who have reported that such species are viable reagents for

intermolecular hydroboration, even of substrates even as hindered as 2,4,4-trimethyl-2-

pentene (Scheme 1I).37

Ohloff et al. have reported an outstanding level of diastereoselectivity achieved by

the hydroboration of isopulegol 1J1 (Scheme 1J).38

The authors attribute a 19:1 ratio of

1,4-diols 1J3 and 1J4 to an intramolecular transition state 1J2 involving a

dialkoxyborane intermediate. However, the dialkoxyborane intermediate was not

observed and the authors did not comment on the low reactivity of the known

dialkoxyboranes 1J5 and 1J6. They did show that the same product ratio was obtained

12

starting from the corresponding isopulegyl borate [(RO)3B] and diborane, evidence that a

disproportionation product is the species responsible for hydroboration.

A variant of the dialkoxyborane species invoked by Ohloff for intramolecular

hydroboration was also proposed by Panek et al. in an unconventional approach to

ODHB.39

They reported a unique result involving diastereoselective hydroboration of

-methoxy--unsaturated esters with dimethylsulfide borane (BMS). The

hydroboration is accompanied by reduction of the ester functionality. Low temperature

studies revealed that ester reduction uncharacteristically precedes hydroboration, which

the authors attribute to an activating effect of the -alkoxy group.40

It was proposed that

the dialkoxyborane 1K2, generated from ester reduction, is the species that undergoes

subsequent intramolecular hydroboration to provide diastereoselectivity opposite to that

predicted by the Kishi model for intermolecular hydroboration.41

Treating the alcohol

analog of 1K1 (1K4) with BMS resulted in neither regio- nor diastereoselectivity. Thus,

the entire -alkoxy-homoallylic ester is apparently the requisite moiety for achieving

selectivity even though the hydroboration itself is proposed to be alkoxy-directed.

In pursuit of (+)-mikrolin 1L3, Smith et al. demonstrated that diastereoselective

hydroxyl-influenced hydroboration is not a consistent phenomenon. In an attempt to

13

synthesize diol 1L2, the homoallylic alcohol 1L1 was treated with an unspecified

hydroborating agent, but 1L2 was not formed (Scheme 1J).42

This demonstrates that the

results reported by Bryson and Ohloff do not represent a general trend. Jung et al. points

out that an alcohol group influences the hydroboration of acyclic 5-hydroxy-2-heptene

1L4, which provides 3,5-diol 1L5 with 73:27 regioselectivity. However, no

diastereoselectivity was observed, which is consistent with Jung‟s ether and acetoxy

results in Equations 3 and 4, so ODHB was dismissed as before.34

OH OH OHOH

OH

THF·BH3

NaOOH

(5)

73 : 271L4 1L5 1L6

14

1.6 Discussion

Theoretically, ODHB can be broken down into three simple processes: 1) a Lewis

acid-base interaction forms an oxygen-borane complex 1M2, 2) an olefin tethered to the

boron-complexed oxygen forms a complex to the borane 1M3, and 3) a B-H bond

adds to the C=C bond. There are multiple reactions with which it remains unclear how

an oxygen can affect the regio- and/or stereocontrol of the transformation without an

interaction with borane (Scheme 1M).

There are two important issues to consider in order to relate section 1.5 to Scheme

1M: 1) how feasible is the formations of each proposed borane species? and 2) how

viable an agent is each intermediate for its corresponding transformation to the next

stage? For each case, these issues revolve around the directing group in question and

how it relates to the mechanistic proposals of Brown and Pasto.

1.6i Intramolecular Hydroboration with Alkoxyboranes

Mechanistically, the proposed transitions states of Bryson (1I2) and and Ohloff

(1J2) are distinct from other oxygen-directed hydroborations. Each alcohol has reacted

with borane to generate an alkoxyborane that resembles Panek‟s transition state structure

1K2. Boranes are well known for reacting with alcohols to form alkoxyboranes, as

illustrated by the Cha results (Scheme 1L), so the formation of alkoxyboranes is not

controversial.37

The important question in this context is whether the resulting species

15

have sufficient reactivity for intramolecular hydroboration, despite the covalent

interaction between boron and oxygen in these structures. Since a Lewis base-borane

complex is no longer the proposed hydroborating species, the mechanistic proposals of

Brown and Pasto no longer apply and there is no problem regarding transition state

bonding. On the other hand, the issue of boron electrophilicity and reactivity remains

critical.

Bryson‟s proposed intramolecular reaction of a monoalkoxy-alkylborane 1I2 is

the most convincing example of an oxygen-directed internal hydroboration. One would

expect the intermediate monoalkoxyborane to have reactivity between that of BH3 and a

dialkoxyborane, and Cha‟s demonstration that alkenes are hydroborated by

thexylalkoxyboranes provides evidence that one alkoxy group does not reduce the

electrophilicity of boron sufficiently to prevent hydroboration.37

Therefore, Bryson‟s

proposal that an oxygen-directed hydroboration occurs with thexylborane is consistent

with the literature precedent.

Another study by Cha et al. investigated the reactivity of thexylalkoxyboranes

1I10 with simple alcohols.43

Hydrogen evolution studies demonstrated that a

stoichiometric amount of various alcohols does not react quantitatively, and that

conversion correlates to the steric bulk of the alcohol used. While they state, “it is best to

defer for the present consideration of the reason why the hydrogen evolution stops

beneath the stoichiometric point,” there appears to be something unique involved with the

incorporation of the thexyl group on boron, considering that it is well known that treating

boranes with alcohols easily forms borates,44

boronates,45

and borinates.46

If the thexyl

group is the key to forming monoalkoxyborane species, Cha‟s work suggests that

16

diastereoselective reaction using THF·BH3 may reflect additional unknown factors that

influence the product ratio. However, this does not rule out participation by an

alkoxyborane 1I2 (R=H).

The case for internal hydroboration via dialkoxyboranes is less strong. As already

mentioned in connection with Scheme 1J, pinacolborane 1J5 and catecholborane 1J6, are

relatively unreactive, respectively requiring heating to 40 °C and 80 °C in order to

hydroborate olefins without metal catalysis.47,48

This is due to two covalently bound

oxygens that donate electron density to the empty p-orbital of boron, rendering it pseudo-

tetravalent and less electrophilic. The behavior of 1J5 and 1J6 raises questions about the

feasibility of an intramolecular hydroboration via dialkoxyborane.

A plausible argument that one might be tempted to make in defense of a room

temperature intramolecular hydroboration with a dialkoxyborane is that the

intramolecular nature of the transformation could provide enough of an entropic

advantage to overcome the diminished electrophilicity of the dialkoxyborane. However,

if this were the governing principle behind such results, ODHB would be a more

common occurrence in the literature. If the entropic advantage of intramolecularity is

large enough, then the mono- and/or dialkoxyboranes generated upon treating unsaturated

alcohols such as Panek‟s 1K4 with BMS would result in regioselective hydroboration.

No such selectivity was observed (Scheme 1K). Additionally, work by Heathcock

indicates that not only is selectivity not achieved upon treating an unsaturated alcohol

with an equivalent of borane, but no reaction is even observed.49

Evidently, other

unknown factors also play a role, culminating in results that are highly substrate

dependant.

17

1.6ii Ether and Acetoxy Direction

Ether/acetoxy directed hydroboration is a more difficult phenomenon to account

for compared with alkoxy direction. Compared with alkoxyboranes, ether-borane

complexes (1M2, R=alkyl) are more transient species in oxygenated solvents due to the

facile equilibrium with the solvent-borane complex. This disadvantage for an ensuing

intramolecular process is supplemented by the fact that there is no clear rationalization

that explains how an unsaturated ether-borane 1M2 can both 1) remain intact and 2) react

with alkene to provide selectivity in the product mixture 1M4. Despite this lack of

understanding, ODHB remains a tempting explanation for the results of Gassman,

Zweifel, and Suzuki, due to the absence of obvious controlling steric and/or electronic

factors.

Ether-borane complexes are well precedented species so there is no doubt that an

ether-containing substrate could form a complex to BH3. According to calculations

published by Rauk et al., dimethylether has a greater affinity than methyl acetate for

boron trifluoride (BF3) (71 kJ/mol vs. 58 kJ/mol).50

This suggests that an acetoxy group

would form a weaker complex to borane than would an acyclic ether. The same study

reports an 82 kJ/mol affinity between THF and BF3. These affinity values raise a

question that challenges the proposals of Narutis, Zweifel, Suzuki, and House: how can

the complexes 1E3, 1F9, 1G2, and (the precursor to) 1H2 form when THF or diglyme is

being used as the reaction solvent?

The Brown or Pasto mechanisms are not consistent with an ensuing ODHB once

the ether-borane complex 1M2 is formed. Brown‟s dissociative mechanism (Scheme 1C)

can account for the formation of -complex 1M3, but not for any selectivity observed in

18

the subsequent hydroboration, as oxygen does not interact with boron in the transition

state. Pasto‟s associative mechanism (Scheme 1D) cannot be applied because it is

constrained by the geometric requirements imposed upon intramolecular SN2-like

transformations, as reported by Beak51

and Baldwin (Scheme 1N).52

OMe

R

B H

H

H

O B

H

H H

Me

'5.5'-Endo-Tet

disfavored

RO

Me

R

BH2O B

H

H H

Me

Scheme 1N: Intramolecular variant of Pasto's Mechanism Conflicts with Geometric Restrictions

1N1 1N2 1N3 1N4

The reports by Zweifel (Scheme 1F) and Suzuki (Scheme 1G) include particularly

intriguing proposals of ODHB and steric effects cannot account for the surprising

regioselectivities. However, oxygen has been proposed to influence the selectivity of

hydroboration with a variety of effects, and alternative explanations are worth evaluating,

since ODHB has proven so difficult to rationalize in the context of ether-direction.

Inductive effects have been investigated in depth by Brown with acyclic allyl,

homoallyl, and crotyl derivatives (Table 1O).28,53,54

Alcohols, ethers, chorides, triflates,

and trifluormethyl groups clearly reduce the anti-Markovnikov regioselectivity achieved

with propene, and increase delivery of borane to C-2 in the crotyl environment (R1=

CH3). The same substituents also work against the normal anti-Markovnikov

regioselectivity of the allylic examples (terminal alkene, R1= H). The extent of the effect

is related to the electron withdrawing capability of the X group, as the trifluoromethyl

group (m = 0.46) effects selectivity more than chloride (m = 0.37). In both the crotyl

and allyl systems, the allylic heteroatom promotes hydroboration at the nearest alkene

carbon relative to the all-carbon analogies. A similar trend is also reported with

substituted styrenes.27

The same trends in the context of 3- and 4- methoxy-cyclohexanes

19

R1 X R1 X R1 X

OH

OHBH3·THF

NaOOH

1O1 1O2 1O3

Table 1O:Inductive Effects of Allylic, Crotylic, and Homoallylic Groups on Hydroboration Regioselectivity

Entry R1 X 1O2 : 1O3 Entry R

1 X 1O2 : 1O3

1 CH3 CH3 50 : 50 8 CH3 OPh 86 : 14

2 H CH3 6 : 94 9 H OPh 14 :86

3 H CH2CH3 7 : 93 10 H CH2OPh 13 : 87

4 CH3 OH 90 : 10 11 CH3 Cl 100 : 1

5 H OH 22 : 72 12 H Cl 40 : 60

6 H CH2OH 14 : 86 13 H CH2Cl 18 : 81

7 H OTf 45 : 55 14 H CF3 74 : 26

are shown in Table 1P, accompanied by anti-diastereoselectivity, which indicates no

complexation between borane and the heteroatom substituted styrenes.27

The same trends

in the context of 3- and 4- methoxy-cyclohexanes are shown in Table 1P, accompanied

by anti-diastereoselectivity, which indicates no complexation between borane and the

heteroatom.

R3

R2 R2

R3

OH

R2

R3

OH

1P1 1P2 1P3

BH3·THF

NaOOH

R1 R1 R1

Table 1P: Allic vs. Homoallyic Effects in Cyclohexene Systems

Entry R1 R2 R3 1P2 : 1P3 trans- : cis- (1P2)

155 H H Cl 96 : 4 89 : 11

255 H H OMe 91 : 9 89 : 11

356 -C(O)N(Me)OMe H OMe “95 : 5” 95 : 5

457 -CH2SO2Ph H OMe 88 : 12 99 : 1

555 H OMe H 56 : 44 61 : 39

Steric interactions provide negligible hindrance to the hydroboration directing

effect of allylic electron-withdrawing groups. Brown has reported that crotyl alcohols,

ethers, and chlorides direct boron delivery to the proximal alkene carbon with

20

dialkylborane reagents disiamylborane and 9BBN (Table 1Q, entries 1-5).58

Gung et al.

have shown that the added bulk at the carbinol carbon of 1-tBu-crotyl alcohol does

nothing to prevent boron incorporation of either BH3 or thexylborane at the proximal

carbon with complete regioselection (Table 1Q, entries 6&7).59

Gung invokes transition

state 1Q4 to propose that hyperconjugation contributes to the excellent regioselectivity

reported, and this is consistent with the data. However, the consistent trend in allylic

examples is that regioselectivity is directly related to the electron withdrawing capability

of the substituent, which polarizes the double bond such that it resists steric preferences.

The same effect is seen in the homoallylic examples, although it is smaller. Cyclic

carbamates are also capable of inductively influencing hydroboration, according to a

report by Sibi, in which the regioselectivity is attributed to the electron withdrawing

capability of the allylic nitrogen (Equation 6).60

There could also be a small contribution

from the homoallylic oxygen in Sibi‟s system.

21

Me X Me X Me X

OH

OH1.R2BH

2. NaOOH

1Q1 1Q2 1Q3

R1 R1

Table 1Q: Hydroboration of Allylic Derivatives vs. Reagent Steric Demand

R1

OHt-Bu

H B HR

R

1Q4

Entry X R1 HB Reagent 1Q2 : 1Q3

158 OH H Sia2BH 87 : 13

258 OH H 9BBN 100 : 0

358 OMe H 9BBN 92 : 8

458 Cl H Sia2BH 100 : 0

558 Cl H 9BBN 100 : 0

659 OH tBu BH3 100 : 0

759 OH tBu ThxBH2 100 : 0

THF·BH3

NaOOH

1R6 X=Boc 20:1 regioselectivity, 16:1 anti-: syn-1R7 X= H 15:1 regioselectivity, 3.4:1 anti-: syn-

C14H29NXO

O

1R4 X= H1R5 X= Boc

C14H29

NXO

O

OH

C14H29

NXO

O

OH(6)

Inductive effects are evident in acyclic substrates (Tables 1O & 1Q; Equation 3),

and cyclic systems (Table 1P), indicating that the conformational mobility is not crucial

for regioselective hydroboration. Keese et al. provide reinforcing evidence in a report on

the hydroboration of 1-substituted norborn-2-enes (Table 1S).61

In this conformationally

locked system, allylic electron withdrawing groups, including methoxy (entry 5),

maintain a significant effect on hydroboration regioselectivity, and the authors point out

that these results indicate that conformational mobility does not play a dominant role in

achieving regioselectivity.

22

Entry X 1R2 : 1R3

1 Cl 74 : 26

2 Br 68 : 32

3 I 65 : 35

4 CH3 52 : 48

5 OMe 75 : 25

6 CH2OMe 54 : 46

Taking these reports into consideration, the Zweifel results remain fascinating

because two similar enyne substrates provide such contrasting results (Scheme 1F).

Inductive effect arguments do not apply because there is no difference in oxygen-olefin

tether length. Switching enol ether geometry could perturb the resonance interaction

between alkyne and methoxy, but one would expect effective electron donation from the

methoxy group in both geometries due to the planar, unhindered nature of the molecules.

Through-space oxygen-olefin orbital interactions have been invoked as a rationalization

for stereoselectivity of hydroboration,34,62

but no report has been found in which it has

been invoked to explain regioselectivity. Brown‟s work with ortho-methoxy-styrene

provides indirect evidence that a through space effect does not account for Zweifel‟s

regioselectivity, because the o-methoxy group leads to increased delivery of boron to the

distal carbon in a „Z-methoxy-ene‟ system (Equation 7). This is attributed to the

resonance electron donating effect of oxygen.

23

XTHF· BH3

NaOOH

X XOH

OH

X=H 18 : 82X=OMe 12 : 88

(7)

Inductive effects must contribute to the reduced anti-Markovnikov selectivity

reported by Suzuki with terminal alkene G1. Allylic and homoallylic electron

withdrawing functionalities consistently provide a preference for delivery of boron to the

proximal alkene carbon. While the influence of a homoallylic substituent is weaker, it can

still be significant. Table 1O, entry 14 shows that three homoallylic fluorines cause a

reversal in selectivity from 1:19 to 3:1 relative to 3 hydrogen atoms. Approximation

using the Boltzmann equation indicates that this is a ca. 2.4 kcal/mol perturbation in G≠,

meaning that each fluorine contributes a noteworthy ~0.8 kcal/mol. Homoallylic ethers

have been shown to influence regioselectivity by ca. 0.1-0.4 kcal/mol (Equation 3; Table

1O, entry 10; Table 1P, entry 5; Table 1S, entry 6) and bishomoallylic ethers, such as the

one in of G1, can also be expected to provide an influence. A Serratosa report also

indicates that a homoallylic acetonide, analogous to the one incorporated into G1,

provides an inductive effect (Equation 8),63

which correlates with Jung‟s homoallylic

ether results (Equation 3). If excess borane is used, one could argue complexation of the

alkoxy groups may lead to greater inductive effects, but this cannot be corroborated by

the experimental details provided. Furthermore, complexation would be reversible, so at

least some of the uncomplexed alkoxy substrate would be present and react faster.

Regardless of these details, questions remain regarding the role of inductive effects, and

whether they alone can account for the reported product mixture.

24

RR

RRHO

THF·BH3

NaOOH

1 : 1 R=R1 =H

2 : 1 R,R1= -OCH2C(Me)CH2O-

R1

RHO

(8)

Whatever the phenomena responsible for ether direction, they are not well

understood and are most likely unique in each case. Through-space orbital interactions

cannot be ruled out completely, but their effect(s) on regioselectivity is as poorly

established as that of OHDB. Thus, there is no conspicuous conclusive evidence to

oppose the ODHB proposals of Zweifel and Suzuki, despite the fact that the mechanistic

pathway(s) remain a mystery. On the other hand, inductive effects cannot be dismissed

as a contributing factor, Zweifel‟s methoxy-ene-ynes not-withstanding.

1.7 Summary of Uncatalyzed Oxygen-directed Hydroboration

Oxygen-directed hydroboration (ODHB) has been a casually invoked concept in

synthetic organic chemistry literature for rationalizing a variety of anomalous regio- and

stereochemical results. The reality is that, beyond some intriguing empirical indications,

there is underwhelming evidence to support a conclusion that ODHB has ever occurred in

any general sense. This does not eliminate the possibility that ODHB is, in fact,

responsible for some of the results presented, nor can it be said that the mechanistic

proposals of either Brown or Pasto provide conclusive insight into how such

transformations transpire.

25

1.8 Metal-Catalyzed Oxygen-Directed Hydroboration

Transition metal-catalyzed hydroboration is a relatively recent development in

hydroboration methodology that provides a mechanistically more straightforward

approach to achieving a directed hydroboration. The inability of the Brown and Pasto

mechanisms to account for oxygen-borane complexes undergoing intramolecular

hydroboration is not a concern in the context of metal catalysis. Transition metals can

insert into the B-H bonds of relatively unreactive dialkoxyboranes such as pinacolborane

and catecholborane.64,65

An olefin can then complex to the metal rather than to boron.

The metal-hydride bond is added across the olefin, followed by reductive elimination to

form the C-B bond, thus achieving a net hydroboration (Scheme 1O). Several studies

have taken advantage of an oxygen atom tethered to the olefin in order to direct the M-H

addition across the olefin by complexing to the metal (Scheme 1T).

26

1.8i Transition Metal Catalysis of Directed Hydroboration

In 1988, Evans specifically targeted alcohol-directed hydroboration in the context

of transition metal catalysis.66

While rhodium(I) successfully promotes the

hydroboration of olefins by catecholborane, alcohols are not viable substrates under such

conditions because they form borates with catecholborane, precluding the desired

transformation. A “net hydroxyl-directed”67

variant was pursued in which the hydroxyl

groups were protected as diphenylphosphites and submitted to the reaction conditions,

resulting in excellent diastereoselectivity. The phosphites were cleaved upon oxidative

workup to generate diol products, which were assayed after acylation (Scheme 1U). The

major limitation of this work was that it required stoichiometric amounts of Wilkinson‟s

catalyst.

Evans et al. improved upon these results several years later by introducing the

first catalytic directed hydroboration using secondary amides as directing groups under

conditions requiring only 5 mol % of iridium catalyst.67

Good diastereoselectivity (91:9)

was achieved on cyclic systems and excellent regioselectivity (99:1) was achieved on

homoallylic amides (Scheme 1V).

27

Fu developed a method in which catalytic rhodium is viable for benzyl ether-directed

hydroboration of a cyclic olefin. The key to this work is the exploitation of ring slippage

in the indenyl ligands on rhodium.68

Ring slippage is a phenomenon observed with

cyclopentadienyl-type ligands in which there is interconversion between 5- and 3

-

complexation to a metal. This conversion to 3-complexation creates an additional

coordination site on (Ind)Rh(C2H4)2, allowing the coordination of both benzyl ether and

olefin components of 4-benzyloxy-1-cyclohexene 1W1 to rhodium. Hydroboration

ensues and oxidative workup provides a mixture of 1W2 and 1W3 isomers, as illustrated

in Table 1W. A solvent study demonstrated that a less coordinating solvent improves

diastereoselectivity, as hexane and CH2Cl2 provide respective diastereoselectivities of

82:18 and 79:21 (Entries 1 & 2) while THF provides only 62:38 diastereoselectivity

(Entry 3). The >10:1 ratios of cis-1,3- : cis-1,4-monoprotected diols in both hexane and

CH2Cl2 are indicative of an ether-directed reaction. A screen of several cyclopentadienyl

28

ligands was also reported. Based on the idea that selectivity is directly proportional to a

ligand‟s propensity for ring slippage, entries 4-7 illustrate that the indenyl ligand has the

best combination of 5- vs 3

- binding and compatibility with other variables.

Entry CpX (mol %) Solvent cis-1R2 cis-1R3 trans-1R2 trans-1R3

1 Indenyl (10) hexane 75 7 7 11

2 Indenyl (10) CH2Cl2 74 5 8 13

3 Indenyl (10) THF 47 15 23 15

4 Indenyl (2.5) 75 7 8 11

5 1,2,3-Me3-indenyl (2.5) 65 10 12 13

6 Cp (2.5) 30 28 30 12

7 Cp* (2.5) 26 29 33 12

Recognizing that three electron donating methyl groups in the indenyl ligand

caused a decrease in selectivity in Fu‟s work, Sowa Jr. et al. pursued increased selectivity

by investigating indenyl ligands incorporating electron withdrawing groups.69

Entries

1-4 of Table 1X illustrate that both diastereo- and regioselectivity (of cis-isomers) are

improved upon using 1-trifluormethylindenyl, 2-trifluormethylindenyl, or

1,3-(bis)trifluoromethylindenyl ligands on rhodium. Corresponding iridium catalysts

were also screened with the same ligands, demonstrating superior selectivities. The best

selectivity was achieved using the most electron deficient indenyl ligand on Ir(COD)

(Entry 8). Coupled with the reports by the Evans group, these results show that iridium is

superior to rhodium in terms of reactivity and selectivity.

29

Entry M CpX (mol %) cis-1R2 cis-1R3 trans-1R2 trans-1R3

1 Rh Indenyl 74 11 9 6

2 Rh 1-CF3-Indenyl 81 6 10 4

3 Rh 2-CF3-Indenyl 81 6 9 4

4 Rh 1,3-(CF3)2-Indenyl 84 3 8 5

5 Ir Indenyl 93 <1 5 2

6 Ir 1-CF3-Indenyl 96 <1 2 2

7 Ir 2-CF3-Indenyl 96 2 2 <1

8 Ir 1,3-(CF3)2-Indenyl 98 2 <1 <1

A report by Gevorgyan et al. adds esters to the list of oxygen-containing

functionalities that direct transition metal-catalyzed hydroboration, which already

includes phosphites, amides, and ethers. Using pinacolborane 1J5 and [Rh(COD)Cl]2,

>99:1 cis diastereoselectivity was achieved with 3,3-disubstituted cyclopropenes.70

Adding (R)-BINAP to the reaction mixture provided excellent enantioselectivity (Table

1Y) .

Entry R R1 cis/trans ee (%) abs. config Yield (%)

1 Me Me >99 : 1 94 1S,2R 94

2 Et TMS >99 : 1 97 1R,2R 99

3 Me Ph >99 : 1 92 1S, 2R 99

30

1.8ii Lanthanide Catalysis in Alcohol-Directed Hydroboration

The previous section has illustrated that a variety of oxygen-containing groups

can direct transition metal-catalyzed hydroboration. However, the only report in the

literature in which conditions compatible with free hydroxyl groups are reported requires

the use of a lanthanide. Evans et al. reported that samarium triiodide (SmI3) can catalyze

the hydroboration of olefins by catecholborane and this methodology was applied to a

homoallylic alcohol to test whether or not oxygen direction could be achieved.71

This

method generated 1,3-pentane-diol with 11:1 regioselectivity from 3-penten-1-ol after

oxidative workup (Scheme 1Z) but the mechanism remains unclear. The authors

acknowledge that ODHB is not confirmed by this result and, as an alternative to the

mechanism one depicted in scheme 1T, they present activated catecholborane 1Z4 as a

potentially relevant species in the hydroboration event(s). No other substrates were

investigated.

31

1.8iii Copper Catalyzed Hydroboration

Hoveyda has reported interesting results with copper-catalyzed hydroboration of

oxygenated alkenes using N-heterocyclic carbene (NHC) complexes.72

Using copper

complex 1AA2, delivery of pinacolatoboron to the -carbon of a variety of oxygenated

styrenic olefins is achieved with >98:<2 regioselectivity (Table V). Using the chiral

NHC 1AA3 provides identical regioselectivity with enantioselectivities as high as 96%

ee. Applying this methodology to non-oxygenated substrates provides identical

regioselectivity, as do other metal-catalyzed hydroborations of styrenes.73

Therefore,

these transformations need not be oxygen-directed and the authors do not propose that

they are. However, the compatibility with the alcohol substituent makes them unique

(entries 4 & 7) in that they might succeed where rhodium has failed66

in providing a

method for directed hydroboration of aliphatic unsaturated alcohols

Entry Catalyst R1 R2 X Solvent Regioselectivity Yield (%) ee (%)

1 1AA2 H CO2Me Na THF >98 : <2 76 -

2 1AA2 H OAc Na THF >98 : <2 82 -

3 1AA2 Me Me Na THF >98 : <2 96 -

4 1AA2 H H Na toluene >98 : <2 80 -

5 1AA3 H Me K THF >98 : <2 75 96-R

6 1AA3 Me Me K THF >98 : <2 51 89-R

7 1AA3 H H K THF >98 : <2 74 96-R

32

1.9 Oxygen-Directed Hydroboration: A Mechanistic Enigma

Several examples of transition metal-catalyzed hydroboration have been presented

above. The mechanisms of these reactions are easily understood compared to the

mechanism(s) of the proposed uncatalyzed ODHB reactions discussed in sections 1.3-1.5.

On the other hand, while the net result of these catalyzed reactions is indeed

hydroboration, the directed aspect of the reaction is the hydrometalation step. Therefore,

it remains debatable whether or not any oxygen-directed hydroboration is well

understood.

33

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63. Carceller, E.; Castello, A.; Garcia, M. L.; Moyano, A.; Serratosa, F.

