university of groningen catalytic enantioselective conjugate ...it should be emphasised that several...

University of Groningen

Catalytic enantioselective conjugate addition of organometallic reagentsde Vries, Andreas Hendrikus Maria

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.

Document VersionPublisher's PDF, also known as Version of record

Publication date:1996

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):de Vries, A. H. M. (1996). Catalytic enantioselective conjugate addition of organometallic reagents. s.n.

CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.

Download date: 18-05-2021

https://research.rug.nl/en/publications/catalytic-enantioselective-conjugate-addition-of-organometallic-reagents(9ef5aa13-4592-4c91-895d-9953750e4902).html

(2.1)

EWG = CHO, COR, CO2R, CONR2, CN, SO2R, NO2, etc.

REWG R

EWGNu

E-REWG

NuNu- E+

Nu-

E+Nu-

E+ R R'E

Nu O

R R'

OENu

R R'

O

1,4-addition1,2-addition

(2.2)

1

Chapter 2

Carbon-Carbon Bond Formation byCatalytic Enantioselective Conjugate Addition

2.1 Introduction

Conjugate addition reactions of carbon nucleophiles to ",ß-unsaturated compounds areamong the most widely used methods for carbon-carbon bond formation in organicsynthesis. It is therefore not surprising that major efforts have been devoted to achieve1

asymmetric conjugate addition despite the often complicated nature of many 1,4-addition reactions. Addition of the nucleophile to the ß-position of an electron-2,3

deficient alkene results in a stabilized carbanion. After protonation of the carbanion (E+

= H ) a ß-substituted product is formed. Quenching of the stabilized carbanion with+

electrophiles provides ",ß-disubstituted products with two newly created stereocenters(Eq. 2.1).

As carbon nucleophiles one can use a variety of organometallic reagents, "classical"Michael donors, carbanions derived from nitro alkanes, nitriles or dithianes, andenolates (and derivatives). Common substrates for conjugate addition reactions are ",ß-unsaturated aldehydes, ketones, esters, amides, nitriles, sulfones, and nitro compounds.Typical problems associated with conjugate addition are regioselectivity andreversibility. Competition between 1,2- and 1,4-addition to enones is governed by4

several parameters, but in general the use of soft carbon nucleophiles results in highselectivities for conjugate addition products (1,4-addition, Eq. 2.2).

X

Y

_ EWGR

X Y

_

REWG+ (2.3)

Chapter 2

2

In Michael additions, which are often executed under thermodynamic controlledconditions employing stabilized carbanions, reversibility is not an uncommon feature(Eq. 2.3). The stereochemistry might be affected by such reversible processes, whereasthe presence of a labile hydrogen at the "-carbon of the product (with respect to EWG)could be another complicating factor as racemisation or epimerisation can occur.

The enormous utility of conjugate addition reactions in synthesis is partly a result ofthe large variety of donor and acceptor compounds that can be employed. Anotherimportant aspect is the high diastereoselectivity often observed. These features havebeen a strong impetus for the development of enantioselective conjugate additions. Theuse of natural product-based Michael type acceptors has been extremely successful,commonly leading to Michael products with high and predictable stereoselectivities.2-4, 5

Stoichiometric asymmetric conjugate additions have been developed along two lines:(1) using a chiral auxiliary-based Michael acceptor i.e. chiral ",$-unsaturated ester,amide, sulfoxide, or (2) by reaction of a chiral reagent with a prochiral electron-2,5, 6

deficient alkene. In the latter case two strategies have been used mainly, namely2,3,6

chiral auxiliary based donors, such as enamines and enol derivatives, and chiral ligandmodified organometallic reagents, in particular chiral cuprates, Grignard reagents,organozincates, and organolithium reagents. Natural product-based and syntheticorganic ligands and auxiliaries have been successfully employed, but highdiastereoselectivities were reached also with organometallic auxiliaries. Asymmetric7

conjugate addition reactions using stoichiometric chiral auxiliary-based Michaeldonors and acceptors and chiral organometallic reagents have been extensivelycovered by reviews and the reader is referred to these papers for specific examples.1-6

It should be emphasised that several chiral auxiliary-based acyclic and cyclic ",ß-unsaturated substrates, enolates, and enamines are now available which giveenantioselectivities exceeding 95% in a variety of reactions. Furthermore, there are anumber of organocopper reagents with chiral non-transferable ligands as well asorganocuprates modified by additional chiral ligands known today, that provide 1,4-addition products with e.e. > 95%.However, only for a limited number of prochiral acyclic and cyclic enones highenantioselectivities are reached (vide infra ). Major improvements are necessary, in3

R R'

O(R'')mMLn +

R R'

R'' OMLn(2.4)

M = Cu, Li, Zn, Mg

Carbon-Carbon Bond Formation by Catalytic Enantioselective Conjugate Addition

3

particular with respect to the scope of chiral reagent-based methods. This becomesevident when one considers applications in practical synthesis of enantiomerically purecompounds employing conjugate addition as a key step.Even more challenging is the development of general methodology for enantioselectivecarbon-carbon bond formation using chiral non-racemic catalysts in combination withreadily available organometallic reagents and Michael donors. A literature survey ofthis area is the subject of this Chapter with the emphasis on enantioselective conjugateaddition catalysed by chiral transition metal complexes.

2.2 Asymmetric metal-mediated 1,4-addition

In order to achieve a rational synthesis of new chiral catalysts for enantioselectiveconjugate addition it is important to consider several factors that might govern the 1,4-addition step. Among these are: (1) the nature of organometallic reagent (R'') M (Eq.m

2.4), (2) the ligands L associated with it, (3) the fact that most of these reagents aren

aggregated in solution (solvent dependent), and (4) the notion that stereoselectivity (aswell as regioselectivity) can be affected by additional ligands, coordinating solventsand salts.

Furthermore, activation of the electron deficient alkene by Lewis acid or cationcomplexation to the carbonyl moiety is often proposed as a means to tether the reagent,catalyst, and enone in order to increase stereoselectivity and enhance reactivity towardsweaker nucleophiles. The coordinating metal can either be from the organometallicreagent, the catalyst, or additional metal ions (i.e. salts). The proposed intermediate Iin the highly enantioselective (90% e.e.) conjugate addition of the (1R,2S)-ephedrine-based mixed cuprate, reported by Corey and co-workers, nicely illustrates additional8

lithium ion coordination between the oxygen of the enone and the cuprate ligand(Figure 2.1).

O Li

Cu

RLi

N

Ph

NO

Ln

II (Ln = I- or THF)

IIII

R R'

OLA

LA = Me3SiCl, BF3

+ (R'')mMLnR R'

R'' OLA

OO O

O+ O

O

IVaIVa IVbIVbIIIIII 99 % 1 %

(2.5b)

(2.5a)

Me2CuLiMe3SiCl-78°C, 2 min

Chapter 2

4

Figure 2.1 Proposed intermediate in the enantioselective conjugate addition of amixed cuprate reported by Corey and co-workers. 8

The use of Lewis acids, in particular Me SiCl or BF , often results in a dramatic increase3 3

of reaction rates in 1,4-addition reactions of cuprates, presumably by enone activation(Eq. 2.5a). Increased stereoselectivity, for instance, almost exclusive formation of IVa9

by Me CuLi addition to III in the presence of Me SiCl (Eq. 2.5b), and the formation2 310

of enol derivatives such as II, which can subsequently be used in electrophilicadditions (tandem 1,4-addition-enolate processes), are additional important advantages.

Lewis acid catalysis has been extremely successful in 1,4-additions of enol silyl ethers(and tin-analogues). The role of the Lewis acid can be an activation of the enone and11

the silyl-enolate leading, via a cyclic transition state V (Figure 2.2), to Michael adductswith high stereoselectivities.

OSi X

MLnO

RR''

R'

VV (XMLn = Lewis acid)

X

H

R'

Y

LnM

B

VIIVII (B = base)VIbVIb (Z-enolate)VIaVIa (E-enolate)

OR

X

LnMO

X

MLn

R

(2.6)

R = i-Pr ; R' = OMe

2 : 98

93 : 7

R = Me ; R' = Ph

+ t-BuR'

R OO

t-BuR'

O R O

O

R'

Si+

R t-Bu

O TiCl4


5

Figure 2.2 Activation of enone and silyl enolate by a Lewis acid.

