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Enantioselective synthesis of natural products containing tertiary alcohols and contributions toa total synthesis of phorbasin BWu, Zhongtao

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Enantioselective synthesis of natural products containing tertiary alcohols

and contributions to a total synthesis of phorbasin B

Zhongtao Wu

The work described in this thesis was carried out at the Stratingh Institute for Chemistry,

University of Groningen, The Netherlands.

This work was financially supported by NRSC-Catalysis program.

Printed by: Gildeprint, Enschede, The Netherlands

Cover design: Zhongtao Wu

Enantioselective synthesis of natural products containing tertiary alcohols and contributions to a total

synthesis of phorbasin B

PhD thesis

to obtain the degree of PhD at the University of Groningen on the authority of the

Rector Magnificus Prof. E. Sterken and in accordance with

the decision by the College of Deans.

This thesis will be defended in public on

Friday 19 June 2015 at 11.00 hours

by

Zhongtao Wu

born on 31 May 1985

in Shandong, China

Supervisor

Prof. A. J. Minnaard

Assessment committee

Prof. H. Hiemstra

Prof. G. Blay

Prof. G. Roelfes

ISBN: 978-90-367-7838-1 (printed version)

978-90-367-7837-4 (electronic version)

To Lei (蕾) & Annie (俣佟)

Table of Contents Chapter 1 Methods for the Preparation of Chiral Tertiary Alcohols and Ethers ............................................................................................................................ 1

1.1 Introduction ....................................................................................................... 2 1.2 Asymmetric dihydroxylation ............................................................................ 4 1.3 Asymmetric epoxidation ................................................................................... 7 1.4 Asymmetric 1,2-Addition of organometallics to ketones ............................... 11 1.5 Recent developments ...................................................................................... 16 1.6 Conclusion ...................................................................................................... 19 1.7 Outline of this thesis ....................................................................................... 20 1.8 References ....................................................................................................... 21

Chapter 2 Catalytic Asymmetric Synthesis of Dihydrofurans and Cyclopentenols with Quaternary Stereocenters ...................................................... 27

2.1 Introduction ..................................................................................................... 28 2.2 Strategies for chiral cyclic ether formation ..................................................... 28 2.3 Results and Discussion ................................................................................... 29 2.4 Conclusions ..................................................................................................... 33 2.5 Experimental Section ...................................................................................... 33 2.6 References ....................................................................................................... 47

Chapter 3 Total Synthesis of (R,R,R)-γ-Tocopherol through Cu-Catalyzed Asymmetric 1,2-Addition .......................................................................................... 51

3.1 Introduction ..................................................................................................... 52

3.2 Retrosynthetic strategy for (R,R,R)-γ-tocopherol ........................................... 53 3.3 Results and discussion .................................................................................... 55 3.4 Conclusion ...................................................................................................... 60 3.5 Experimental section ....................................................................................... 60 3.6 References ........................................................................................... 74

Chapter 4 A Protecting Group-free Synthesis of the Colorado Potato Beetle Pheromone .................................................................................................................. 79

4.1 Introduction ..................................................................................................... 80 4.2 Synthetic strategy for (S)-1,3-dihydroxy-3,7-dimethyl-6-octen-2-one 1 ........ 81

4.3 Results and Disscussion .................................................................................. 82 4.4 Conclusion ...................................................................................................... 83 4.5 Experimental section ....................................................................................... 83 4.6 References ....................................................................................................... 90

Chapter 5 Contributions to a total Synthesis of Phorbasin B ........................... 93 5.1 Introduction ..................................................................................................... 94 5.2 The reported synthesis of phorbasin C ............................................................ 94 5.3 Retrosynthesis of phorbasin B ........................................................................ 95 5.4. Results and discussion ................................................................................... 97 5.5 Conclusion .................................................................................................... 101 5.6 Experimental section ..................................................................................... 102 5.7 References ..................................................................................................... 110

English Summary ..................................................................................................... 113 Nederlandse Samenvatting ...................................................................................... 117 Acknowledgements .................................................................................................. 121

Chapter 1

Methods for the Preparation of Chiral Tertiary Alcohols and

Ethers This chapter gives an introduction on the prominent asymmetric synthesis of tertiary alcohols and ethers and the applications of asymmetric dihydroxylation and epoxidation of olefins in natural product synthesis. The new developments in this field are also summarized.

Chapter 1

1.1 Introduction Quaternary stereocenters, that means, carbon stereocenters without a

carbon-hydrogen bond, are a widely encountered structural motif in natural compounds and pharmaceuticals. [1] Among these quaternary stereocenters, the preparation of chiral enantiopure tertiary alcohols and ethers represents an important, but also a very challenging field. To access these compounds, their asymmetric synthesis is of particular importance, due to the fact that racemic mixtures of tertiary alcohols are difficult to resolve.

Applicable on both small and large scale, the kinetic resolution of a racemic mixture is one of the most common approaches for the production of enantiomerically pure compounds.[2] Many (bio)catalysts have been developed for the kinetic resolution of secondary alcohols via esterification, or hydrolysis of the preformed ester.[3] The (enzymatic) kinetic resolution of tertiary alcohols has turned out to be way more difficult, however, and suffers from low enzyme activities and selectivities.[4] In addition, dynamic kinetic resolution involving in situ racemization of the unwanted enantiomer is not readily achieved in the case of tertiary alcohols.[5] The synthesis of enantiopure secondary alcohols is nowadays also readily accomplished by asymmetric hydrogenation of ketones with transition metals and alcohol dehydrogenases,[6] however, these strategies obviously do not apply for tertiary alcohols.

An additional complication is that chiral tertiary alcohols, and in particular benzylic and allylic tertiary alcohols, are prone to acid-catalyzed racemization via an SN1 pathway and elimination via an E1 pathway. All together this makes the development of new approaches for the synthesis of chiral enantiopure tertiary alcohols and ethers an important challenge.

HOR1

R2 O

1 Tocopherols (R1 = H or Me; R2 = H or Me)

OOH

OH

2 Pheromone of the Colorado potato beetle

O

HHO

OHO

OH

HH

3 Cortisol

R

OHO

4 (−)-Acylfulvene, R = H5 (−)-Irofulven, R = CH2OH

O

O

OOCH3

OH

H

6 (−)-Ovalicin

Figure 1. Natural compounds containing tertiary alcohols and ethers

2

Introduction

Over the past decade, progress has been made in the (asymmetric) synthesis of enantiopure tertiary alcohols not only via established approaches, e.g. the aldol reaction[7] and asymmetric hydroxylation,[8] but also applying new strategies. In 2008, the group of Aggarwal reported a novel method to prepare chiral tertiary alcohols with very high enantiospecificity from enantiopure secondary alcohols via an enantiodivergent conversion[9] (Scheme 1). Depending on the use of either a borane or a boronic ester, both enantiomers of a series of benzylic tertiary alcohols were obtained from one enantiomer of the secondary alcohol. Knochel et al., in 2005, presented a highly enantiospecific preparation of tertiary alcohols by copper-mediated allylic SN2 substitution.[10] Starting from enantiopure allylic pentafluoro benzoates, like 15, allylic substitution was followed by oxidation and Baeyer-Villiger rearrangement. This sequence afforded tertiary alcohol 17 with an ee of 92-99% (Scheme 2). Although from a retrosynthetic point of view not always elegant, the “good old” Baeyer-Villiger rearrangement, being strictly stereospecific, is somewhat underestimated.