Regioselective Functionalization of Cis-Bicyclo[3.3.0]octenone Derivatives.

Oxymercuration/Reduction versus Hydroboration/Oxidation. Acetal Groups as

Regioselective and Stereoselective Control Elements. Chem. Lett. 1984, (5), 775.

64. Kono, H.; Ito, K.; Nagai, Y. Oxidative Addition of 4,4,6-Trimethyl-1,3,2-

dioxaborinane and Benzo[1,3,2]dioxaborole to

Tris(triphenylphosphine)halogenorhodium. Chem. Lett. 1975, (10), 1095.

65. Crudden, C. M.; Hleba, Y. B.; Chen, A. C. Regio- and Enantiocontrol in the

Room-temperature Hydroboration of Vinyl Arenes with Pinacol Borane. J. Am.

Chem. Soc. 2004, 126, 9200.

66. Evans, D. A.; Fu, G. C.; Hoveyda, A. H. Rhodium(I)-Catalyzed Hydroboration of

Olefins- The Documentation of Regiochemical and Stereochemical Control in

Cyclic and Acyclic Systems. J. Am. Chem. Soc. 1988, 110, 6917.

67. Evans, D. A.; Fu, G. C.; Hoveyda, A. H. Rhodium(I)-Catalyzed and Iridium(I)-

Catalyzed Hydroboration Reactions - Scope and Synthetic Applications. J. Am.

Chem. Soc. 1992, 114, 6671.

68. Garrett, C. E.; Fu, G. C. Exploiting (5)- to (3)-indenyl ring slippage to access a

directed reaction: Ether-directed, rhodium-catalyzed olefin hydroboration. J.

Org. Chem. 1998, 63, 1370.

69. Brinkman, J. A.; Nguyen, T. T.; Sowa, J. R. Trifluoromethyl-substituted indenyl

rhodium and iridium complexes are highly selective catalysts for directed

hydroboration reactions. Org. Lett. 2000, 2, 981-983.

70. Rubina, M.; Rubin, M.; Gevorgyan, V. Catalytic enantioselective hydroboration

of cyclopropenes. J. Am. Chem. Soc. 2003, 125, 7198.

71. Evans, D. A.; Muci, A. R.; Sturmer, R. Samarium(III)-Catalyzed Hydroboration

of Olefins with Catecholborane- A General Approach to the Synthesis of Boronate

Esters. J. Org. Chem. 1993, 58, 5307.

39

72. Lee, Y. M.; Hoveyda, A. H. Efficient Boron-Copper Additions to Aryl-Substituted

Alkenes Promoted by NHC-Based Catalysts. Enantioselective Cu-Catalyzed

Hydroboration Reactions. J. Am. Chem. Soc. 2009, 131, 3160.

73. Burgess, K.; Ohlmeyer, M. J. Transition-Metal Promoted Hydroborations of

Alkenes, Emerging Methodology for Organic Transformations. Chem. Rev. 1991,

91, 1179.

40

Chapter 2: Metal-Free Oxygen-Directed Hydroboration

2.1 A New Approach to Heteroatom-Directed Hydroboration

Despite repeated efforts over many years and several tantalizing empirical results

that suggest oxygen-directed hydroboration (ODHB), definitive examples of this process

remain elusive.1-13

Evans‟ metal catalyzed reactions of catecholborane with several

unsaturated alcohols, phosphinites, and carboxamides are the only methods known to

date with established synthetic potential for a range of substrates.2-5

Another case of

ODHB involving an -methoxy--unsaturated ester was encountered by Panek et al.6,13

using Me2S·BH3 (BMS). This example approaches the regioselectivity of the Evans result

with a homoallylic alcohol (8:1 vs. 11:1), but appears to be a special case reflecting

unusual reactivity due to the combined presence of an ester and an alkoxy group in the

starting material. The other historical examples reveal interesting perturbations of

hydroboration stereoselectivity or regioselectivity by oxygen substituents,7-12

but these

reactions generally do not give useful product ratios. The purpose of the work described

in this chapter is to demonstrate a mechanistically distinct version of ODHB using metal-

free conditions that provide regiocontrol in the hydroboration of generic homoallylic

alcohols.

The dissociative mechanism of hydroboration presented by Brown and widely

accepted by the chemical community suggests that heteroatom-directed hydroboration is

not possible, in that it requires a trivalent borane species to form via dissociation from a

Lewis base complex before it can react with an olefin (Scheme 2A).14-19

On the other

hand, Pasto has reported an associative mechanism that involves an olefin complexing to

a borane and undergoing hydroboration while the borane maintains an interaction with a

41

Lewis base (Scheme 2B).20,21

This lesser-known mechanistic proposal has received

support in the literature22-24

and is one source of inspiration for the pursuit of

intramolecular hydroboration via activation of heteroatom-borane complexes.

Another source of inspiration is a study by Schleyer et al., who have supported an

SN2-like complexation of an olefin to a borane-Lewis base complex as the mechanism for

intermolecular hydroboration.22

The simplest version of this reaction cannot occur

intramolecularly in a 5- or 6-membered cyclic transition state, based on the work of

Beak25

and Baldwin,26

because the 180° orbital geometry required to form the trigonal

bipyramidal SN2 transition state via 5-endo-tet and 6-endo-tet transition states is

disfavored. Therefore, the „5.5-endo-tet’ transition state 2C2 necessary to invoke an

42

intramolecular variant of Pasto‟s mechanism is also disfavored. On the other hand,

5-exo-tet and 6-exo-tet processes are highly favored in contrast to the 5-endo-tet and 6-

endo-tet. Thus, if one could introduce an exo-leaving group on boron, then the concepts

put forth by Pasto and Baldwin would no longer be dissonant in the context of an

intramolecular hydroboration pathway (Scheme 2C). Previous work in the Vedejs group

investigated the effects of introducing such a leaving group into homoallylic amine-

borane systems with good results, as described below.27,28

Homoallylic amine-iodoboranes 2D3 were generated by activating purified

amine-boranes 2D1 with iodine (I2) according to the work of Ryschkewitsch.29

These

amine-iodoboranes, while designed to allow intramolecular olefin-borane complexation

via an SN2-like associative pathway, might also achieve the desired complex 2D5 via a

dissociative SN1 pathway (Scheme 2D), although no evidence for this was found. Once

the intramolecular -complex 2D5 is formed, hydroboration can occur by either a fused-

(2D8) or bridged (2D7) bicyclic transition state to generate 1,3- and 1,4-aminoalcohols

2D11 and 2D10, respectively, upon oxidation. The kinetic advantage of 5-membered

ring formation, and the greater thermodynamic stability of the fused bicyclic transition

state 2D8, led to the prediction that 1,3-aminoalcohols 2D11 would predominate in the

product mixture. The expected selectivity was observed: up to >20:1 selectivity was

achieved with both E- and Z-1,2-disubstituted olefin substrates.27,28

In the case of a

terminal olefin, anti-Markovnikov selectivity was drastically reduced from 1:19

(expected with THF·BH3)30

to 1:3. Furthermore, -substituted styrene (R=Ph) provided a

2:1 preference for the 1,3-amino-alcohol 2D11 after oxidative workup, in contrast to the

typical 1:5 ratio expected for -substituted styrene.30

43

2.2 Regioselectivity via Metal-Free Alcohol-Directed Hydroboration

The goal of the work reported in the remainder of this chapter was to develop a

metal-free method for oxygen-directed hydroboration through application of the amine-

direction precedents to the hydroboration of homoallylic alcohols, alkoxides, and ethers.

The investigation began with a focus on alcohol-directed hydroboration.

While an analogous activation approach for alcohol-directed hydroboration using

a potentially exocyclic leaving group might appear to be facile (Scheme 2E), amine-

44

borane and alcohol-borane complexes are very different in terms of stability. This leads

to restrictions on the alcohol system that were of no concern in the amine system. While

many amine-boranes can be generated by stirring the amine with THF·BH3 and then

purified by chromatography or crystallization, these are not options for alcohol-boranes

in the context of ODHB. Alcohol-boranes spontaneously evolve hydrogen gas at or

below room temperature to generate the presumably undesired alkoxy boranes

RO(3-n)BH(n), thereby eliminating the option of purification by chromatography.

Furthermore, generating an alcohol-borane in ethereal solvents commonly associated

with hydroboration is not practical for ODHB since the solvent would compete for

45

borane complexation. Thus, if alcohol-directed hydroboration is to occur in an analogous

fashion compared to the amine case, the alcohol-boranes must be generated and activated

in situ at low temperatures with no ethereal solvents present.

Dichloromethane (DCM) was a straightforward solvent choice based on work

from both the Brown and Vedejs groups.27,31

Choosing a borane carrier was a more

delicate matter in that the ideal carrier must find a balance between the contrasting

properties of 1) forming a sufficiently strong complex with borane to minimize the

concentration of undesired Lewis base in solution and 2) forming a weak enough borane

complex to allow the substrate to complex to borane. Thioanisole was chosen based on a

study by Brown, which reported that borane dissolves in thioanisole with 3 M

concentration despite a relatively weak complex between PhSMe and BH3.32

Such

solutions are not commercially available due to their instability over time, but are

relatively easy to generate in 10 mL batches by bubbling excess diborane gas through

neat PhSMe. This procedure consistently provided borane concentrations of 2.5 M.

The first investigations into the activated borane approach to ODHB were carried

out with 3-penten-1-ol in DCM and thioanisole-borane [Ph(Me)S·BH3] activated by

iodine (Table 2F; Entries1-7). A favorable regioselectivity of 7:1 for 1,3-pentanediol was

achieved in the initial experiment in which the substrate/borane solution was activated at

-40 °C and was then warmed to between -20 °C and 0 °C (Entry 1). Subsequent control

experiments demonstrated that unactivated Ph(Me)S·BH3 was capable of hydroborating

substrate at -40 °C, resulting in a reduced 3:1 regioselectivity for 1,3-diol 2F2 (Entry 3)

due to undesired background reaction. Regioselectivities were dramatically improved by

introducing both Ph(Me)S·BH3 and iodine to the substrate solution at lower temperatures.

46

Entry R1 R2 Activator X (°C) T1 (h) T2 (h) 1,3-: 1,4- Conversion

1 Ph Me I2 -40 1 5 7 : 1 total

2 Ph Me - -20 6 n/a 3 : 1 total

3 Ph Me - -40 6 n/a 3 : 1 partial

4 Ph Me - -78 6 n/a - trace

5 Ph Me I2 -60 1 5 13 : 1 total

6 Ph Me I2 -78 1 5 18 : 1 total

7 Ph Me I2 -78 5 n/a 18 : 1 trace

8 Me Me I2 -78 1 10 4.4 : 1 partial

9 Me Me I2 -78 1 19 4.4 : 1 total

Entries 5 and 6 display regioselectivities of 13:1 and 18:1 from activation temperatures

of -60 °C and -78 °C, respectively. Entry 7 shows that the reaction had to be warmed

from -78 °C to proceed at an acceptable rate.

These results with Ph(Me)S·BH3 were an encouraging indication that ODHB

could be achieved in analogous fashion to the amine-directed methodology. However,

the short-lived nature of Ph(Me)S·BH3 solutions, coupled with safety concerns for its

generation, and its unenviable odor led to the pursuit of alternative borane sources for a

method viable on scale. Dimethylsulfide borane (BMS) was investigated because it is

commercially available. Its scent would be forgivable if it could provide comparable

regioselectivity to Ph(Me)S·BH3. Not only did BMS fail to provide comparable

47

regioselectivity (4.4:1 vs. 18:1), it required longer reaction times to achieve total

conversion (Table 2F; Entries 8 & 9).

Previous statements pertaining to the characteristics of an ideal borane carrier are

perhaps misleading in that the most ideal borane carrier in the pursuit of ODHB is no

carrier at all. Therefore efforts were made to generate solutions of (di)borane in DCM.

A DCM·BH3 stock solution approach was studied by bubbling excess diborane gas

through DCM cooled to -78 °C. Borane concentrations of 0.44M were generated in

DCM, but loss of borane was observed upon warming. Table 2G illustrates that stock

solutions of 1:1 PhSMe:BH3 generated in situ from a variety of borohydrides were also

not viable as storable reagents. Sodium borohydride (NaBH4) failed to generate any

detectable borane due to the insolubility of NaBH4 in DCM, but tetrabutylammonium

borohydride (nBu4NBH4) did give excellent initial concentrations of borane upon

treatment with iodine. It was hypothesized that replacing the sulfide carrier with an

alcohol substrate would allow borane retention in solution to achieve ODHB upon

activation with I2, but uncertainty would remain regarding the timescale for activation vs.

the timescale for reaction of the alcohol with borane to generate borates and H2 gas.

% BH3 in solution

R After 3 h After 15 h After 7 d

Na 0 0 0

n-Bu4N 90 66 50

Bn(Et)3N - 54 47

48

Conversion of the unsaturated alcohol substrate was achieved using in situ borane

generation from nBu4NBH4 followed by iodine activation, but regioselectivity dropped

from 18:1 to ~ 2:1. To ensure that this decrease in selectivity was not due to the absence

of sulfide, PhSMe was added to the reaction solution. As no change in regioselectivity

was observed, it was concluded that presence of sulfide has no effect on the reaction

(Scheme 2H). On the other hand, replacing I2 with triflic acid (TfOH) as the borane-

generating and activating reagent provided excellent >20:1 regioselectivity with 3-nonen-

1-ol under sulfide-free conditions (Scheme 2I). By itself, this result is significant in that

it confirms that sulfide is not necessary for achieving good regioselectivity. Considering

the impact that TfOH activation had on the eventual development of an ODHB method

for alcohols, this result proved to be absolutely critical.

49

The I2-activated Ph(Me)S·BH3 method that provided excellent selectivity on 3-

penten-1-ol (Table 2F; Entry 6) failed to provide comparable results on more complex

substrates. Even 3-hexen-1-ol failed to give good regioselectivities. Yields were also

too low to be synthetically practical. Fortunately, it was discovered that TfOH-activated

BMS achieved moderate to good yields on a variety of substrates with superior

regioselectivity than that of the I2-Ph(Me)S·BH3conditions. Best results were achieved

when BMS was preactivated with TfOH before addition of substrate (Table 2J).33

All alkyl-substituted substrates provided 1,3-diols with excellent

regioselectivities. Selectivity is not highly dependent on olefin geometry, although trans-

olefins provide a somewhat improved result, as 28:1 and 37:1 regioselectivities were

achieved on cis- and trans- 3-hexen-1-ol, respectively (Table 2J; Entries 2&3).

Branching at C-5 is directly related to regioselectivities as demonstrated by the secondary

cyclohexyl group and the tertiary tbutyl group, respectively, providing 56:1 and 82:1

regioselectivities (Entries 5&6).

Aromatic substituents have a strange and unexpected effect on substrate reactivity

that seemingly relates to their proximity to the olefin. The styrenic olefin in entry 7

underwent only trace conversion even after extended reaction times. While the styrene

system was of particular interest due to the electronic perturbation of the olefin by the

phenyl ring, it had been expected that this perturbation would be a challenge in terms of

regioselectivity rather than reactivity. In general, -substituted styrenes undergo

intermolecular hydroboration to generate benzylic boranes with a 5:1 regioselectivity

preference due to the conjugative electronic effect of the phenyl ring. However, the

observed drop in reactivity in this case cannot be attributed only to conjugation, as

50

ROH R

OH

OH

1.

CH2Cl2, -78°C2.3. MeOH, NaOOH

-78°C to -20°C, time

Me

S

Me

BH3, TfOH

Table 2J: Regioselectivities Achieved Under Optimized Conditions

ROH

OH

2J1 2J2 2J3

a R= CH3b R= CH2CH3c R= Z-C2H5

d R= nCH5H11e R= cC6H11f R= tC4H9

g R= Phh R= Bni R= (CH2)2Ph

Entry Stg Time (h) Yield 2J2 : 2J3

1 2J1a 10 41% >20 : 1

2 2J1b 10 51% 37 : 1

3 2J1c 5 51% 28 : 1

4 2J1d 10 69% > 20 : 1

5 2J1e 5 80% 56 : 1

6 2J1f 5 56% 82 : 1

7 2J1g 20 < 3% n/d

8 2J1h 10 22% n/d

9 2J1i 5 59 % >20 : 1

inserting a methylene tether between the phenyl ring and olefin does not restore reactivity

comparable to that of the alkyl substrates (Entry 8). Not until a second methylene linker

is added to the phenyl-olefin tether does reactivity return to expected levels (Entry 9).

The styrenic system behaves well in the amine directed hydroboration. Therefore, a 1:1

substrate-borane complex would be expected to behave well in the alcohol system.

However, a 1:1 complex is not a realistic assumption to make with a single equivalent of

activated borane present, let alone the two equivalents present in the reaction mixture

(standard conditions). It is tentatively proposed that activated borane forms a -complex

51

to the aromatic ring that inductively deactivates the olefin. Adding a methylene tether

reduces the inductive effect and a second methylene group renders it insignificant.

Having achieved excellent regioselectivity on a variety of homoallylic alcohols

the next goal for this work was to confirm that the regioselectivity was due to ODHB.

This was investigated by running competition experiments in the presence of excess

cyclohexene. Not only was no cyclohexanol observed upon oxidative workup of these

reactions, but the yield of the desired diols actually increased by 10 % (Table 2K). This

is believed to be due to the cyclohexene behaving as a scavenger of acidic species in

solution.

Entry R Regioselectivity Yield (without additive) Cyclohexanol Observed

1 Me >20 : 1 51% (41%) none

2 Et >20 : 1 66% (51%) none

These acidic species are responsible for catalyzing a cyclization side reaction that

went unobserved until special care was taken with the reaction mixture of 6-phenyl-4-

hexen-1-ol 2L1. 2-Phenethyltetrahydrofuran 2L3 was recovered in low yield due to its

surprising volatility (Scheme 2L), but its formation suggests that a similar side reaction

accounts for the moderate yields in Table 2J. Despite good conversion of the aliphatic

substrates in Table 2J, the moderate yields were initially baffling because the volatile

tetrahydrofurans have the same mass as the corresponding starting materials, rendering

52

assay of the crude reaction mixtures by nominal mass spectrometry ineffective. Thus the

missing mass balance is attributed to the volatile tetrahydrofuran side products.

The successful ODHB of homoallylic alcohols led to the investigation of other

unsaturated alcohol substrates. 4-Hexen-1-ol 2M1 was used to study a bis-homoallylic

alcohol with unexpected results. It was believed that good regioselectivity for 1,4-diols

would be achieved in such systems for the same kinetic and thermodynamic reasons that

one would expect to account for the formation of 1,3 diols from homoallylic systems.

However, 1,4-hexane-diol 2M2 was generated with a modest 4.4:1 regioselectivity

compared to 1.6: 1 using THF·BH3 (Scheme 2M).

OHOH

OH

OH

OH

1. THF·BH3, THF, 0 °C

2. NaOOH

1.6 : 1

OHOH

OH

OH

OH

1. BMS, TfOH, DCM -78 to -20 °C

2. NaOOH

4.4 : 1

Scheme 2M: Investigating Bishomoallylic Substrates

2M1 2M2 2M3

2M1 2M2 2M3

53

In 1972 Brown reported that intramolecular hydroboration of thexyl-4-

pentenylborane 2N1 favors the five membered ring 2N2. This must be due to a kinetic

preference for five-membered ring formation, considering the well known preference of

dialkylboranes to react with anti-Markovnikov selectivity.34

On the other hand, in the

case of thexyl-5-hexenylborane 2N4, the kinetic preference for six-membered ring

formation does not begin to compete with the inherent preference of the dialkylborane for

anti-Markovnikov regioselectivity (Scheme 2N). Negligible regioselectivity was also

achieved upon I2 activation of bishomoallylic amine-boranes 2O1 (Scheme 2O).28

These

two reports, in addition to the results with 2M1 support the conclusion that regioselective

delivery of borane to an olefin from the -position of a simple acyclic substrate is

inherently difficult, regardless of the element at the -position, attached to boron.

Entry Olefin Geometry R Yield (%) 1,4- : 1,5-

1 E H 95 2 : 1

2 Z H 91 2 : 1

3 Z Bn 63 1.5 : 1

54

The results with the bishomoallylic alcohol precluded the study of longer olefin-

borane tethers so a shorter (allylic) tether was briefly evaluated using 2-hexen-1-ol.

However, the conditions used on the homoallylic substrates did not consume olefin in the

allylic system. The reduced reactivity is attributed to 1) the alcohol-borane complex

inductively deactivating the olefin and 2) the thermodynamically disfavored [2.2.0]

fused- 2P2 and [2.1.1]-bridged 2P5 bicyclic transition states through which an

intramolecular transformation would have to proceed (Scheme 2P).

OH

1. BMS, TfOH, DCM -78 to -20 °C

2. NaOOH

BMS,TfOH

BMS,TfOH

O

BH H

OTf

H

O

BH H

OTf

H

B OH

n-Pr

H

disfavored

disfavored

BO

OH

OH

H

H OTf

n-Pr

Scheme 2P: Allylic Alcohols are Not Viable Substrates

OTf2P1 2P2

2P3 2P4

2P1 2P5

2.3 Pursuing Diastereoselectivity via Metal-Free Alcohol-Directed Hydroboration

Having developed a method capable of regiocontrol in the hydroboration of

homoallylic alcohols, the new procedure was applied to a variety of secondary alcohols to

investigate its utility in the context of diastereocontrol. Isopulegol 2Q1 was an ideal

initial substrate as it is commercially available and had been previously studied by Ohloff

55

(Scheme 2Q).7 However, a background reaction run to confirm Ohloff‟s 19:1

diastereoselectivity did quite the opposite. Treating isopulegol with 1M THF·BH3

provided only 5:1 diastereoselectivity favoring 2Q2. The (unknown) reason for this

discrepancy compared to the literature result is of little importance because treating

TfOH-activated BMS with isopulegol followed by subsequent oxidative workup provided

superior diastereocontrol (>30 : 1) in the generation of 1,4-diols 2Q2 and 2Q3 (Scheme

2Q). This increase is tentatively attributed to ODHB, but the reaction proved

surprisingly complex.

OHOH

H

OH

OH

H

OH

OHOH

OH

1.

CH2Cl2, -78°C2.3. MeOH, NaOOH

-78°C to -20°C, 5h

Me

S

Me

BH3, TfOH

OH

OTf

H2O

O

H

BH2OTf

OTf

OH OH

H

OH

OH

H

OH

1. THF·BH3, THF

2. MeOH, NaOOH

95 %5 : 1

32%>30 : 1

18% 11%

Scheme 2Q: Diasteroselectivity Achieved on Isopulegol

2Q1 2Q2 2Q3

2Q1 2Q2 2Q3 2Q4 2Q5

2Q6 2Q7

OH

OTf

2Q8

Two side products were produced under ODHB hydroboration conditions.

Isolating the isomeric 1,3-diol 2Q4 in 18% yield presented the possibility that the

hydroxyl directing effect might overcome the strong preference for anti-Markovnikov

56

hydroboration. However, the identification of citronellol 2Q5 as the second byproduct

indicated that acidic side reactions were interfering. Since isopulegol can be prepared by

acid catalyzed cyclization of citronellal, the reverse transformation should also be

feasible under these conditions.35

Protonating the olefin of isopulegol would lead to a

tertiary triflate 2Q6 that can undergo ring opening via carbocation 2Q7, to form

protonated citronellal 2Q8, which is envisioned as being reduced by an activated borane

species in solution to provide citronellol. Generation of 1,3-diol 2Q4 might come from

either 2Q6 or 2Q8 upon aqueous workup. Cyclohexene did not suppress these side

reactions.

Secondary homoallylic alcohols were submitted to TfOH-activated BMS

conditions to investigate diastereoselectivity. Although no mechanistic evidence for

ODHB had been obtained at this stage of the investigation, several speculative rationales

had emerged, one of which assumes the simplest version of alcohol-directed

57

hydroboration, shown in Scheme 2R. A priori, diastereoselectivity on E-substrates was

expected based on chair-like transition states 2R1 and 2R3. Syn-1,3-diols were expected

to be favored, as they would be derived from the transitions state 2R1, in which the olefin

is in the extended conformation. The alternative conformer 2R3 should be disfavored

due to the A-1,3 strain generated between the olefin and the pseudoaxial proton next to

oxygen. Contrary to these predictions, only negligible diastereoselectivity was observed

with 4-decen-2-ol 2R5 and 2,2-dimethyl-5-docecen-3-ol 2R6 (Scheme 2R).

It was hypothesized that using a Z-olefin would lead to increased

diastereoselectivity due to the drastic steric interaction between the alkyl substituent and

the psuedoaxial carbinol proton in the disfavored transition state 2S3. However, similarly

poor results were observed on Z-substrates despite incorporating t-butyl groups at the

58

carbinol and distal olefinic carbons (Scheme 2S). It is important to note that almost no

regioselectivity was observed in either the E- or Z- systems. Apparently, the steric

environment of the secondary alcohol had prevented a useful alcohol-borane interaction.

Since excellent regioselectivity had only been achieved with primary alcohols, an

experiment with 2-isopropyl-3-penten-1-ol 2T1 was designed. Moving the chiral center

from the carbinol carbon to C-2 would allow a better alcohol-borane interaction while

bulkiness of the isopropyl group should provide a stereochemical bias. Excellent

regioselectivity was restored by using the primary alcohol. However, the C-2 isopropyl

group provided no diastereoselectivity. This result indicates that the A-1,3 interaction of

both psuedoaxial olefin and carbinol proton in transition state 2T4 is insufficient to

provide a stereochemical preference over the psuedoequatorial transition state 2T3,

assuming that the cyclic mechanism has been presented correctly.

Another approach to achieving diastereoselectivity was taken in which a bulkier

hydroborating agent was investigated. TfOH-activated phenylborane was chosen because

the introduction of steric bulk is accompanied by delocalization of electron density

59

involving boron. Generation of the desired borane species was confirmed by forming its

N,N-dimethyl-4-amino-pyridine (DMAP) complex in two different routes. Treating

lithium phenylborohydride36

with an equivalent of TfOH to generate phenylborane

followed by a second (activating) equivalent of TfOH and subsequent addition of an

equivalent of DMAP generated a species with a 11

B NMR signal at = +5ppm. An

identical signal was observed upon treating DMAP-phenylborane complex with an

OH OH

OH

22 : 1 regioselectivity

n-pentyl

OH

n-pentyl

OH

8 : 1 regioselectivity1 : 1 diastereoselectivity

BH

HH

Li

BH

HH

Li

OH

BOTf

HDMAP

TMSCl BH

HDMAP B

H

HDMAP

H2

TfOH

11B : -4ppm

H2

TfOHLiOTf

BH

H

TfOH

H2

BOTf

H

DMAP

11B : 5ppm

1.

CH2Cl2, -78°C2.3. MeOH, NaOOH

-78°C to -20°C

, TfOH

BH

HH

Li

1.

CH2Cl2, -78°C2.3. MeOH, NaOOH

-78°C to -20°C

, TfOH

Scheme 2U: Pursuing Diastereoselectivity with Phenyl(triflate)borane

2U1 2U2 2U3

2U4 2U5 2U6

2J1e 2J2e

2S7 2U9

60

equivalent of TfOH. Thus it was concluded that the signal at = +5ppm represents the

DMAP complex of Ph(OTf)BH, which confirms generation of Ph(OTf)BH in the first

route (Scheme 2U).

Treating a solution of Ph(OTf)BH with 4-cyclohexyl-3-buten-1-ol 2J1e provided

1,3-diol 2J2e with 22:1 regioselectivity upon oxidative workup, demonstrating that the

new reagent was capable of ODHB. However, submitting both the E- and Z- isomers of

2,2-dimethyl-5-dodecen-3-ol 2S7 to the Ph(OTf)BH conditions provided moderate

regioselectivity and no diastereoselectivity. The resistance of acyclic homoallylic

alcohols towards diastereo-induction necessitates further consideration of the feasibility

of the proposed mechanism.