The high level of regulation in V that might be reached in these cases offers attractivepossibilities for the development of new chiral Lewis acid catalysts for 1,4-addition.Moreover, stereoselectivity appears to be strongly Lewis acid- and substituent-dependent, as is illustrated in Eq. 2.6.12

Figure 2.3

When enolate anions or other stabilized carbon nucleophiles are involved in conjugateaddition reactions in the presence of chiral metal catalysts, the catalyst can exert its

R''O H

H R'LnM

O R

X H

R'H

HOR''

R

XH

OLnM

(2.7a)

(2.7b)

anti

syn

R''

O

X

O

R

R'

R''

O

X

O

R

R'

Chapter 2

6

stereodirecting effect via formation of a chiral metalenolate VI (Figure 2.3) or bycomplexation and activation of the Michael donor VII (or both donor and acceptor).The geometry of the enolate (VIa or VIb) is a decisive factor in the B-face selectivityand syn-anti diastereoselectivity. Finally, it should be noted that the stereochemical13

result of 1,4-additions of enolate type carbon nucleophiles strongly depends onchelation or non-chelation control. 6,13

In Eq. 2.7a and Eq. 2.7b the open transition state model and the closed (chelated)transition state model for metalenolate additions to enones, leading to syn- and anti-adducts, respectively, are given for the case of a Z-enolate.

A number of highly diastereoselective conjugate additions of metalenolates has beendeveloped, strongly stimulated by the results of stereoselective aldol reactions using6,14

well defined E- and Z-metalenolates and by exploring the coordination properties ofseveral metals (in particular B, Li, Ti and Mg). Again enolate geometry, solvent,counterion, metal catalyst, and mode of addition can have a strong influence on thestereochemical result and all these variables need to be considered in designing aneffective chiral catalyst for 1,4-addition.The use of chiral metal catalysts for enantioselective carbon-carbon bond formationusing organometallic reagents and other carbon nucleophiles will be described in thenext sections. For the sake of completeness conjugate addition reactions using chiralcrown ethers and bases are included.

CuBr Me2S (cat.)2.14 or 2.15 (cat.)

.HMPA, R3SiClTHF, -78°C

14-74% e.e.

RMgX+

2.2

(2.8)R

OO


7

2.3 Enantioselective conjugate addition of Grignard reagents

Chiral copper complexes as catalystsRapid progress has been made in recent years towards highly enantioselectiveconjugate addition reactions of chiral, ligand modified, cuprates and organocopperreagents with non-transferable ligands based on Grignard and organolithiumcompounds. It is surprising that despite many attempts, only very recently the first3

examples of successful 1,4-additions of Grignard reagents catalysed by chiral coppercomplexes were reported, albeit modest selectivities and limited scope were reached.Lippard and co-workers described the first catalytic conjugate addition of n-BuMgBrto 2-cyclohexen-1-one (2.2) (Eq. 2.8). Using a copper(I) complex derived in situ from15

chiral N,N'-dialkylaminotropone imine (H-(R)-CHIRAMT, 2.14, Figure 2.5), 3-butylcyclohexanone was obtained in 14% e.e. The enantioselectivity of the reaction issignificantly increased by the addition of hexamethylphosphoric triamide (HMPA) andsilyl reagents (see Section 2.2).

Both HMPA and a bulky silyl reagent seem to be essential to reach high e.e.'s. Thehighest enantioselectivity (e.e. 74%, yield 53-57%) is obtained using 2 equivalents oft-butyldiphenylsilylchloride, 2 equivalents of HMPA and 4 mol% of chiral ligands 2.14or 2.15. The role of HMPA and the silyl reagent remains rather obscure at present, butit seems that these additives suppress the uncatalysed conjugate addition. A slightly16

higher e.e. (78%) is obtained when a stoichiometric amount of copper and chiral ligandis used. Compared to n-BuMgCl poor enantioselectivities were found with MeMgCl orEtMgCl (30 and 14% e.e. respectively). Interestingly, the reaction with MeMgCl gave(R)-3-methylcyclohexanone in excess, instead of the S enantiomer obtained in thereaction with n-BuMgCl. This reversal indicates that the Grignard reagent is involvedin the rate determining step of the reaction. Other enones are converted as well, thoughno enantioselectivity was observed. All these effects clearly demonstrate the complexnature of the catalytic sequence and in particular further study of additive effects willbe necessary. Since the pioneering work of Lippard and co-workers several othergroups have reported catalytic enantioselective conjugate additions of Grignard

2.1 n = 0 ; X = CH22.2 n = 1 ; X = CH22.3 n = 2 ; X = CH22.4 n = 1 ; X = O

X

O

( )n

R R'

O

2.5 R, R' = Ph 2.6 R = Ph ; R' = Me 2.7 R = Me ; R' = Ph 2.8 R = Ph ; R' = CPh3 2.9 R = Ph ; R' = t-Bu2.10 R = Ph ; R' = p-MeOPh2.11 R = p-MeOPh ; R' = Ph2.12 R = p-ClPh ; R' = Ph2.13 R = Ph ; R' = p-ClPh

(R' = i-Pr, t-Bu ; X = Cl, Me, OMe)

MeMgI+

2.6 R' = Me ; X = H

R'

O

X

2.16 (cat.)

Et2O, 0°C(2.9)

45-76% e.e.

R'

O

X

Chapter 2

8

reagents. The relevant results will be described in this section. The substrates and chiralcatalysts are compiled in Figure 2.4 and 2.5, respectively.

Figure 2.4 Substrates used in catalytic enantioselective conjugate additio nreactions of Grig nard and dialkylzinc reagents (see sections 2.3 and 2.5).

Van Koten and co-workers have reported the use of chiral copper(I) arenethiolate (2-[1-(R)-(dimethylamino)ethyl]phenylthiolate copper(I), (2.16)) as a catalyst for theenantioselective addition of MeMgI to benzylideneacetone (2.6) (Eq. 2.9). The17

enantioselectivity is highly dependent on the mode of addition. Only controlled,simultaneous addition of solutions of MeMgI and of 2.6 (at equal concentration) tocatalyst 2.16 (9 mol%) in diethyl ether afforded a relatively high enantioselectivity(76% e.e.). This indicates that a cuprate reagent rather than free MeMgI is involved inthe reaction.

Using the optimal parameters found for MeMgI, the scope of this reaction has beenexamined for other Grignard reagents (n-BuMgI and i-PrMgI, 45 and 10% e.e.,respectively) and various acyclic enones (Eq. 2.9). Substrates with different para

2.22

N N PhPh

ZnCl Ot-Bu

NN

OH

OHOHN

PPh2

Me2N O

N NOH

2.25

2.26 2.27 2.28

OH

OH

NH2

NOH

H

i-Pr

SH N

O

R

2.17 R = Me2.18 R = i-Pr2.19 R = t-Bu2.20 R = benzyl

2.16 (trimer)

2.24 2.23

2.21

OSH

OO

O

ON

N

R

R

H

2.14 R = Ph2.15 R = 1'-naphthyl

N

S Cu


9

substituents on the aromatic ring and steric bulk next of the carbonyl group gaveproducts with slightly lower enantioselectivities (45-72% e.e.). However, the use ofchalcone (2.5) (or cyclohexenone) furnished the 1,4-product with an e.e. of 0%.

Figure 2.5 Chiral ligands and complexes used as catalysts in the conjugate additionof Grignard reagents to enones.

Copper(I) thiolate complexes derived in situ from chiral mercaptophenyloxazolines2.17-2.20, were reported by Zhou and Pfaltz to be effective in the 1,4-addition of n-BuMgCl to cyclic enones 2.1-2.3 (Eq. 2.10). Highest enantioselectivities were reached18

only when the Grignard reagent was added slowly at -78EC to the solution of enone,catalyst, and two equivalents of HMPA. The methyl and i-propyl derivatives 2.17 and2.18 were found to be the most effective ligands, whereas the bulky derivative 2.19gave markedly lower e.e.'s. Significant enantioselectivities were found only in thepresence of HMPA. The use of trialkylchlorosilanes as additives (vide supra ) resulted

O

( )n

O

R( )n

CuI (cat.)2.18 (cat.)

HMPATHF, -78°C

16-87% e.e.

RMgX+

2.1-2.3

(2.10)

70-92% e.e.2.2-2.4

(2.11)X

O

( )n

X

R

O

( )nn-alkylMgCl+

CuI (cat.)2.22 (cat.)

Et2O, -78°C

Chapter 2

10

in substantial loss of selectivity. With ligand 2.18 the enantioselectivity of the 1,4-product increased with ring size of the cyclic enone (cyclopentenone, 16-37% e.e.;cyclohexenone, 60-72% e.e.; cycloheptenone, 83-87% e.e.). With respect to the18

Grignard reagent it was found that i-PrMgCl gave consistingly higher e.e.'s than n-BuMgCl, whereas PhMgBr gave virtually racemic products. Despite the strong analogybetween chiral catalysts 2.16 and the copper catalyst derived from ligands 2.17-2.20,only low enantioselectivities (e.e. < 20%) with acyclic enones were reported in thelatter case.