Apart from these enantiospecific processes, the focus in research has mostly been on catalytic enantioselective processes, the most prominent ones being discussed below.

H

OCONiPr2Me

Ar

sBuLiEt2O

−78 oC20 min

Li

OCbMeAr

RB(OR')2Retention

InversionRB(R')2

B(OB')2

OCbMeAr

R∆

R

B(OR')2Me

Ar

H2O2NaOH

ArR OH

B(R')2

OCbArMe

R R

B(R')2ArMe

ArR OH∆

H2O2NaOH

7 8

9 10 11

12 13 14Cb = N,N-diisopropylcarbamoyl

Scheme 1. Lithiation-borylation of chiral secondary carbamates leading to tertiary alcohols

Me

Ph OCOC6F5Et2Zn

CuCN•2LiClTHF Me

Et Ph

16 (69%, 99% ee)

1) oxidation

2) Baeyer-Villiger rearrangement

17 (70%, 99% ee)

OH

EtPh

15OBn

BnO OBn

Scheme 2. Enantiospecific preparation of tertiary alcohol 17 by copper-mediated allylic SN2 substitution

3

Chapter 1

1.2 Asymmetric dihydroxylation Generally, the dihydroxylation of olefins is achieved by oxidation with a transition

metal oxo-species. An important landmark in this field is the asymmetric dihydroxylation with OsO4/dihydroquinine acetate by Sharpless in 1980. In this initial system, stoichiometric amounts of ligand and OsO4 were required,[11] which made this reaction somewhat unattractive due to the high cost and the toxicity of OsO4. Subsequently, however, this stoichiometric procedure was transformed into a highly effective catalytic process due to the application of N-methyl morpholine N-oxide as the co-oxidant.[12] Inorganic co-oxidants were investigated as well[13] for the re-oxidation of Os(VI) glycolate in the reaction, and inexpensive K3Fe(CN)6 (potassium ferricyanide) turned out to be versatile.[14] According to the supposed mechanism, two competitive catalytic cycles exist in the Sharpless asymmetric dihydroxylation, the primary cycle (desired) affording high ee, and the secondary cycle (undesired) affording low ee (Scheme 3). The use of a two-phase system suppressed the secondary catalytic cycle,[15] and since then K3Fe(CN)6 together with the second generation ligands (DHQD)2PHAL and (DHQ)2PHAL, and K2OsO2(OH)4

are combined into the known commercial available “AD-mix-α or AD-mix-β”.[16] The absolute configuration of the diol products can be predicted using an empirical model (Scheme 4). In this mnemonic device, the olefin is oriented following the size constrains (RL = Large substituent, RM = Medium-sized substituent, and RS = Small substituent), and then this olefin is dihydroxylated from the top or the bottom face using AD-mix-β or AD-mix-α, respectively.[17]

OsO

O O

O

L

R1

R4

OOOs

LO

O

OsO

O OO

Ohigh ee

H2O

OHHO

Primary cylce

R2

R3

OHHO

H2O

L

Secondary cycleOs

O

O

OO

O

R1

R2R3

R4

oxidant

L

R1

R2R3

R4

R1 R3R2 R4

osmium(VI)glycolate

R1

R4R2

R3

R1

R2R3

R4

R1

R2

R3

R4

R2R1 R3

R4

low ee Scheme 3. Catalytic cycles in the Sharpless catalytic asymmetric dihydroxylation

4

Introduction

H

RMRS

RL

"HO OH"

"HO OH"

AD-mix-β

AD-mix-α

HORS

RL HRM

OH

RL

RSH

RM

HO OH

organic solvent/H2O

NNO O

N

MeO

N

OMeH H

N N

Et

(DHQ)2PHAL

NNO O

N

MeO

N

OMeH H

NN

(DHQD)2PHAL

Et

AD-mix-α: (DHQ)2PHAL + K2OsO2(OH)4 + K3Fe(CN)6 AD-mix-β: (DHQD)2PHAL + K2OsO2(OH)4 + K3Fe(CN)6

Et

Et

Scheme 4. Sharpless asymmetric dihydroxylation and the prediction of the

stereochemistry

Regarding the synthesis of chiral tertiary alcohols, the use of 1,1-disubstituted, trisubstituted and tetrasubstituted olefins are appropriate substrates[13] in the Sharpless asymmetric dihydroxylation, and give good yields and selectivities[16a, 18] (Table 1) . An important discovery was that the addition of CH3SO2NH2 accelerated the reaction dramatically,[16a] which is crucial for the application of this reaction for a number of steric hindered and in particular tetrasubstituted olefins,[19] and even α,β-unsaturated ketones.[20]

AD-mix-β AD-mix-α

ee ee

99 (R, R) 97 (S, S)

94 (R) 93 (S)

OMe95 (R) 96 (S)

OMe

99 (R) 98 (S)

OTBS

MeO99 (R) 97 (S)

AD-mix-β AD-mix-αee eeolefins olefins

Me

83 (R, R) 85 (S, S)

OTBS

93 (R) 95 (S)

O

98 (1S, 2R)

Table 1. Catalytic asymmetric dihydroxylation of olefins according to Sharpless

Since the first asymmetric dihydroxylation has been reported, the reaction has been

studied extensively not only with OsO4,[21] but also with osmium-free methodologies,[22] e.g. permanganate[23] and ruthenium oxide.[24] Different kinds of substrates, for example, divinyl ketones, symmetrical conjugated dienes,[25] dienes

5

Chapter 1

with isolated double bonds,[26] and 1,1-disubstituted allylic alcohols and derivatives have been explored as well.[27]

The construction of tertiary alcohols using dihydroxylation of alkenes is a very important approach in natural products synthesis.[28] Takano et al. reported the synthesis of (+)-verrucosidin 21 in 1988[29] (Scheme 5). In their work, allylic ether 18 was stereoselectively dihydroxylated into diol 19 by OsO4/NMO, and this tertiary alcohol subsequently afforded tetrahydrofuran 20 also containing a chiral tertiary alcohol. Paterson et al. accomplished the stereocontrolled introduction of the chiral tertiary hydroxyl groups at C6, C11 and C12 of (+)-(9S)-dihydro-erythronolide A 25 by osmylation[30] (Scheme 6). The dihydroxylation of silyl enol ether 22 gave a single α-hydroxy ketone 23 by using catalytic OsO4, NMO and quinuclidine. The C11-C12 double bond was not affected even after a longer reaction time. In subsequent work, the authors reduced the C5 ketone followed by TBS deprotection to give tetraol 24. Finally, selective dihydroxylation of the double bond of 24 could be achieved with excess OsO4 in moderate yield.