Intramolecular hydroboration in analogous hydrocarbon systems is known to

provide diastereoselectivity with three-to-five atom tethers between boron and an

olefin.37-42

Still has reported diastereocontrol in the internal hydroboration step starting

61

from of diene and thexylborane. Dienes 2,5-dimethyl-1,4-hexadiene 2V1 and

2,7-dimethyl-2,7-octadiene 2V7 provide diastereo-enriched diol mixtures as expected

from sequential inter- and intramolecular transformations. Diols 2V5 and 2V6 were

generated in a 15:1 ratio upon treating E-2,6-dimethyl-1,4-heptadiene 2V4 under the

same conditions. The authors state “only in the case of [2V4] is some ambiguity

involved, and this is presumably due to a steric interaction between the isopropyl and

thexyl substituents.” The issue of intramolecular hydroboration is of particularl interest

in the case of 2V4, as the intermediate generated by monohydroboration is a hydrocarbon

analog for 2R5-borane and 2R6-borane complexes. A specific transition state was not

proposed for these substrates.

Chair-like transition states have been suggested, involving boranes 2W1,

generated by hydroboration of a diene precursor. Yokoyama proposes that intramolecular

hydroboration occurs via cyclic transitions states 2W2a and 2W2b.41,42

The lack of A-

1,3 strain between R3 and R

Z in 2W2b is responsible for the selectivity. The steric bulk

of thexylborane is key, as THF·BH3 provides poor selectivity. Acyclic diastereocontrol is

clearly achievable via intramolecular hydroboration in the all-carbon substrates, based on

the results of Still and Yokoyama. The contrasting lack of diastereoselectivity with the

oxygen analogs (homoallylic alcohols of section 2.3) cannot be accounted for by

inserting oxygen into Yokoyama‟s proposed transition states. The poor selectivity with

the original activated borane conditions (Schemes 2R, 2S, & 2T) is perhaps less

confusing considering the result in entry 1 of Table 2V. On the other hand, the steric

bulk of the PhB(H)OTf reagent should provide improved selectivity, acting as a steric

62

entry R1 R

2 R

3 R

E R

Z anti- : syn- reference

1 H H Me -(CH2)5- 76 : 24 41

2 H Thx Me -(CH2)5- 96 : 4 41

3 H Thx Me CH2OBn Me 96 : 4 42

4 H Thx Me Me CH2OBn >98 : <2 42

replacement for a thexyl group, but no improvement was observed. Thus, the mechanism

of the alcohol directed hydroboration is clearly more complicated than initially proposed,

based on these contrasts with the hydrocarbon analogy.

2.4 Mechanistic Investigations

Mechanistic studies were done with the intent of supporting an intramolecular

pathway. The first experiment investigated the activated borane reagent using 11

B NMR

spectroscopy. A -20 °C solution of BMS 2X1 (11

B: = -20.7 ppm, q, J= 104 Hz) in

CH2Cl2 was treated with slightly less than one equiv of TfOH to provide a 11

B triplet at

= -1.6 ppm (J= 128 Hz), which is believed to represent the expected dimethyl sulfide

complex of triflate borane 2X2.

63

To investigate the reactivity activated borane 2X2 with alcohols without the

complication of olefin reactivity interfering, 2X2 was treated with ethanol at -78 °C and

warmed to -20 °C while monitoring by 1H NMR spectroscopy. Interestingly, the proton

NMR spectra taken at -78 ºC and -20 °C showed a temperature dependant signal shift. At

-78 °C a single peak was observed for both the methylene (= 3.76 ppm) and methyl (=

1.2 ppm) protons of ethanol. As the sample warms, the methylene (= 3.76; 3.94 ppm)

and methyl (= 1.2; 1.29 ppm) protons appear as two signals. After 10 min at -20 °C the

more downfield signal is dominant. This observation suggests that either 1) the alcohol

does not complex to the sulfide-complexed BH2OTf or 2) an ethoxyborane is forming at

the elevated temperature. The latter was addressed with hydrogen evolution studies.

Quantitative hydrogen evolution upon treating 2X2 with an alcohol would prove

that complex 2X3 is transitory under reaction conditions, which would eliminate the

possibility of the envisioned mechanistic pathway. Hydrogen evolution studies began

with a control experiment in which a -20 °C DCM solution of Me2S·BH3 was treated

with ethanol, generating 9% of the theoretical amount of H2 over 90 minutes (Equation

2). Boron NMR spectroscopy of the resulting mixture was complex but no

monoalkoxyborane was observed at the expected value (= ~50 ppm). These results

indicate that ethoxyboranes are not formed under such conditions.

64

SB

Me

Me

H

H

H

EtOH (0.51 mmol) CH2Cl2

-20 °C, 90 minH2

9%

(2)

2X1

.6 mmol .05 mmol

A more intricate experiment was required to investigate the real reaction

conditions. The first stage of the experiment involved measuring the amount of hydrogen

evolved from the activation of 2X1 with TfOH. Treating a -78 °C solution of 2X1 with

1 equivalent of TfOH led to the collection of >90% of the theoretical amount of H2.

Substrate was then added via addition funnel to the reaction mixture at -78 °C. No gas

evolution was observed at -78°C. Upon warming to -20 °C, ca. 10% of the theoretical

volume of H2 was collected (Scheme 2X). Assuming that complexes of the alcohol and

BH2OTf are the species observed at low temperature, then they appear not to decompose

to monoalkoxyboranes at -20°C: 11

B NMR spectroscopy does not reveal

monoalkoxyborane peaks in the expected range (= 50 to 55 ppm) amid complex signals

including maxima at = -20.7 ppm, -8.43 ppm, -1.7 ppm, and +35.2 ppm. Broad signals

obscure the spectrum in the range of -18 ppm < < +24 ppm.

SB

Me

Me

H

H

H TfOH

CH2Cl2, -78 °CS

B

Me

Me

H

H

OTfH2

>90%

OH

Et

CH2Cl2, -78 °C30 min

OB

H

HOTf

H

Et

" "

-78 to -20 °C

45 minH2

10%

Scheme 2X: Hydrogen Evolution Studies

2X1 2X2

2X3

65

The requisite species for achieving intramolecular hydroboration, according to the

original mechanistic proposal, is the substrate-BH2OTf complex 2X3 (Scheme 2X). The

proton remaining on oxygen, along with the resulting positive charge, serves to activate

the tetravalent boron by making it more electrophilic. Hydrogen evolution studies

indicate that a small (ca. 10%) amount of 2X3 undergoes hydrogen evolution which

could form an alkoxyborane 2Y5, (Scheme 2Y) by reacting with an external hydride

source, or perhaps more plausibly, the corresponding trifluorosulfonyloxy analogue 2Y1

if hydrogen evolution involves the internal hydride of 2X3. While monoalkoxyboranes

are not confirmed as hydroborating species, formation of alkoxyborane 2Y5 should not

be taken to preclude ODHB. Similarly, formation of 2Y1 has not been detected nor does

it have any precedent in the literature, but that does not mean that 2Y1 can be ruled out as

one of the species capable of undergoing internal hydroboration.

The reaction conditions include two equivalents of activated borane. This enables

potentially unreactive intermediate 2Y5 (Scheme Y) to complex to another molecule of

activated borane, forming the bis-borane species 2Y6, which is analogous to 2Y3 where

the activating proton has been replaced by a Lewis acid. Thus, the transition state 2Y2

can still be achieved by all substrates regardless of any possible monoalkoxyborane

formation. Monitoring the reaction of trans-3-hexen-1-ol by 11

B NMR spectroscopy

provided very complex spectra, but no downfield species (= 70-80 ppm) indicative of

trivalent 2Y1 or either of the borenium ions 2Y6 or 2Y7 was observed. The spectra do

not define a clear mechanistic picture, but the 11

B signal at = -8.43 ppm (tetravalent

boron; buried triplet, JBH= ~128 Hz) lends support for the formation of complex 2X3.

Brown has reported the 11

B signal of a similar species BH2Cl·OEt2 as a triplet at = -5

66

OB

H

HOTfH

R

OB

H

OTf

R

BH2O

R

OTf H2B

OR

X H

TfO

OB

H

H

R

BH

HTfO

OH

R

OH

Scheme 2Y: Loss of Hydrogen Does Not Preclude ODHB

2Y1 2X3 2Y2 2Y3

2Y5 2Y4

- H2

BH2O

R

TfO

X

2Y6

OB

H

H

R

2Y7

Me2S·BH2OTf

ppm with a JBH= 136 Hz.43

Therefore, the originally envisioned mechanism, in which

2X3 forms complex 2Y3 via 2Y2, remains feasible.

2.5 Alkoxide-Directed Hydroboration

Acid-catalyzed side reactions are the main inconvenience of using alcohols to

direct hydroboration with triflate-activated borane as demonstrated by formation of

tetrahydrofuran 2L3 from 2L1, and 2Q4 and 2Q5 from isopulegol 2Q1. The alcohol-

borane complex 2X3 that is believed to be responsible for intramolecular delivery of

borane is also a species that could possibly generate TfOH, leading to catalysis of

undesired reaction pathways. Thus, undesired reactions might be unavoidable with

alcohols. Lithium alkoxide substrates were investigated for this reason.

The best substrate in the alcohol series was 4-cyclohexyl-3-buten-1-ol 2J1e; it

provided an 80% yield of diol with 9% of recovered starting material (RSM), while the

rest of the mass was presumably lost due to acid-catalyzed formation of a volatile

tetrahydrofuran. The corresponding lithium alkoxide 2AA1e was studied to see if better

mass balance could be obtained without losing regioselectivity. Almost quantitative

(98%) mass balance was achieved upon treating TfOH-activated BMS with 2AA1e,

67

followed by oxidation with NaOOH. Regioselectivity favoring 1,3-diol 2U8 remained

excellent (>20 : 1), however, a decrease in yield was observed (Scheme 2Z).

A detailed investigation of the alkoxide-directed hydroboration was initiated to draw

comparison to the alcohol series. Comparable regioselectivity was achieved on all

aliphatic substrates. The reactivity of phenyl-substituted substrates continued to suffer,

presumably due to the same inductive deactivation effects of arene-borane complexes

discussed in relation to Table 2J. Comparing diol yields from alcohols with those from

alkoxides reveals no consistent advantage. Substrates with little steric bulk at C-4

provide greater yields in the alkoxide experiments (Table 2AA, entries 1 & 2) while

substrates with bulkier C-4 substituents provide greater yields in the alcohol experiments.

The improved results with unhindered substrates are reminiscent of the results with

Ph(Me)S·BH3/iodine conditions studied initially, which were only effective on

3-penten-1-ol (Table 2F). It appears that only substrates unhindered at C-5 benefit from

the alkoxide reaction conditions. The bis-homoallylic alkoxide of 2M1 (2X2) was also

investigated, and the selectivity was comparable to the selectivity for 2M1 (Equation 3).

68

Entry Stg Time (h) Yield Regioselectivity

1 2AA1a 5 70% >20 : 1

2 2AA1b 5 90% >20 : 1

3 2AA1d 5 38% > 20 : 1

4 2AA1e 5 60% >20 : 1

5 2AA1f 5 44% >20 : 1

6 2AA1g 20 < 3% n/d

7 2AA1h 20 28% n/d

8 2AA1i 5 42 % 16 : 1

Neither the alcohol nor alkoxide method is perfect. The

alcohol method generally provides greater yields but acid

catalyzed side reactions destroy some starting material. The

alkoxide method preserves material but, in addition to generally

low diol yields, the procedure is relatively inconvenient as it

requires a system that incorporates a cold-jacketed addition

funnel (Figure 2-1). However, the preservation of starting material in the alkoxide case

69

presented the possibility that conversion could be improved. The effect of “TfOBH2”

stoichiometry on conversion was investigated in an effort to achieve higher conversion to

diol. Entries 1-4 of Table 2BB illustrate that diol yield does increase with additional

reagent, but starting material starts decomposing by an unknown pathway(s) with 4

equivalents of activated borane added (Entry 4). Yields never surpassed that which was

obtained in the alcohols series (Entry 7).

OROH

OH

1.

CH2Cl2, -78°C2.3. MeOH, NaOOH

-78°C to -20°C, 5h

Me

S

Me

BH3

, TfOH

Table 2BB: Alkoxide Conditions vs Alcohol Experiments

2J2e2J1e R =H2AA1e R =Li

Entry R Equiv „BMSOTf‟ Additive Regioselectivity Yield RSM

1 Li 1.1 - >20 : 1 16% 76%

2 Li 2 - >20 : 1 60% 38%

3 Li 3 - >20 : 1 65% 29%

4 Li 4 - >20 : 1 70% 7%

5 H 1.1 - >20 : 1 55% 23%

7 H 2 - >20 : 1 80% 9%

A search for a viable acid scavenger was undertaken in an attempt to suppress

acid catalyzed side reactions without the use of nbutyl lithium (nBuLi). With acidic

conditions providing the best reactivity, and alkoxide conditions preventing undesired

side reactions, it was hypothesized that using hindered amines as acid scavengers would

provide the benefits of both to provide optimal yield. Cyclohexene was included in the

study because of the results in Table 2K. This was an opportunity to confirm the

70

hypothesis that acid catalysis is responsible for the generation of 2Q4 and 2Q5 from

isopulegol 2Q1 under alcohol direction conditions.

Table 2CC illustrates that suppression of 2Q4 and 2Q5, accompanied by

increased yields and good diastereoselectivity, was achieved with diisopropylethylamine

(Hunig‟s base) or 2,6-di-tert-butyl-4-methyl-pyridine. However, the 1,3-diol was still

observed in the hindered amine experiments (Entries 3 & 4), while the lithium alkoxide

approach essentially eliminated this product (Entry 5). The total suppression of 1,3-diol

2Q4 and citronellol 2Q5 in the alkoxide experiment supports the hypothesis that both

2Q4 and 2Q5 are generated via acid-catalyzed side reactions that are not completely

avoidable with an amine acid scavenger. This does not discount the possibility that the

amine proton scavengers could be effective on other substrates, as 2,2-disubstituted

olefins are more inclined to undergo protonation than 1,2-disubstituted olefins like 2J1.

As mass balance was best with the hindered pyridine in Table 2BB, this additive was also

tested with 2J1e. However, oxidative workup revealed poor conversion to the 1,3-diol

with good regioselectivity (Equation 4).

71

OROH

H

OH

OH

H

OH

OH

OH

additive

1.

CH2Cl2, -78°C2.3. MeOH, NaOOH

-78°C to -20°C, 5h

Me

S

Me

BH3

, TfOH

OH

Table 2CC: Investigating Alkoxide Conditions on Isopulegol

2Q1 2Q2 2Q3 2Q4 2Q5

Entry R additive Q2+Q3 Q2 : Q3 Q4 Q5 RSM

1 H - 32% >30 : 1 18% 11% 20%

2 H (1 equiv)

30% >30 : 1 22% 4% 10%

3 H N(1 equiv)

52% >20 : 1 2% 0% 18%

4 H

50% >20 : 1 9% 0% 28%

5 Li - 70% ND trace 0% 21%

OH OH

OH

1.

CH2Cl2, -78°C2.3. MeOH, NaOOH

-78°C to -20°C, 5h

Me

S

Me

BH3

, TfOH

2J2e2J1e

NBut tBu

Me

22% yield>20 : 1

2J1e

63%

(4)

Lithium alkoxide experiments provided no discernable advantage in the context of

diastereoselectivity on acyclic substrates. Homoallylic secondary alkoxides generated

from trans- 5-decen-2-ol and trans-2,2-dimethyl-dodecen-2-ol provided nearly

identically poor regio- and stereoselectivity in comparison to the corresponding alcohols

(Equation 5). Because of these results and the more difficult alkoxide vs. alcohol

procedure, further investigation of secondary alkoxides was not pursued.

72

The one constant in the substrates used to probe acyclic diastereoselection is that

the functionality at the chiral center can easily occupy a pseudo-equatorial position of a

chair-like transition state. To ensure that a substituent occupies the psudeo-axial position

at the carbinol carbon of a chair-like transition state one must use a tertiary alcohol. Thus

lithium 1-allyl-cyclohexanoxide 2DD1 was treated with TfOH-activated BMS conditions.

Surprisingly, 1,3-diol 2DD2 was recovered in 33% yield with 10:1 Markovnikov

3:1 regioselectivity12% yiled

OLi BMS + TfOH1.

CH2Cl2 -78 to -20ºC2. MeOH, NaOOH

H

H OH

OB

H

H

H

OB

H

H

H

LiLi

vs.H

H

OTfOTf

OLi

10:1 regioselectivity33% yield

BMS + TfOH1.

CH2Cl2 -78 to -20ºC2. MeOH, NaOOH

OH

OH

OBH

OB

H

LiLi

vs.

H

H

OTfOTf

Scheme 2DD: Effect of Psuedo-Axial Substituent at Carbinol Position

H

HOH

2DD1 2DD2

2DD3 3DD4

2DD5 2DD6

2DD7 2DD8

73

regioselectivity. This was unexpected because of the 1:19 anti-Markovnikov selectivity

reported for terminal olefins under normal conditions. The selectivity is believed to be

due to destabilization of the [3.1.1] bridged bicylic transition 2DD4 required for anti-

Markovnikov hydroboration by a steric interaction between bridging hydride and the

pseudo-axial component of the cyclohexane ring. This conclusion is supported by the

fact that lithium 3-buten-1-oxide 2DD5 provides only 3:1 Markovnikov regioselectivity

(Scheme 2DD). Tertiary alkoxides were not investigated further because the reaction of

Me2S·BH2OTf with 2DD1 led to a complex mixture of products. This is presumably due

to the tertiary center participating in transformation involving easily displaced species

upon interaction between alkoxide and excess activated borane

2.6 Ether-Directed Hydroboration

Ether-directed hydroboration was investigated in an effort to differentiate the

oxygens in the final products. The methyl ether of 4-cyclohexyl-3-butanol 2EE1 was

treated with standard preactivation conditions to provide 2EE2 in 20 : 1 regioselectivity.

In contrast to the alcohol substrates, an in situ method was better than the preactivation

procedure, providing monoprotected 1,3-diol 2EE2 with improved selectivity of 50 : 1 in

60% yield (Scheme 2DD).

OMe

1. BMS, TfOH CH2Cl2, -78 to -20°C

2. NaOOH, MeOH

OMe

OH

61% yield50: 1 regioselectivity

OMe

1. BMS, TfOH CH2Cl2, -78 to -20°C

2. NaOOH, MeOH

OMe

OH

20: 1 regioselectivity

Preactivation Method:

In situ Method:

Scheme 2EE: Effect of Order of Addition on Homoallylic Ethers

2EE1 2EE2

2EE1 2EE2

OMe

OMe

OH

OH

2EE3

2EE3

74

This successful ether direction is mechanistically relevant (vide infra), but a

methyl group is not a synthetically convenient protecting group. Collaboration with Dr.

Guoqiang Wang and Ms. Sarah Breed led to the discovery that an allyl ether can

effectively direct hydroboration (Equation 6), providing a conveniently mono-protected

1,3-diol that can be manipulated without interference from the primary oxygen. In situ

activation provided mono-allyl protected 1,3-diol with 27 : 1 regioselectivity in 55%

yield while minimizing diol formation (<5%) and monohydroboration of the allyl group

(<5%) after oxidation. The poor reactivity of allylic substrates in the alcohol series

(Scheme 2P) sheds light on why the chemoselectivity is so good in this reaction.

Intramolecular hydroboration of the proximal (allylic) alkene is disfavored due to

strained transition states and inductive deactivation of the olefin upon oxygen-borane

interaction. Thus, the chemoselectivity supplements the regioselectivity of 27:1 as

support for an intramolecular reaction pathway.

2.7 Mechanistic Insights

This work provides the first transition metal free method for a substrate-directed

hydroboration using generic homoallylic alcohols, alkoxides, and ethers. However, the

mechanistic picture is not as clear as was hoped. Scheme 2FF illustrates that all three

categories investigated (alcohols; alkoxides; ethers) could follow simple and analogous

mechanistic pathways via 2Y2 to provide regioselectivity. As previously discussed,

75

alcohol-borane complexes 2X3 evolve substoichiometric quantities of H2 gas,

presumably to form an alkoxyborane 2Y1 or derived species, but this is a minor pathway

below -20 °C. Alkoxide-borane complexes 2FF1 could release lithium triflate in a

somewhat analogous fashion, providing the same alkoxyborane 2Y1. However, the

methyl ether-borane complex 2FF2 cannot evolve methane or methyl triflate and still

provide monoprotected diol upon oxidative workup. This demonstrates that the

alkoxyborane 2Y1 is not an obligatory intermediate for the ODHB to occur, which

supports the possibility that all three species 2X3, 2FF1, and 2FF2 follow the envisioned

pathway to form olefin boron complexes 2Y3 via an associative mechanism akin to the

76

pathway proposed by Pasto for intermolecular hydroboration. However,

diastereoselectivity has not been achieved on acyclic alcohol or alkoxide substrates,

demonstrating that the reaction mechanism(s) is not as straightforward as envisioned.

The striking contrast with the all-carbon intramolecular hydroboration is not understood,

although nearly all of our data were obtained using the unhindered reagents derived from

Me2S·BH2OTf. The steric bulk of PhB(H)OTf did not provide a result analogous to the

thexylborane reactions previously reported with the all-carbon carbon substrates and no

diol products were observed attempts to generate the more closely analogous activated

reagent ThxB(H)OTf as described in the next section.

2.8 Testing Intramolecular Hydroboration of Thexylalkoxyboranes

Cha has reported thexylalkoxyboranes as viable intermolecular hydroboration

reagents44

and Bryson has proposed a similar intermediate undergoing intramolecular

hydroboration to account for unexpected diastereoselectivity (Scheme 2GG).45

Therefore, the hypothesis that thexylalkoxyboranes might undergo unactivated oxygen-

directed intramolecular hydroboration was investigated in the context of homoallylic

77

alcohols. A 1:1 solution of 3-penten-1-ol and ThxBH2 was generated at -50 °C to prevent

intermolecular hydroboration. Warming to 0 °C led to the observation of bubbling and a

11B NMR signal at = +51 ppm, which correlates to Cha‟s value for thexylethoxyborane

(= +50.4 ppm). This indicates that the desired intermediate was formed. The

thexylalkoxyborane solution was stirred at rt for 12h and oxidized with NaOOH to

provide 1,3-diol 2F2 with only 2:1 regioselectivity and 40% yield. This demonstrates

that the unactivated thexylalkoxyborane approach to intramolecular hydroboration is not

viable for regioselective hydroboration of acyclic homoallylic alcohols (Scheme 2HH).

Triflic acid activated thexylborane ThxB(H)OTf was also investigated with the

notion that it could improve diastereoselectivity of ODHB. Treating ThxBH2 with triflic

acid followed by 4-nonen-2-ol 2R5 at -78 °C did not produce diol upon warming to -20

°C and oxidation with NaOOH. Submitting the simpler substrate 3-octen-1-ol 2HH2 to

identical conditions did not produce diols 2HH3 (Scheme 2HH). This ended

investigation into ODHB with thexylborane.

OH

H2B

THF, -50 to 0°C

O BH

11B = +51 ppm

1. 0 °C to rt, 12h

2. NaOOH

OH

OH

2F1 2F22 : 1

40% yield

2HH1

Scheme 2HH: Investigating Oxygen-Directed Hydroboration with Thexylborane

unactivated:

activated:

BH21. , TfOH

2. NaOOH

CH2Cl2-78 to -20 °C

OH

R

2HH2 R= H 2R5 R= Me

OH

R

OH

2HH3 R=H 2R8 R=Me

78

2.9 Summary

Described above is the investigation of an alternative mechanistic proposal for

ODHB, which has been derived from the work of Pasto,20, 21

Schleyer,22

Beak,25

and

Ryschkewitsch.29

This borane activation approach has proven applicable to heteroatom-

directed hydroboration in the context of homoallylic amines,27, 28

and it was hoped that it

would provide some semblance of clarity to the topic of ODHB, discussed in the previous

chapter. Homoallylic alcohols, alkoxides, and ethers have now been shown to undergo

highly regioselective intramolecular hydroborations upon application of the borane

activation approach using triflic acid to generate TfOBH2 or equivalent species.

However, a clear mechanistic picture remains elusive. Poor diastereoselectivity on chiral,

branched acyclic substrates demonstrates that the mechanism(s) of these transformations

is not straightforward, and argues against the simplest version of the mechanism that had

been our working model. Mechanistic studies have not provided significant clarity, and

have not resulted in a more convincing mechanistic proposal. Therefore, while generic

ODHB has now been achieved without the use of metal catalysts, the chemical

community still awaits mechanistic understanding of oxygen-directed hydroboration.

79

Experimental

Substrates 5b and 5c are commercially available, while 5a,46

5d,47

5e,48

5f,47

5g,49

5h,50

and 5i51

have been reported in the literature. Alcohols 2J1d, 2J1e, and 2J1f were

prepared using methods reported by Kocienski et al.,47

2J1g, 2J1h, and 2R5 were

prepared by the method of Maryanoff et al.,49

and 2J1i was prepared using the method of

Negishi et al.52

The following diols have been reported previously: 2J2a,5

2J3a,53

2J2b,54

2J3b,54

2J2d,55

2J3d,56

2J2e,57

2J3e,58

2J2f,58

2J3f,59

2J2g,60

2J3g,53

2J2h,61

2J3h,57

2J3i,59

and 2DD2.62

Preparation of borane-thioanisole complex (BH3·SMePh)

The procedure combines features reported in prior work32,63

as follows: NaBH4 (4.56 g,

0.120 mol) was suspended in 60 mL of diglyme using a 250 mL rb flask fitted with an

addition funnel (nitrogen atmosphere throughout). To a separate flask at 0 °C, connected

to the first using a gas dispersion tube, was added thioanisole (5.08 g, 0.040 mol). Iodine

(15.1 g, 0.060 mol) in 60 mL of diglyme was then added dropwise to the NaBH4

suspension causing bubbling that indicated generation of diborane (B2H6). The gas was

passed into neat thioanisole via a gas dispersion tube and any diborane that was not

reacted was passed through a second outlet and quenched with acetone. Upon

completion of the iodine addition, a gentle nitrogen flow was used to push any remaining

diborane into the acetone-containing vessel. The BH3·SMePh was then capped and

stored at -20 °C. The determination of molarity was performed by measuring out 0.50

mL of BH3·SMePh into a flask with 2.0 mL of CDCl3. The solution was cooled to 0 °C

and an excess amount of dimethylbenzylamine (0.3-0.4 mL) was added dropwise. The

80

mixture was stirred for 30 min and analyzed by 1H NMR. The ratio between the

downfield shifts of 4.0 ppm for the complexed amine and 3.4 ppm for uncomplexed

amine was used to calculate the concentration of BH3·SMePh. Typically a range of 3-4

M was obtained.

ODHB of homoallylic alcohols; reaction of 2J1e with Me2S·BH3/TfOH.

CH2Cl2 (16 mL) in a 50 mL rb flask was cooled to -78 °C. Neat Me2S·BH3 (BMS; 300

L, 3.03 mmol) was added followed by TfOH (270 L, 3.04 mmol) dropwise. Each drop

of TfOH initially froze on the surface, forming a white solid that dissipated after a few

seconds of stirring. Gas evolution was observed. This solution was stirred for 35 min

before dropwise addition of a solution of 2J1e (0.214 g, 1.39 mmol) in CH2Cl2 (11 mL).