A third catalytic system based on chiral copper(I) thiolate complexes was described bySpescha and Rihs. The chiral complex, prepared in situ from the lithium salt of19

1,2,5,6-di-O-isopropylidene-3-thio-"-O-glucofuranose (2.21) and CuI, gave high yieldsand regioselectivities exceeding 98% in the addition of n-BuMgCl to enone 2.2. Theenantioselectivity is strongly dependent on the reaction conditions and variation of alarge number of reaction parameters resulted in e.e.'s up to 60%. The catalytic reactionwas carried out by slow simultaneous addition of a solution of n-butylmagnesiumhalide and a solution of enone to a solution of the copper complex in order to avoidexcess of reagents. A remarkable dependency on the halide in the Grignard reagent wasobserved and with PhMgBr only an e.e. of 20% was found. Reproducible results werefound upon addition of a radical scavenger (2,2,6,6-tetramethylpiperidin-N-oxyl,TEMPO). Together with the dependency of the enantioselectivity on the turnovernumbers, salts, and solvents these findings typically illustrate the complex nature ofthese catalytic systems.Recently, Tomioka and Kanai reported the use of a chiral bidentate phosphine ligandin the copper catalysed addition of Grignard reagents to cyclic enones. The addition20

of several n-alkylmagnesium chlorides to enones 2.2 or 2.3 in the presence of 8 mol%of CuI and 32 mol% of 2.22 gave 1,4-products in good yields and with relatively highenantioselectivities (70-92% e.e., Eq. 2.11).

(2.12)

2.2

+ i-PrMgX

15-33% e.e.

O

i-Pr

O

THF, -90°C

ZnCl2 (cat.)2.24-2.28 (cat.)


11

Grignard reagents, such as Me-, Ph-, and i-Pr-magnesium chloride and Grignardreagents prepared from the corresponding bromides or iodides, gave low e.e.'s and pooryields. Remarkably, the addition of n-butyl- or n-hexylmagnesium chloride to 5,6-dihydro-2H-pyran-2-one (2.4) was also effective, furnishing synthetically interestingchiral intermediates (90% e.e.).Without doubt, the copper catalysts are highly promising in enantioselective conjugateadditions of Grignard reagents and the first examples of e.e.'s exceeding 95% seem tobe in close reach. One of the major problems to deal with, besides tuning of ligand andreaction conditions, are the different aggregates of the catalyst which are in equilibriumwith each other, as they apparently are formed in the reaction medium. The aggregateformation probably depends on the concentration of reactants and additives, and resultsin different catalytically active species with different enantioselectivities.

Chiral zinc complexes as catalystsThe development of chiral zinc(II) complexes as catalyst for 1,4-addition reactions wasbased on the discovery of Isobe and co-workers of the facile conjugate addition oflithium triorganozincates. Subsequent studies resulted in selective alkyl group21

transfer from mixed trialkylzincates, the use of alkoxides as non-transferable ligands,22

and 1,4-additions of Grignard reagents mediated by N,N,N',N'-tetramethylenediaminezinc dichloride as reported by Jansen of our research group. 23

Stimulated by these results stoichiometric and catalytic amounts of chiral diaminezinccomplex 2.23 (Figure 2.5) were used in the 1,4-addition of i-PrMgBr to cyclohexenone(2.2). A catalytic amount (1 mol %) of 2.23 substantially increases yields,regioselectivities towards 1,4-adducts and enantioselectivities of the conjugate addition(21% e.e.). A number of chiral catalysts were prepared in situ from chiral ligands 2.24-24

2.28 and ZnCl and screened in the model reaction (Eq. 2.12).225

In all cases yields and regioselectivities are excellent and the highest enantioselectivity(33%) was found with 5 mol% of chiral ligand 2.28 and i-PrMgBr as Grignard reagent.

N N

OZn

C6H5

MgR

X

R

O

Chapter 2

12

The enantioselectivity depends furthermore on a number of variables:25

- With other alkyl- and aryl-Grignard reagents lower e.e.'s, as compared to i-PrMgX, were found.

- Both regio- and enantioselectivity improved by decreasing the temperature.- The effect of chloride or bromide in RMgX on the enantioselectivity reverses

with different chiral ligands. Similar effects have been observed in cuprateadditions.19

- A significant improvement of the enantioselectivity due to the presence oflithium ions was observed and the catalyst has preferentially to be prepared fromthe lithium salt of the ligand (for the lithium ion effect, see also Section 2.2).

- Higher enantioselectivities were attained by slow addition of i-PrMgX to asolution containing substrate and catalyst. It appears to be essential to keep alow concentration of organometallic species to prevent uncatalysed addition.

The modest enantioselectivities and the sensitivity to a large number of variables makeit difficult to postulate a catalytic cycle. However, the enantioselective 1,4-addition canbe rationalized by a model shown in Figure 2.6, given for the catalyst based on ligand2.28.

Figure 2.6 Propo sed intermediate in the zinc catalysed conjugate addition o fGrignard reagents to 2.2.

Binding of the Grignard reagent via coordination of magnesium to the alkoxide exo tothe bicyclic zinc complex can take place. Activation of the substrate, via coordinationto zinc, involves a pentacoordinated zinc(II) intermediate, which brings Grignardreagent and enone in close proximity to allow alkyl transfer. In this stage a third metal(i.e. lithium) could be involved as proposed for cuprate additions (see also section 2.2).It should be noted that scrambling of both alkyl groups has been observed.The zinc catalysed 1,4-addition of Grignard reagents is attractive as high yields andregioselectivities are found although it is obvious that the enantioselectivity needs

(36 mol%)

(2.13)

HONH

NR*OH =

2.29(R)-(-)-muscone85% yield99% e.e.

O

(CH2)6

O

(CH2)6

MeLi, THFtoluene, -78°C

[R*OCuMe2Li2]

2.30


13

substantial improvement.

2.4 Catalytic enantioselective conjugate addition of organolithium reagents

The high reactivity commonly found for organolithium reagents compared to Grignardreagents and the preference for 1,2-addition make the development of an efficientcatalyst for conjugate addition of RLi a particularly challenging goal. Significantenantioselectivities in catalytic alkyllithium additions have not been reported untilTanaka and co-workers recently realized the chiral alkoxycuprate catalysed addition26

of MeLi to (E)-cyclopentadec-2-en-1-one (2.29) affording (R)-(-)-muscone with e.e.99% (Eq. 2.13).

The chiral catalyst was prepared from amino alcohol ligand 2.30 by sequential additionof MeLi, CuI, and MeLi. The conditions for the catalyst preparation are very critical toreach high enantioselectivities. The use of 1 equivalent of THF, presumably as externalligand to the chiral cuprate, increases the e.e. significantly. Under optimised conditions,36 mol% of chiral ligand 2.30 provides muscone virtually enantiomerically pure andin high yield. Despite impressive e.e.'s in this case further implementation awaitseffective catalysis at lower catalyst concentration and high selectivities with otherenones.The enantioselective addition of phenyl- and 1-naphthyllithium to 1- and 2-naphthalenecarboxylic esters of 2,6-di-t-butyl-4-methoxyphenol (BHA) catalysed bychiral diether 2.32 was reported by Tomioka and co-workers (Eq. 2.14).27

O OBHA CH2OHR

toluene- 45°C

2.32 (cat.)RLi

i. LiEt3BHii. MeOHiii. NaBH4

LiO OBHA

R

2.31

2.32

MeO OMe

Ph Ph 67-75 % e.e.

(2.14)

BA

Me

Zn

Me

N

N145°

1.98 Å

Me2Zn

2N N

N

180°

1.95 Å

Me Zn Me

Chapter 2

14

This is an interesting case of ligand-accelerated organometallic carbon-carbon bondformation. The 1,4-addition in the absence of chiral ligand 2.32 was sluggish. Both28

1- and 2-hydroxymethyl substituted dihydronaphthalene derivatives have beenobtained via this catalytic process.

2.5 Conjugate addition of dialkylzinc reagents catalysed by chiral nickelcomplexes

Enantioselective carbon-carbon bond formation by 1,2-addition of organozinc reagentsto aldehydes has become one of the most successful and active area's of asymmetricsynthesis in recent years. Although dialkylzinc reagents react extremely sluggish with29

carbonyl compounds, effective catalysis has been achieved by several ligands andtransition metal complexes. The catalytic effect was explained by changes in geometryand bond energy of the zinc reagents. For example, dimethylzinc has a linear structure30

and is not reactive towards aldehydes or ketones (Figure 2.7). Upon coordination oftriazine a tetrahedral configuration at the zinc atom and an elongated zinc-carbon bondis found, resulting in enhanced reactivity of the dialkylzinc reagent.