O

OBnOsO4 (5 mol%)

NMOacetone/H2O, 0 oC

O

OBn

OHOH

O

HO OH

OAc18 19 (dr>15:1) 20

O

O

OH O

O

OMe

(+)-verrucosidin 21 Scheme 5. Synthesis of (+)-verrucosidin 21

In 2000, Armstrong et al. accomplished the synthesis of (+)-zaragozic acid C 28

with four contiguous stereocenters, of which C3 to C6 were constructed by a double Sharpless asymmetric dihydroxylation reaction of diene 26. This double dihydroxylation could not be achieved in one-pot, but took two steps. The first dihydroxylation was performed with Super AD-Mix (commercial AD-Mix supplemented with extra ligand (5 mol%) and OsO4 (1 mol%)) while in the second step the resulting mixture of regioisomeric triols was subjected to 1 mol% of OsO4, 5 mol% of (DHQD)2-PHAL and 2 eq of NMO to afford the desired pentaol 27[31] (Scheme 7).

6

Introduction

O

O

OTBS

OTBS

OSiMe3 O

O

OTBS

OTBS

O

OsO4, NMOquinuclidineacetone/H2O20 oC, 1 h

22 23 (85%)

OHi. Zn(BH4)2

Et2O20 oC, 0.5 h

ii. 40% HF (aq)CH3CN

20 oC, 2 h

OsO4THF

20 oC, 5 d

O

O

OH

OH

OH

24 (66%)

OH

O

O

OH

OH

OH

OHOH

HO

(+)-(9S)-dihydroerythronolide A 25 (42%) Scheme 6. Synthesis of (+)-(9S)-dihydroerythronolide A 25

OBn

OBn

OH

BnO BnO

OH

OBn

OBn

OH

OH

OHOH

i. AD-mix-β, OsO4 (1 mol%)(DHQD)2PHAL (5 mol%)

CH3SO2NH2 (2 eq), K2S2O8

tBuOH/H2O0 oC to r.t., 4 d

ii. OsO4 (1 mol% ), NMO (2 eq) (DHQD)2PHAL (5 mol%)

acetone/H2O

27 (45%, ee 76%)

r.t. 3.5 d

Ph O

O

OO

HO2C

OH

HO2CCO2H

Ph

OAcOH

(+)-zaragozic acid C 28

26

Scheme 7. Synthesis of (+)-zaragozic acid C 28 1.3 Asymmetric epoxidation

The asymmetric epoxidation of olefins is another powerful method to synthesize chiral tertiary alcohols (which need a subsequent stereo-controlled ring-opening process) and ethers. Vanadium[32] and chiral molybdenum[33] catalysts were investigated for asymmetric epoxidation of allylic alcohols in as early as 1970, but the first practical method for asymmetric epoxidation was developed by Sharpless and Katsuki in 1980.[34] The prochiral or chiral allylic alcohols afforded epoxides with high yields and excellent ee by Ti(IV) alkoxide-catalyzed epoxidation with tert-butyl hydroperoxide. Initially, this epoxidation employed a stoichiometric amount of titanium (IV) tetraisopropoxide as well as enantiopure diethyl tartrate (DET). Later, Sharpless’ group developed this methodology into a catalytic asymmetric epoxidation, using 5-10% catalyst.[35] The substrates for the Sharpless asymmetric epoxidation are restricted to allylic alcohols due to the essential coordination of titanium to this hydroxyl group in the reaction.[36] With an empirical model, the enantioselectivity of the Sharpless asymmetric epoxidation can be predicted for prochiral allylic alcohols (Scheme 8). By using (+)- or (-)-tartrate, the system affords reagent controlled epoxidation of the allylic alcohols with good enantioselectivity regardless of the

7

Chapter 1

substitution pattern[34] of the substrate and, an important bonus, high chemoselectivity in the presence of other olefins.

R1 R2

R3 OH

(−)-tartrate

(+)-tartrate

Ti(iPrO)4, tBuOOHCH2Cl2, −20 oC

R3

OH

R2R1

O

R3

OH

R2R1

O

Scheme 8. Sharpless asymmetric epoxidation

In 1990, Jacobsen and Katsuki reported the enantioselective epoxidation of

unfunctionalized olefins using (salen)manganese complexes,[37] while more recently unfunctionalized cis-olefins also were used successfully in regioselective and enantioselective epoxidation catalyzed by metalloporphyrins.[38] In 1996, the Shi epoxidation of trans-olefins was disclosed[39] (Scheme 9). Using a fructose-derived ketone as catalyst and oxone as oxidant, trans and trisubstituted olefins could be epoxidized very effectively with high enantioselectivities orthogonal to a variety of functional groups. The pH of the Shi asymmetric epoxidation should be controlled carefully as Baeyer-Villiger reaction decomposes the catalyst at a lower pH and a higher pH the oxone is destroyed.

R2

R1 R3

R2

R1 R3

O

Shi's catalyst

H2O/CH3CNpH 7~10

Oxone, NaHCO3

O OO

OO

O

Shi's catalyst Scheme 9. The Shi asymmetric epoxidation

Yamamoto developed in 1999 a new chiral vanadium-based catalyst for the

asymmetric epoxidation of allylic alcohols with ligand 29 (figure 2), this catalyst gave much higher selectivity than the previous chiral vanadium complexes.[40] More recently, this catalyst system was improved by redesigning the hydroxamic acid-bearing binaphthyl group into a novel α-amino acid-based hydroxamic acid ligand.[41] With ligand 30, the asymmetric epoxidation of allylic alcohols could be carried out at a convenient temperature (0 oC) and a low catalyst loading (1% vanadium). Subsequently, a new C2-symmetric bishydroxamic acid 31 was designed by the same group.[42] This bidentate ligand solved several practical problems, e.g.

8

Introduction

brought success in the asymmetric epoxidation of cis-substituted allylic alcohols, allowed a lower catalyst loading and a high tolerance to air and moisture. In contrast to the ligand-deceleration observed in other vanadium/ligand catalysts,[43] a ligand-accelerated vanadium-catalysed epoxidation of allylic alcohols was reported in the same year by Malkov.[44] Epoxide hydrolysis was successfully suppressed by choosing suitable ligands (Figure 3) and lowering the reaction temperature to – 20 oC in a mixture of water and methanol.

OMe

N

O

HO

29

N

O

O

O

NOH

30

N

N

OHOH

O R

RO

R = CHPh2, CH2CPh3, CH(3,5-dimethylphenyl)2, etc.