The clear solution was stirrred at -20 °C for 10 h and was then treated slowly with a

solution of 20% NaOH (4.8 mL) in MeOH (5.2 mL). The mixture was stirred 30 min at -

20 ºC before being stirred vigorously at 0 °C for slow dropwise addition of 35% H2O2

(2.4 mL ) in MeOH (2.6 mL). This mixture was warmed to rt and stirred for 10 h before

transferring to a separatory funnel with 75 mL of Et2O. Brine (10 mL) was then added,

and the aqueous layer was extracted with Et2O (3x, 75 mL). The combined organic

layers were dried (MgSO4), concentrated (aspirator), and purified by flash

chromatography (silica gel) using 30% EtOAc in hexanes to give 0.194 g of 2J2e (80%)

as a 56:1 mixture with 2J3e according to the NMR assay described below. All other

substrates 2J1 reported in Table 2 were reacted under analogous conditions.

81

Derivatization with 2-(trifluoromethyl)benzoyl chloride for NMR assay of

regioselectivity.

A sample of 2J2e/2J3e ( 0.024 g, 0.136 mmol) was taken up in CH2Cl2 (1 mL) and

cooled to 0 °C in a 10 mL rb flask. Neat 2-(trifluoromethyl)benzoyl chloride (0.1 mL,

0.68 mmol) was added dropwise to the magnetically stirred solution followed by DMAP

(0.085 g, 0.69 mmol) in CH2Cl2 (1 mL). The clear solution was treated with Et3N (0.08

mL, 0.57 mmol) and removed from the ice bath. The solution gradually became yellow-

orange over 6h at rt. The reaction was loaded directly onto a preparatory TLC plate and

was developed twice with 10% EtOAc/hexane. The UV active band with Rf of 0.25 was

extracted with EtOAc. Concentration (aspirator) gave pure diaroylated product (0.069 g,

0.13 mmol) in 97% yield. Regioisomer ratios were established by comparing integrals

for carefully phased, expanded 1H NMR spectra as follows:

2-(trifluoromethyl)benzoate from 2J2a/2J3a: The methyl triplet (0.90 ppm) from 2J3a

ester was compared to the methyl doublet of 2J3a ester (1.2 ppm).

2-(trifluoromethyl)benzoate from 2J2/2J3 b,c,d,e,i: The 3-CH(O) methine proton was

compared to the 4-CH(O) methine proton.

2-(Trifluoromethyl)benzoate from 2J2f/2J3f: The t-butyl singlet (0.90 ppm) from 2J3f

ester was compared to the 13

C satellite peaks of the t-butyl singlet (0.97 ppm by 1H

NMR) from 2J2f ester.

82

Table 2II NMR Data and Ratios from Controls Using Excess BH3·THF and ODHB

precursor

alcohols

ester from alcohol 2J2

C(3)H (ppm)

ester from alcohol 2J3

C(4)H (ppm)

2J3 : 2J3

(excess BH3)a

2J3 : 2J3

(ODHB)

2J2a/2J3a m, 5.19-5.33 m, 5.19-5.33 4.3 : 1b >20 : 1

2J2b/2J3b m, 5.23-5.31 m, 5.04-5.11 2 : 1 37 : 1

2J2c/2J3c m, 5.23-5.31 m, 5.04-5.11 2 : 1 28 : 1

2J2d/2J3d m, 5.29-5.35 m, 5.17-5.23 2 : 1 >20 :1

2J2e/2J3e m, 5.42-5.49 m, 5.05-5.11 2.7 : 1 56 : 1

2J2f/2J3f N/A N/A 2 : 1 82 : 1

2J2i/2J3i m, 5.34-5.41 m, 5.25-5.29 2 : 1 >20 : 1

(a) Control experiments: see procedure from 2J1i to 2J2i/2J3i, below, THF·BH3. (b) Me2S·BH3 in THF

instead of THF·BH3

Control experiments; hydroboration of 2J1i with THF·BH3 and characterization of

2J2i.

To a 0 °C solution of 2J1i (0.059 g, 0.33 mmol) in THF (2 mL) was added excess

THF·BH3 (1 mL, 1 mmol). The solution was stirred for 4h before treating with premixed

20% NaOH (0.8 mL) and 35% H2O2 (0.4 mL) dropwise. The reaction mixture was

transferred to a separatory funnel containing brine and extracted with Et2O. The organic

layers were combined, dried over MgSO4, and concentrated (aspirator). According to

NMR assay after derivatization as described above, the crude mixture gave a 2:1 ratio of

2J2i:2J3i. Purification via silica gel chromatography in 70% EtOAc in hexanes eluted

pure 2J2i: HRMS-ES+ (m/z): [M + Na]

+ calcd for C12H18O2, 217.120; found, 217.121.

1H

NMR (400 MHz, CDCl3, ): 1.47-1.59 (m, 2H). 1.62-1.82 (m, 4H), 2.33 (br s, 1H), 2.41

(br, s, 1H). 2.64 (t, J= 8 Hz, 2H), 3.77-3.84 (m, 1H), 3.84-3.91 (m, 2H), 7.16-7.20 (m,

3H), 7.25-7.30 (m, 2H) 13

C NMR (100 MHz, CDCl3, ): 27.30, 35.80, 37.35, 38.28,

83

61.88, 72.162, 125.79, 128.32, 128.40, 142.24. IR (neat, cm-1

): 3350 (br), 2950(s), 2860

(m). Regioisomer 2J3i was eluted in later fractions, and was identified by comparison

with literature data.59

ODHB of 2J1b in the presence of cyclohexene.

CH2Cl2 (60 mL) in a 250 mL rb flask was cooled to -78 °C under nitrogen. Neat BMS

(1.1 mL, 11.11 mmol) was added followed by TfOH (1 mL, 11.26 mmol) dropwise.

Each drop of TfOH initially froze on the surface, forming a white solid that dissipated

after a few seconds of stirring. Gas evolution was observed but no temperature change

was detected by internal temperature monitoring. This stirred for 30 min before addition

of a solution of 2J1b (0.68 mL, 5.55 mmol) and cyclohexene (3.0 mL, 29.6 mmol) in

CH2Cl2 (30 mL) over 45 min. The internal temperature rose 2-3 degrees during addition.

The clear solution was stirrred at -20 °C for 10 h and was then treated slowly with a

solution of 20% NaOH (6.0 mL) in MeOH (6.0 mL). The mixture stirred 30 min at -20

ºC and was then stirred vigorously at 0 °C for slow dropwise addition of 35% H2O2 (3.0

mL ) in MeOH (3.0 mL). This mixture was warmed to rt, stirred for 20 h, and transferred

to a separatory funnel using 75 mL of Et2O and 8 mL of brine. The aqueous layer was

extracted with Et2O (4x, 75 mL) and the organic layers were combined, dried over

MgSO4, filtered, concentrated (aspirator), and purified via silica gel chromatography

using 50% EtOAc in hexanes to give 0.456 g of 2J2b as a >20:1 mixture with 2J3b. The

product was contaminated with 13% dimethylsulfone. A 62% yield of diols was

calculated based on the NMR ratio of sulfone and diol signals.

84

Hydroboration of isopulegol 2Q1 with TfOH-activated BMS.

A -78 °C solution of BMS (490 L, 4.9 mmol) in CH2Cl2 (16 mL) was treated with

TfOH (450 L, 4.9 mmol) under N2. The mixture became a solution as gas evolution

was observed. A solution of isopulegol 2Q17 (0.25 g, 1.6 mmol) was added over 30 min

to the -78 ºC solution. The reaction was stirred at -20 ºC for 10 h before adding a mixture

of 5 N NaOH (5.4 mL) and MeOH (6 mL), followed by 30% H2O2 diluted with H2O (3

mL) over 30 min. The reaction stirred for 12 h at rt before transferring to a separatory

funnel containing satd K2CO3 (8 mL) and Et2O (100 mL). The aqueous layer was

extracted with Et2O (4X 50 mL). The organic layers were combined, dried over Na2SO4,

filtered, concentrated (aspirator), and purified via silica gel chromatography using 10%

EtOAc in hexanes (500 mL), 30% EtOAc in hexanes (600 mL), and 35% EtOAc in

hexanes (400 mL) to give 0.051 g 2Q17 (20%), 0.028 g citronellol 2Q5

64 (11%), 0.0483 g

1,3-diol 2Q465

(17%), and 0.0923 g of 1,4-diols 2Q27 and 2Q3

7 (32%, >30 : 1

diastereoselectivity). The same conditions were used for entries 3 & 4 of Table 2CC,

except 1.12 equiv of the appropriate amine was introduced as part of the substrate

solution in CH2Cl2.

Monitoring the ODHB of 2J1b using 11

B and 1H NMR spectroscopy.

CD2Cl2 (3 mL) in a 10 mL rb flask was cooled to -78 °C. Neat BMS (60 L, 0.61 mmol)

was added followed by TfOH (55 L, 0.62 mmol). Each drop of TfOH initially froze on

the surface, forming a white solid that dissipated after a few seconds of stirring (gas

evolution). This stirred for 30 min and was then treated with a solution of 5b (0.030 g,

0.3 mmol) in CD2Cl2 (2 mL) dropwise. The solution was cannulated into an oven-dried,

N2-flushed, septum-capped NMR tube submersed in a -78 °C bath and 11

B and 1H spectra

85

were taken at -78 °C. The sample was kept in a -78 °C bath while the probe was warmed

to -20 °C and 1H spectra were then taken over 2.5 h – once every 5 min for the first 45

min followed by one every 15 min. The first 3 spectra contained a signal at 12.5 ppm

that disappeared by the 20th

min at -20 °C. Olefin signals remained, but were nearly gone

after 2.5 h. Using the same sample, 11

B spectra were taken at 2 min, 5 min, 15 min, 45

min, 2 h, and 2.5 h after warming to -20 °C. At 5 min signals appeared at -20.6 ppm

(residual BMS), -2.5 ppm (tentatively, TfOBH2), 7.5 ppm (broad) and -8 ppm (broad).

At 45 min all of the aforementioned signals were present but a new broad signal appeared

at 34 ppm. At 2.5 h the signals at 34 and 7.5 ppm had broadened to the point of almost

disappearing while the signal at -8 had sharpened slightly, appearing as a broadened

triplet. The signal at -2.5 ppm dominated all 11

B spectra and the signal and -20.6

diminished over time.

Attempt at non-catalyzed ODHB with thexyl-3-pentenoxyborane 2HH1

O B

2HH1

H

A sample of 2,3-dimethyl-2-butene (0.25 mL, 2.1 mmol) was added to a 0 °C solution of

0.95 M THF·BH3 (2.1 mL, 2 mmol) under N2. The reaction stirred for 3 h while

warming to rt. The solution was then cooled to -30 °C and 3-pentenol (0.26 mL, 2.1

mmol) was added. After 75 min at -30 °C 11

B NMR spectroscopy revealed a dominant

signal at = +51 ppm, which is assigned as 2HH1. The reaction was then stirred for 12 h

at rt before adding premixed 20% NaOOH (1 mL) and 35% H2O2 (0.4 mL) and stirring

for 7 h. The reaction mixture was transferred to a seperatory funnel containing brine (3

86

mL) and Et2O (40 mL). The aqueous layer was extracted Et2O (4X 40 mL). The organic

layers were combined, dried over MgSO4, filtered, concentrated (aspirator), and purified

via silica gel chromatography using 50% EtOAc in hexanes (300 mL), 60% EtOAc in

hexanes (200 mL), and EtOAc (200 mL) to give 0.037 g of 3-pentenol (18%) and 0.1 g of

a 2:1 mixture of 1,3- and 1,4-diols (40%).

Hydroboration of 2J1e using PhB(OTf)H 2U5

Lithium phenylborohydride 2U1 was prepared according to the report by Graham et al.66

A -78 °C suspension of 2U1 (0.10 g, 1 mmol) in CH2CL2 (4 mL) was treated with TfOH

(160 L, 1.8 mmol) dropwise under N2. A solution of 2J1e (0.07 g, 0.46 mmol) in

CH2Cl2 (2 mL) was added to the activated phenylborane solution, which was then

warmed to -20 °C and stirred for 5 h. The reaction was treated with premixed 20%

NaOH (0.8 mL) and MeOH (1.5 mL) followed by 35% H2O2 (0.4 mL) in MeOH (1.5

mL). The reaction was stirred for 10 h, then transferred to a seperatory funnel containing

brine (3 mL) and Et2O (40 mL). The aqueous layer was extracted Et2O (4X 40 mL). The

organic layers were combined, dried over MgSO4, filtered, concentrated (aspirator), and

purified via silica gel chromatography using 50% Et2O in hexanes (150 mL) and 70%

EtOAc in hexanes (300 mL), to give 0.016 g of diols 2J2e & 2J3e (20%). Derivatization

and NMR assay as described above showed 22:1 regioselectivity. Hydroboration of 2S7

using 2U5 was done in analogous fashion.

ODHB of 2J1e via the lithium alkoxide 2AA1e.

BMS (60 L, 0.61 mmol) was taken up in 3 mL of CH2Cl2 placed in a 2-neck 25 mL rb

flask fitted with a cold-jacketed addition funnel containing a solution of 2J1e (0.045 g,

0.29 mmol) in 2 mL of CH2Cl2. Both flask and funnel were cooled to -78 °C. TfOH (55

87

L, 0.62 mmol) was added dropwise to the rb flask. Each drop of TfOH initially froze on

the surface, forming a white solid that dissipated after a few seconds of stirring (gas

evolution observed). After stirring for 30 min, n-BuLi (2.11M, 150 L, 0.33 mmol) was

added dropwise to the addition funnel, swirling the apparatus after addition was

complete. The resulting alkoxide solution was then added dropwise into the activated

borane solution at -78 °C, and the reaction was then warmed to -20 °C and stirred for 5 h

before MeOH (1 mL at -20°C) was added dropwise. This stirred vigorously at 0 °C for

30 min followed by addition of premixed 20% NaOH (0.6 mL) and 35% H2O2 (0.3 mL)

dropwise. This stirred for 12 h and was then transferred to a separatory funnel containing

1 mL of saturated K2CO3 solution using 20 mL Et2O. The aqueous layer was extracted

with Et2O (4x, 20 mL). The organic layers were combined, dried over MgSO4, and

concentrated (aspirator). The crude product was diaroylated as described above to give

0.097 g of the 2-(trifluoromethyl)benzoate of 2J2e for NMR assay (64% over 2 steps;

63:1 mixture with the regioisomer from 2J3e).

Preparation of E-4-cyclohexyl-1-methoxy-3-butene (2EE1).

OMe

2EE1

Sodium hydride (0.151 g, 3.77 mmol) was supended in THF (4 mL) and cooled to 0 °C in

a 25 mL rb flask. A solution of 5i (0.269 g, 1.75 mmol) in THF (2 mL) was added

dropwise and the reaction was allowed to warm to rt for 1 h. The suspension was cooled

to 0 °C and neat MeI (0.23 mL, 3.71 mmol) was added dropwise. The reaction and

warmed to rt for 2 h, quenched with H2O, and stirred for 15 min. The mixture was

88

transferred to a separatory funnel with 20 mL of Et2O and extracted with Et2O (3x, 20

mL). The organic layers were combined, dried over MgSO4, concentrated (aspirator),

and purified via silica gel chromatography using 2% Et2O in hexanes to give 0.149 g of

13 (50%). HRMS-CI+ (m/z): [M + H]

+ calcd for C11H20O, 169.159; found, 169.159.

1H

NMR (400 MHz, CDCl3, ): 0.99-1.31 (m, 5H), 1.57-1.74 (m, 5H), 1.85-1.96 (m, 1H),

2.26 (q, J= 6.8 Hz, 2H), 3.34 (s, 3H), 3.38 (t, J= 7.2 Hz, 2H) 5.23-5.49 (m, 2H). 13

C

NMR (100 MHz, CDCl3, ): 26.04, 26.16, 33.00, 33.03, 40.65, 58.52, 72.77, 123.48,

138.57. The sample contained 12% Z-isomer (quartet at 2.34 ppm and singlet at 3.35

ppm by 1H NMR). IR (neat, cm

-1): 2925(s), 2850 (m).

Control experiment hydroboration of 13; preparation of 4-cyclohexyl-3-hydroxy-1-

methoxy-butane (2EE2) and 4-cyclohexyl-4-hydroxy-1-methoxy-butane (2EE3).

OMe

OH2EE2

OMe

OH

2EE3

To a 0 °C solution of 13 (0.040 g, 0.26 mmol) in THF (1 mL) was added excess

THF·BH3 (1 mL, 1 mmol). The solution stirred for 2h before treating with premixed

20% NaOH (0.8 mL) and 35% H2O2 (0.4 mL) dropwise. The reaction mixture was

transferred to a separatory funnel containing brine and extracted with Et2O. The organic

layers were combined, dried over MgSO4, and concentrated (aspirator). Crude 1H NMR

showed a 1.4:1 ratio of 2EE2:3EE3. Silica gel chromatography with 15% EtOAc in

hexanes eluted 2EE2; HRMS-CI+ (m/z): [M + H]

+ calcd for C11H22O2, 187.170; found,

187.169. 1H NMR (400 MHz, CDCl3, ): 0.80-1.00 (m, 2H), 1.08-1.31 (m, 4H), 1.37-

1.52 (m, 2H), 1.60-1.73 (m, 6H), 1.77-1.85 (m, 1H), 2.89 (br s, 1H), 3.35 (s, 3H), 3.51-

3.59 (m, 1H), 3.6-3.67 (m, 1H), 3.86-3.94 (br m, 1H). 13

C NMR (100 MHz, CDCl3, ):

89

26.16, 26.31, 26.56, 32.91, 33.87, 34.06, 36.80, 45.28, 58.82, 68.60, 71.69. IR (neat, cm-

1): 3420 (br), 2920(s), 2850 (m). Pure 15 was eluted in later fractions; HRMS-CI

+ (m/z):

[M + H]+ calcd for C11H22O2, 187.170; found, 187.170.

1H NMR (400 MHz, CDCl3, ):

0.95-1.48 (m, 8H). 1.60-1.87 (m, 7H), 2.32 (br s, 1H), 3.35 (s, 4H, -OCH3 + -CH-O).

3.42 (dt, J= 1.2, 4.8 Hz, 2H). 13

C NMR (100 MHz, CDCl3, ): 26.19, 26.33, 26.48, 26.53,

27.95, 29.2, 31.49, 43.70, 58.56, 73.08, 75.85. IR (neat, cm-1

): 3420 (br), 2920(s), 2850

(m).

In Situ activation method for ODHB of 2EE1.

13 (0.10 g, 0.59 mmol) was taken up in CH2Cl2 (10 mL) and cooled to -78 °C in a 25 mL

rb flask. Neat BMS (120 L, 1.21 mmol) was added dropwise and the resulting solution

was stirred for 30 min before being treated slowly with neat TfOH (105 L, 1.18 mmol)

dropwise. Each drop of TfOH acid initially froze on the surface, forming a white solid

that dissipated after a few seconds of stirring. Gas evolution was observed. The clear

solution was stirred at -20 °C for 10 h and treated slowly with a solution of 20% NaOH

(0.6 mL) in MeOH (1.0 mL). The mixture stirred 10 min before being stirred vigorously

at 0 °C for slow dropwise addition of 35% H2O2 (0.3 mL ) in MeOH (0.7 mL). This

mixture was warmed to rt and stirred for 10 h before transferring it to a separatory funnel

containing 3 mL of brine using 30 mL of Et2O. The aqueous layer was extracted with

Et2O (3x, 25 mL) and the organic layers were combined, dried over MgSO4, concentrated

(aspirator), and purified via silica gel chromatography using 20% EtOAc in hexanes to

give 0.067 g of 2EE2 (61%) as 50:1 mixture with 2EE3 along with 16% of recovered 13.

A trace (<1%) of demethylated alcohol (2J1e) was observed, but demethylated products

2J2e or 2J3e were not detected.

90

Synthesis of trans-2,2-dimethyl-5-dodecen-3-ol 2R6

OH

2R6

2R6 was synthesized using the method of Negishi et al.49

A 0 °C solution of 1-heptyne

(2.36 mL, 18 mmol) in hexanes (40 mL) was treated with a solution of DIBAL-H (3.2

mL, 18 mmol) in hexanes (16 mL) under N2. The transfer of DIBAL-H was completed

with hexanes (2 mL). The reaction was stirred for 30 min at rt before warming to 55 °C

for 4 h. The reaction was then cooled to rt and 1.42 M nBuLi (12.67 mL, 18 mmol) was

added dropwise. The reaction became a white sludge while stirring for 20 min before a

solution of tbutyl-oxirane (2.4 mL, 19.7 mmol) in hexanes (20 mL) was added via

cannulation under N2. The reaction was stirred for 24 h at rt before cooling to 0° C and

adding 3N HCl (10 mL), which stirred for 1 hwhile warming to rt. Satd Rochelle‟s salt

(30 mL) was added to the reaction, which was then transferred to a separatory funnel.

The aqueous layer was removed and rinsed with hexanes (2X, 80 mL). The organic layer

were combined, dried over MgSO4, filtered, and concentrated (aspirator), and purified

via silica gel chromatography in 15% EtOAc in hexanes followed by kugelrohor

distillation to provide 2R6. Yield was not recorded. (1H NMR (500 MHz, CDCl3, ):

0.88 (t, J= 7.5 Hz, 3H). 0.91 (s, 9H), 1.22-1.40 (m, 6H), 1.65 (d, J= 3 Hz, 1H). 1.85-

1.94 (m, 1H), 2.02 (q, J= 7.5 Hz ,2H), 2.27-2.34 (m, 1H), 3.19 (dt, J= 11 Hz, 2.5 Hz,

2H), 5.39-5.47 (m, 1H), 5.52-5.59 (m, 1H).

91

Synthesis of cis-2,2,7,7-tetramethyl-5-octen-3-ol 2S6 and cis-2,2-dimethyl-5-dodecen-

3-ol 2S7.

OH

2S6OH

2S7

To a -78 °C solution of 3,3-dimethyl-1-butyne (3.7 mL, 30 mmol) in THF (30 mL) was

added 1.38 M nBuLi (21 mL, 29 mmol), under N2. The reaction stirred for 20 min at -78

°C before neat tbutyl-oxirane (4 mL, 33 mmol) was added dropwise, followed by

BF3·OEt2 (3 mL, 24.3 mmol). The reaction stirred for 2.5 h at -78 °C before 15 mL of

satd NaHCO3 was added. The reaction warmed to 0 °C over 10 h. The THF layer was

separated from the aqueous layer, which was then rinsed with Et2O (2X 40 mL). The

organic layers were combined, dried over MgSO4, filtered, and concentrated to provide

crude 2,2,7,7-tetramethyl-5-octyn-3-ol. To a 0 °C solution of cyclohexene (9.8 mL, 97

mmol) in Et2O (30 mL) was added 10 M BMS (4.6 mL, 46 mmol) dropwise under N2.

The reaction stirred at 0 °C for 3 h before the solvent was blown down with N2 through

the septum followed by placing the white powder under high vac.67

The white powder

was suspended in THF (20 mL) and cannulated into a 0 °C solution of 2,2,7,7-

tetramethyl-5-octyn-3-ol (19.56 mmol) in THF (10 mL). The transfer was completed

with THF (2X 10 mL) and the reaction stirred for 14h at rt. The reaction was cooled to 0

°C and AcOH (15 mL, 250 mmol) was added. The reaction was heated to 60 °C for 90

min. Solvent was removed via rotovap and the residue was treated with 1:1 CH2Cl2: 4M

KOH (60 mL) and stirred for 40 h. The mixture was transferred to a separatory funnel

and the organic layer was removed from the aqueous layer, which was rinsed with

92

CH2Cl2 (3X 30 mL). The organic layer were combined and rinsed with satd NH4Cl (3X

25 mL) and Brine (40 mL), dried over MgSO4, filtered, concentrated (aspirator), and

purified via silica gel chromatography using 2% Et2O in hexanes to give 1.5 g of cis-

2,2,7,7-tetramethyl-5-octen-3-ol 2S6 (42%): (1H NMR (400 MHz, CDCl3, ): 0.93 (s,

9H). 1.12 (s, 9H), 1.27 (br s, 1H), 2.32 (m, 2H). 3.23 (dt, J= 9.2 Hz, 4 Hz, 1H), 5.26 (m,

1H), 5.54 (dt, J= 12 Hz, 2 Hz, 1H). Analogous conditions were used with 1-heptyne or

methyloxirane to generate 2S568

and 2S7. (1H NMR (400 MHz, CDCl3, ): 0.89 (t, J=

6.8 Hz, 3H). 0.93 (s, 9H), 1.22-1.40 (m, 6H), 2.0-2.26 (m, 4H). 3.09 (dt, J= 10 Hz, 3.2

Hz, 1H), 5.4-5.49 (m, 1H), 5.54-5.63 (dt, J= 12 Hz, 2 Hz, 1H).

Synthesis of trans-2-isopropyl-3-pentenol 2T1

OH

2T1

To a -78 °C solution of 3-pentenoic acid (0.2 mL, 1.93 mmol) in HMPA (2 mL) and THF

(8 mL) was added 1.28 M (3.92 mL, 5 mmol) under N2. The reaction stirred for 30 min

before addition of 2-iodopropane (0.24 mL, 2.4 mmol) in THF (2 mL). The reaction

stirred for 3 h, warming to 0 °C. 1 N HCl (4 mL) was added to quench the reaction,

which was transferred to a separatory funnel containing Et2O (40 mL). The aqueous

layer was extracted with Et2O (4X 40 mL). The organic layers were combined, dried

over MgSO4, filtered, and concentrated. Reduction of the crude mixture with LAH (0.31

g, 11.2 mmol) followed by silica gel chromatography in 10% EtOAc in hexanes provided

0.072 g of synthesis of trans-2-isopropyl-3-pentenol 2T1 (29%). 1H NMR (500 MHz,

93

CDCl3, ): 0.86 (d, J= 7 Hz, 3H). 0.89 (d, J= 7 Hz, 3H), 1.52 (br s, 1H), 1.62 (m, 1H).

1.72 (dd, J= 6.5 Hz, 1.5 Hz, 3H), 1.95 (m, 1H), 3.38 (t, J= 10 Hz, 1H), 3.63 (dd, J= 10.5

Hz, 5 Hz, 1H), 5.22 (m, 1H), 5.56 (dq, J= 15 Hz, 6.5 Hz, 1H). 13

C NMR (125 MHz,

CDCl3, ): 18.13, 19.58, 20.77, 28.89, 52.53, 64.09, 129.25, 130.53.

ODHB with 2T1

To a -78 °C solution of 10.1 M BMS (60 L, 0.61 mmol) in CH2Cl2 (3 mL) was added

TfOH (50 L, 0.55 mmol) dropwise under N2. This stirred for 30 min at -78 °C before

adding a solution of 2T1 (0.141 g, 0.32 mmol) and cyclohexene (0.16 mL, 1.58 mmol) in

CH2Cl2 (2 mL). The reaction mixture was then stirred for 10 h at -20 °C before adding

20% NaOH (0.4 mL) in MeOH (0.6 mL) followed by 35% H2O2 (0.2 mL). The reaction

mixture stirred for 12 h at rt before transferring it to a separatory funnel containing brine

(2 mL) and Et2O (25 mL). The aqueous layer was extracted with Et2O (4X, 25 mL). The

organic layers were combined, dried over Na2SO4, filtered, concentrated (aspirator), and

purified via silica gel chromatography in 20% EtOAc in hexanes to collect 0.016 g of one

1,3-diol diastereomer (35%) and 0.015 g of the other (32%). No 1,4-diol regioisomer

was observed. Top 1,3-diol diastereomer: 1H NMR (400 MHz, CDCl3, ): 0.92 (d, J= 7

Hz, 3H). 0.96 (t, J= 7.6 Hz, 3H), 1.01 (d, J= 7 Hz, 3H), 1.18 (m, 1H). 1.56-1.65 (m, 2H),

1.97 (oct, J= 6.4 Hz, 1H), 2.66 (br s, 1H), 2.91 (br s, 1H), 3.81 (m, 1H), 3.88-3.98 (m,

1H). Bottom 1,3-diol diastereomer: 1H NMR (400 MHz, CDCl3, ): 0.95 (d, J= 6.4 Hz,

6H). 1.03 (t, J= 7.2 Hz, 3H), 1.5-1.68 (m, 4H), 2.74 (br s, 2H). 13.74-3.89 (m, 3H).