Figure 2.7 Stru ctures of dimethylzinc ( A) and its adduct with 1,3,5 -

R R'

O

R R'

O(2.15)

2.5-2.13 43-95% e.e.

Et2Zn+

Ni(acac)2 (cat.)2.33-2.43 (cat.)

CH3CN, -30°C


15

trimethylhexahydro-1,3,5-triazine ( B).

Several catalytic 1,4-additions of diethylzinc to acyclic enones employing chiral nickelcomplexes have been developed. The substrates and chiral catalysts are compiled inFigure 2.4 and Figure 2.8, respectively. Based on work of Luche and Greene and co-workers, an enantioselective modification of the nickel catalysed alkyl transfer from31

diethylzinc to chalcone (2.5) was found by Soai and co-workers. The chiral catalyst,32

prepared in situ from NiBr and (1S,2R)-N,N-di-n-butylnorephedrine (2.33), afforded2

(R)-1,3-diphenylpentan-1-one in 32% yield with 48% enantiomeric excess. Higheryields (> 70%) were achieved with Ni(acac) instead of NiBr , although large amounts2 2

33

of chiral ligand are required. A remarkable achiral ligand effect was observed.Preparation of the chiral catalyst from 6 mol% of Ni(acac) , 14 mol% of chiral ligand2

2.33 or 2.34, and 7 mol% of 2,2'-bipyridine in acetonitrile raised the enantioselectivityup to 90%.34

2.35 2.36

NOH

2.37 2.38

OHSO

PhN

Et

2.39 R = t-Bu2.40 R = (CH2)3Si_{Sup}

2.33 2.34

N(n-Bu)2

Ph Me

HON N

t-Bu t-BuOH HO

Nt-Bu

OH

Ph Me

HO N

NH

O

NHR

OONi

+ PF6

_

NOH

Ph

Cr(CO)3

2.41

NNPhH

n-pentyl

2.42

Ph OBn

OH

N

O 2.43

Chapter 2

16

Comparable yields and enantioselectivities have been reached with nickel catalystsprepared in situ from C -symmetric bipyridine 2.35 and chiral pyridine 2.36, as2

35 36

reported by Bolm and co-workers and amino alcohol 2.37 as found by Jansen in ourlaboratory.37

The nickel catalysed enantioselective conjugate addition of diethylzinc to chalcone wasalso performed using optically active ß-hydroxysulfoximines as chiral ligands. The38

ligand structure was optimised and an e.e. of up to 70% was reached with ligand 2.38.

Figure 2.8 Chiral ligands and complexes used as catalysts in the conjugate additionof diethylzinc to acyclic enones .

Sánchez and co-workers reported the conjugate addition of diethylzinc to enones byhomogeneous and supported cationic chiral nickel complexes 2.39 and 2.40, based onproline amide ligands. Under homogeneous conditions e.e.'s of 75-77% were reached39

using 5 mol% of catalyst 2.39 at -10EC. Although the addition reactions were slowerwith the supported chiral complexes 2.40, the enantioselectivities were raised to 95%.The relatively high enantioselectivities observed with a chiral ligand-to-nickel ratio of1, compared to ratios of more than 2 in other studies, are explained by the fact32-38,40-42

+ Et2Zn CuI (cat.)2.44 (cat.)

toluene20°C

2.2

NP

OPh

N

i-Pr2.44

70 % yield32 % e.e. (S)

(2.17)

O

Et

O


17

that a single chiral complex is used. Competing catalysis by achiral Ni(acac) (or other2

complexes, see: Eq. 2.16) presumably cannot take place, as often happens in othercatalytic reactions. An attractive feature of this system is also the easy removal andrecovery of the chiral catalyst.

Ni(acac) + 2 L W Ni(acac)L + L W NiL (2.16)2 2* * * *

1,2-Disubstituted arene-chromium complex 2.41 was also employed as chiral ligand inthe nickel catalysed 1,4-addition. Modest e.e.'s were found strongly depending on40

amount of catalyst and structure of chromium complex. Recently, two other examplesof the nickel catalysed asymmetric conjugate addition of diethylzinc to acyclic enoneswere reported. With diamine 2.42 or amino alcohol 2.43 diethylzinc was added to41 42

acyclic enones furnishing the 1,4-products in good yields and with e.e.'s ranging from58-89%.All reports reveal the following observations:- The presence of acetonitrile (or another nitrile) as solvent, and presumably as

stabilizing ligand to nickel, appears to be essential in all cases. - Nickel acetylacetonate was found to be the nickel source of choice.- The enantioselectivity strongly depends on the ligand-to-nickel ratio and the

concentration of the in situ prepared chiral catalyst.- A limited number of alkylzinc reagents and substrates has been successfully

used so far in the 1,4-addition reactions described.. Various acyclic enones (2.5-2.13, Figure 2.4) give high e.e.'s., however, 2-cyclohexenone (2.2) and "-ß-unsaturated esters gave racemic products and low yields.36

Soai and co-workers reported that enantioselective conjugate addition to enones alsoproceed with chiral amino alcohol as catalyst without the use of transition metals,although at much lower rates. After 4 days of reaction time, 1,4-products with e.e.'s43

of 70-80% were obtained using 25 mol% of 2.34.Recently, Alexakis and co-workers reported the first example of copper catalysedenantioselective conjugate addition of diethylzinc to 2-cyclohexenone (Eq. 2.17). The44

use of 10 mol% of CuI and 20 mol% of trivalent phosphorous ligand 2.44 resulted in

2.582.45

(2.18)O

O O

OMe

O

+

O O

OMe2.63-2.68 (cat.)

[Co(acac)2 (cat.)]

Chapter 2

18

an enantioselectivity of 32%. Under the same conditions chalcone gave racemicmaterial.

All these efforts represent a significant advance in the field of catalyticenantioselective conjugate addition reactions, however, there is no general solution tothe problem of achieving efficient catalysis for a wide variety of enones.

2.6 Catalytic Michael additions

Chiral metal complexes as catalystsCarbon-carbon bond formation via Michael additions are most frequently performedunder conditions of base catalysis. The conjugate addition of 1,3-dicarbonylcompounds to enones can also be efficiently catalysed by metal complexes. Among theadvantages of transition-metal catalysed Michael additions are the high yields that areoften found under mild reaction conditions, whereas side reactions, frequentlyencountered in base catalysed Michael additions, are avoided. Several catalyticMichael additions employing chiral metal complexes have been developed. TheMichael donors and acceptors and chiral catalysts are compiled in Figures 2.9 and 2.10,respectively.Brunner and Hammer were the first to report significant enantioselectivity in atransition-metal catalysed Michael addition. The addition of methyl-1-oxo-2-45

indanecarboxylate (2.45) to methyl vinyl ketone (MVK, 2.58) in the presence of 3mol% of a chiral cobalt(II) complex, derived in situ from Co(acac) and (1S,1S)-(-)-1,2-2

diphenylethylenediamine (2.63), provided the Michael product with anenantioselectivity of 66% (Eq. 2.18).

In further investigations, the Co(acac) -(-)-1,2-diphenylethylenediamine catalyst was2


19

examined in the Michael addition of unsymmetrical 1,3-dicarbonyl donors undervarious conditions. Using MVK, di-t-butyl methylenemalonate (2.62), and acrolein46

(2.59) as Michael acceptors and Michael donors 2.46 and 2.48, enantioselectivities upto 37% were reached. Under the reaction conditions the enantioselectivity was almosttemperature independent, no racemisation took place and the conjugate addition wasirreversible.Desimoni and co-workers also investigated the model reaction given in Eq. 2.18,employing chiral copper(II) complexes 2.64-2.67. All copper complexes are based on47

Schiff base ligands derived from salicylaldehyde and chiral amino alcohols and arepresumably dimeric structures. Furthermore there is evidence that H O is bound to the2

copper atom in these complexes resulting in six coordination around each copper atom.The enantioselectivity strongly depends on the solvent and the chiral catalyst. Withcatalyst 2.64 enantioselectivities up to 54% were found in CCl . A negative factor4

seems to be the ability of the solvent to compete with the chiral ligand for metalcomplexation. Introduction of a phenyl substituent in the chiral catalyst structure (2.65)drastically reduces the e.e. (7%). Increase of the rigidity of the catalyst byincorporating an additional hydroxyl group that can act as an axial ligand in 2.66 and2.67 raised the e.e. to 70% (based on optical rotations). Nearly quantitative yields47

were observed with 1-10 mol% of copper(II) catalyst at -20EC in CCl .4

O O

OMe

2.45

OR

O O

2.46 R = Et2.47 R = Bn

O O

OEt

2.48

NCOR

O

2.49 R = Me2.50 R = Et2.51 R = i-Pr2.52 R = t-Bu

R R'

O

RO OR

O O

R'

2.53 R = Me ; R' = H2.54 R = i-Pr ; R' = H2.55 R = t-Bu ; R' = H2.56 R = Bn ; R' = H2.57 R = Bn ; R' = Me

t-BuO Ot-Bu

O O

2.622.58 R = H ; R' = Me2.59 R = H ; R' = H2.60 R = Me ; R' = H2.61 R = Me ; R' = Me

Michael acceptors :

Michael donors :

Chapter 2

20

Figure 2.9 Michael donors and acceptors used in enantioselective Michae ladditions .