31

Figure 2. Ligands for vanadium-based epoxidation catalysts according to Yamamoto

NH

O NOH

Ph Ph

S OONH

O NOH

Ph Ph

S OON

O NOH

Ph Ph

O

O

32 33 34 Figure 3. Ligands for vanadium-catalysed epoxidation according to Malkov

Building on the vanadium catalyzed asymmetric epoxidation of allylic alcohols

with ligand 30, the Yamamoto group also achieved the asymmetric epoxidation of homoallylic alcohols in moderate to good enantioselectivities using ligand 35.[45] To show the utility of this method, it was applied to the total synthesis of (-)-α- and (-)-8-epi-α-bisabolol (38 and 39) starting from (S)-limonene. In this synthesis, homoallylic alcohol 36 was epoxidized to give 37 in 84% yield and 90% de (whereas (8R)-37 was obtained in 82% yield and 94% de using L-35). This key epoxide afforded the chiral tertiary alcohol structure in the target compound (-)-α-bisabolol 38 in a number of steps (Scheme 10).

9

Chapter 1

N

O

O

O

NOH

Ph

Ph

35

OH OHO2 mol% VO(OiPr)3

6 mol% D-35cumene hydroperoxide (1.5 eq)

toluene, 0 oC84%, 90% de

HO

(−)-(4S, 8S)-α-bisabolol 38

HO

(−)-(4S, 8R)-epi-α-bisabolol 39

36 37

using ligand L-35 Scheme 10. Concise and stereoselective synthesis of (-)-α- and (-)-8-epi-α-bisabolol

(38 and 39)

In recent years, additional progress has been achieved in the asymmetric epoxidation of allylic alcohols and homoallylic alcohols[46] with catalysts based on vanadium as well as other metals, for example, with zirconium(IV), hafnium(IV)[47] and iron.[48] This has been extended to bishomoallylic alcohols and β,β-disubstituted enones. Several reviews have been published on this topic.[49] Tandem reactions for the enantio- and diastereoselective one-pot generation of functionalized epoxy alcohols using titanium-based catalysts have also been summarized.[50] Chiral enantiopure epoxides are, as noted before, important starting materials for the construction of tertiary alcohols. McDonald prepared oxepanes containing a chiral tertiary alcohol by endo,endo-oxacyclizations of 1,5-diepoxides.[51] The key step in the total synthesis of (+)-madindoline A 41 and (-)-madindoline B 42, two chiral tertiary alcohols synthesized by Omura and Smith, was achieved by Sharpless asymmetric epoxidation.[52] In their work, the epoxidation of the indole double bond furnished the hydroxyfuroindole ring directly (Scheme 11). In 2002, Curran reported the first asymmetric total synthesis of (20R)-homocamptothecin 46 based on Stille coupling and Sharpless asymmetric epoxidation as key steps.[53] The chiral tertiary alcohol part of 45 resulted from the reductive ring-opening of epoxide 44 (Scheme 12). In 2005, Morimoto reported the total synthesis of (+)-aurilol 51, a cytotoxic bromotriterpene polyether.[54] In this synthesis, the chiral tertiary alcohols were derived from their corresponding epoxides, prepared in turn by either Sharpless epoxidation or Shi epoxidation. (Scheme 13)

10

Introduction

N

OH

OO

(+)-DETTi(OiPr)4tBuOOH

45%

N

OO

O

HO

H N

OO

O

HO

H

40 (+)-madindoline A 41 (−)-madindoline B 42

+

Scheme 11. A key step in the synthesis of (+)-madindoline A 41 and (-)-madindoline

B 42

N OMeTMS

CH2OH

OMOMO

N OMeTMS

CH2OH

OMOM

Ti(OiPr)4, tBuOOHL-(+)-DET

79%, 93% ee

N OMeTMS

CH2OH

OMOMOH

LAH

NN

O

OEtHO

O

(20R)-homocamptothecin 46

100%

43 44 45

Scheme 12. Key steps in the synthesis of (20R)-homocamptothecin 46

SEMO

OH

O

O1M NaOH

1,4-dioxanereflux, 5 h

O

SEMO OH

HO HH OH O

SEMO

HO HH OH

OO

O

CSACH2Cl2

r.t., 10 min O

SEMO

HO HHO

OO

H OHO

O

O OOH

Br

H OH

OH

H H

H

47 48 49

50 (+)-aurilol 51 Scheme 13. Key steps in the synthesis of (+)-aurilol 51

1.4 Asymmetric 1,2-Addition of organometallics to ketones

One of the most straightforward ways to prepare chiral enantio-enriched tertiary alcohols is, at least in principle, the asymmetric addition of carbon nucleophiles to ketones. This elementary transformation, and in particular the addition of organometallics, has been studied over a long period.[55] Many kinds of organometallics, e.g. organoboron, organolithium, organosilicon, organoaluminium, diorganozinc[56] and organomagnesium (Grignard) reagents have been used for this purpose.[57]

11

Chapter 1

Ketones, being less reactive than aldehydes, usually require reactive organometallics to afford chiral tertiary alcohols via asymmetric addition. However, the use of Grignard and organolithium reagents causes side reactions like enolization and Meerwein-Ponndorf-Verley-type reduction of the substrate. A way to circumvent these problems is the use of less reactive organozinc reagents with activation of either the carbonyl group or the organozinc reagent, or even both. In 1998, Yus described the first enantioselective addition of Et2Zn and Me2Zn to ketones.[58] With camphor-derived hydroxysulfonamide 52, this system, in the presence of an excess of Ti(OiPr)4, gave a good performance in the 1,2-addition of Et2Zn and Me2Zn to in particular aryl alkyl ketones (Table 2). A practical limitation of this reaction is the long reaction time (4-14 days). Subsequently, different kinds of hydroxysulfonamide ligands were designed for the addition of diethylzinc to ketones (Figure 4). The development of bis(hydroxysulfonamide) 54 assisted the asymmetric addition of Et2Zn and Me2Zn to ketones affording tertiary alcohols with improved yields and excellent ee.[59] The reaction requires as low as 2% catalyst loading and also a much shorter reaction time (in most cases < 2 d). In 2008, Ramón and Yus synthesized the Fréchet dendrimer-based isoborneolsulfonamide ligand 55 for the continuous-flow synthesis of chiral tertiary alcohols.[60] The catalyst derived from 55 promoted the 1,2-addition of Et2Zn, Me2Zn and in situ generated phenylzinc to simple aryl alkyl ketones giving the products with ee’s up to 99%. A different type of ligand, chiral bifunctional phosphoramide 56, was developed by Ishihara in 2007 (Figure 5).[61] The chiral phosphoramide-Zn(II) complex 57 (1-10 mol%) catalyzed the addition of Ph2Zn and Et2Zn to ketones very efficiently with high enantioselectivities (ee up to 98%).