94

References for Chapter 2

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100

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101

Chapter 3: The Impact of Ipc2BH on Synthetic Organic Chemistry

The creation of chiral centers in asymmetric fashion is a cornerstone of organic

synthesis and a frontier whose limits will be pushed for generations to come. Almost

fifty years ago, hydroboration earned the distinction of being one of the first synthetically

practical, non-enzymatic methods for generating an asymmetric center. This was

achieved by H. C. Brown through the generation of a C2-symmetric boron environment

in diisopinocampheylborane (Ipc2BH). While Brown immediately recognized the

ground-breaking nature and potential of the asymmetric induction, the C2-symmetric

nature of the reagent was initially unheralded. The following chapter will illustrate the

impact of Brown‟s discovery over the past half century in the context of 1) the evolution

of asymmetric hydroboration and 2) the development of C2-symmetric boron species as

enantioselective reagents for organic synthesis.

3.1: The Evolution of Asymmetric Hydroboration

3.1i: Diisopinocampheylborane

In 1961, just five years after hydroboration in ethereal solvents was first reported,1

Brown and Zweifel discovered that hydroboration of the naturally abundant chiral

terpene -pinene 3A1 stops at the dialkylborane stage to asymmetrically form the

C2-symmetric dialkylborane diisopinocampheylborane (Ipc2BH) (3A2). This is

attributed to the steric bulk of both 3A1 and 3A2 preventing further reaction.

Fortunately, further reaction of 3A2 occurs with less hindered substrates. Olefins such as

cis-2-butene, cis-3-hexene, and norbornene react with 3A2 to provide (R)-2-butanol (R)-

3A3, (R)-3-hexanol (R)-3A4, and (1R,2S)-exo-norborneol 3A5 with respective

enantiomeric purities of 87%, 91%, and 83% after oxidative workup (Scheme 3A).2

102

NaBH4, BF3·OEt2

Diglyme

3A1

1. cis-2-butene

2. NaOOH

OH

90 % yield 87% ee1.

2. NaOOH

H

OH

62% yield83% ee

1. cis-3-hexene

2. NaOOH

OH

81% yield91% ee

Scheme 3A: The First Reported Asymmetric Hydroborations with Ipc2BH

B

H

3A2 3A3

3A43A5

Obtaining (R)-3A4 with an enantiomeric purity of 91% is of particular importance: since

-pinene was available in 90% purity, this indicates that the formation of 3A2 occurs

with complete enantioselectivity.

High enantioselectivity is elusive with a broader range of olefins. While

cis-1,2-disubstituted (Type II) olefins are excellent substrates for asymmetric

hydroboration with Ipc2BH (3A2), the more hindered trans-1,2-disubstituted (Type III)

and trisubstituted (Type IV) olefins lead to lower enantioselectivities and loss of pinene

from 3A2 via retrohydroboration during the reaction. In the case of trans-2-butene two

equivalents of substrate are consumed for every equivalent of pinene released in the

reaction, while only one equivalent of the more hindered 1-methyl-cyclopentene is

consumed for each equivalent of pinene released. Brown reports that the loss of pinene is

the result of the equilibrium between the Ipc2BH dimer 3B1 and

triisopinocampheyldiborane 3B2 (Ipc3B2H3), which then reacts with the substrate at the

103

less substituted boron. 3 In the case of 3-methyl-cyclopentene, the initial hydroboration

must lead to a species (presumably 3B5) with sufficient steric bulk to prevent a second

hydroboration. Conversely, the less hindered trans-2-butene can react a second time,

accounting for the different ratios of consumed substrate : recovered pinene (Scheme

3B). Also worthy of note is the fact that the low enantiomeric purities observed in these

cases were opposite to those predicted by Brown‟s model for Ipc2BH.

Enantiomeric purities of alcohols derived from the hydroboration of 1,1-

disubstituted (Type I) olefins with Ipc2BH (A2) are also low. In the case of 2-methyl-1-

butene, Ipc2BH generates (R)-2-methyl-1-butanol (R)-C1 with 21% ee (Scheme 3C).

Brown noted that reduced selectivity is to be expected in cases where the boron does not

become directly attached to the stereogenic carbon,4 and differentiating a methyl group

104

from an ethyl group presents a challenge for any asymmetric transformation. Increasing

the steric differentiation of the olefin substituents using 2,3-dimethyl-1-butene leads to

(R)-2,3-dimethyl-1-butanol (R)-3C2 with 30% ee after oxidative workup (Scheme 3C).

Partial loss of pinene (9 % and 7 %, respectively) is observed in these reactions,

suggesting, though not explicitly concluded by Brown, that Ipc3B2H3 3B2 is contributing

to the results.

Almost twenty years after the discovery of 3A2, Brown published an improved

synthesis of the reagent, making it readily available in 99% enantiomeric purity from

92% enantio-enriched pinene.5 This enables greater selectivity with type II olefins in

tetrahydrofuran (THF) at -25 °C. The increased purity of the reagent and lower reaction

temperatures are necessitated by the switching of solvent from diglyme to THF leading to

increased formation of monoisopinocampheylborane 3F2 (IpcBH2), which interferes with

selectivity at room temperature. More hindered substrates require higher reaction

temperatures, which lead to the aforementioned loss of pinene, rendering the improved

3A2 less effective. A summary of the selectivities achieved with 3A2 is provided in

Table 3D.

105

Table 3D: Asymmetric Hydroboration with Diisopinocampheylborane

Type of Olefin Substrate ee of Alcohol (%)

II 2-butene 98 (R)a

II 3-hexene 93 (R)a

II norbornene 83 (1S,2S)a

III 2-butene 13 (S)b

IV 1-Me-cyclopentene 22 (S,S) b

I 2-Me-1-butene 21 (R)b

I 2,3-dimethyl-1-butene 30 (R) b

a) Achieved with the 99% enantiopure 3 in THF @-25 °C5

b) Achieved with 92% enantiopure 3 in diglyme @ rt.3, 4

3.1ii: Monoisopinocampheylborane

Ten years passed between the report that monoisopinocampheylborane 3F2

(IpcBH2) can be generated in situ from triisopinocampheyldiborane 3B2 and the report

introducing pure IpcBH2 as a hydroborating reagent.6 Synthesis of 3F2 cannot be

achieved by simply treating a single equivalent of pinene with a stoichiometric amount of

BH3·THF because the reaction cannot be stopped at the monohydroboration stage.7

Brown et al. circumvented this complication by generating IpcBH2·triethylamine

complex 3E3 from thexylborane-triethylamine complex (ThxBH2·NEt3) 3E1 and pinene

3A1 (Scheme 3E). The thexyl group serves as a protecting group for the borane: initially

preventing the formation of Ipc2BH·NEt3 before undergoing retro-hydroboration to

generate tetramethylethylene (TME) 3E2 and the desired complex 3E3. Hydroboration

studies were conducted by treating 3E3 with an equivalent of BH3·THF to free the

IpcBH2, followed by 1-methyl-cyclopentene, 2-methyl-2-butene, or 1-methyl-

cyclohexene. Subsequent oxidation led to (1S,2S)-2-methyl-cyclopentanol (1S,2S)-3E4,

(S)-3-methyl-2-butanol (S)-3E6, and (1S,2S)-2-methyl-cyclohexanol (1S,2S)-3E5 with

55% ee, 53% ee, and 72% ee, respectively.

106

A revised synthetic route was developed before IpcBH2 was presented as a

reagent for hydroborating other types of olefins. The convenience and optical purity

provided by the route displayed in Scheme 3E was surpassed by an approach involving

treatment of Ipc2BH 3A2 with N,N,N,N-tetramethylethylene-diamine (TMEDA) followed

by equilibration at 34 °C to form the TMEDA·2BH2Ipc complex 3F1 with loss of pinene

(Scheme 3F). TMEDA·2BH2Ipc complex 3F1 can be formed with enantiomeric purity

approaching 100% from 94% ee pinene, and 3F1 releases IpcBH2 (3F2) upon treatment

with BF3·OEt2. The byproduct TMEDA·2BF3 (3F3) precipitates from THF but 3F3 is

inert so it‟s removal is not necessary for hydroboration to occur smoothly.8

107

Scheme 3F: Improved Synthesis of IpcBH2

3F1

B

H

3A2

BH3·SMe2 TMEDA

3A13F1

3F1BF3·OEt2

B

H

H F3B N

N BF3

3F2 3F3

H

B

H

N

N B

H

H

Table 3G summarizes the results of a series of publications following this revised

synthesis of IpcBH2 3F2, illustrating its synthetic utility.9-11

It is important to note that

Ipc2BH (A2) and IpcBH2 3F2 are complimentary in terms of substrate scope: while 3A2

only works well on Type II olefins, 3F2 works well on Types III and IV but poorly on

Type II olefins. It is also convenient that both of these reagents can generate either

desired enantiomer due to the commercial availability of both (+) and (-) -pinene. Table

3P is provided for a direct comparison of asymmetric hydroboration reagents. Despite all

the advantages of Brown‟s Ipc2BH (3A2) and IpcBH2 (3F2), the only substrates that are

beyond optimization are 1-phenyl-cyclopentene and, arguably, Type II olefins. Every

other substrate provides opportunity for improvement, and Type I olefins in particular.

108

Table 3G: Enantioselective Hydroboration with Monoisopinocampheylborane

B

H

H

3F2

1. Substrate, THF

2. NaOOH

OHAlcohol +

a) Result published using method from Scheme D 12

Substrate Product Yield

(%)

ee

(%)

Substrate Product Yield

(%)

ee

(%)

Ph

Ph

HO1S, 2R

92

100

OH

S

NRa

23.6

Ph

Ph

HO1S, 2R

79

88

EtEt EtEt

OH

S

NRa

19.7

Ph

Ph

OH

2S, 3R

89

81

OH

S

73

73

Ph Ph

OH

2S, 3S

91

82

Et

Et Et

Et

OH

S

83

75

Ph

Et

Ph

Et

OH

2S, 3R

87

85

Ph Ph

OH

R

72

75

Et

Ph

Et

Ph

OH

2S, 3S

95

85

109

3.1iii: Dilongifolylborane

Despite the complementary nature of Ipc2BH (3A2) and IpcBH2 (3F2), Brown

pursued a reagent that could stereoselectively hydroborate both hindered and unhindered

olefins, proposing that the defining characteristic of such a reagent would be a steric

environment simultaneously more hindered than 3F2 and less hindered than 3A2. These

requirements were met by the hydroboration of the sesquiterpene (+)-longifolene 3H1 to

form dilongifolylborane 3H2.13

The reagent is convenient to synthesize because the

hydroboration of 3H1 stops at the diakylborane stage, at which point 3H2 precipitates

from ether. While the bulkiness of 3H2 makes its steric requirement greater than that of

3F2, the fact that the C-B carbons are primary enables the steric requirement to be less

than that of 3A2. This does allow the use of 3H2 for hydroboration of a broader range of

olefins with good selectivity (Table 3H). However, Type I and Type II olefins are not

3H1

HBH

BH3·SMe2

Et2O

H3H2

1. Substrate

2. NaOOH H2O2

H

HO

Alcohol

Table 3H: Enantioselective Hydroboration with Dilongifolylborane

3H3

Substrate Alcohol Yield (%) ee (%) Substrate Alcohol Yield (%) ee %

OH

R

71

78

Et Et

OH

R

76 75

EtEt EtEt

OH

R

81

71

HO

1R, 2R

83 63

OH

R

79

70

Et

Et

HO1R, 2R

81 59

110

discussed in this report and the selectivities reported for type II and type IV olefins are

not as synthetically useful as those for 3A2 and 3F2.

3.1iv: Limonylborane

Jadhav synthesized limonylborane 3I3 from another naturally abundant terpene:

limonene 3I1. Treating 3I1 with monochloroborane etherate (BH2Cl·OEt2) forms the

bicyclic chloroborane 3I2, which is converted to 3I3 by LiAlH4 in the presence of the

alkene substrate. While 3I3 does provide reasonable enantioselectivities for all but type I

olefin substrates, the selectivities, once again, do not approach those achieved with

Ipc2BH 3A2 and IpcBH2 2F2 (Table 3I).

BCl

BH2Cl·OEt2Alcohol +

HO

HO

Table 3I: Enantioselective Hydroboration with Limonylborane

LiAlH4 BH

3I1 3I2 3I3

1. Substrate

2. NaOOH

3I4

Substrate Alcohol Yield (%) ee (%) Substrate Alcohol Yield (%) ee (%)

OH

R

78

55

HO

R

75

5.2

OH

R

75

58.6

HO

1R, 2R

77

46

OH

R

70

66.5

111

3.1v: (R,R) and (S,S)-2,5-Dimethyl-borolane and Related Reports

Not until 1985 was Brown‟s dominance in the field of asymmetric hydroboration

faced with strong competition. Foregoing the Brown approach of forming chiral (di)alkyl

boranes by hydroborating terpenes, but returning to a C2-symmetric species, Masamune

targeted (R,R)-2,5-dimethylborolane (R,R)-3J7 using an approach involving chiral

resolution via amino alcohol complexes.14

The synthetic route, illustrated in Scheme 3J,

is quite arduous. The borolane ring is assembled as an aminodialkylborane 3J2 by

treating (diethylamino)dichloroborane with bis-Grignard reagent 3J1. After

methanolysis to methoxyborolane 3J3, multiple resolutions with aminoalcohols allow

isolation of enantio-enriched material. N,N-dimethylethanolamine preferentially

complexes to cis-3J3 to form 3J4, which precipitates from Et2O, allowing separation of

112

racemic trans-3J4 from the solution. (S)-Prolinol selectively forms complex 3J5 from

(R,R)-3J3, allowing for separation from its enantiomer (S,S)-3J3, which can be recovered

as an enriched complex to (S)-valinol (not pictured). Complex 3J5 undergoes

methanolysis to form (R,R)-3J3, which is reduced by LiAlH4 to form the lithium

borohydride-etherate 3J6. Treating 3J6 with excess methyl iodide (MeI) abstracts a

hydride, allowing borolane dimer 3J7 to form.15

One of the most impressive aspects of

the synthesis is that it was undertaken with the knowledge that 3J7 might dimerize and

then isomerize into 2,5,5,9-tetramethyl-1,6-diborocyclodecane, 3J8. The analogous

conversion occurs with the parent borolane, rendering it incapable of hydroboration.16, 17

Fortunately, the isomerization is slow enough that 3J7 can be used as a reagent for

exceptionally enantioselective hydroboration with any generic prochiral olefin except

Type I (Table 3K). This work could have rendered Brown‟s Ipc2BH 3A2 and IpcBH2

3F2 obsolete if not for the incredibly challenging synthesis of 3J7. Masamune‟s work has

yet to be duplicated in any context reported in the literature but the proof of concept

provides a challenge to the chemical community to find a more synthetically viable

method of generating enantio-pure C2-symmetric hydroboration agents.

113

B

H

H

Li·OEt2

1. Substrate, MeI, Et2O

2. NaOOH

3J9

Alcohol +

OH

OH

Table 3K: Enantioselective Hydroboration with (R,R)-2,5-Dimethylborolane

4K1

Substrate Alcohol Yield (%)

ee (%)a

Substrate Alcohol Yield (%)

ee (%)a

OH

S

75 97.6 HO

(S,S)

89 100

OH

S

71 99.5

HO

(S,S)

60 95.6

EtEt

EtEt

OH

S

83 99.9

OH

S

97 99.3

Et

Et

EtEt

OH

S

83 99.5

OH

S

90 94.2

HO

H

S

85 1.5

a) adjusted to compensate for the slight cis-borolane impurity present during the reaction.

Hodgetts and coworkers tried to answer the challenge by targeting the more

hindered borolane, 2,5-diisopropyl-borolane 3L5.18

Optimum conditions were developed

for diastereoselective hydroboration of 2,7-dimethyl-2,6-octadiene 3L1 to favor trans-

2,5-diisopropyl-borolane. Treating 3L1 with dimethylsulfide monobromoborane

(BH2Br·SMe2) in carbon tetrachloride at 76 °C provides 4 : 1 trans-selectivity in 70 %

overall yield. The undesired cis-borolane forms complex 3L3 upon treatment with

pyrrolidinoethanol, allowing purification of racemic trans-methoxyborolane via cannula

114

filtration and distillation to provide 3L4 in 63% yield. However, no further progress

towards an enantiopure hydroborating reagent was reported, leaving Masamune‟s legacy

unfulfilled (Scheme 3L). Despite taking Masamune‟s arduous aminoalcohol resolution

approach, the improved borolane ring synthesis via diastereoselective hydroboration

rather than bis-Grignard addition makes Hodgetts' work noteworthy, as it doubles the

yield of racemic-trans-borolane after separation from the undesired cis-isomer.

1.BH2Br·SMe2

CCl4, 76 °C2. MeOH

B

OMe

4 : 1 d.r.

70%

OHN

hexanes, -78 °C B

OMe

racemic

B

H

(S,S) or (R,R)

BN

O

3L1 3L2 3L4 3L5

3L3

Scheme 3L: Hodgett's Progress Toward Enantiopure 2,5-Diisopropylborolane

Knochel recognized the significance of C2-symmetry in asymmetric

hydroborating reagents and pursued what he refers to as pseudo-C2-symmetric

monoalkylboranes 3M1-3, in which C2-symmetric alkyl appendages are incorporated on

boron.19

Considering the general difficulty in achieving chiral induction with Type I

olefins due to the spatial separation of the chiral boron environment from the prochiral

center of the substrate,4 it is understandable that the enantioselectivity achieved with 3M2

is lower than that achieved with borolane 3J7 (Table 3M). Not only is the selectivity

low, but the syntheses of boranes 3M1 and 3M2 involve 9-10 steps and will not be

elaborated in this text. Psuedo-C2-symmetric boranes are clearly not worthy successors

to Masamune‟s borolane, as their syntheses are longer and their selectivities are inferior.

115

Table 3M: Enantioselective Hydroboration with Knochel’s boranes

Borane Substrate Yield (%)

ee (%)

Borane Substrate Yield (%)

ee (%)

Ph Ph

BH2

3M1

59

38 Ph Ph

BH2

3M1

68

38

BH2

3M2

54

55

BH2

3M2

67

64

Ph Ph

BH2

3M3

57

29 Ph Ph

BH2

3M3

66

52

3.1vi: B-H-9-Boracyclo[3.3.2]decanes

Less than two years ago, came a report of a reagent that improved upon the 30%

ee hydroboration with Type I olefins achieved by Brown in 1964. The Soderquist group

combined a version of Masamune‟s resolution technique with an ingenious homologation

approach to access chiral bicyclic boranes reminiscent of Jadhav‟s limonylborane 3I3.20

Exploiting single carbon homologation capabilities of boron, B-methoxy-9-

borabicylco[2.2.1]nonane (B-MeO-9-BBN) 3N1 was converted into B-methoxy-10-

trimethylsilyl-9-borabicylco[3.3.2]decane 3N2a and B-methoxy-10-phenyl-9-

borabicylco[3.3.2]decane 3N2b using the appropriately substituted diazomethane

reagents. Each enantiomer is isolable by crystalization via sequential treatment with the

two enantiomers of pseudoephedrine (Scheme 3N).

116

B

OMe

RCHN2

hexanesreflux, 10 h

BTMS

OMe

Ph Me

NHMeHO

racemic

BTMS

Ph

Me

NHMe

O

MeCN

BTMS

OMe

BTMS

PhMe

MeHNO

PhMe

MeHN OH

3N2a R= TMS: 97 %3N2b R= Ph: 90 %

3N3a(S): R= TMS: 38 %3N3b(S): R= Ph: 39.5 %

Scheme 3N: Generation and Resolution of Soderquist's 9-Boracyclo[3.3.2]decanes

3N1

3N3a(R): R= TMS: 28 %3N3b(R): R= Ph: 28 %

3N2

The enantiopure complexes 3N3a and 3N3b are reduced to their respective

borohydrides 3O1 and 3O2, followed by hydride abstraction with TMSCl to generate the

chiral reagent for hydroboration, similar to the approach of Masamune (Table 3O).

Enantioselectivities from 28 to 98% ee are achieved with Type I olefins, which sets this

work apart from its predecessors.21

The 10-TMS- and the 10-Ph-9-borabicylco-

[3.3.2]decane reagents 3O1 and 3O2 are similar to Brown‟s Ipc2BH 3A2 and IpcBH2

3F2 in that neither is ideal for all four olefin types, although they complement each other

in terms of substrate scope. Table 3P has been compiled for convenient comparison of

asymmetric hydroborating agents. Soderquist‟s reagents are clearly best for Type I

olefins and hold their own with Masamune‟s borolane with Type III olefins. Synthetic

route aside, Masamune‟s borolane is the best reagent for Type IV olefins and Type II

olefins, which also provide comparable enantioselectivities upon treatment with Brown‟s

Ipc2BH 3A2.

117

Borane Source

Substrate Alcohol Yield (%)

ee (%)

Borane Source

Substrate Alcohol Yield (%)

ee (%)

3O1-R

OH

S

98 84 3O2-S

OH

S

90 32

3O1-R

OH

R

95 95 3O2-S

OH

S

90 96

3O1-R

HO

H

S

87

40

3O2-S

OH

S

79 74

3O1-R

HO

H

S

60

56

3O2-S

HO

H

R

84 92

3O1-R Ph PhHO

H

S

83

66

3O2-S

D

Ph Ph

D

HO

H

R

97 92

3O1-S

HO

H

R

82

52

3O2-S Ph PhHO

H

R

95 78

3O1-S

D

Ph Ph

D

HO

H

R

86

98

3O2-R

HO

H

S

83 28

3O2-R

HO

H

S

97 38

118

3.1vii: Summary of Asymmetric Hydroboration

In summary, the major breakthroughs in asymmetric hydroboration include

Brown‟s terpene-hydroboration approach, Masamune‟s C2-symmetric borolane

approach, and Soderquist‟s bicyclicborane approach. All three incorporate a resolution

of some kind: Brown‟s IpcBH2 from Ipc2BH are resolvable using TMEDA and both

Masamune and Soderquist use chiral aminoalcohols for resolving borane enantiomers.

Both the Brown ipc-derived reagents and the two Soderquist reagents 3O1 and 3O2

complement each other to allow good enantioselectivity with all four types of prochiral

alkene substrates. However, neither of those four reagents approach the versatility of

Masamune‟s C2-symmetric borolane, which provides both 1) a standard by which other

asymmetric hydroboration reagents are judged, and 2) an obvious indication as to how

said standard could be surpassed.

119

120

3.2 C2-Symmetric Boron Reagents in Organic Synthesis

The synthetic application of Brown‟s C2-symmetric diisopinocampheylboron

(Ipc2B-) moiety is not limited to hydroboration. It has been used in a wide variety of

asymmetric transformations including ketone reductions, aldol reactions, and several

different variations of aldehyde allylation. It has also provided a model for implementing

new C2-symmetric boron species in the context of the aforementioned transformations

and others.

3.2i Asymmetric Aldol Reactions Using C2-Symmetric Borons as Lewis Acids

In 1984, Meyers used diisopinocampheylborane triflate (Ipc2BOTf) to investigate

an alternative to Evans‟ chiral auxiliary approach to asymmetric aldol reactions.

Whereas Evans has achieved stereoselective aldol reactions by forming a boron enolate

from an enantio-enriched substrate 3Q1 with a racemic boron Lewis acid (Scheme 3Q),22

Meyers proposed using a racemic substrate with an enantio-enriched boron Lewis acid.23

Treating 2-ethyl-4,4-dimethyl-2-oxazoline 3R1 with Ipc2BOTf provides azaenolate 3R2,

which provides the threo-addition product 3R4 with ≥9 : 1 diastereoselectivity and 77%

ee after treatment with an aldehyde followed by subsequent oxidative workup with H2O2

(Table 3R). While these selectivities do not eclipse those achieved by Evans it is clear

that the C2-symmetric boron environment generates significant enantioinduction.

O

SMeNO

O B

OTf

OB(nBu)2

SMeNO

O

H

O

THF-78 °C

O

SMe

NO

O OH

>99 : 1 Erythro 96.8% ee

Scheme 3Q: Evans' Chiral Auxiliary Approach to Stereoselective Aldol Chemistry

3Q1 3Q2 3Q3

121

O

N

Ipc2BOTf

iPr2NEt

O

N

B(Ipc)2

RH

O

Et2O, -78 °C

O

N

Me

OH

R

threo-3R4

N

OB O

Ipc

Ipc

H

RH2O2

Table 3R: Stereoselectivity of Ipc2B Azaenolates in Aldol Reactions

3R1 3R2 3R3

Entry R Threo : Erythro ee (%)

1 Et 92 : 8 77

2 nPr 91 : 9 77

3 nPent 90 : 10 77

4 iPr 91 : 9 85

5 chex 95 : 5 84

6 tBu 94 : 6 79

Meyers‟ success inspired Paterson to investigate a more traditional chiral enolate

equivalent using Ipc2BX species with ethyl and methyl ketones.24,25

It was found that

treating an ethyl ketone 3S1 with Ipc2BOTf and Hunig‟s base in CH2Cl2 at -78 °C

provides a >97:3 preference for the Z-enolates 3S2. Treating the Z-enolate with an

aldehyde followed by oxidative workup provides excellent syn-diastereoselectivity and

enantioselectivity (Table 3S). Enolization of diethylketone with Ipc2BCl and Et3N occurs

with modest selectivity to generate a 4:1 E- : Z- mixture of enol borinates. Treating this

mixture with methacrolein followed by H2O2 generates a 4:1 anti:syn aldol mixture,

which is to be expected. However, the corresponding anti-aldol product is generated in

<20% ee and the syn-aldol product is generated in 80% ee, which is 11% lower than the

result reported in entry 1 of Table 3S. Paterson et al. point out that “enol

diisopinocampheylborinates with E configuration are unlikely to be useful for

asymmetric anti aldol reactions.” Investigation of methylketone-derived enol borinates

led to the observation of good enantio-induction using either Ipc2BCl or Ipc2BOTf.

122

Interestingly, the enantiofacial selectivity of aldehydes with methyl ketone-derived enol

borinates (re-face) is the opposite of that for the ethyl ketone analogs (si- face).

Table 3S: Stereoselectivity of Enol Borinates in Aldol Reactions

R1

OIpc2BOTfiPr2NEt

CH2Cl2-78 °C

R1

OB(Ipc)2

> 97 :3 Z-

R2H

O

OB

O

Ipc

SL

M

H R2H2O2

R1

O

Me

OH

R2

Major Isomer

3S1 3S2 3S3 3S4

Entry R1 R

2 syn : anti ee (%) yield (%)

1 Et H2C=C(Me) 98 : 2 91 78

2 Et nPr 97 : 3 80 92

3 Et iPr 96 : 4 86 75

4 Et 2-furyl 96 : 4 80 84

5 Ph H2C=C(Me) 98 : 2 91 97

6 iPr H2C=C(Me) 95 : 5 88 99

7 iBu H2C=C(Me) 97 : 3 86 79

Masamune26,27

and Reetz28,29

have investigated asymmetric

aldol reactions with enol borinates generated from their respective

C2-symmetric borolanes. The Masamune reagent 3T5 was

generated from the borolane triflate 3T3 while the Reetz reagents

3T6 was done using borolane chloride 3T4. Table 3T illustrates that enolates generated

from either borolane consistently provide excellent enantioselectivity. Both groups

rationalize their enantioselectivities using a Zimmerman-Traxler model 3S5. While the

selectivities from Tables 3S and 3T cannot be directly compared, other work by Reetz30

and Paterson25

indicates that these 2,5-trans-disubstituted borolanes provide superior

enantio-induction compared to the Ipc2B moiety.