An in situ prepared chiral cobalt(II) catalyst derived from Co(acac) and diamino diol2

ligand 2.68 was also tested in the addition of 2.45 to MVK (Eq. 2.18). With 4-14 mol%48

of 2.68, acceptable yields (46-81%) but low e.e.'s (3-38%) were found. This asymmetriccatalysis is a property of the metal ligand complex and not of the ligand itself (the freeligand 2.68 appears to favour the opposite absolute stereochemistry). With Ni(acac) ,2instead of Co(acac) , a lower enantioselectivity was found.2

48

Recently, Ito and co-workers reported a rhodium catalysed enantioselective Michaeladdition of "-cyanocarboxylates 2.49-2.52 to Michael acceptor 2.58 (Eq. 2.19). The49

chiral catalyst was prepared in situ from RhH(CO)(PPh ) and the trans chelating chiral3 3

diphosphine ligand 2,2''-bis[1-(diphenylphosphino)ethyl]-1,1''-biferrocene (TRAP,2.69). Enantioselectivities ranging from 72-84% (for i-propyl-"-cyanocarboxylate)were observed.

H2NNH2

OH

OH

2.682.64 R = Et2.65 R = Ph2.66 R = (CH2)3OH2.67 R = CH2OH

2.69 TRAP

NCOORb

H

2.70

2.63

H2N NH2

PhPh

2

NO

O

R

Cu

Fe Fe

PPh2

Ph2P

NH

N+Me3

OH-

2.71

NCOR

O+

O

R'

2.49 - 2.52 2.58 or 2.59

2.69 (cat.)RhH(CO)(PPh)3 (cat.)

benzene, 3°C RO R'

OO

NC(2.19)


21

Figure 2.10 Chiral ligands and complexes used as catalysts in enantioselectiv eMichael additions .

The reactions of 2.51 with a large variety of vinyl ketones or acrolein (2.59) proceedwith 83-89% e.e. High catalyst efficiency was observed even with 0.1 mol% of 2.69(84% e.e.) whereas high yields are generally found. Trans chelation of the chiral ligandto rhodium appears to be essential for high e.e.'s as common cis chelating diphosphines,such as BINAP, DIOP, or Chiraphos, resulted in low enantioselectivities. It is proposedthat the activated cyanoacetic ester is bound to rhodium through the cyano nitrogen andthat in the enolate intermediate the enantioselective carbon-carbon bond formationoccurs at the carbon atom rather distant from the metal center (Figure 2.11). Only aconcave chiral ligand such as TRAP would effect the remote enantiofacialdifferentiation. The X-ray crystal structure of trans-[RhCl(CO){(R,R)-(S,S)-n-BuTRAP}], which bears a n-Bu group instead of a Ph group as in 2.69, reveals thatrhodium has a nearly planar coordination geometry. The conformation of the ligand50

is essentially C -symmetric, and the chloro and carbonyl groups on rhodium, which may2

be replaced by a prochiral substrate in a catalytic asymmetric reaction, are completelyburied in the chiral cavity created by the ferrocenyl backbone and the n-Bu groups.

(smaller)

(larger)(TRAP)Rh

OR'CN

-O

electrophile (R)-product

(S)-productelectrophile

Chapter 2

22

Figure 2.11 Proposed mechanism in the rhodium catalysed enantioselective Michaeladdition of "-cyanocarboxylates to vinyl ketones .

Yamaguchi and co-workers reported the first catalytic asymmetric Michael addition ofa simple malonate ion to prochiral enones and enals. Asymmetric induction was51

observed when the Michael addition of dimethyl malonate (2.53) to prochiral acceptorscatalysed by the lithium salt of L-proline, was carried out in chloroform. Highercatalytic activity and enantioselectivity was attained with the rubidium salt 2.70.Enantioselectivities up to 88% were achieved with 5 mol% of 2.70, malonates (2.54 and2.55), and various Michael acceptors such as aliphatic and aromatic enones (2.6, 2.60and 2.61), cyclic enones 2.2 and 2.3, and acrolein. A small amount of water was foundto promote the reaction. Yields of Michael products were very low with catalyticamounts of the rubidium salt of N-methyl-L-proline or free L-proline. Thus, both thesecondary amine moiety and the metal carboxylate moiety of 2.70 are essential for highcatalytic activities. Reversible iminium salt formation to provide chiral Michaelacceptors could account for the above asymmetric inductions (Figure 2.12).Independent experiments demonstrated a high reactivity of an unsaturated iminium salt,derived of 2.6 and pyrrolidine, towards malonate addition. 51

2.6, 2.59-2.61 2.2 or 2.3N

COO-

NR2'' =

R'

NR2''

R

+

-CH(CO2i-Pr)2

( )n

NR2''+

-CH(CO2i-Pr)2

(2.20)2.25

THF, 0°C

R

O O

R'R''

THF, 0°C

2.72

R

R''

O

OR' La

OO+La(O-i-Pr)3


23

Figure 2.12 Proposed mechanism in the rubidium catalysed enantioselective Michaeladdition .

This reversible iminium salt formation, creating differentiation of enantiofaces of theprochiral Michael acceptor has also been applied successfully with ammoniumhydroxide 2.71 (Figure 2.10), easily prepared from (S)-proline. The reaction of52

malonate 2.53 or 2.56 with cyclic enone 2.1 or 2.2 was conducted in the presence of1,1,1,3,3,3-hexafluoro-2-propanol to reduce the basicity of the catalyst. The additionproducts were isolated in moderate yields (50-60%) and with enantioselectivitiesranging from 56-71% e.e. Recently, Shibasaki and co-workers reported a chiral lanthanum complex, which ishighly effective as catalyst in enantioselective Michael additions of malonates to cyclicenones. Investigations in order to create an effective catalyst revealed that the53

lithium-free complex 2.72, derived from 2,2'-dihydroxy-1,1'-binaphthyl (BINOL)(2.25), La(O-i-Pr) , and a dialkyl malonate furnishes the corresponding products in high3

yields and e.e.'s ranging from 75-95% (Figure 2.13). The mode of addition in thepreparation of the ester enolate catalyst 2.72 and the removal of THF and i-PrOH afterthis preparation is essential for effective catalysis (Eq. 2.20). Remarkably, with MVKand malonate 2.47, affording a product with a stereogenic center on the 4-position, anenantioselectivity of 62% was achieved.

R

R''

O

OR' La

OO

O

( )n

[OO* O

R''

OR

OR'

La

( )n

R

O O

R'R''

O

R''

OR

OR'

( )n

2.1 or 2.2

2.47, 2.53, 2.56 or 2.57

2.72

Chapter 2

24

Figure 2.13 Proposed mechanism for the asymmetric Michael reaction catalysed bya chiral lanthanum complex.

In subsequent studies the same yields and enantioselectivities were reported by analkali metal containing trimeric complex, derived of La(O-i-Pr) , (R)-BINOL (33

equivalents) and NaO-t-Bu (3 equivalents). With this catalyst the reaction of chalcone54

(2.5) with malonate 2.53 proceed smoothly to give the Michael product in 77% e.e.(93% yield), whereas with catalyst 2.72 only 7% e.e. was found.Very recently this heterobimetallic catalysis concept was extended with thedevelopment of an amphoteric asymmetric complex from aluminium, lithium and (R)-BINOL. Efficient complex preparation from LiAlH and two equivalents of (R)-BINOL55

4

in THF afforded heterobimetallic catalyst 2.73, which gave excellent yields andenantioselectivities (91-99%) in the Michael addition of several malonates to cyclicenones 2.2 or 2.3. Al NMR studies revealed that the carbonyl group of the enone is27

coordinated to the aluminum. This mechanistic feature gave the opportunity to trap theAl-enolate with an electrophile. The reaction of cyclopentenone (2.1), diethylmethylmalonate and 3-phenylpropanal in the presence of 10 mol% of 2.73 gave thethree-component coupling product as a single diastereomer in 91% e.e. (64% yield)(Eq. 2.21). This is the first example of a catalytic asymmetric tandem Michael-aldol55

reaction.