OHO2S

R1 R2

O+ R3

2Zn Ti(OiPr)4/CaH2/4 oC

52

52 (20%)/toluene R1 R2

R3 OH

R3 = Et, Me

Et

OHMe

nBuOHMe

nBuOHEt

89%, 89% ee 95%, 83% ee 78%, 86% ee

MeOHEt

Br

Et OH

83%, 81% ee

25%, 89% ee

MeOHEt

36%, 51% ee

MeOHEt

SOHEt

72%, 31% ee 42%, 43% ee

NH

Table 2. Asymmetric addition of Et2Zn and Me2Zn to ketones with

hydroxysulfonamide 52

12

Introduction

NHNH

SO2MeHO

SO2 Me

OH

NHNH

SO2

HO

SO2

OH

53 54

NHNH

SO2

SO2

OH

S

O

O

O

O

Ph

Ph

O

OPh

Ph

n

n

55 (n = 0, 1)

Figure 4. Hydroxysulfonamide ligands for the addition of Et2Zn to ketones

NHN P(1-Np)2

iPr

O

56

N N P(1-Np)2

iPr

O

57

ZnEtO

ZnEt

Et

Figure 5. A combined Lewis acid (Zn (II)) -Lewis base (phosphoramide) catalyst 57

In addition to the extensive studies on the Et2Zn, Me2Zn and Ph2Zn[62] addition to

ketones, the ethylation and methylation of α-ketoesters and the alkynylation of ketones using organozinc reagents were also investigated.[56]

Due to the advantages of Grignard reagents, being inexpensive, readily available and highly reactive, it has always been one of the most popular choices for carbon-carbon formation. The research on the asymmetric addition of organomagnesium reagents to ketones started in 1953,[63] but initially gave no useful results,[64] until Seebach’s first successful asymmetric addition of Grignard reagents to ketones (Table 3).[65] The TADDOL-derived reagents 59 were prepared by deprotonation of TADDOL with 2 equivalent of a primary alkyl Grignard reagent, and subsequently 1 additional equivalent of Grignard reagent was added to the resulted solution. The chiral tertiary alcohols were formed with the highest selectivity at -100 oC. In this system, steric hindrance either from the Grignard reagent or from the ketone decreased the rate of the reaction drastically. Given the reactivity of Grignard reagents, the control of this addition has always been difficult.

13

Chapter 1

O

OAr Ar

Ar Ar

OHOH

O

OAr Ar

Ar Ar

OO

Mg + RMgX +MgX23 eq RMgX R1 R2

O

THF−100 oC, 9-14h

OH

RR1R2

Ar = Ph, 2-naphthyl R = primary alkyl groups

OH

60%, >98% eeBr

Et

OH

60%, 98% eeMeO

Et

OH

76%, 92% ee

Et OH

28%, 89% ee

Et

OH

75%, 98% ee

SEt

OH

43%, 96% ee

N

Et

OH

51%, 96% ee

NEt

OH

96%, >99% ee

Et

OH

64%, 83% ee

OEt

OH

53%, 66% ee

S Et

OH

24%, 90% ee

Et

OH

55%, 71% ee

5958

Table 3. Enantioselective addition of primary alkyl Grignard reagents to ketones

The state of the art in the preparation of chiral enantio-enriched tertiary alcohols by

catalyzed enantioselective addition of carbon nucleophiles to ketones has been summarized in two contributions to Chemical Reviews, in 2008[7a] and 2011.[66] this revealed that the catalytic asymmetric 1,2-addition of Grignard and organolithium reagents to ketones was lacking.

In 2012, Harutyunyan and Minnaard reported the first copper catalyzed enantioselective 1,2-addition of alkyl Grignard reagents to α-methyl-α,β-unsaturated ketones.[67] The reaction was carried out with 5 mol% CuBr⋅SMe2 and 6 mol% of the ligand rev-Josiphos in tBuOMe at –78 oC (Table 4). This catalyst system does not require the use of stoichiometric amounts of additives though needs β-branched Grignard reagents to obtain tertiary alcohols with excellent enantioselectivities. A complete shift of the, normally overwhelming, selectivity of Cu(I)-organometallics for conjugate addition to 1,2-addition took place using this catalyst/substrate combination. Later, this method was also applied in the catalytic asymmetric addition of Grignard reagents to aryl alkyl ketones[68] and α-bromo-α,β-unsaturated ketones (Scheme 14).[69] The corresponding tertiary alcohols were obtained in good yields and enantioselectivities of up to 98%. This system provides a convenient, though not unrestricted, route to enantio-enriched allylic and benzylic tertiary alcohols which are important classes of building blocks for organic synthesis.[70]

14

Introduction

61 6 mol% FeCy2P

Ph2P

61

Ph R1

Me

O

Ph R1

Me

HO R2R2MgBr

tBuOMe, −78 oC

CuBr.SMe2 5 mol%

PhMe

HO 3

95%, ee 66%

Ph PhMe

HOPh

83%, ee 62%

Ph PhMe

HO

94%, ee 84%

Ph PhMe

HO

87%, ee 76%

PhMe

HO

96%, ee 84%

PhMe

HO

95%, ee 92%

Et

Et

PhMe

HO Cy

95%, ee 88%

Ph iBuMe

HO

92%, ee 96%

Et

Et

60 62

Table 4. Cu(I) catalyzed 1,2-addition of Grignard reagents to α-methyl enones

X

R1

O R2MgBr

61 6 mol%tBuOMe, −78 oC

CuBr.SMe2 5 mol%

X

R1

HO R2

X = Me, CF3, Br, Cl, FR1 = Me, Et

R2 = branched alkyl groups

R1

Br

O

R1

Br

HO R2R2MgBr

61 6 mol%tBuOMe, −78 oC

CuBr.SMe2 5 mol%

R2 = branched alkyl groupsR1 = Ph, pBrC6H4, pCF3C6H4, Cy

63 64

65 66

Scheme 14. Cu(I) catalyzed 1,2-addition of Grignard reagents to aryl alkyl ketones

and α-bromo-enones.

A large asymmetric amplification in the catalytic enantioselective 1,2-addition of Grignard reagents to enones was observed during recent studies.[71] This amplification originates from the solubility differences between the enantiopure and the racemic complexes of a transition metal with diphosphine ligands. To understand this amplification phenomenon, structural characterization of the copper complexes of both racemic and enantiopure ferrocenyl diphosphine ligands was carried out.[72]

To investigate the influence of the electronic and steric properties of the ligand in this 1,2-addition, five new chiral ferrocenyl diphosphine ligands of the Josiphos family were synthesized (Figure 6).[73] Some improvement was obtained in the regio- and enantioselectivity of the addition to α-H-substituted enones using the ligand 70, containing tert-butyl substituents in the diarylphosphine moiety. The clear message from this study is that the precise structure of the ligand is very critical, with rev-Josiphos (close to) optimal.