123

O

SC(Et)3

R1

3T1 R1= H

3T2 R1= Me

BR2 R2

X4T3 R2= Me, X= OTf

4T4 R2= Ph, X= Cl

SC(Et)3

O

R1

B

R2

R2 R3H

O

O

SC(Et)3

R1

R3

OH

Table 3T: Comparing the Masamune and Reetz Borolanes in Aldol Reactions

3T5 R2= Me

3T6 R2= Ph

3T7

Entry R1 R

2 R

3 anti- : syn- Yield of 3T7 (%) ee (%)

a

1 H Me nPr - 82 91.2

2 H Ph nHex - 78 95

3 H Me iPr - 81 91.5

4 H Ph iPr - 72 92

5 H Me cHex - 95 90.1

6 H Ph cHex - 87 95

7 Me Me nPr 33 : 1 91 97.9

8 Me Ph nHex >155 : 1 36 100

9 Me Me iPr 30 : 1 85 99.5

10 Me Ph iPr >155 : 1 82 99

11 Me Me cHex 32 : 1 82 98

12 Me Ph cHex >155 : 1 58 98.7

13 Me Me tBu 30 : 1 95 99.9

14 Me Ph tBu >155 : 1 68 94.3

Corey has also approached the problem of asymmetric aldol transformations by

application of a C2-symmetric five-membered boracycle to the formation of chiral

enolates.31

N,N’-disulfonyl-1,4-trans-diphenyl-2,5-diaza-borolanes 3U2 and 3U3 were

studied for convenient comparison to the work of Paterson, Reetz, and Masamune. The

enol borinate generated from diethylketone and 3U2 reacts with various aldehydes to

provide >94 : 6 syn-diasteroselectivity and excellent enantioselectivity (Table 3U, Entries

1-3). The diastereoselectivity indicates the formation of a Z-enol borinate and the

enantioselectivities surpass those achieved by Paterson et al. The enol borinate generated

from phenyl thioacetate and 3U2 reacts with aldehydes to provide enantioselectivities

similar to those reported by Reetz and Masamune (Table 3T, entries 4&5).

124

Bromoboracyle 3U2 is incapable of enolizing the phenylthio ester of propionic acid but

3U3 can. The resulting Z-enol borinate is an excellent complement to the E-enolates

reported by Reetz and Masamune (Table 3T), as it provides >94 : 6 syn-

diastereoselectivity and excellent enantioselectivities upon treatment with aldehydes

(entries 6 & 7).

O

R1

R2

NB

N

Ph Ph

SS

O

OAr

O

O

Ar

Br

R3H

O

B

O

O

H

R3

H

N

N

R2

R1

Ph

Ph

SO2

O2SAr

Ar

O

R1

R2

R3

OH

Table 3U: Aldol Reactions with B-Bromo-N,N'-disulfonyl-1,4-trans-diphenyl-2,5-diaza-borolanes

3U1

3U2: Ar= tol3U3: Ar= pNO2-C6H4

3U4 3U5

Entry R1 R

2 R

3 Ar syn- : anti- yield (%) ee (%)

1 Et Me Et p-CH3-C6H4 >98 : 2 91 >98

2 Et Me iPr p-CH3-C6H4 98 : 2 85 95

3 Et Me Ph p-CH3-C6H4 94.3 : 5.7 95 97

4 PhS H iPr p-CH3-C6H4 - 82 83a

5 PhS H Ph p-CH3-C6H4 - 84 91 a

6 PhS Me iPr p-NO2-C6H4 94.5 : 5.5 72 97

7 PhS Me Ph p-NO2-C6H4 98.3 : 1.7 70 95

a) The isolated enantiomer is the opposite of the one illustrated

This section serves as a demonstration of both the versatility and influence of

Brown‟s C2-symmetric Ipc2B moiety. Paterson and Meyers have made it clear that ipc

borane reagents have synthetic applications beyond hydroboration, as do the

C2-symmetric Masamune and Reetz borolanes. These borolanes participate in aldol

125

reactions to provide excellent diastereo- and enantioselectivities that surpass and/or

complement those achieved by Corey et al. with C2-symmetric 2,5-diazaborolanes. The

versatility of several of these chiral boron environments will be demonstrated further in

the following sections.

3.2ii Asymmetric Allylations Using C2-Symmetric Allyl-Boron Species

Brown et al. have extensively studied a variety of asymmetric allylations with

B-allyl-diisopinocampheylboranes (Table 3V).32-36

Allylation of several -branched

alkyl aldehydes provides secondary homoallylic alcohols with good enantioselectivity

(83-90% ee; entries 1-3).32

Analogous methallylation34

(entries 4-6) and isoprenylation33

(entries 7 & 8) have also been achieved, (89-96% ee). Similarly, crotylation using either

E- or Z-crotyldiisopinocampheylborane generates highly diastereo-enriched alcohols with

excellent enantioselectivity (entries 9-14).35,36

These high selectivities have been

attributed to six-membered transition states resembling erythro-3V3 and threo-3V3.

Corey has also applied his C2-symmetric B-allyl-N,N’-disulfonyl-1,4-trans-

diphenyl-2,5-diaza-borolane 3W1 to the allylation of aldehydes. The enantioselectivities

(≥95% ee) meet if not exceed those previously reported (Table 3W).37

126

Ipc2B

R1

R2

R3

H R4

O

R1

R2 R3R4

OH

Table 3V: Enantioselectivity with Diisopinocampheylborane Allylation Reagents

O

B

CH3

H

H

R

S

S

ML

L M

erythro-3V3

O

B

H

H3C

H

R

S

S

ML

L M

threo- 3V33V1 3V2

Entry R1 R2 R3 R4 Yield (%) threo- : erythro- ee (%) Configuration

1a H H H nPr 72 - 87 R

2a H H H iPr 86 - 90 S

3a H H H tBu 88 - 83 S

4b Me H H nPr 56 - 91 S

5b Me H H iPr 57 - 96 R

6b Me H H tBu 55 - 90 R

7b H Me Me nPr 79 - 92 S

8b H Me Me iPr 73 - 89 S

9a H Me H Et 70 >99 : 1 90 - 10a H Me H CH2=CH 65 >99 : 1 90 - 11a H Me H Ph 79 >99 : 1 88 - 12a H H Me Et 70 1 : 99 90 - 13a H H Me CH2=CH 63 1 : 99 90 - 14a H H Me Ph 72 1 : 99 88 -

(a) (+)--pinene was used. (b) (-)--pinene was used

Entry R ee (%) configuration

1 nPent 95 S

2 cHex 97 R

3 PhCH2=CH 97 R

4 Ph 95 R

127

The Roush group has also reported good enantioselectivities for the allylation of

simple aldehydes using 2-allyl-1,3,2-dioxaborolane-4,5-dicarboxylic esters derived from

tartrate esters 3X1.38,39

These C2-symmetric reagents and their E-crotyl analogs have

also been investigated in the context of double asymmetric synthesis with the

-dialkoxyaldehydes 3X2 and 3Y1. Roush et al. discovered that, when using aldehyde

3X2, the diastereoselectivity of alcohol formation can be reversed by simply switching

the enantiomer of diisopropyltartrate (DIPT) from which the reagent is generated. The

diastereoselectivies are not identical, which indicates that there is a matched vs.

mismatched effect, albeit a minor one. The anti-diastereoselectivity is good with either

enantiomer of the crotylating reagent (Table 3X).

OO

O

H

O

BO

CO2R

CO2RO

O

OH

OO

OH

R1R1

Table 3X: Stereoselectivity with 2-Allyl-1,3,2-dioxaborolane-4,5-dicarboxylic Esters

3X1

3X2

3X3 3X4

R1

Entry R1 tartrate anti- : syn- 3X3 : 3X4 Yield (%)

1 H (+)-DIPT - 96 : 4 91

2 H (˗)-DIPT - 8 : 92 -

3 Me (+)-DIPT 96 : 4 87 : 9 87

4 Me (-)-DIPT 98 : 2 2 : 96 85

The aldehyde 3Y1 apparently creates a greater matched vs. mismatched effect in

the context of simple allylation. While the (-)-DIPT-derived reagent provides excellent

96% dr, the (+)-DIPT-derived reagent provides only 18% dr of the opposite

anti-enantiomer. Other (+)-tartrate esters were screened to find that the highest

selectivity that could be achieved was 24% dr, with (+)-diethyltartrate [(+)-DET] (Table

128

3Y, Entries 1-3). Interestingly, the corresponding crotylation provides comparable dr and

good anti-diastereoselectivities with both DIPT-derived boronate enantiomers (Entries 4-

5). While there are clearly mismatched scenarios that lead to poor selectivity in certain

cases, this methodology provides convenient access to a variety of acyclic

polyoxygenated moieties in a stereocontrolled fashion.

OO

O

H

OO

OH

OO

OH

R1R1

O

BO

CO2R

CO2R

Table 3Y: Stereoselectivity with 2-Allyl-1,3,2-dioxaborolane-4,5-dicarboxylic Esters

3X1

3Y1

3Y2 3Y3

R1

Entry R1 tartrate anti- : syn- 3Y2 : 3Y3 Yield (%)

1 H (+)-DET - 68 : 32 63

2 H (+)-DIPT - 64 : 36 -

3 H (˗)-DIPT - 2 : 98 94

4 Me (+)-DIPT 97 : 3 93 : 4 88

5 Me (-)-DIPT 92 : 8 4 : 88 80

As with hydroboration and aldol chemistry, C2-symmetric boron species allow

significant progress in the field of asymmetric allylation of aldehydes. Again, Brown‟s

Ipc2B moiety has provided a foundation upon which others have built: Corey‟s

diazaborolane provides improved selectivity for allylation while Roush‟s tartrate-derived

boronates have demonstrated significant allylation and crotylation applications in double

asymmetric synthesis.

129

3.2iii Asymmetric Reduction of Ketones with C2-Symmetric Boron Species

The final common application for Brown‟s Ipc2B moiety is the reduction of

ketones by B-chloro-diisopinocampheylborane (Ipc2BCl or DIPCl). Aryl-alkyl ketones

are the best substrates for DIP-Cl, providing almost perfect enantioselectivity, while the

enantioinduction achieved on dialkyl ketones depends on -substitution of one of the

alkyl functionalities. These trends are presented in Table 3Z: only 4% ee is achieved in

DIPCl reduction of 2-butanone (entry 1) but adding a 3-methyl group provides 32% ee

(entry 2) and adding another provides 93% ee (entry 3), which is almost as high as the

selectivity achieved on acetophenone and indanone (entries 5&6).40, 41

Table 3Z: Reduction of Prochiral Ketones with (-)-Ipc2BCl

Entry Ketone ee (%) configuration

1 2-butanone 4 S

2 3-methyl-2-butanone 32 S

3 3,3-dimethyl-2-butanone 93 S

4 2,2-dimethylcyclopentanone 71 S

5 acetophenone 98 S

6 1-indanone 97.4 S

Masamune‟s borolane 3J9 is a complementary to DIP-Cl, in that it reduces

dialkyl ketones with excellent enantioselectivity.42

Borolane 3AA1 by itself is not a

selective reducing reagent. However, in the presence of its corresponding mesylate

3AA2, which serves as a chiral Lewis acid,15

superb enantioselectivity is achieved on a

variety of dialkylketones (Table 3AA). No aryl-alkyl ketones were studied. However,

the commercially available DIP-Cl is a much more convenient reagent for the asymmetric

reduction of aryl-alkyl ketones reduction due to the difficult synthesis of 3J9.

130

B H B OMs

MsOH

O

R1 R2

Table 3AA: Reduction of Ketones Using the Masamune Borolane

OH

R1 R2B

H

H

Li·OEt2

3J9 3AA1 3AA2 3AA3

Entry R1 R

2 yield (%) ee (%) configuration

1 Me Et 75 80.3 R

2 Me Bn 69 98.9 R

3 Me iPr 69 100 R

4 Me cHex 83 99.5 R

5 Me tBu 72 99.3 R

6 nBu iBu 72 96.8 R

Kagan has pursued asymmetric reduction of ketones using C2-symmetric

oxazaborolidine catalysts.43

Treating acetophenone with 10 mol% of either 3BB2 or

3BB4 and stoichiometric THF·BH3 provides 1-phenyl-ethanols S-3BB3 and R-3BB3 in

65% ee and 38% ee, respectively (Scheme 3BB). These results are significant because of

the substoichiometric amounts of chiral species used. All of the other applications

discussed previously require stoichiometric amounts of asymmetric reagent(s).

131

3.2iv: C2-Symmetric Boron Species as Ligands

Kagan has also investigated asymmetric hydrogenation using C2-symmetric

phenylboronate 3CC5 derived from his (R,R)-DIOP ligand.44

This chiral ligand was

designed to have a dual role. The phosphines are ligands for rhodium while the boronate

can participate in a Lewis-acid/base interaction with the substrate to be hydrogenated.

However, ligand 3CC5 provides reasonable selectivities on several substrates: N-acetyl

dehydrophenylalanine 3CC1 and ketopantolactone 3CC3 are both hydrogenated with

3CC5/(RhClCOD)2 to yield 3CC2 and 3CC4 in 73% ee and 54% ee, respectively. The

boronate does not provide an advantage over the dimethyl acetal of DIOP, which

provides selectivities of 81% ee & 52% ee with 3CC1 and 3CC3, respectively.

Scheme 3CC: Asymmetric Hydrogenation with Boron Ananlog of DIOP Ligand

HPh

N CO2H

H

O

HPh

N CO2H

H

O

HO

O

O

HO

O

O

H(RhClCOD)2

3CC5, H2

3CC1 3CC2 3CC3 3CC4

(RhClCOD)2

3CC5, H2

HPh

N CO2H

H

O

HPh

N CO2H

H

O

HO

O

O

HO

O

O

H(RhClCOD)2

DIOP, H2

3CC1 3CC2 3CC3 3CC4

(RhClCOD)2

DIOP, H2

OB

OPPh2

PPh2H

H

Ph

3CC5

O

OPPh2

PPh2H

HDIOP

100% yield 73% ee

100% yield 54% yield

100% yield 81% ee

100% yield 52% ee

132

3.3: Summary

The C2-symmetric diisopinocampheylborane discovered by Brown in 1962 has

led to a multitude of breakthroughs in asymmetric synthesis, not only as a practical

asymmetric hydroboration reagent, but also as the starting point for enantioselective

allylation, reduction, and aldol reactions. In the realms of hydroboration, ketone

reduction, and aldol reactions, the standards for enantioselectivity set using the Ipc2B-

moiety have been surpassed by the Masamune trans-2,5-dimethyl-borolane.

Unfortunately, said borolane is inconvenient to synthesize. Corey‟s diazaborolane

moiety has proven to be a superior reagent for allylation and aldol reactions and is

conveniently produced. These results, in addition to the allylation studies published by

Roush, demonstrate that C2-symmetric (hetero)borolanes are effective boron species for

asymmetric synthesis.

133

References for Chapter 3

1. Brown, H. C.; Rao, B. C. S. A New Technique for the Conversion of Olefins Into

Organoboranes and Related Alcohols. J. Am. Chem. Soc. 1956, 78, 5694.

2. Brown, H. C.; Zweifel, G. Hydroboration as a Convenient Procedure for

Asymmetric Synthesis of Alcohols of high Optical Purity. J. Am. Chem. Soc. 1961,

83, 486.

3. Brown, H. C.; Ayyangar, N. R.; Zweifel, G. Hydroboration.19. Reaction of

Diisopinocampheylborane with Representative Trans + Hindered Olefins

(Triisopinocampheyldiborane as Reagent for Configurational Assignment of

Alcohols + Olefins via Hydroboration. J. Am. Chem. Soc. 1964, 86, 1071.

4. Zweifel, G.; Munekata, T.; Brown, H. C.; Ayyangar, N. R. Hydroboration. 20.

Reaction of Diisopinocampheylborane with Representaive 2-Methyl-1-alkenes -

Convenient Synthesis of Optically Active 2-Methyl-1-Alkanols. J. Am. Chem. Soc.

1964, 86, 1076.

5. Brown, H. C.; Desai, M. C.; Jadhav, P. K. Hydroboration. 61.

Diisopinocampheylborane of High Optical Purity - Improved Preparation and

Asymmetric Hydroboration of Representative Cis-Disubstituted Alkenes. J. Org.

Chem. 1982, 47, 5065.

6. Brown, H. C.; Yoon, N. M. Monoisopinocampheylborane - New Chiral

Hydroborating Agent for Relatively Hindered (Trisubstituted) Olefins. J. Am.

Chem. Soc. 1977, 99, 5514.

7. Brown, H. C.; Klender, G. J. Organoboranes. 2. Preparation and Properties of

Alkyldiborane Containing Bulky Alkyl Substituents. Inorg. Chem. 1962, 1, 204.

8. Brown, H. C.; Schwier, J. R.; Singaram, B. Simple Synthesis of

Monoisopinocampheylborane of High Optical Purity. J. Org. Chem. 1978, 43,

4395.

9. Mandal, A. K.; Jadhav, P. K.; Brown, H. C. Monoisopinocampheylborane - And

Excellent Chiral Hydroborating agent for Phenyl-Substituted Tertiary Olefins -

Synthesis of Alcohols Approaching 100-Percent Enantiomeric Excess. J. Org.

Chem. 1980, 45, 3543.

10. Brown, H. C.; Jadhav, P. K. High Asymmeric Induction in the Chiral

Hydroboration of Trans- Alkenes with isopinocampheylborane - evidence for a

Strong Steric Dependence in Such Asymmetric Hydroborations. J. Org. Chem.

1981, 46, 5047.

134

11. Brown, H. C.; Jadhav, P. K.; Mandal, A. K. Hydroboration. 62.

Monoisopinocampheylborane, an Excellent Chiral Hydroboration Agent for

Trans-disubstituted and Trisubstituted Alkenes- Evidence for a Strong Steric

Dependence in Such Asymmetric Hydroborations. J. Org. Chem. 1982, 47, 5074.

12. Mandal, A. K.; Yoon, N. M. Anomalies in Asymmetric Hydroboration of Olefins

with 1-1 Adduct of (+)-Alpha-Pinene and BH3·THF. J. Organomet. Chem. 1978,

156, 183.

13. Jadhav, P. K.; Brown, H. C. Dilongifoylborane- A New Effective Chiral

Hydroborating Agent with Intermediate Steric Requirements. J. Org. Chem. 1981,

46, 2988.

14. Masamune, S.; Kim, B. M.; Petersen, J. S.; Sato, T.; Veenstra, S. J.; Imai, T.

Organoboron Compounds in Organic Synthesis. 1. Asymmetric Hydroboration J.

Am. Chem. Soc. 1985, 107, 4549.

15. Masamune, S.; Kennedy, R. M.; Petersen, J. S.; Houk, K. N.; Wu, Y.

Organoboron Compounds in Organic-Synthesis. 3. Mechanism of Asymmetric

Reduction of Dialkyl Ketones with (R,R)-2-5-Dimethylborolane. J. Am. Chem.

Soc. 1986, 108, 7404.

16. Brown, H. C.; Negishi, E. Bisborolane- Highly Elusive Bisboracyclane. J. Am.

Chem. Soc. 1971, 93, 6682.

17. Brown, H. C.; Negishi, E. Boraheterocycles via Cyclic Hydroboration.

Tetrahedron 1977, 33, 2331.

18. Laschober, G.; Zorzi, M.; Hodgetts, K. J. Synthesis of (+/-)-trans-2,5-

diisopropylborolane. Molecules 2001, 6, 244.

19. Graf, C. D.; Knochel, P. Asymmetric hydroboration with new chiral

monoalkylboranes bearing a non-stereogenic, chirotopic center. Tetrahedron

1999, 55, 8801.

20. Gonzalez, A. Z.; Roman, J. G.; Gonzalez, E.; Martinez, J.; Medina, J. R.; Matos,

K.; Soderquist, J. A. 9-Borabicyclo[3.3.2]decanes and the Asymmetric

Hydroboration of 1,1-Disubstituted Alkenes. J. Am. Chem. Soc. 2008, 130, 9218.

21. Thomas, S. P.; Aggarwal, V. K. Asymmetric Hydroboration of 1,1-Disubstituted

Alkenes. Angew. Chem. Int. Ed. 2009, 48, 1896.

22. Evans, D. A.; Bartroli, J.; Shih, T. L. Enantioselective Aldol Condensations. 2.

Erythro-Selective Chiral Aldol Condensations via Boron Enolates. J. Am. Chem.

Soc. 1981, 103, 2127.

135

23. Meyers, A. I.; Yamamoto, Y. Stereoselectivity in the Aldol Reaction:The Use of

Chiral and Achiral Oxazolines as Their Boron Azaenolates. Tetrahedron 1984,

40, 2309.

24. Paterson, I.; Lister, M. A.; McClure, C. K. Enantioselective Aldol Condensations

- The Use of Ketone Boron Enolates with Chiral Ligans Attached to Boron.

Tetrahedron Lett. 1986, 27, 4787.

25. Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann, R. C.; McClure, C. K.;

Norcross, R. D. Enantio- and Diasteroselective Aldol Reactions of Achiral Ethyl

and Methyl Ketones with Aldehydes: The Use of Enol

Diisopinocampheylborinates. Tetrahedron 1990, 46, 4663.

26. Blanchette, M. A.; Malamas, M. S.; Nantz, M. H.; Roberts, J. C.; Somfai, P.;

Whritenour, D. C.; Masamune, S.; Kageyama, M.; Tamura, T. Synthesis of

Bryostatins. 1. Construction of the C(1)-C(16) Fragment. J. Org. Chem. 1989, 54,

2817.

27. Masamune, S.; Sato, T.; Kim, B. M.; Wollmann, T. A. Organoboron Compounds

in Organic Synthesis. 4. Asymmetric Aldol Reactions. J. Am. Chem. Soc. 1986,

108, 8279.

28. Reetz, M. T. Asymmetric C-C Bond Formation Using Organometallic Chemistry.

Pure Appl. Chem. 1988, 60, 1607.

29. Reetz, M. T.; Rivadeneira, E.; Niemeyer, C. Reagent Control in the Aldol

Addition of Chiral Boron Enolates Based of the 2,5-Diphenylborolane Ligand

System. Tetrahedron Lett. 1990, 31, 3863.

30. Reetz, M. T.; Kunisch, F.; Heitmann, P. Chiral Lewis-Acids for Enantioselective

C-C Bond Formation. Tetrahedron Lett. 1986, 27, 4721.

31. Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. Practical Enantioselective

Diels-Alder and Aldol Reactions Using a New Chiral Controller System. J. Am.

Chem. Soc. 1989, 111, 5493.

32. Brown, H. C.; Jadhav, P. K. Asymmetric Carbon-Carbon Bond Formation via B-

Allyldiisopinocampheylborane. Simple Synthesis of Secondary Homoallylic

Alcohols with Excellent Enantiomeric Purities. J. Am. Chem. Soc. 1983, 105,

2092.

33. Brown, H. C.; Jadhav, P. K. 3,3-Dimethylallyldiisopinocampheylborane: A NOvel

Reagent for Chiral Isoprenylation of Aldehydes. Synthesis of (+)- and (-)-

Artemisia Alcohol in Exceptionally High Enantiomeric Purity. Tetrahedron Lett.

1984, 25, 1215.

136

34. Brown, H. C.; Jadhav, P. K.; Perumal, P. T. Asymmetric Methallylboration of

Prochiral Aldehydes with Methallyldiisopinocamphenylborane - Synthesis of 2-

Methyl-1-alken-4-ols in Greater-Than 90% Enantiomeric Purities. Tetrahedron

Lett. 1984, 25, 5111.

35. Brown, H. C.; Bhat, K. S. Chiral Synthesis via Organoboranes. 7.

Diastereoselective and Enantioselective Synthesis or erythro- and threo--

Methylhomoallyl Alcohols via Enantiomeric (Z)- and (E)-Crotylboranes. J. Am.

Chem. Soc. 1986, 108, 5919.

36. Brown, H. C.; Bhat, K. S. Enantiomeric (Z)- and (E)-

Crotyldiisopinocampheylboranes. Synthesis in High Optical Purity of all Four

Possible Stereoisomers of -Methylhomoallyl Alcohols. J. Am. Chem. Soc. 1986,

108, 293.

37. Corey, E. J.; Yu, C. M.; Kim, S. S. A Practical and Efficient Method for

Enantioselective Allylation of Aldehydes. J. Am. Chem. Soc. 1989, 111, 5495.

38. Roush, W. R.; Walts, A. E.; Hoong, L. K. Diastereo- and Enantioselective

Aldehyde Addition Reactions of 2-Allyl-1,3,2-dioxaborolane-4,5-dicarboxylic

Esters, a Useful Class of Tartrate Ester Modified Allylboronates. J. Am. Chem.

Soc. 1985, 107, 8186.

39. Roush, W. R.; Halterman, R. L. Diisopropyl Tartrate Modified (E)-

Crotylboronates: Highly Enantioselective Propionate (E)-Enolate Equivalents. J.

Am. Chem. Soc. 1986, 108, 294.

40. Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V. Highly Efficient

Asymmetric Reduction od -Tertiary Alkyl Ketones with

Diisopinocampheylchloroborane. J. Org. Chem. 1986, 51, 3394.

41. Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V. Chiral Synthesis via

Organoboranes. 14. Delective Reductions. 41. Diisopinocampheylchloroborane,

an exceptionally Efficient Chiral Reducing Agent. J. Am. Chem. Soc. 1988, 110,

1539.

42. Imai, T.; Tamura, T.; Yamamuro, A.; Sato, T.; Wollmann, T. A.; Kennedy, R. M.;

Masamune, S. Organoboron Compounds in Organic Synthesis. 2. Asymmetric

Reduction of Dialkyl Ketones with (R,R)-2,5-Dimethylborolane or (R,R)-2,5-

Dimethylborolane. J. Am. Chem. Soc. 1986, 108, 7402.

43. Dubois, L.; Fiaud, J. C.; Kagan, H. B. Enantioselective Borane Reduction of

Acetophenone Catalyzed by Oxaborolidines Derived from Chiral

Diethanolamines. Tetrahedron: Asymmetry 1995, 6, 1097.

44. Borner, A.; Ward, J.; Kortus, K.; Kagan, H. B. A Boron Analog of DIOP:

Synthesis and Properties. Tetrahedron: Asymmetry 1993, 4, 2219.

137

Chapter 4: Asymmetric Hydroboration with N-Tosyl-(R,R)-2,6-diisopropyl-1,4-

borazinane

4.1 C2-Symmetric Boranes as Ideal Hydroborating Agents

Hydroboration holds the distinction of being the first practical, non-enzymatic,

enantioselective reaction in the annals of synthetic organic chemistry. Despite this head

start, the search continues for an ideal asymmetric hydroborating agent. Brown‟s seminal

works with diisopinocampheylborane (Ipc2BH) and monoisopinocampheylborane

(IpcBH2) have stood the test of time, providing complementary species for the

asymmetric hydroboration of a variety of alkenes (Types II, III, & IV – Equation 1).1-8

Much more recently, Soderquist‟s work with 9-boracyclo[3.3.2]decanes represents

dramatic progress in addressing the longstanding problem of asymmetrically

hydroborating Type I alkenes.9 Despite the undeniable importance of these developments

it is Masamune‟s trans-2,5-dimethylborolane [(R,R)-4A1]10,11

that serves as the closest

example of an ideal asymmetric hydroborating reagent in the literature.