(2.21)

2.73

OO

Li

AlOO

91% e.e.

O

Ph

OHH

CO2EtCO2Et

H2.73 (cat.)

THF, RTPh H

O+EtO OEt

O O+ 2.1


25

Chiral amines and crown ethers as catalysts The use of chiral amines as catalyst in the Michael addition reaction was reported byLångström and Bergson in 1973. The addition of methyl-1-oxo-2-indanecarboxylate56

(2.45) to acrolein (2.59) using optical active 2-(hydroxymethyl)quinuclidine (2.74,Figure 2.14) provided optical active Michael product (see Eq. 2.18).Wynberg and co-workers studied the model reaction of the same Michael donor withMVK as Michael acceptor and quinine (2.75) as chiral base (1 mol%). The Michael57

product is produced in almost quantitative yield with e.e.'s up to 76%, depending onsolvent and temperature (Eq. 2.18). Several variations of chiral base, Michael donorand acceptor, and reaction conditions were examined in detail but enantioselectivitiesexceeding 76% were not reached in these studies.58,59

Several attempts were reported to facilitate removal of the chiral catalyst from thereaction mixture by attaching it to a polymer. With alkaloids 2.75, 2.77, and 2.78anchored to cross-linked polystyrene or co-polymerized with acrylonitrile, the60 61

Michael additions given in Eq. 2.18 proceed with low and moderate e.e.'s, respectively.Insertion of spacer groups between the alkaloid and the polymer backbone improvesthe enantioselectivity to 65%. This is almost the same value as was found in the62

reaction with non-polymer bound alkaloid. When the model reaction (Eq. 2.18) wasperformed under high pressure lower e.e.'s were found.63

2.74

2.75 R = - ; X = -2.76 R = CH2Ph ; X = F

2.79 R = C12H25 ; X = F2.80 R = C12H25 ; X = Br2.81 R = CH2Ph ; X = Br2.82 R = CH2Ph ; X = Cl

OO

O

OO

O

2.83

NOH

S

N

OMe

N

R

OH+X

_+

R

N

N

R'

HO

R X_

2.77 R' = OMe ; R = - ; X = -2.78 R' = H ; R = CH2Php-CF3

X = Br

HO N

Ph

R+

X_

2.86 R = Me2.87 R =

MeO

CH2O

O

O

O

OO

O O

OO

O

OO

R

RO

O

O

4

2.84 2.85

Chapter 2

26

Figure 2.14 Chiral amines and crown ethers used in Michael additions.

The model reaction was also performed under phase transfer conditions. Withquartenary ammonium halides, derived from methionine, the reaction is sluggish andhardly enantioselective. Significant improvements were achieved with [p-64

(trifluoromethyl)benzyl]-chinchoniniumbromide (2.78) as phase transfer catalyst and2-propylindanone as Michael donor, and under solid-liquid phase transfer conditions65

in presence of quaternary ammonium salts, 2.80-2.82, derived from N-methylephedrine(a typical example is given in Eq. 2.22).66

+ (2.22)PhPh

O

N CO2Et

O

H

CO2Et

PhPh

NEtO2C CO2Et

OH O

48-57% yield60-68% e.e.

2.5

2.80-82 (cat.)KOH (cat.)

Ph CO2Me

R

+

R = H, Me

OMe

OOMe

CO2Me

RPh

O

(2.23)2.84 (cat.)base (cat.)


27

Higher enantioselectivities have been reached using chiral catalysts prepared bycomplexation of a base to a chiral crown ether. Cram and Sogah found that with 4 mol%of a bis-ß-naphthol derived optically active crown ether 2.83 (Figure 2.14) andpotassium t-butoxide as the base, the Michael product (Eq. 2.18) was isolated in 48%yield with an e.e. of 99%.67

Crown ether 2.84 was used similarly in the reaction of methyl acrylate and methyl 2-phenylpropionate or methyl phenylacetate (Eq. 2.23). The highest e.e.'s in the latter65

reactions were achieved with potassium amide as base (83% and 65% e.e.,respectively). In both cases the R crown ether gave the S product.

In the presence of KOt-Bu, crown ethers 2.83 and 2.84, were also used as chiral catalystin the anionic (Michael type) polymerization of methacrylate esters to give highlyisotactic helical polymers.68

Following these fascinating reports, several groups have been investigated other chiralcrown ethers as catalysts in the reaction given in Eq. 2.23. Enantioselectivities did not69

rise above 81%. A remarkable high enantioselectivity of 79% was achieved with simpleC -symmetric chiral crown ether 2.86 derived from 2S,3S-butanediol. With chiral2

69d

crown ether 2.85, Yamamoto and co-workers investigated the Michael addition ofmethyl phenylthioacetate to cyclopentenone to give the Michael product in 60% yieldwith an e.e. of 41% (Eq. 2.24). With crown ether 2.87 Koga and co-workers were able69c

to enhance the enantioselectivity to 68% in this reaction.70

AIBNBu3SnH2.85 or

2.87 (cat.)KOt-Bu(cat.)

2.1 PhS CO2Me+

SPh

CO2Me

O

CO2Me

O

(2.24)

41-68% e.e

2.79-2.81or 2.76(cat.)

R = Ph, Me

(2.25)R

O

Ph

O2N

CH3NO2+R

O

Ph

NH

R

2.88 R = CH2NHPh2.89 R = CONH22.90 R = CH2OH

Chapter 2

28

2.7 Nitroalkane additions

In recent years, Michael addition reactions of nitroalkanes to activated alkenes haveattracted considerable attention in part due to the availability of various syntheticmethods for the conversion of the nitro group to other functional groups. Only a few71

enantioselective nitromethane additions to enones catalysed by alkaloids andderivatives have been reported. With quaternary salts derived of quinine or N-methylephedrine (2.76, 2.79-2.81, Figure 2.14) as chiral phase transfer catalysts andexcess of inorganic salts (KF, NaOH or KOt-Bu) enantiomeric excesses up to 26% werereached in the addition of nitromethane to chalcone (Eq. 2.25). With the free alkaloids72

as chiral bases no reaction takes place in aprotic solvents. In methanol addition takesplace although without enantioselectivity.

Under high pressure (900 MPa) both quinine (2.75) and quinidine (2.77) (10 mol%)catalyse the nitromethane addition in aprotic solvents liketoluene, with high conversion and e.e.'s up to 60%.63, 73

These results shows that high pressure is actuallyadvantageous in performing sluggish asymmetric reactionscomposed of rather inert reactants and/or poor catalysts.Botteghi and co-workers reported the first example of atransition-metal catalysed enantioselective nitroalkaneaddition to enones (Eq. 2.25). The catalyst was prepared74

2.91 ( = L* )

2.5MeS

SSnL*(OTf)2.91 (cat.)Sn(OTf)2 (cat.)

CH2Cl2, -78°C

NNH

SSiMe3

MeS (2.26)+ MeS

S

PhPh

O


29

in situ from Ni(acac) and proline-derived ligands 2.88-2.90. Using a large excess of2

nitromethane, enantioselectivities up to 17% where reached although long reactiontimes are required. With benzylideneacetone slightly higher e.e.'s (24%) but low yieldswere found. A decrease of Michael donor-to-acceptor ratio appears to increase theasymmetric induction. With equimolar amounts of donor and acceptor the chemicalyield of the Michael product is rather low, but an enantioselectivity of 61% is found(ligand 2.89). The observed increase in e.e. might well be a solvent effect. An increase48

in solvent polarity (nitromethane vs benzene) produces a decrease in stereoselectivityin the same reaction catalysed by alkaloid bases under phase transfer conditions. 58b

Asymmetric catalysis is confirmed to be a property of metal complexes in this case asthe ligands alone do not catalyse the reaction.Yamaguchi and co-workers noted a reaction of 2-nitropropane and 2-cyclohexenone(2.2) or (E)-3-penten-2-one (2.61) in the presence of 5 mol% of rubidium salt 2.70. 51

The products were obtained with yields of 61% and 48% and e.e.'s of 58% and 69%,respectively .

2.8 Miscellaneous

Two additional successful approaches to catalytic asymmetric Michael addition needto be mentioned, which use chiral Lewis acids as catalysts. Mukaiyama and co-workersused a chiral tin complex derived in situ from tin(II) triflate and chiral diamine 2.91 inthe Michael addition of trimethylsilyl enethiolate to enones (Eq. 2.26). When the75

trimethylsilyl enethiolate was added slowly to the reaction mixture, in order to suppressthe competing uncatalysed addition, enantioselectivities up to 70% were reached. It isproposed that metal exchange of tin and silicium initially takes place to generate achiral tin(II) enethiolate and Me SiOTf. Activation of the enone by Me SiOTf induces3 3

the Michael addition of the chiral tin(II) enethiolate along with the regeneration of thetin(II) triflate-diamine complex.