15

Chapter 1

68

Cy2P

(o-tolyl)2P

FeCy2P

(3,5-(CF3)2C6H3)2P

FeCy2P

(p-methoxyphenyl)2P

Fe

70

Cy2P

(3,5-tBu2-4-methoxy-C6H3)2P

Fe Cy2P

Ph2PiBu

Fe

6967

71 Figure 6. Ligand variation based on rev-Josiphos.

Important new developments in this connection were reported very recently and

involve the catalytic asymmetric alkylation of acylsilanes[74] and aryl heteroaryl ketones.[75] The alkylation of acylsilanes 72 gives access to aryl- and vinyl-substituted α-hydroxysilanes 73 with quaternary stereocenters in high yields and enantioselectivities (Scheme 15). In this system, β-branched Grignard reagents are not a requirement for high enantioselectivity, the chiral catalyst could be recovered and re-used without loss in activity, and a mixture of two Lewis acids led to the best results.

R1 SiPh2Me

O

R1 SiPh2MeHO R2

R2MgBr

61 6mol%

tBuOMe, −78oC

CuBr.SMe2 5mol%

R1 = Aryl- or vinyl- subtituents

CeCl3 (1 eq), BF3.Et2O (1 eq)

72 73

Scheme 15. Catalytic asymmetric alkylation of acylsilanes 72

1.5 Recent developments The method reported by Aggarwal et al. in 2008 for the preparation of enantiopure tertiary alcohols from enantiopure secondary alcohols was a new development in this field (Scheme 1).[9] Initially, the reaction worked well only for simple substrates not containing sterically hindered carbamates, boronic esters or aryl groups with electron withdrawing substituents. It was found that erosion of the ee resulted from reversibility of the second step, leading back to the starting lithiated carbamate which is prone to racemization upon warming. The remedy to suppress this dissociation-racemization was the use of either MgBr2/MeOH or less sterically hindered neopentyl boronic esters instead of pinacol boronic esters.[76] In 2013, this lithiation-borylation methodology also afforded access to several α-heterocyclic tertiary alcohols in good to excellent yields and excellent enantioselectivity.[77] Starting with the enantioselective synthesis of boron-substituted quaternary carbons as well, a different approach was reported in 2010 by Hoveyda for the synthesis of 16

Introduction

chiral tertiary alcohols.[78] This was achieved via NHC-Cu-catalyzed enantioselective conjugate boronate additions to trisubstituted alkenes in acyclic α,β-unsaturated carboxylic esters, ketones, and alkyl thioesters. The resulting boron-substituted quaternary stereocenters were oxidized to the corresponding tertiary alcohols 76 (Scheme 16). Meanwhile, the enantioselective synthesis of allylboronates bearing a quaternary boron-substituted stereocenter, as precursors for tertiary allylic alcohols, succeeded.[79] A different NHC-catalyzed intramolecular crossed benzoin reaction was developed by Ema and Sakai in 2009.[80] In their work, bicyclic tertiary alcohols 78 with two consecutive quaternary stereocenters were synthesized with high stereoselectivity (Scheme 17).

G R

O R1chiral Cu-NHC complex

B2(pin)2oxidation

R = alkyl or arylG = alkoxy, alkyl or alkylthio

G R

O R1 B(pin)

G R

O R1 OH

74 75 76

Scheme 16. Hoveyda’s strategy to chiral tertiary alcohols 76

mn

O

O

CHO

n = 1 or 2 or 3m = 1 or 2

O

OOH

n m

up to > 99% ee (> 99% de)

NHC cat.base

solvent77 78

Scheme 17. Intramolecular crossed benzoin reaction catalyzed by an NHC

organocatalyst With a chiral sulfoxide as an auxiliary, Ready et al. showed the asymmetric addition of simple alkynyl, aryl and vinyl organometallics to aryl ketones.[81] Tertiary alcohols are generated in diastereomerically pure form, and enantiopure after removal of the tolyl sulfoxide via reductive lithiation (Scheme 18).

O

CH3

S

(p-Tol)

O −78 oC, THF, 3 h

H3C OH

PhS

H3C OH

79 80 (95%, dr ~ 50:1) 81 (97%, ee 96%)

Ph Li/CeCl3Ph

nBuLi−78 oC, THF, 0.5 hO

(p-Tol)

Scheme 18. Asymmetric synthesis of tertiary benzylic alcohols using chiral sulfoxide An important direction in the construction of enantiopure tertiary alcohols is the

17

Chapter 1

preparation of tertiary homoallyl alcohols. This could be realized by the asymmetric allylation of ketones via different approaches, e.g. Nozaki-Hiyama-Kishi reactions, allylborations, indium-mediated allylations, titanocene-catalyzed Barbier-type allylations and auxiliary-mediated or catalytic allylsilane transfer.[7a, 82] In 2005, Soderquist designed 10-Ph-9-BBD reagent 82 (Figure 7), B-allyl-10-Ph-9-borabicyclo[3.3.2]decanes, for the asymmetric allylboration of ketones to prepare chiral homoallylic tertiary alcohols.[83] This new BBD reagent showed high selectivity for a wide range of prochiral ketones. In their subsequent research, B-allenyl- and B-(γ-trimethylsilylpropargyl)-10-Ph-9-BBDs (83 and 84) were designed for the asymmetric synthesis of propargyl and α-allenyl tertiary alcohols from ketones.[84] And the design of borabicyclodecane (BBD)-derived 1,3-diborylpropenes 85 in 2009 led to selective asymmetric allylboration, first of ketones and subsequently of aldehydes.[85] Recently, they also achieved access to highly functionalized tert-carbinols via asymmetric γ-alkoxyallylboration of ketones with 86. Loh, in 2009, developed a highly enantioselective indium(III)-pybox catalyzed ketone-ene reaction (Scheme 19).[86] This asymmetric keton-ene reaction of methyl trifluoropyruvate 87 with various olefins gave enantioenriched homoallylic alcohols 90 with ee’s up to 98%. In Laschat’s work, the Evans aldol reaction was employed for the preparation of the required chiral tertiary homoallylic alcohols.[82]

(−)-82R

B

PhTMS

(−)-84R

B•

Ph

(+)-83S

B BTMS

Ph

trans-85SS

B

Ph

(±)-86

B

PhOMe

Figure 7. BBD reagents developed by Soderquist.

Enantioenriched tertiary allylic alcohols containing a tetrahydrofuran or tetrahydropyrrole are important structural units in natural compounds. A rhodium-catalyzed asymmetric tandem cyclization developed by Xu in 2014 afforded a new access to this kind of heterocyclic tertiary allylic alcohols.[87] The reaction was carried out with nitrogen- or oxygen-bridged 5-alkynones and arylboronic acids in the presence of [Rh(COE)2Cl]2 as the metal precursor and a commercially available chiral BINAP ligand. The corresponding chiral tertiary alcohols were obtained with ee’s up 18

Introduction

to 99%.

OMeF3C

O

OR2

R1+

InCl3 (10 mol%)AgSbF6 (20 mol%)

87 88

(+)-894Å MS, r.t.