Masamune‟s borolane (R,R)-4A1 could have rendered Brown‟s IpcXBH(3-X)

reagents synthetically inconsequential if not for the staggering effort involved in its

synthesis. Type II, III, and IV alkenes undergo hydroboration with (R,R)-4A1 to provide

alcohols with >95% ee after oxidation.11

No other single reagent can claim such

versatility, which falls short of perfection only in that <5% ee was observed with Type I

alkenes. Borolane (R,R)-4A1 is generated in seven air-sensitive steps from bis-Grignard

reagent 4A4, including a prolinol resolution that provides diastereo-enriched 4A3

138

(Equation 2) from the mixture of trans-2,5-dimethylborolane enantiomers. Perhaps more

courageous than the synthesis itself is that it was undertaken knowing that (R,R)-4A1

might irreversibly form an unreactive species 4A6 (Equation 2), as borolane 4A7 forms

1,6-diboradecane 4A9 at room temperature (Equation 4).12,13

In pursuing an ideal hydroborating agent, it cannot be ignored that two of the

most significant asymmetric hydroborating reagents known, Masamune's (R,R)-4A1 and

Brown's Ipc2BH, both incorporate a C2-symmetric boron environment. While the

significance of (R,R)-4A1 has not gone unnoticed,14-16

its legacy remains unfulfilled. In

an effort to expand upon what is known about cyclic C2-symmetric boranes, hopefully to

develop easier synthetic access, and perhaps also to improve upon (R,R)-4A1, we

targeted C2-symmetric borinanes and their symmetrical heteroatom-containing analogs as

described below.

Three proposed improvements to the Masamune protocol were investigated in the

pursuit of a six-membered trans-2,6-disubstituted-boracycle: 1) assemble the boracycle

with trans-diastereoselectivity, 2) increase the steric bulk of the chiral substituents by

139

incorporating isopropyl groups, and 3) use an amino acid as a complexing agent for

resolution of boracycle mixture. Diastereoselective ring assembly would conserve

material in comparison to racemic boracycle generation from 4A4. Increased steric bulk

of the isopropyl substituents vs. Masamune's methyl groups should help to maintain

enantioselectivity in case the more flexible borinane environment promotes a looser

hydroboration transition state compared to the borolane system. It is conceivable that the

isopropyl groups might even provide greater stereoinduction than methyl groups,

depending on conformational preferences of the borinane compared to the borolane.

Resolution of diastereomers as well as enantiomers with a single complexing reagent

would streamline the overall process and an amino acid complex should help suppress the

air-sensitivity issues that contribute to the inconvenience of the Masamune protocol by

forming a more stable complex with the cyclic borane.

4.2 Diastereoselective Assembly of trans-2,6-Diisopropyl-(4-hetero)borinanes

Diastereoselective assembly of C2-symmetric trans-2,6-diisopropyl-borinanes

and their 4-hetero-analogs was initially pursued by Mr. John Nelson. 2,8-Dimethyl-2,7-

nonadiene 4B1a was treated with I2-activated DMAP·BH3 (DMAP·BH2I) or THF·BH3 in

an effort to achieve diastereoselective generation of trans-2,6-diisopropyl-borinane-

DMAP complex 4B4a. In the case of THF·BH3, it was envisioned that the trisubstituted

alkenes would provide excellent anti-Markovnikov regioselectivity in an intermolecular

hydroboration step to provide intermediate 4B2a, which would undergo subsequent

intramolecular, anti-Markovnikov hydroboration to provide borinane 4B3a. Addition of

DMAP should then produce the complex 4B4a for convenient assay of

diastereoselectivity in the crude product by 1H NMR spectroscopy. Alternatively, 4B4a

140

should be formed directly from 4B1a and DMAP·BH2I, generated in situ from

DMAP·BH3 and iodine.17-20

Given the differences in boron substituents at the

intramolecular hydroboration stage from 4B2a or from 4B7a, we expected to have

several options for fine-tuning hydroboration diastereoselectivity to favor the desired

trans-4B4a. However, the simpler reagent THF·BH3 proved to react with the best trans-

selectivity with all of the substrates.

Preliminary NMR assay of the product mixture left no doubt that the minor

product from 4B1a and THF·BH3 is the symmetrical DMAP complex cis-4B4a, and by

implication, supported the unsymmetrical structure trans-4B4a for the major complex.

However, both cis- and trans-4B4a were somewhat unstable upon silica gel

chromatography and could not be purified. To corroborate the NMR assays, the mixture

of hydroboration products was therefore converted into diols 4B5a and 4B6a in excellent

141

yield via standard oxidation conditions (Table 4C, entries 1&2). Both diols were

symmetrical as expected and could be assayed by HPLC. The DMAP·BH2I conditions

afforded 4B5a and 4B6a in a ratio of 7.8:1, reflecting predominant cis-

diastereoselectivity in the internal hydroboration step from 4B7. On the other hand, the

THF·BH3 conditions provided a 1:1.9 ratio of 4B5a:4B6a, corresponding to modest

trans-diastereoselectivity from 4B2a.

Entry X Conditionsa Time (h) Yield (%) 4B5:4B6

1b CH2 A 0.5 99 7.8 : 1

2b CH2 B 0.5 92 1 : 1.9

3b SO2 A 18 88 4.0 : 1

4b SO2 B 0.5 99 1 : 1.3

5 NTs A 14 90 5.8 : 1

6 NTs B 0.5 98 1 : 3.6

7c NTs B 24 NR 1 : 5.6

d

(a) Conditions A: DMAP·BH3 (1.2 equiv) was activated with I2 (0.6 equiv)

in DCM at 0 °C. After warming to rt, 10 was added, the solution was

stirred (time), and was quenched with NaOOH/MeOH. Conditions B:

A rt solution of 10 in THF was treated with 1.0 M THF·BH3 (1.2 equiv)

and stirred (time) prior to quenching with NaOOH/MeOH. (b) Assayed

as the dibenzoyl derivative. (c) Performed at -30 °C. (d) Ratio

determined by NMR assay of crude diol.

It was hypothesized that the inductive effect of incorporating an electron

withdrawing group (EWG) at the 4-position of the borinane might sufficiently stabilize

the DMAP-boron complex, allowing for isolation. The same inductive effect might also

help to improve diastereoselectivity in the 4-hetero-borinane hydroborations. Studies

with diprenyl sulfone 4B1b confirmed the former hypothesis, as both cis- and trans-

142

DMAP complexes 4B4b were stable to silica gel chromatography despite being difficult

to separate from one another. However, improved diastereoselectivity was not observed;

lower cis diastereoselectivity (4:1) was found under DMAP·BH2I conditions and marginal

trans diastereoselectivity (1:1.3) was observed using THF·BH3 (entries 3 & 4). Thus the

primary concern became achieving better diastereoselectivity without sacrificing stability

of the DMAP complex.

N,N-Diprenyl-4-toluenesufonamide 4B1c was investigated because the N-tosyl

group should stabilize the DMAP complex 4B4c by electron withdrawal and its tendency

to improve crystalinity might facilitate diastereomer separation and resolution of trans-

4B3c. As in the prior examples 4B1a and 4B1b, the DMAP·BH2I conditions favored cis

diastereoselectivity with 4B1c (5.8:1), but THF·BH3 provided improved 1:3.6 trans

diastereoselectivity at rt. Selectivity was increased to 1:5.6 upon conducting the

hydroboration at -30 °C (Table 4C, entries 5-7). The diastereomeric mixture 4B4c was

separable by silica gel chromatography, and both cis and trans diastereomers were

obtained in crystalline form. The structure of trans-4B4c was established by X-ray

crystallography, which also confirmed that the enantiomers were not resolvable by

recrystalization, as both enantiomers were contained in the unit cell of the crystals.

It is proposed that the diastereoselectivity of 4B3c is derived from boat-like

transition state 4D1eq with a pseudo-equatorial isopropyl group being favored over the

boat-like transition state 4D1ax, which is thermodynamically less stable due to the

pseudo-axial isopropyl group (Scheme 4D). A chair-like transition state is unlikely, as

one would expect a diequatorial conformation leading to cis-4B3c to dominate such a

143

transformation. Thus, a chair-like transition state correlates well with the DMAP·BH3

results.

N

H

i-Pr

H

H

Ts

NB

H

N

B

H

N

B

Htrans-4B3c

cis-4B3c

Scheme 4D: Diastereoselective Formation of N-Tosyl-trans-2,6-diisopropyl-1,4-borazinane

4B1c

4D1ax

4D1eqTs

Ts

Ts

THF·BH3

-30ºC

favored

disfavored

5.6:1 diasteroselectivity

H

i-Pr

Ts

NB

H

H H

4.3 Resolution of (R,R)-2,6-Diisopropyl-1,4-borazinane Ring with Alanine

No method exists for predicting an ideal amino alcohol for crystallographic

resolution of a given racemic borane species, and chromatographic separation of

diastereomers is precluded by the instability of amino alcohol-borane complexes. Thus,

it came as little surprise that alaninol, phenylalaninol, valinol, and ephedrine complexes

of 4B4c all failed to provide convenient crystallization conditions and decomposed on

silica gel. It was hypothesized that using an amino acid would provide a more stable

complex from 4B4c due to the greater electron demand of the carboxyl group, a factor

that might allow for chromatographic separation of the resulting diastereomeric mixture.

144

The separation of borazinane 4B3c diastereomers and resolution of racemic trans-

4B3c was investigated by Mr. John Nelson. Generating alanine complex 4E2 was

complicated by the poor solubility of alanine in THF. Heating borazinane 4B3c in the

presence of alanine was out of the question for fear of ruining the trans-diastereomeric

excess via retro-hydroboration/hydroboration pathways. To avoid this potential

complication, B-methoxy-1,4-borazinane 4E1 was generated by methanolysis of 4B3c at

-30 °C. Heating the more stable 4E1 with l-alanine at 45 °C generated complex 4E2

(Scheme 4E). Not only was chromatography viable for separating the diastereomers, but

the trans-4E2 diastereomers could be separated by crystallization. The (R,R)-

N N

i-Pri-Pr

Ts

B

1. BH3·THF -30 °C, 20 h

2. MeOH, -30 °C to rt

Ts

OMe

N

i-Pri-Pr

Ts

B

OMecis-4E1

4E11. l-Alanine, 45 ºC

2. recrystalization

B

N

i-Pri-Pr

Ts

H2N O

Ol-(R,R)-4E2

1. d-Alanine, 45 ºC

2. recrystalizationB

N

i-Pri-Pr

Ts

H2N O

Od-(S,S)-4E2 1. l-Alanine, 45 ºC

2. chromatography

B

N

i-Pri-Pr

Ts

H2N O

Ol-(R,R)-4E2

B

N

i-Pri-Pr

Ts

H2N O

Ol-(S,S)-4E2

B

N

i-Pri-Pr

Ts

H2N O

Ol-cis-4E2

Scheme 4E: Separation of Diastereomers and Resolution of 1,4-Borazinane Enantiomers

N

i-Pri-Pr

Ts

B

OMe(S,S)-4E1(R,R)-4E1

2.8 : 2.8 : 14B1c

63%

145

diastereomer (98:2 dr) was particularly easy to isolate, as it precipitated almost

immediately upon dissolving the crude product in methylene chloride. Two

crystalizations provided l-(R,R)-4E2 in 27% yield. Treating 4E1 with d-alanine

provided the d-(S,S)-4E2 enantiomer in similar fashion. On the other hand,

crystallization conditions for facile separation of the remaining mixtures have not been

elucidated. Silica gel chromatography can separate the three diastereomers (63% yield)

but yield must be sacrificed for separation or vice versa because 4E2 is not completely

stable on silica gel. While 4E2 is stable to air upon isolation it is not as robust in

solution. After several crystallizations the mixture undergoes

degradation. Oxidative pathways are at least partially responsible as

evidenced by the isolation of side product 4E3 and by the fact that

using deoxygenated solvents for crystallization suppresses

degradation.

4.4 Transforming l-(R,R)-4E2 into a Viable Asymmetric Hydroborating Agent

Having resolved the trans-diastereomers of alanine complex 4E2, conversion to

the corresponding lithium dialkyl borohydride 4F1 was investigated with a screen of

lithium hydride reagents: lithium aluminum hydride (LAH), lithium

trimethoxyaluminum hydride [Li(MeO)3AlH],21

lithium monoethoxy-aluminum hydride

[Li(EtO)AlH3],9 super hydride (LiEt3BH), and lithium tri-tert-butoxy-aluminum hydride

[Li(tBuO)3AlH]. The first two reagents produced a proton-coupled triplet by 11

B NMR at

= -20 ppm, which is assigned as 4F1. However, these reductions also produced

undesired boron species [= -35 ppm, -4.2 ppm (LAH); 2 to 10 ppm (Li(MeO)3AlH)].

Li(EtO)AlH3 and super hydride generated multiple boron species, according to 11

B NMR

B O

N

MeO

Ts

4E3

146

spectroscopy. The only reagent found to cleanly generate the desired boron species was

Li(tBuO)3AlH.

The single drawback of using Li(tBuO)3AlH for the reduction of 4E2 was that the

resulting borohydride 4F1 could not be isolated from the non-boron-containing side

products. Therefore, an in situ approach was taken to investigate hydroboration. Treating

crude 4F1 with the hydride abstracting agents TMSCl or TMSOTf generated an unknown

tetravalent species 4F2 with a 11

B NMR signal at = -10 ppm. This signal is too far

upfield to represent either the trivalent borazinane 4B3c or its dimer 4F3 (Scheme 4F)

according to a comparison with di-t-butyl-borane (= 47 ppm), which is reported in a

mixture also containing 11

B signals at = -20.1, -17.2, -13.6, -.02, 24, 51.7, 83 ppm,22

and

the borolane dimer 4A5 (= 31.5 ppm)10

or diborane (B2H6; = 18 ppm).23

Isolation of

complex 4B4c upon treatment of 4F2 with DMAP confirmed that species 4F2 is a

147

relatively weak Lewis base complex of the borazinane 4B3c. The Lewis base remains

undefined but is probably a reduced alanine residue. Considering the tetravalent nature

of 4F2, it was no surprise that hydroboration was not observed upon treating 4F2 with 1-

octene.

It was proposed that potassium salts of the reduction residues would be more

convenient to remove due to their poorer solubilities, thus enabling generation of free

borazinane 4B3c. Soderquist‟s activated potassium hydride (KH*) was used initially to

investigate the degree of substitution at boron in the reaction intermediates, but turned out

to be critical to the generation of borohydride 4G1 (Scheme 4G).24,25

While precipitated

148

solids were observed throughout the KH* reduction, cannulation of the borohydride

solution away from the residues and subsequent hydride abstraction with TMSCl resulted

in a product that remained soluble in THF. However, the solution did not contain

borazinane 4B3c , the unknown complex 4F2, or dimer 4F3 according to 11

B NMR

monitoring. Instead, a more downfield signal (= +11.5 ppm) of a new unknown species

4G2 was generated. Treating 4G2 with 1-octene followed by reductive workup with

KH* led to the observation of a proton-coupled doublet by 11

B NMR at = -18.3 ppm (J=

79.1 Hz), which is assigned as the potassium trialkylborohydride 4G3 (Scheme 4G).

Subsequent oxidation with NaOOH and benzoylation provided octyl benzoate 4G4 in

22% yield, suggesting marginal hydroboration reactivity for the unknown species 4G2.

This marginal reactivity caused concern that the hydroboration observed might

possibly be due to formation of BH3 from decomposition of 4G2. Therefore, the Type III

alkene ethylidene-cyclohexane was treated using identical hydroboration conditions to

probe for any enantioselectivity, which would confirm a chiral boron environment being

involved in the transformation (Scheme 4G). Reductive workup with KH* provided a

proton-coupled 11

B doublet at = -18 ppm (J= 81.3 Hz), which is assigned as

potassium trialkylborohydride 4G5. Subsequent oxidation with NaOOH followed by

acylation gave the acetate 4G6 in low yield, but 19% ee was observed by GC assay on a

chiral support. In addition to the observation of trialkylborohydrides 4G3 and 4G5 from

the reductive workup of the hydroboration of 1-octene and ethylidenecyclohexane,

respectively, this enantioinduction provided further evidence that the borazinane ring

remains intact and participates in hydroboration. However, the tetravalent 11

B chemical

149

shift and marginal reactivity of 4G2 indicate that an unidentified Lewis base „Y‟

interferes with reactivity by inhibiting dissociation to 4B3c.

The Lewis base reduction byproducts from the generation of lithium borohydride

4F1 or potassium borohydride 4G1 had to be addressed in order to accurately evaluate

the true potential of borazinane 4B3c. Solvent rinsing and crystallization attempts were

made to remove the undesired species but all were unsuccessful. A Lewis acid screen

including BF3·OEt2, TMSOTf, Zn(OTf)2, Cu(OTf)2, and LiOTf was done expecting to

achieve competitive complexation to the undesired Lewis base contaminants, thus freeing

trivalent 4B3c and/or dimer 4F3. However, no dominant boron species resembling 4B3c

or dimer 4F3 was observed by NMR in any case. A Lewis acid screen including

BF3·OEt2, TMSOTf, Cu(OTf)2, Sc(OTf)3, AgOTf, (C6F5)3B, and MgBr2 was undertaken

to investigate the possibility of competitive complexation of DMAP from complex 3B4c,

but this was also unsuccessful. It became evident that removing alanine from diastereo-

enriched alanine complex l-(R,R)-4E2 prior to reduction to the borohydride would be the

most efficient way of generating pure potassium borohydride (R,R)-4G1.

Masamune generated pure borohydride 4A2 from prolinol complex 4A3

(Equation 2) by methanolysis followed by distillation and reduction of the resulting

methoxyborolane.11

However, a variety of methanolysis conditions were unsuccessful in

cleanly converting alanine complex 4E2 to B-methoxy-borazinane4 E1. On the other

hand, hydrolysis conditions reported by Burke et al. for unmasking boronic acids from

N-methyliminodiacetic acid complexes26

were used with 4E2 to generate a single 11

B

NMR signal at = +53 ppm (Scheme 4H). This shift corresponds to methyl borinates

(45 ppm < < 54 ppm),27

indicating the formation of the desired borinic acid (R,R)-4H1.

150

(2)

B

N

i-Pri-Pr

Ts

OH

KH*1. aq. NaOH2. Na3PO4

(R,R)-4H1

B

N

i-Pri-Pr

Ts

H2N O

O

(R,R)-4E211B = +53 ppm

B

N

i-Pri-PrH H

Ts

K

(R,R)-4G1

alanine

B

N

i-Pri-PrH H

Ts

K

(R,R)-4G1

TMSCl

THF

heterogeneous mixture;

no 11B NMR signalsB

N

i-Pri-Pr

nC8H17

Ts

11B = +87 ppm (in Et2O)

4H3

N

i-Pri-Pr B

Ts

O H

11B = +17.9 ppm

TMSCl,Et2O

N

i-Pri-Pr B

H

Ts

(R,R)-4B3c

NaOOH

N

i-Pr i-PrOH OH

4B6c

+nC8H18OH

Ts

+

N

i-Pr OH

Ts

H

4H54H4

1-octene 1-octene

Scheme 4H: Alanine-Free Hydroboration

(R,R)-4H2

The corresponding borinic anhydride was not observed by mass spectrometry, but the

possibility that it is present in the crude product has not been eliminated. No distillation

was needed before reduction because 1H NMR spectroscopy showed that no trace of

alanine remained after aqueous extraction. Soderquist‟s KH* reduced (R,R)-4H1 into

(R,R)-4G1 very cleanly in THF according to 11

B NMR spectroscopy. Addition of

distilled hexanes to a concentrated THF solution of (R,R)-4G1 led to its precipitation as a

151

white sludge. Placing the ether-rinsed sludge under high vacuum formed a bubble of

amorphous solid, which disintegrated into a white powder upon agitation.

Treating a mixture of the isolated borohydride powder 4G1 in Et2O with TMSCl

resulted in a heterogeneous mixture with no soluble boron species observed by NMR.

However, upon addition of 1-octene, a trivalent 11

B signal was observed at = +87 ppm,

which is assigned as B-octyl-borazinane 4H3 (Scheme 4H). Treating a THF solution of

4G1 with TMSCl provided a boron species with a clean 11

B signal at = +17.9 ppm,

which is similar to the chemical shift of the bridged dimer B2H6 (= +18 ppm),23

but is

too far upfield relative to the borolane dimer 4A5 (= 31.5 ppm)10

and other

dialkylborane dimers (= 23-27 ppm)27

to be assigned as a H-bridged dimer.

Calculations done by Mr. Aleksanders Prokofjevs predict a 11

B NMR shift of 27 ± 3 ppm

for dimer 4F3. The possibility of a hydride-bridged [R2(H)B-H-

B(H)R2] species was eliminated based on the upfield shifts of NaB2H7

(= -25.3 ppm),27

the intramolecularly bridged species 4H6 (-4.9

ppm),28

and Li(Et3B)2H (= +8.7 ppm).29

Treating potassium borohydride (R,R)-4G1 with a solution of TMSCl in CH2Cl2

provided shifts of = +25 and +71 ppm by 11

B NMR spectroscopy, which are

respectively assigned as the dimer 4F3 and the monomer (R,R)-4B3c. The observation of

two species in CH2Cl2 and a single (third) species in THF lead to the conclusion that the

11B signal at +17.9 ppm in THF is the THF·borazinane complex (R,R)-4H2. This

chemical shift value is downfield compared to the THF complex of 9-BBN (= +14

ppm),30

but 4H2 may be somewhat deshielded by the N-Ts subunit compared to the

9-BBN environment.

B BH HHK

4H6

152

Addition of 1-octene to a solution of 4H2 resulted in the observation of a 11

B

NMR signal at = +86.5 ppm (Scheme 4H). Oxidative workup of 1-octene

hydroborations in both Et2O and THF reactions provided 1-octanol,13

diol (S,S)-4B6c (85-

91%), and the alcohol byproduct S-4H5 (<5%).14

For unknown reasons, complex 4H2

was not observed by 11

B NMR upon treating the crude KH* reduction reaction mixture

with TMSCl. Thus, precipitating (R,R)-4G1 from THF-hexane in its powdered form is

absolutely crucial for achieving hydroboration in THF.

Developing conditions for hydroboration enabled comparisons between the

presumed source of 4B3c and Masamune‟s borolane 4A1 in terms of substrate scope and

enantioselectivity. Initial screening of the four alkene types was done specifically using

substrates that had been tested by Masamune et al.3 Ether was used as the solvent due to

the volatility and low molecular weight of some of the alcohol products. At room

temperature enantioselectivity with 4B3c was good for the Type II alkene cis-3-hexene

(86.4% ee - Table 4I; entry 2), and moderate for Type IV alkene ethylidenecyclohexane

(44.6% ee – entry 9). By comparison, the Masasmune borolane 4A1 provides 99.9% ee

with cis-3-hexene and 99.3% ee with ethylidenecyclohexane3 while Brown‟s ipc2BH

provides 93% ee with cis-3-hexene5 and ca. 20% ee with Type IV alkenes.

3 However,

enantioselectivity with 4B3c was poor for the type I and type III alkenes 2-methyl-1-

butene (<5% ee – entry 1) and trans-3-hexene (3.8% ee – entry 7), respectively. By

comparison, Masamune borolane 4A1 provides 1.5% ee and 99.5% ee for the respective

substrates3 while Brown‟s Ipc2BH provides 21% ee with 2-methyl-1-butene

4 and ca. 13%

ee for Type III alkenes.3

153

Ensuing optimization studies used the type II alkene cis-1,4-diphenyl-2-butene

due to advantages in assay and product recovery, and demonstrated that Et2O promotes

marginally better enantioselectivity (86.4% ee) than THF (85.2 % ee), toluene (84% ee),

and CH2Cl2 (79.2% ee) in the generation of R-1,4-diphenyl-2-butanol R-4I2 (Table 4I;

entries 2-3, 5-6). In an attempt to improve enantioselectivity, the reaction was conducted

at -20 °C in THF, a solvent that ensures reagent solubility at the lower temperature.

Instead of the expected outcome, a slight decrease in enantioselectivity was observed

(80.2% ee; entry 4). With solvent and temperature optimizations having no substantial

effect, the enantioselectivity trends of borazinane 4B3c remain more reminiscent of

Brown‟s Ipc2BH than of the Masamune borolane 4A1.

Like ipc2BH, borazinane 4B3c works well specifically with type II alkenes, which

is attributed to uncanny structural similarity for the transition states. Brown proposed

transition state conformation 4J1/4J2 for ipc2BH and Houk provided support for this

geometry with theoretical studies.3,31

Borazinane (R,R)-4B3c fits into this model

beautifully, assuming a chair conformation 4J3. According to Brown‟s model, transition

state 4J4 would form upon approach of cis-1,4-diphenyl-2-butene (Scheme 4J).

Subsequent hydroboration and oxidation would provide (R)-4I2, which is the enantiomer

obtained in 86% ee. On the other hand, there is crystallographic evidence that both the

alanine complex l-(R,R)-4E2 and the DMAP complex 4B4c exist in a twist-boat

boracycle conformation in the solid state. Thus it is possible that non-bonded interactions

in (R,R)-4B3c may cause it to adopt more of a twist boat conformation 4J7. The reduced

versatility and enantioselectivity of 4B3c compared to 4A1 is consistent with

Masamune's proposal that monomeric borolane 4A1 prefers a trans-diaxial envelope

154

Entry Alkene Type Solvent Product ee (%)

1 b I ether 4I1 < 5

2 c Ph Ph

II ether 4I2 86.4f,g

3 c Ph Ph

II THF 4I2 85.2g,h

4 c Ph Ph

II THF 4I2 80.2g,i

5 c Ph Ph

II CH2Cl2 4I2 79.2g

6 d Ph Ph

II Toluene 4I2 84g

7 d II ether 4I3 84.6

8 d III ether 4I3 3.8

9e

IV ether 4I4 44.6

j

(a) Procedure: To a stirred mixture of 23 at rt in solvent was added

alkene (4 equiv) followed by TMSCl (1 equiv). After stirring 20 h,

oxidation with NaOOH at 0 °C gave alcohol products, which were

purified by chromatography prior to derivatization and/or assay. (b)

Assayed by GC. (c) Assayed by HPLC. (d) Assay after conversion to

TMS ether. (e) Assayed after acetylation. (f) R-4I2 recovered in 72%

yield. (g) R-enantio-selectivity. (h) R-4I2 recovered in 61% yield. (i) -

20 °C. (j) S-enantioselectivity

conformation in solution,11

a conformation that cannot be adopted by the isopropyl

groups of 4B3c. Transition state 4J8 illustrates that a (pseudo)diaxial relationship can be

achieve by the protons on C-2 and C-6, presenting the possibility that the reduced

enantioselectivity of 4B3c is due to less bulky diaxial substituents adjacent to boron

compared with 4A1. 1H NMR decoupling experiments with DMAP complex (R,R)-4B4c

in THF have revealed two coupling constants of J=10.8 Hz and 11.2 Hz between the

155

methine and methylene protons of the ring, providing evidence against borazinane

(R,R)-4B3c existing in chair conformation 4J3 in solution.

The overall generation of borazinane 4B3c, already simplified by

diastereoselective ring assembly and stability of its alanine complex, was streamlined

further upon discovery that a one pot in situ reduction-hydroboration sequence was viable

in Et2O. A heterogeneous mixture of l-alanine complex l-(R,R)-4E2 and KH* (4 equiv)

was stirred in Et2O before addition of cis-1,4-diphenyl-2-butene and TMSCl (3 equiv).

Subsequent oxidative workup provided (R)-4I2 in 37% yield and 86% ee (Equation 5).