2.92

1) 2.92 (cat.)Cl2Ti(Oi-Pr)2 (cat.)MS 4Å, ether, 0°C

2) H3O+

O

O

PhOH

OH

PhPh

PhPh

R = Ph, t-Bu 36-68% yield53-55% e.e

(2.27)N OMeO

O O

O

O

R+ N O

MeOO O

ON

O

R

Chapter 2

30

Catalytic asymmetric Michael additions of morpholine derived enamines to methyl(E)-4-oxo-4-(2-oxo-1,3-oxazolidin-3-yl)-2-butenoate with modest yields but promisinge.e.'s were found by Narasaka and co-workers (Eq. 2.27). The chiral catalyst is76

prepared in situ from Cl Ti(Oi-Pr) and (2R,3R)-1,4-diol, 2.92, derived from tartaric2 2

acid. The course of the titanium-catalysed addition reaction of enamines withunsaturated acid derivatives was strongly depending on the enamine structure. Contraryto the Michael reaction of the enamines given above, the reactions of 2,2-disubstitutedenamines with the same Michael acceptor were found to afford optically activecyclobutanes. The in situ prepared chiral catalyst was also used successfully in Diels

Alder and [2+2] cycloadditions, ene reactions, and hydrocyanations.

2.9 Conclusions

The current stage of enantioselective synthesis of ß-substituted carbonyl compoundsusing chiral catalysts has been reviewed in this chapter. Remarkable progress has beenmade in the last few years on the enantioselective synthesis of ß-substituted carbonylcompounds by conjugate addition catalysed by chiral metal complexes. Except for anearly report by Brunner on cobalt-catalysed Michael additions, the first successfulenantioselective conjugate addition reactions catalysed by metal complexes appearedin 1988. A number of examples are currently known of both Michael type additions and1,4-additions of organometallic reagents catalysed by chiral metal complexes withenantioselectivities exceeding 80%. The large variety of chiral metal complexes andligands that have shown modest enantioselectivities are the stepping stones for thedevelopment of highly selective catalysts in the near future.


31

1. a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Tetrahedron Organic ChemistrySeries, No. 9; Pergamon: Oxford, 1992. b) Winterfeldt, E. Kontakte (Darmstadt) 1987, 20; 1987, 37.

2. a) Schmalz, H.-G. in Comprehensive Organic Synthesis; Trost, B.M.; Fleming, I., Eds.; Pergamon:Oxford, 1991; Vol 4, Chapter 1.5. b) Wynberg, H. in Topics in Stereochemistry; Eliel, E.L.; Wilen, S.,Eds.; Wiley-Interscience: New York, 1986; Vol. 16, p 87. c) Tomioka, K.; Koga, K. in AsymmetricSynthesis; Morrison, J.D., Ed.; Academic: New York, 1983; Vol. 2, p 201.

3. Rossiter, B.E.; Swingle, N.M. Chem. Rev. 1992, 92, 771.

4. House, H.O. Modern Synthetic Reactions 2 ed.; W.A Benjamin, Inc: Menlo Park, California, 1972;nd

Chapter 9.

5. Feringa, B.L.; de Lange, B.; Jansen, J.F.G.A.; de Jong, J.C.; Lubben, M.; Faber, W.; Schudde, E.P. PureAppl. Chem. 1992, 64, 1865.

6. a) Jansen, J.F.G.A.; Feringa, B.L. in Houben-Weyl, Stereoselective Synthesis of Organic Compounds;Hoffmann, R.W.; Mulzer, J.; Schaumann, E. Eds.; Georg Thieme Verlag: Stuttgart, 1995, Chapter1.5.2.3. b) Nogradi, M. Stereoselective Synthesis; VCH Publ.: Weinheim, 1987.

7. See for instance: a) Davies, S.G.; Walker, J.C. J. Chem. Soc., Chem. Commun. 1985, 209. b) Liebeskind,L.S.; Welker, M.E. Tetrahedron Lett. 1985, 26, 3079.

8. Corey, E.J.; Naef, R.; Hannon, F. J. Am. Chem. Soc. 1986, 108, 7114.

9. Aoki, Y.; Kuwajima, I. Tetrahedron Lett. 1990, 31, 7457 and references therein.

10. Corey, E.J.; Boaz, N.W. Tetrahedron Lett. 1985, 26, 6015, 6019.

11. Mukaiyama, T.; Tamura, M.; Kobayashi, S. Chem. Lett. 1986, 1017 and references therein.

12. Heathcock, C.H.; Norman, M.H.; Uehling, D.E. J. Am. Chem. Soc. 1985, 107, 2797.

13. Van Draanen, N.A.; Arseniyadis, S.; Crimmins, M.T.; Heathcock, C.H. J. Org. Chem. 1991, 56, 2499.

14. a) Corey, E.J.; Peterson, R.T. Tetrahedron Lett. 1985, 26, 5025. b) Corey, E.J.; Magriotis, P.A. J. Am.Chem. Soc. 1987, 109, 287. c) Yamaguchi, M.; Hasebe, K.; Tanaka, S. Minami, T. Tetrahedron Lett.1986, 27, 959. d) Enders, D.; Müller, S.; Demir, A.S. Tetrahedron Lett. 1988, 29, 643, and referencestherein.

15. a) Villacorta, G.M.; Rao, C.P.; Lippard, S.J. J. Am. Chem. Soc. 1988, 110, 3175. b) Ahn, K.-H.; Klassen,R.B.; Lippard, S.J. Organometallics 1990, 9, 3178.

A wealth of information has already been gathered on the factors effecting catalyticactivity and selectivity. A picture emerges of conjugate addition reactions being oftenextremely delicate and complex processes, in particular due to the appearance ofvarious catalytically active complexes (in equilibrium) during the reaction and thesensitivity to the conditions of the reaction. The scope of organometallic reagents,Michael donors, and enones in these enantioselective processes has been limited so far.With a few exceptions model reactions have been studied only. It is evident that thedevelopment of highly selective catalysts for conjugate addition with a broad scope isa major challenge in current asymmetric synthesis.

2.10 References

Chapter 2

32

16. For a discussion on the effect of silyl reagents on the conjugate addition of organocuprates, see: Bertz,S.H.; Miao, G.; Rossiter, B.E.; Snyder, J.P. J. Am. Chem. Soc. 1995, 117, 11023 and references therein.

17. a) Lambert, F.; Knotter, D.M.; Janssen, M.D.; van Klaveren, M.; Boersma, J.; van Koten, G.Tetrahedron: Asymmetry 1991, 2, 1097. b) van Klaveren, M.; Lambert, F.; Eijkelkamp, D.J.F.M.; Grove,D.M.; van Koten, G. Tetrahedron Lett. 1994, 35, 6135. c) van Koten, G. Pure Appl. Chem. 1994, 66,1455.

18. a) Zhou, Q.-L.; Pfaltz, A. Tetrahedron Lett. 1993, 34, 7725. b) Zhou, Q.-L.; Pfaltz, A. Tetrahedron 1994,50, 4467.

19. Spescha, M.; Rihs, G. Helv. Chim. Acta 1993, 76, 1219.

20. Kanai, M.; Tomioka, K. Tetrahedron Lett. 1995, 36, 4275.

21. Isobe, M.; Kondo, S.; Nagasawa, N.; Goto, T. Chem. Lett. 1977, 679.

22. a) Watson, R.A.; Kjonaas, R.A. Tetrahedron Lett. 1986, 27, 1437. b) Kjonaas, R.A.; Hoffer, R.K. J. Org.Chem. 1988, 53, 4133.

23. Jansen, J.F.G.A.; Feringa, B.L. Tetrahedron Lett. 1988, 29, 3593.

24. Jansen, J.F.G.A.; Feringa, B.L. J. Chem. Soc., Chem. Commun. 1989, 741.

25. Jansen, J.F.G.A.; Feringa, B.L. J. Org. Chem. 1990, 55, 4168.

26. Tanaka, K.; Matsui, J.; Suzuki, H. J. Chem. Soc., Perkin Trans. I, 1993, 153.

27. Tomioka, K.; Shindo, M.; Koga, K. Tetrahedron Lett. 1993, 34, 681.

28. For a discussion about ligand-accelerated asymmetric catalysis, see: Berrisford, D.,J.; Bolm, C.;Sharpless, K.B. Angew. Chem., Int. Ed. Engl. 1995, 34, 1059.

29. For reviews see: a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49. b) Soai, K.;Niwa, S. Chem. Rev. 1992, 92, 833.