ClCH2CH2Cl

R1 OMeR2

O

F3C OH

90

yield up to 99%,ee up to 98%

NO

N N

OH

H H

H

(+)-89

Scheme 19. In(III)-pybox catalyzed asymmetric ketone-ene reactions of methyl

trifluoropyruvate 87 with olefins

With an improved RhI/BINAP-catalyzed 1,2-addition of organoaluminum reagents to cyclic enones, Zezschwitz et al. in 2013 synthesized 5-7 membered cyclic tertiary allylic alcohols with excellent enantioselectivity and in high yield using only 1 mol% catalyst [88] compared to 5 mol% in the previously reported system.[89]

In 2007, Cheng published a cobalt-catalyzed diastereoselective reductive [3 + 2] cycloaddition of allenes and enones.[90] In this reductive coupling, enones act as the three-carbon nucleophile adding exclusively to the internal double bond of allenes to form cyclopentanols with high diastereoselectivity in the presence of zinc as reducing agent and water as proton source. And in 2012, the authors reported a new synthesis, also catalyzed by cobalt, of bicyclic tertiary alcohols 93 with high regio- and enantioselectivity via [3 + 2] cycloaddition of alkynes and cyclic enones 92 (Scheme 20).[91] Cheng’s system provides an advantage from a practical point of view, e.g. the cobalt catalyst is air-stable, relatively inexpensive, zinc is a mild reducing agent, and uses water as proton source.

R2

R1

OH

R3R4nR1 R2

O

R3R4

n+

CoI2, Zn, ZnI2(R,R,S,S)-Duanphos

1,4-dioxane

n = 1 or 2up to 99% ee

91 92 93

R1, R2 = alkyl or arylR3, R4 = H or Me

Scheme 20. The enantioselective reductive [3 + 2] cycloaddition of alkynes 93 with cyclic enones 92.

1.6 Conclusion

In this chapter, different approaches for the asymmetric synthesis of tertiary

19

Chapter 1

alcohols and ethers have been introduced. In these approaches, the catalytic asymmetric dihydroxylation and epoxidation of olefins have gained wide acceptance and applications in natural products synthesis. The catalytic asymmetric addition of organometallics to ketones as a straightforward, and from a retrosynthesis point of view preferred, way to prepare enantio-enriched tertiary alcohols attracts more and more attention and has been realized by several transition metal-catalyzed systems. This approach is however far from mature. 1.7 Outline of this thesis

In this thesis, the copper-catalyzed asymmetric 1,2-addition of Grignard reagents to α-bromo-α,β-unsaturated ketones has been applied in the asymmetric synthesis of dihydrofurans and cyclopentenols and in the total synthesis of (R,R,R)-γ-tocopherol. The second part of this thesis gives an introduction to a novel, protecting group-free, synthesis of the Colorado potato beetle pheromone and efforts on the total synthesis of phorbasin B.

In chapter 2, a novel asymmetric synthesis of dihydrofurans and cyclopentenols has been developed, based on the copper-catalyzed 1,2-addition of Grignard reagents to enones in combination with Sonogashira coupling/cyclization and ring-closing metathesis. Employing this approach, dihydrofurans with an oxygen-containing tertiary stereocenter, and chiral tertiary cyclopentenols are efficiently prepared. The absolute stereochemistry of the products has been established as well.

In chapter 3, based on the asymmetric copper-catalyzed 1,2-addition of Grignard reagents to ketones, (R,R,R)-γ-tocopherol has been synthesized in 36% yield over 12 steps (longest linear sequence). The chiral center in the chroman ring was constructed with 73% e.e. by the 1,2-addition of a phytol-derived Grignard reagent to an α-bromo enone prepared from 2,3-dimethylquinone.

In chapter 4, a novel synthesis of the aggregation pheromone of the Colorado potato beetle, Leptinotarsa decemlineata, has been developed based on a Sharpless asymmetric epoxidation in combination with a chemoselective alcohol oxidation using catalytic [(neocuproine)PdOAc]2OTf2. Employing this approach, the pheromone was synthesized in 3 steps, 80% yield and 86% ee from geraniol.

Finally, in chapter 5, progress in the asymmetric synthesis of phorbasin B is described. Starting from readily available materials, the required chiral centers of the substituted 2-cyclohexen-1-one part were constructed by Evans aldol reaction and Rubottom reaction, whereas the chiral center in the side chain is provided by copper-catalyzed asymmetric allylic alkylation of a diene bromide. 20

Introduction

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S.-J. Jeon, H. Li, C. García, L. K. LaRochelle, P. J. Walsh, J. Org. Chem. 2004, 70, 448-455.

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23

Chapter 1

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24

Introduction

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25

Chapter 1

26

Chapter 2

Catalytic Asymmetric Synthesis of Dihydrofurans and

Cyclopentenols with Quaternary Stereocenters In this chapter, a novel asymmetric synthesis of dihydrofurans and cyclopentenols is described. Copper-catalyzed 1,2-addition of Grignard reagents to enones, combined with Sonogashira coupling/cyclization or ring-closing metathesis, provided two different kinds of dihydrofurans with medium to high enantioselectivities. Parts of this chapter have been published: Z. Wu, A. V. R. Madduri, S. R. Harutyunyan, A. J. Minnaard, Eur. J. Org. Chem. 2014, 575-582.

Chapter 2

2.1 Introduction Functionalized chiral five-membered cyclic ethers, e.g. dihydro- and tetrahydrofuran

derivatives, are ubiquitous structural units in natural products.[1] Also due to their wide-spread applications,[2] for example, as probe molecules for chemical reactions,[3] in complex pharmaceuticals, and in commodity chemicals,[2, 4] the synthesis of compounds containing chiral (dihydro)furans has been intensively studied.[3, 5]

The asymmetric synthesis of five-membered ring ethers in which the oxygen is connected to a tertiary or quaternary stereocenter is of particular importance. Ring closing by face-selective attack of an oxygen nucleophile to an alkene is most commonly used. In this process, the alkene is activated either by Lewis acids including protonation,[6] via allylic substitution,[7] or conjugate addition[8] or alternatively via ring-opening of the corresponding epoxide[9] or haluronium ion.[10] Alternatively, asymmetric ring-closing olefin metathesis has been applied.[11]

For cyclic ether formation using the alternative approach, e.g. alkylation of a chiral tertiary alcohol followed by ring-closing, literature is particularly scarce. This is easily explained by the limited examples of effective methods for the enantioselective synthesis of the latter.

2.2 Strategies for chiral cyclic ether formation

Recently, our group reported on the use of a copper/Josiphos-type catalyst system to accomplish the enantioselective 1,2-addition of Grignard reagents to α,β-unsaturated ketones (Scheme 1).[12] This leads to chiral enantioenriched tertiary allylic alcohols.[13] We realized that upon subsequent alkylation on oxygen to the corresponding ethers, and together with suitable ring-closing reactions, this strategy will provide a useful method for the synthesis of chiral five-membered cyclic ethers. As the quaternary stereocenter formed is obviously not prone to racemization and not involved in the ring-closing reaction, the latter process should not lead to erosion of ee. As an additional task, we planned to unambiguously establish the absolute configuration of the tertiary alcohols and ethers formed in this way, as reliable data on these compounds are practically absent.