The low yield is attributed to the heterogeneity of the reduction step causing poor

conversion of (R,R)-4E2 to (R,R)-4G1 although this cannot be confirmed due to neither

species being soluble in Et2O. Diol (S,S)-4B6c was recovered in 95% yield, which, in

addition to the enantioselective formation of (R)-4I2, indicates that the borazinane ring is

not compromised throughout the reaction. Soderquist‟s KH* proved essential once

again,16

despite its insolubility, as attempted borane generation via a one-pot procedure

156

with ether-soluble Li(tBuO)3AlH failed to give alcohol (R)-4I2 after oxidative workup.

The yield provides room for improvement, but this development demonstrates that a one

pot procedure can replace three sensitive steps in the Masamune protocol (Equation 1) if

one uses an amino acid rather than an amino alcohol for chiral borane resolution and

diastereomer separation.

4.5 Other Applications for the N-Tosyl-(R,R)-2,6-diisopropyl-1,4-borazacycle

Borazinane (R,R)-4B3c was also tested to see if it could

achieve asymmetric reduction of ketones, as the Masamune borolane

4A1 is also an effective reagent for the asymmetric reduction of

ketones in the presence of its corresponding mesylateborane (R,R)-4J9.

Masamune has reported that treating a 4:1 mixture of borolane 4A1 and mesylate (R,R)-

4J9 in pentane with 1-phenyl-2-propanone provided (R)-1-phenyl-2-propanol (R)-4K2 in

98.9% ee.10,32

The Lewis-acid 4J9 is necessary for stereoinduction, as <5% ee is

achieved without it. No reduction product 4K2 was observed upon treating a pentane

suspension of borohydride (R,R)-23 with 1.2 equiv of MsOH followed by 1-phenyl-2-

propanone, but switching the solvent to toluene provided (R)-4K2 in 35% ee (Scheme

4K). This result suggests that (R,R)-4K1 was generated, which raised interest in utilizing

157

the chiral boracycle of (R,R)-4B3c as a Lewis acid. This led to an investigation of

generating a chiral borenium species for Diels-Alder catalysis.

B

N

i-Pri-PrH H

Ts

K(R,R)-4G1

O

MsOH(1.2 equiv)

solvent, rt

(R,R)-4K1

OH

(0.8 equiv) (0.2 equiv)

-20 °C

Pentane: Not observedToluene: 35% ee

N

i-Pri-Pr B

H

Ts

(R,R)-4B3c

N

i-Pri-Pr B

OMs

Ts

4K2

Scheme 4K: Asymmetric Reduction with 4B3c and Corresponding Mesylate

1.

2. DMAP

There are several reports of borenium species acting as chiral catalysts for Diels-

Alder chemistry33-38

but none of them are derived from DMAP-borane complexes.

DMAP complexes of several boranes of varying degrees of substitution were treated with

MsOH and monitored by 11

B NMR in order to investigate if the species would be tri- or

tetravalent in DCM. Treating DMAP·BH3 4L1, DMAP·BH2Ipc 4L3, DMAP·BH(chex)2

4L5, and borazinane complex 4B4c with MsOH generated 11

B shifts of = +0.6 ppm,

= +6.6 ppm, = +11.7 ppm, = +9.7 ppm, respectively. These shifts are indicative of a

tetravalent species believed to be 4L2, 4L4, 4L6,and 4L7 (Scheme 4L). Increasing the

steric bulk at boron generates a more downfield 11

B signal, indicating a more trivalent

nature, which correlates to the mesylate interaction with boron being weakened by the

alkyl groups. In order to pursue a more reactive species, complex 4B4c was treated with

triflic acid to introduce a weaker complexing anion. This generated a 11

B NMR signal at

+15.8 ppm, which has been assigned as 4L8. Treating a -78 °C solution of 4L8 (7 mol%)

in DCM with methacrolein (1 equiv) followed by cyclopentadiene (5 equiv) generated

cycloadduct 4L9 with 97:3 endo:exo diastereoselectivity and 41% ee in 64% yield. It is

interesting that 4L8 catalyzes the reaction at all considering its tetravalent nature. The

158

enantioselectivity and yield suggests that the borazinane not only remains intact under the

reaction conditions but turns over as a catalyst.

159

4.6 Summary

The synthesis of N-tosyl-(R,R)-2,6-diisopropyl-1,4-borazinane 4B3c incorporates

diastereoselective assembly of the boracycle via cyclic of diene 4B1c, resolution of

dialkylborane diastereomers via alanine complexation rather than amino alcohol

complexation, and the ability to achieve hydroboration from the amino acid complex in a

single pot process. Despite its synthetic advantages, the hydroboration and reduction

results with 4B3c stand as the latest affirmation of how impressive the Masamune

borolane 4A1 is in terms of its synthetic versatility. These studies have also revealed that

DMAP complexes of chiral dialkylboranes, while not useful for resolution/separation of

diastereomeric borane mixtures, can be stable precursors to borenium catalysts such as

4L8 for asymmetric Diels-Alder cycloadditions.

This work represents the first report of a six-membered boracycle with a

C2-symmetric 2,6-dialkylborane environment and it shows promise in multiple

applications. However, if the asymmetric induction of these borazinane species is

representative for six-membered boracycles, then future efforts toward C2-symmetric

asymmetric boracycles should focus on 5-membered rings rather than 6-membered rings.

160

Experimental

Compounds 4B1, 4B4, 4B5, 4B6, 4B1c, 4E1, 4E2, and 4E3 were prepared and

characterized in the unpublished work of Mr. John Nelson.

In Situ Generation of borohydride 4F1.

N

i-Pri-Pr BH H

Li

Ts

4F1

A sample of trans-4E2 (0.0963 g, 0.24 mmol) was taken up in distilled, degassed THF (2

mL) under nitrogen and cooled to 0 °C. A solution of Li(tBuO)3AlH (0.246 g, 0.97

mmol) in THF (2 mL) was cannulated dropwise into the cooled solution of 4E2. THF

(0.5 mL) was used to complete the transfer of Li(tBuO)3AlH. The reaction was allowed

to stir for 1 h at rt before an NMR sample was cannulated into an NMR tube. 11

B NMR

spectroscopy displayed a signal at = -20 ppm (t, JBH= 78.9 Hz) which is assigned as

4F1.

Generating the unknown borazinane complex 4F2 and DMAP complex 4B4c

N

i-Pri-Pr BHX

Ts

4F2Li

N

i-Pri-Pr BDMAPH

Ts

trans-4B4c

A sample of trans-4E2 (0.1025 g, 0.25 mmol) was taken up in distilled, degassed THF (2

mL) under nitrogen and cooled to 0 °C. A solution of Li(tBuO)3AlH (0.256 g, 1.0 mmol)

in THF (2 mL) was cannulated dropwise into the cooled solution of 4E2. THF (0.5 mL)

161

was used to complete the transfer of Li(tBuO)3AlH. The reaction was allowed to stir for

1 h at rt before distilled, degassed TMSCl (115 L, 0.9 mmol) was added dropwise to the

reaction. The reaction stirred for 15 minutes before an NMR sample was cannulated into

an NMR tube. 11

B NMR spectroscopy displayed a broad signal at = -10 ppm with no

apparent B-H coupling, which is assigned as 4F2. DMAP (0.22 g, 1.87 mmol) was

dissolved in THF (4 mL). The resulting solution was added to the NMR sample (0.5 mL)

and the original reaction mixture (3.5 mL). The resulting mixtures were combined and

concentrated. Purification by column chromatography in 2:3 EtOAc:hexanes eluted

0.086g of 4B4c (77%), identified by comparing 1H NMR spectra with authentic material.

In Situ hydroboration of 1-octene via borohydride trans-4G1

B

N

i-Pri-Pr

Ts

HH

Ktrans-4G1

B

N

i-Pri-Pr

Ts

H nC8H17

K

4G3

B

N

i-Pri-Pr

Ts

H

c-hex

Me

K

4G5

B

N

i-Pri-Pr

Ts

HY

4G2

K

KH in mineral oil *(0.21 g) was activated as described by Soderquist.25

A sample of

trans-4E2 (0.10, 0.26 mmol) was taken up in distilled THF (3mL). The resulting solution

was cannulated into the KH* and stirred for 1 h. The resulting mixture was cannulated

into a culture tube under nitrogen and centrifuged. The supernatant solution was

cannulated into a re-sealable flask and degassed via freeze-pump-thaw. In a glove box,

an aliquot was transferred to an NMR tube and treated with TMSOTf. Monitoring by 11

B

NMR spectroscopy lead to the observation of a dominant signal at = +11.5 ppm, which

is an unknown species 4G2. 1-octene (70 L, 0.44 mmol) was added to the reaction,

followed by TMSCl (40 L, 0.31 mmol). A second batch of KH* was generated from

162

KH in mineral oil (0.20 g). The hydroboration mixture was cannulated onto the second

batch of KH* under nitrogen and stirred for 30 min. An aliquot was cannulated into an

oven dried, N2-flushed, septumed NMR tube. 11

B NMR spectroscopy displayed a signal

at = -18.3 ppm (d, JBH= 81.3 Hz), which is assigned as 4G3. The aliquot was combined

with the reaction mixture, then cannulated into a culture tube and centrifuged. The

supernantant solution was cannulated into a clean flask and treated with TMSCl (40 mL,

0.31 mmol) followed by premixed satd NaOH in MeOH (0.9 mL) and 35% H2O2 (0.9

mL). The reaction mixture was transferred to a separatory funnel containing brine and

extracted with Et2O. The organic layers were combined, dried over MgSO4, and

concentrated (aspirator). The crude reaction mixture was taken up in CH2Cl2 (3 mL) and

treated with Bz2O (0.25 g, 1.11 mmol), Et3N (0.3 mL, 2.15 mmol), and DMAP (0.07 g,

0.58 mmol). The benzoylation was quenched with water and transferred to a separatory

funnel. Ether (10 mL) was added and the organic layer was rinsed with 1 N HCl and satd

NaHCO3. Each water layer was back extracted with hexanes. The organic layers were

combined, dried over MgSO4, and concentrated (aspirator), and purified via silica gel

chromatography using 10% Et2O in hexanes to give 0.0131g of 4G439

(22%). The same

procedure was used to generate 4G5 [= -18 ppm (JBH= 81.3 Hz)] and 4G640

was

generated using analogous hydroboration / reduction / oxidation conditions followed by

acylation. The enantioselectivity of 4G6 was assayed by GC on a Chrompack Chirasil

Dex (25m x 0.32 mm x 0.25 mm) column (90 °C, 1 mL/min)40

: (S)-11.3 min , (R)-15.4

min.

163

One-pot procedure for hydroboration with l-(R,R)-4E2

In a glove box, a sample of l-(R,R)-4E2 (0.10 g, 0.25 mmol) was

added to a flask containing KH*(0.04 g, 1.05 mmol) prepared as

before. This mixture was suspended in Et2O (10 mL) and stirred

vigorously for 20 h at rt before addition of cis-1,4-diphenyl-2-

butene (100 L, 0.48 mmol) followed by TMSCl (100 L, 0.78 mmol). The resulting

mixture was stirred for 20 h before cooling to -78 °C for addition of premixed 20%

NaOH (2 mL) and 35% H2O2 (1 mL). The mixture was warmed to rt and stirred for 8 h

before transferring it to a separatory funnel containing brine (5 mL). The aqueous layer

was extracted with Et2O (4 x 20 mL). The organic layers were combined, dried over

MgSO4, and concentrated (aspirator), and purified via silica gel chromatography using

10%, 15%, and 30% EtOAc : hexanes to give 0.022 g of alcohol 4I2 (37%),40

0.082 g of

diol 4B6c (95%), and 0.003 g of the elimination side product 4H5 (3%). The

enantiomeric excess of 4I2 was assayed as described later in data for Table 4I.

Compound 4H5: ESMS m/z: 258.4 (M+1). 1H NMR (400 MHz, CDCl3): 0.87 (d, J=

6.8 Hz, 3H, CH3), 0.91(d, J= 6.8 Hz, 3H, CH3), 1.65 (m, 1H, CH), 1.92 (br d, J= 4.4 Hz,

1H, OH), 2.43 (s, 3H, CH3), 2.81 (ddd, J= 4.4 Hz, 8.3 Hz, 12 Hz, 1H, CH2N), 3.13 (ddd,

J= 3.2 Hz, 8 Hz, 12 Hz, 1H, CH2N), 3.4 (m, 1H, CH-O), 4.88 (br s, 1H, NH), 7.32 (dd,

J= 8.8 Hz, 0.8 Hz, 2H, Ar H), 7.75 (d, J= 8.8 Hz, 2H, Ar H). 13

C NMR

(CDCl3z,) 143.5, 136.7, 128.8, 75.4, 46.6, 31.9, 21.5, 18.5, 17.8.

N

i-Pri-Pr

Ts

BH2N O

O

(R,R)-4E2

164

Generating alanine free (R,R)-4G1

A sample of l-(R,R)-4E2 (1.02 g, 2.5 mmol) was converted to (R,R)-4H1 using the

method of Burke et al.26

Thus, a solution of 4E2 in THF (3 mL) was treated with 1M

NaOH (0.8 mL) and stirred vigorously open to the air for 10 min. The reaction was then

treated with 0.5 M aq Na3PO4 (3 mL) and Et2O (3 mL) and stirred for 30 min, adding

distilled H2O (~10 mL) to dissolve the white precipitate that formed. The reaction

mixture was poured into a separatory funnel and the organic layer collected. The water

layer was extracted with Et2O (1x 20 mL). Some extra water had to be added once more

to dissolve white precipitates upon addition of Et2O. The organic layers were combined,

dried over MgSO4, filtered, and concentrated (aspirator followed by High-Vac for 30

min). 11

B NMR spectrospocopy indicated a single boron species at = +53 ppm, which is

tentatively assigned as borinic acid 4H1. Based on ESMS m/z = 259 amu for M-1+Na

(Calc‟d 260 amu). No m/z for the corresponding borinic anhydride or borinic acid was

observed but this does not eliminate the possiblility that borinic anhydride was present

and was hydrolytically cleaved under the ESMS conditions (H2O, MeOH, NaCl). The

crude product was taken up in distilled THF (20 mL) and cannulated into a flask

containing KH* (0.51 g, 12 mmol) under nitrogen at rt. The transfer was completed with

THF (5mL) and the reaction stirred for one hour at rt. The resulting mixture was

transferred to a culture tube and centrifuged. The supernatant liquid was cannulated into

a RB flask containing a magnetic stir bar and was blown down with N2 until ~3 mL of

solution remained. This solution was stirred vigorously while hexane (2 mL) was added

dropwise. A white powder-like solid started to precipitate. As more hexanes (13 mL)

was added the powder congealed into a gum-like mass as the mixture was stirred. The

165

solvent was decanted via syringe, and the residual gum was then rinsed with hexanes (20

mL) and Et2O (20 mL). Residual solvent was blown off with N2 and high vacuum was

applied, causing the gel to form an amorphous bubble, which disintegrated into 0.53 g of

powder (59%) upon agitation. This (R,R)-4G1 powder was stored and dispensed in a

glove box. (R,R)-4G1: 1H NMR (500 MHz, THF-D8): 0.31 (br s, 2H, B-CH), 0.71(q,

JBH= 77 Hz, 2H, BH2), 1.00 (d, J= 6.5 Hz, 6H), 1.02 (d, J= 6.5 Hz, 6H), 1.59 (m, 2H, -

CHMe2), 2.49 (s, 3H, CH3), 2.92 (br s, 2H, -CH2N), 3.1 (br s, 2H, -CH2N), 7.37 (d, J= 8

Hz, 2H, Ar H), 7.69 (d, J= 8 Hz, 2H, Ar H).

Establishing Hydroboration yield by NMR internal standard

In the glove box, a sample of (R,R)-4G1 (0.1007 g, 0.28 mmol) was suspeneded in Et2O

(8 mL) under N2 and stirred vigorously at rt as cis-1,4-diphenyl-2-butene (100 L, 0.48

mmol) was added followed by TMSCl (35 L, 0.27 mmol). The mixture was stirred for

20 h, removed from the glovebox, and cannulated into a 0 °C mixture of 20% NaOH (2

mL), 35% H2O2 (1.1 mL), and 1:1 MeOH:Et2O (3 mL). The mixture was warmed to rt

and stirred for 8 h before transferring it to a separatory funnel containing brine (5 mL).

The aqueous layer was extracted with Et2O (4 x 20 mL) and the organic layers were

combined, dried over MgSO4, and concentrated (aspirator). Ph3CH (0.205 g, 0.840

mmol) was added to the crude product mixture and an NMR spectrum was taken in

CDCl3. The methine proton of Ph3CH (= 5.72 ppm) integrated to 3.91, the methyl

group of diol 4B6c (= 2.54 ppm) integrated to 3.00, and the methylene group of alcohol

4I2 (= 2.75 ppm) integrated to 1.88. This indicates that 0.215 mmol of 4B6c and 0.202

mmol of 4I2 (94% relative to 4B6c) were generated. Purification via silica gel

166

chromatography using 10%, 15%, and 30% EtOAc : hexanes gave 0.077 g 4B6c (0.223

mmol), and 0.046 g of 4I2 (0.204 mmol, 91.5% relative to 4B6c).

Generation of 4H2 and 4H3

N

i-Pri-Pr B

Ts

O H

(R,R)-4H2

B

N

i-Pri-Pr

nC8H17

Ts

4H3d8

In a glovebox, a solution of (R,R)-4G1 (0.057 g, mmol) in THF (3 mL) was treated with

TMSCl (20 L, 0.15 mmol). An aliquot was transferred to a dry NMR tube and 11

B

spectroscopy revealed a single signal at = +17.9 ppm. The species assigned as 4H2 also

appears to be present by 1H NMR spectroscopy (500 MHz, THF-D8): 0.97-1.03 (m,

2H, B-CH), 1.03-1.09 (m, 12H, CH3), 2.02-2.13 (m, 2H, -CHMe2), 2.52 (s, 3H, CH3)

3.10-3.29 (m, 4H, -CH2N), 7.45-7.49 (m, 2H, Ar H), 7.75-7.79 (m, 2H, Ar H). Treating

the solution with 1-octene led to observation of a signal at +86.5 ppm, which has been

assigned as 4H3.

167

Hydroboration with 4F3 and 4B3 in Methylene Chloride

N

i-Pri-Pr B

Ts

N

i-Pr i-PrB

Ts

H H

4F3

N

i-Pri-Pr B

H

Ts

(R,R)-4B3c

In the glove box, a sample of (R,R)-4G1 (0.072 g , 0.2 mmol) in a dry culture tube was

treated with a solution of TMSCl (26 L, 0.2 mmol) in CD2Cl2 (5 mL). The resulting

mixture was centrifuged, a precipitate-free aliquot was transferred to a dry NMR tube,

and 11

B spectroscopy revealed a signals at = +71 ppm, +52 ppm, and +25 ppm in a ratio

of ca. 3:1:2. The peak at +52 ppm is attributed to partial oxidation of the sample, the

peak at +71 ppm is assigned as the monomer 4B3c and the peak at +25 ppm is assigned

as the dimer 4F3. The 1H NMR spectrum in of this mixture in CD2Cl2 is clean, but a

mixture is evident. 1H NMR (400 MHz, CD2Cl2): 0.64 (qd, JBH= 34.8 Hz, J= 6.8Hz,

1H, B-H), 0.72-.96 (m, 12H, CH3), 1.72-1.78 (m, 2H, -CHMe2), 2.37 (s, 3H, CH3) 2.78-

3.03 (m, 2H, -CH2N), 3.03-3.16 (m, 2H, -CH2N), 3.63(m, 2H, B-CH), 7.20-7.32 (m, 2H,

Ar H), 7.48-7.61 (m, 2H, Ar H). The NMR sample was transferred back to the original

mixture, which was then treated with cis-1,4-diphenyl-2-butene (100 L, 0.48 mmol) and

stirred for 20 h, removed from the glovebox, and cannulated into a 0 °C mixture of 20%

NaOH (2 mL), 35% H2O2 (1.1 mL), and THF (3 mL). The mixture was warmed to rt and

stirred vigorously for 16 h before transferring it to a separatory funnel containing brine (5

mL). The aqueous layer was extracted with Et2O (3 x 20 mL). The organic layers were

168

combined, dried over MgSO4, concentrated (aspirator), and purified via silica gel

chromatography using 10%, 15%, and 30% EtOAc : hexanes to give 0.021 g of alcohol

4I2 (49%), 0.049 g of diol 4B6c (72%), and 0.003 g of the fragmentation side product

4H5 (4%).

Hydroboration procedure starting with (R,R)-4G1 powder (Table 4I)

In the glove box, a sample of (R,R)-4G1 (0.103 g, 0.28 mmol) was suspeneded in Et2O (8

mL) at rt and stirred vigorously as 1-octene (100 L, 0.62 mmol) was added followed by

TMSCl (35 L, 0.27 mmol) under nitrogen. The mixture was stirred for 20 h, and an

aliquot was removed. 11

B NMR spectroscopy showed a signal at = +87 ppm (br s),

which is assigned as 4H3. The reaction mixture was removed from the glovebox and

cannulated into a 0 °C mixture of 20% NaOH (2 mL), 35% H2O2 (1.1 mL), and 1:1

MeOH:Et2O (3 mL). The mixture was warmed to room temp and stirred for 8 h before

transferring it to a separatory funnel containing brine (5 mL). The aqueous layer was

extracted with Et2O (4 x 20 mL) and the organic layers were combined, dried over

MgSO4, concentrated (aspirator), and purified via silica gel chromatography using 40%

Et2O : pentane to give 0.021 g of octanol (57%), 0.06 g of diol 4B6c (62%), and 0.003 g

of the fragmentation side product 4H5 (4%).

Table 4I Data

Each substrate in Table 4I was hydroborated using analogous hydroboration / and

oxidation conditions. The enantioselectivity of terminal alcohol 4I1 was assayed by GC

on a Chrompack Chirasil Dex (25m x 0.32 mm x 0.25 mm) column (90 °C, 1 mL/min):

9.5 min, 9.7 min; as was the trimethylsilylether of 4I341

(90 °C, 1 mL/min): (R)-13.8 min

(minor), (S)-14.45 min (major); and the acetate of 4I4 (90 °C, 1 mL/min)40

: (S)-11.3 min

169

(major) , (R)-15.4 min (minor). The ee of 4I2 was assayed by HPLC on a Chiralcel-OD

column (5% IPA: Hexanes, 1 mL/min): (S)-13 min (minor), (R)-19.6 min (major).42

The

assignment of stereochemistry in table 4I is confirmed by the work of Blakemore42

and

Stampfer.40

Entry Alkene Type Solvent Product ee (%)

1 b I ether 4I1 < 5

2 c Ph Ph

II ether 4I2 86.4f,g

3 c Ph Ph

II THF 4I2 85.2g,h

4 c Ph Ph

II THF 4I2 80.2g,i

5 c Ph Ph

II CH2Cl2 4I2 79.2g

6 d Ph Ph

II Toluene 4I2 84g

7 d II ether 4I3 84.6

8 d III ether 4I3 3.8

9e

IV ether 4I4 44.6

j

(a) Procedure: To a stirred mixture of 23 at rt in solvent was added

alkene (4 equiv) followed by TMSCl (1 equiv). After stirring 20 h,

oxidation with NaOOH at 0 °C gave alcohol products, which were

purified by chromatography prior to derivatization and/or assay. (b)

Assayed by GC. (c) Assayed by HPLC. (d) Assay after conversion to

TMS ether. (e) Assayed after acetylation. (f) R-4I2 recovered in 72%

yield. (g) R-enantio-selectivity. (h) R-4I2 recovered in 61% yield. (i) -

20 °C. (j) S-enantioselectivity

170

Asymmetric reduction of 1-phenyl-2-propanone

A sample of (R,R)-4G1 (0.099 g, 0.27 mmol) was suspended in toluene (3 mL) under

nitrogen, treated with MsOH (22 L, 0.34 mmol), and stirred vigorously for 2 h at rt.

The reaction was cooled to -40 °C before 1-phenyl-2-propanone was added. The reaction

was stirred at -20 °C for 48 h before quenching with a solution of DMAP (0.0361g, 0.3

mmol) in toluene (2 mL). The reaction was concentrated and purified by silica gel

chromatography using 40% Et2O in pentane to give 1-phenyl-2-propanol 0.002 g 4K2

(< 10%). The ee of 4K2 was assayed by HPLC with a Chiralcel OD-H column (1.5%

IPA: hexane, 0.5 mL/min): (S)-enantiomer:16.6 min (major); (R)-enantiomer:17.8 min

(minor)43

to provide 35% ee.

Generating Mesylate Complexes of DMAP Borenium Cations

HB

H

MsO BMsO i-Pr B

MsOi-Pr

N

Ts

DMAPDMAP

DMAP

BH

MsO

DMAP

4L2 4L4 4L6 4L7

Complexes 4L2, 4L4, 4L6, and 4L7 were generated in situ by treating DCM solutions of

their DMAP-borane precursors with methanesulfonic acid in a glovebox. 4B4c (0.02 g,

0.2 mmol) in 1 mL of DCM was treated with MsOH (7 L, 0.1 mmol) to generate a new

species observed by 11

B NMR spectroscopy at = +9.7 ppm, which is assigned as

tetravalent 4L7. Starting material was also evident by 11

B NMR spectroscopy (~1:1).

4L318

( 0.04 g, 0.15 mmol) in 1 mL DCM was treated with MsOH (7 L, 0.15 mmol) to

generate a new species observed by 11

B NMR spectroscopy at = +6.6 ppm, which is

assigned as tetravalent 4L4. 4L118

( 0.02 g, 0.16 mmol) in 1 mL DCM was treated with

171

MsOH (10 L, 0.15 mmol) to generate a new species observed by 11

B NMR

spectroscopy at = +0.6 ppm, which is assigned as tetravalent 4L2. Dicylcohexylborane

was generated as previously reported,44

and was quenched with an equivalent of DMAP

and concentrated (aspirator, then high vacuum) to give crude 4L5 (11

B = +2.5 ppm).

Treating a solution of crude 4L5 (0.046 g, 0.015 mmol) with MsOH (10 L, 0.15 mmol)

generated a new species observed by 11

B NMR spectroscopy at = +11.6 ppm, which is

assigned as tetravalent 4L6.

Asymmetric Diels-Alder catalysis with 4L8

A sample of (R,R)-4B4c (0.084 g, 0.19 mmol) was taken up in

CH2Cl2 (8 mL). TfOH (10L, mmol) was added, causing gas

evolution. 11

B NMR spectroscopy enabled observation of a boron

species at = +15.8, which is assigned as 4L8, and an unknown

species at = -14 ppm. The reaction was stirred for 10 minutes

before cooling to -95 °C and adding methacrolein (0.25 mL, 3.03

mmol) followed by cyclopentadiene (1.22 mL, 14.9 mmol).33

The reaction stirred at -78

°C for 10 h before quenching with a solution of DMAP (0.10 g, 0.83 mmol). The

solution was concentrated and purified by silica gel chromatography using 2% Et2O in

hexanes to give 0.3 g of 4L9 (64%). Enantioselectivity was assayed with by chiral GC

using Chrompack Chirasil Dex (25 m x 0.32 mm x 0.25 mm) column (1.3 mL/min, 100

°C) after NaBH4 reduction to the corresponding alcohol 2-methyl-bicyclo[2.2.1]hept-2-

ene-2-methanol.45

Minor diastereomer: 33.6 min (minor) and 35.3 min (major): 25% ee.

Major diastereomer: 37.4 min (minor) and 38.7 min (major): 41% ee.

i-Pr B

TfO

i-Pr

N

N

N

Ts

4L8

172

References for Chapter 4

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