30. a) Boersma, J. In Comprehensive Organometallic Chemistry; Wilkinson, G.; Stone, F.G.A.; Abel, E.W.,Eds.; Pergamon: Oxford, 1982, Vol. 2, Chapter 16. b) Knochel, P.; Singer, R.D. Chem. Rev. 1993, 93,2117.

31. Greene, A.E.; Lansard, J.-P.; Luche, J.-L.; Petrier, C. J. Org. Chem. 1984, 49, 931.

32. Soai, K.; Hayasaka, T.; Ugajin, S.; Yokoyama, S. Chem. Lett. 1988, 1571.

33. Soai, K.; Yokoyama, S.; Hayasaka, T.; Ebihara. K. J. Org. Chem. 1988, 53, 4148.

34. Soai, K.; Hayasaka, T.; Ugajin, S. J. Chem. Soc., Chem. Commun. 1989, 516.

35. Bolm, C.; Ewald, M. Tetrahedron Lett. 1990, 31, 5011.

36. Bolm, C.; Ewald, M.; Felder, M. Chem. Ber. 1992, 125, 1205.

37. Jansen, J.F.G.A.; Feringa, B.L. Tetrahedron: Asymmetry 1992, 3, 581.

38. Bolm, C.; Felder, M.; Müller, J. Synlett 1992, 439.

39. Corma, A.; Iglesias, M.; Martín, V.; Rubio, J.; Sánchez, F. Tetrahedron: Asymmetry 1992, 3, 845. Forthe synthesis of 2.39 and 2.40, see: Corma, A.; Iglesias, M.; del Pino, C.; Sánchez, F. J. Organomet.Chem. 1992, 431, 233.

40. Uemura, M.; Miyake, R.; Nakayama, K.; Hayashi, Y. Tetrahedron: Asymmetry 1992, 3, 713.


33

41. Asami, M.; Usui, K.; Higuchi, S.; Inoue, S. Chem. Lett. 1994, 297.

42. Fujisawa, T.; Itoh, S.; Shimizu, M. Chem. Lett. 1994, 297.

43. Soai, K.; Okudo, M.; Okamoto, M. Tetrahedron Lett. 1991, 32, 95.

44. Alexakis, A.; Frutos, J.; Mangeney, P. Tetrahedron: Asymmetry 1993, 4, 2427.

45. Brunner, H.; Hammer, B. Angew. Chem., Int. Ed. Engl. 1984, 23, 312.

46. Brunner, H.; Kraus, J. J. Mol. Cat. 1989, 49, 133.

47. a) Desimoni, G.; Quadrelli, P.; Righetti, P.P. Tetrahedron 1990, 46, 2927. b) Desimoni, G.; Dusi, G.;Faita, G.; Quadrelli, P.; Righetti, P. Tetrahedron 1995, 51, 4131.

48. Botteghi, C.; Paganelli. S.; Schionata, A.; Boga, C.; Fava, A. J. Mol. Cat. 1991, 66, 7.

49. Sawamura, M.; Hamashima, H.; Ito, Y. J. Am. Chem. Soc. 1992, 114, 8295.

50. Sawamura, M.; Kuwano, R.; Ito, Y. Angew. Chem., Int. Ed. Engl. 1994, 33, 111.

51. a) Yamaguchi, M.; Shiraishi, T.; Hirama, M. Angew. Chem., Int. Ed. Engl. 1993, 32, 1176. b)Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org. Chem. 1996, 61, 3520.

52. Kawara, A.; Taguchi, T. Tetrahedron Lett. 1994, 35, 8805.

53. Sasai, H.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1994, 116, 1571.

54. Sasai, H.; Arai, T.; Satow, Y.; Houk, K.N.; Shibasaki, M. J. Am. Chem. Soc. 1995, 117, 6194.

55. Arai, T.; Sasai, H.; Aoe, K.; Okamura, K.; Date, T.; Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1996,35, 104.

56. Långström, B.; Bergson, G. Acta Chem. Scand. 1973, 27, 3118.

57. Hermann, K.; Wynberg, H. J. Org. Chem. 1979, 44, 2238.

58. a) Wynberg, H.; Helder, R. Tetrahedron Lett. 1975, 4057. b) Wynberg, H.; Greijdanus, B. J. Chem. Soc.,Chem. Commun. 1978, 427. c) Kobayashi, N.; Iwai, K. J. Pol. Sci., Pol. Lett. Ed. 1982, 20, 85. d) Heisler,T.; Janowski, K.; Prager, R.H.; Thompson, M.J. Aust. J. Chem. 1989, 42, 37.

59. For related enantioselective Michael addition of "-i-propyl-3,4-dimethoxybenzyl cyanide to severalenones with e.e. < 11%, see: Brunner, H.; Zintl, H. Monatsh. Chem. 1991, 122, 841. For conjugatecyanide addition to enones with e.e. < 45%, see: Dehmlow, E.V.; Sauerbier, C. Liebigs Ann. Chem.1989, 181.

60. a) Hermann, K.; Wynberg, H. Helv. Chim. Acta 1977, 60, 2208. b) Hodge, P.; Khoshdel, E.; Waterhouse,J. J. Chem. Soc., Perkin Trans. I 1983, 2205.

61. a) Kobayashi, N.; Iwai, K. J. Am. Chem. Soc. 1978, 100, 7071. b) Kobayashi, N.; Iwai, K.; J. Pol. Sci.,Pol. Chem. Ed. 1980, 18, 923.

62. Inagaki, M.; Hiratake, J.; Yamamoto, Y.; Oda, J. Bull. Chem. Soc. Jpn. 1987, 60, 4121.

63. Sera, A.; Takagi, K.; Katayama, H.; Yamada, H.; Matsumoto, K. J. Org. Chem. 1988, 53, 1157.

64. Banfi, S.; Cinquini, M.; Colonna, S. Bull. Chem. Soc. Jpn. 1981, 54, 1841.

65. Conn, R.S.E.; Lovell, A.V.; Karady, S.; Weinstock, L.M. J. Org. Chem. 1986, 51, 4710.

66. Loupy, A.; Sansoulet, J.; Zaparucha, A.; Merienne, C. Tetrahedron Lett. 1989, 30, 333.

67. Cram, D.J.; Sogah, D.Y. J. Chem. Soc., Chem. Commun. 1981, 625.

Chapter 2

34

68. Cram, D.J.; Sogah, D.Y. J. Am. Chem. Soc. 1985, 107, 8301.

69. a) Alonso-López, M.; Martín-Lomas, M.; Penadés, S. Tetrahedron Lett. 1986, 27, 3551. b) Alonso-López, M.; Jiminez-Barbero, J.; Martín-Lomas, M.; Penadés, S. Tetrahedron 1988, 44, 1535. c) Takasu,M.; Wakabayashi, H.; Furuta, K.; Yamamoto, H. Tetrahedron Lett. 1988, 29, 6943. d) Aoki, S.; Sasaki,S.; Koga, K. Tetrahedron Lett. 1989, 30, 7229. e) Maarschalkerwaart, D.A.H.; Willard, N.P.; Pandit,U.K. Tetrahedron 1992, 48, 8825. f) Crosby, J.; Stoddart, J.F.; Sun, X.; Venner, M.R.W. Synthesis, 1993,141.

70. Aoki, S.; Sasaki, S.; Koga, K. Heterocycles, 1992, 33, 493.

71. a) Seebach, D.; Colvin, E.W.; Lehr, F.; Weller, T. Chimia 1979, 33, 1. b) Ono, N.; Kaji, A. Synthesis1986, 693. c) Seebach, D.; Missbach, M.; Calderari, G.; Eberle, M. J. Am. Chem. Soc. 1990, 112, 7625.

72. a) Colonna, S.; Hiemstra, H.; Wynberg, H. J. Chem. Soc., Chem. Commun. 1978, 238. b) Annunziata,R.; Cinquini, M.; Colonna, S. Chem. Ind. 1980, 238. c) Colonna, S.; Re, A.; Wynberg, H. J. Chem. Soc.,Perkin Trans. I 1981, 547.

73. Matsumoto, K.; Uchida, T. Chem. Lett. 1981, 1673.

74. Schionata, A.; Paganelli, S.; Botteghi, C.; Chelucci, G. J. Mol. Cat. 1989, 50, 11.

75. a) Yura, T.; Iwasawa, N.; Narasaka, K.; Mukaiyama, T. Chem. Lett. 1988, 1025. b) Iwasawa, N.; Yura,T.; Mukaiyama, T. Tetrahedron 1989, 45, 1197.

76. Hayashi, Y.; Otaka, K.; Saito, N.; Narasaka, K. Bull. Chem. Soc. Jpn. 1991, 64, 2122.

university of groningen catalytic enantioselective conjugate ...it should be emphasised that several...

Documents