R2MgBr

R1

HO R2

R1

O

X X

5 mol% CuBr.SMe2

−78 oC, overnighttBuOMe

X = Br, Me

Fe

(S, RFe)-L

6 mol% (S, RFe)-LCy2P

Ph2P

Scheme 1. Asymmetric Cu-catalyzed 1,2-addition of Grignard reagents to enones

28

Catalytic asymmetric synthesis of dihydrofurans and cyclopentenols with quaternary stereocenters

Based on the product of the enantioselective 1,2-Grignard addition reaction, several approaches for ring-closure were selected (Scheme 2). In case the substituent X is bromide, it had already been shown that Sonogashira reaction readily leads to the corresponding enyne.[12c] Base-induced intramolecular hydro-alkoxylation following a literature procedures[14] leads then directly to substituted dihydrofurans (route A).

Ph OH

Ph

Ph R1

Br Ph R1

OR2 HOR1 R2

R2

Ph R1

OH

A B

C (R2 = butenyl)

OR1

R2Ph

Ph

OR1R2

OH

R1

Scheme 2. Strategies for chiral cyclic ether formation

Upon allylation of the hydroxy group in the addition product, formally 1,6-dienes

are formed. These should be very suitable substrates for ring-closing olefin metathesis, leading to chiral dihydrofurans with a double bond at the 3,4-position (route B). In turn, these out-of-conjugation alkenes can be further functionalized to provide highly substituted tetrahydrofurans.

Employing butenylmagnesium bromide in the asymmetric addition reaction gives a direct access to 1,6-dienes as well (route C). Although the enantioselectivity of the addition reaction in this particular case is less satisfactory (the reaction requires branched Grignard reagents to reach excellent ee values), we wanted to pursue this approach, as subsequent ringclosure via olefin metathesis leads to chiral allylic cyclopentenols. Formally, these originate from addition of a carbon nucleophile to cyclopentenone,[15] but this reaction in an enantioelective fashion is not known. Alternatively, 1-methyl-2-cyclopentenol has been prepared from linalool using ring-closing metathesis.[16]

2.3 Results and Discussion

The study commenced with the preparation of the enantioenriched tertiary allylic alcohols via catalytic asymmetric addition of Grignard reagents to the corresponding enones. These α-bromo enones 1, in turn, are readily obtained by aldol condensation of benzaldehyde and the appropriate ketone, followed by dibromination/HBr elimination.[17]

29

Chapter 2

R1

HO R2

R1

O

Br Br

1 2

5 mol% CuBr.SMe2

−78 oC, overnight

R2MgBr

2* yield (%) ee (%)R2R1 (1)

Me (1a)

Ph (1b)

(CH3)2CHCH2

Et2CHCH2

(CH3)2CHCH2

Me (1a)

Me (1a)

2a

2c

2d

2b

85 86

82 94

63 98

70 75CyCH2

*The absolute configuration of 2 is R, vide infra.

6 mol% (S, RFe)-LtBuOMe

Table 1. Asymmetric 1,2-addition to α-bromo enones 1

Upon treatment of the α-bromo enones 1a and 1b with isobutylmagnesium bromide

in the presence of CuBr•SMe2 (5 mol%) and (S, RFe)-L (6 mol%) in methyl tert-butyl ether (MTBE) at –78 oC, the desired chiral tertiary alcohols 2a and b were obtained in good yields and good to excellent enantioselectivities (Table 1).[12] In addition, 1a was used in the addition of (2-ethyl)butylmagnesium bromide and cyclohexylmethylmagnesium bromide leading to the corresponding alcohols. As expected, the reactions could be performed on gram scale without deterioration in yield or ee except for 2d, in which a longer reaction time led to a slightly lower ee.

With the products 2 in hand, the Sonogashira reactions, as part of route A, were carried out using 5 mol% Pd(PPh3)2Cl2 and 10 mol% CuI as the catalysts in Et3N. The corresponding enynes 3a-3d were isolated in high yields (Table 2).[18] Subsequent treatment with tBuOK in DMSO for 1 h at 60 ºC afforded the desired cyclized products 4a-d in good yields.[14a] It has been shown that 3-benzylidene-2,3-dihydrofurans are strongly fluorescent compounds.[19]

Synthesis of the 2,5-dihydrofurans 7, via route B, also started from the chiral tertiary alcohols 2. Debromination with tBuLi in dry Et2O at –78 ºC for 0.5 h,[20] followed by aqueous work up, yielded the desired products 5a-c in good isolated yields (Table 3). Alkylation of the hydroxyl groups in 5 turned out to be surprisingly difficult and substituents other than allyl could not be introduced. Under optimized conditions, comprising the use of 1.5 eq allyl bromide, 1.5 eq NaH and 3.0 eq HMPA in refluxing dry THF,[21] 6a-c were however prepared in high to excellent yield. Remarkably, 2d refused to react under all conditions, presumable due to steric hindrance.

30


PhenylacetyleneCuI, Pd(PPh3)2Cl2, H2O Ph R1

HO R2

Ph

tBuOKDMSO

O

R1

R2Ph

Ph3 4

Ph R1

HO R2

Br

2

Et3N80 oC, overnight 60 oC, 1 h

2 R2R1

Me

Ph

(CH3)2CHCH2

Et2CHCH2

(CH3)2CHCH2

Me

Me

2a

2c

2d

2b

88

92

80

84

3 4

80

91

72

82

3a

3c

3d

3b

4a

4c

4d

4ba

a E/Z = 5 : 1

CyCH2

OPh

Ph

O

Ph

Ph

Ph

O Et

Et

Ph

Ph

OCy

Ph

Ph

yield (%) yield (%)

Table 2. Synthesis of 3-benzylidene-2,3-dihydrofurans 4

Ph R1

AllylO R2tBuLi

Ph R1

HO R2

O

R1

R2

5 6

7

Et2O−78 oC, 0.5 h

Ph R1

HO R2

Br2

Allyl BromideNaH, HMPA

THFreflux, 4 h

2 yield (%)

R2R1

Me

Ph

(CH3)2CHCH2

Et2CHCH2

(CH3)2CHCH2

Me

2a

2c

2b

84

82

87

5 6 yield (%)

93

84

97

5a

5c

5b

6a

6c

6b

7 yield (%)

7a

7c

7b

85

82

90

O

O

Ph

O Et

Et

HG' IIDCM

r.t., 2 h

Table 3. Synthesis of 2,5-dihydrofurans 7

31

Chapter 2

Compounds 6a-c were subsequently transformed into the corresponding 2,5-dihydrofurans 7a-c by treatment with 5 mol% Hoveyda-Grubbs second generation catalyst in dichloromethane (Table 3).[22] The reactions went fully selective to complete conversion and the high yields are probably only reduced because of the volatility of the products.

For the synthesis of cyclopentenols according to route C, butenylmagnesium bromide was added to 1a and its α-methyl (instead of α-bromo) analogue 1c (Scheme 3).[12] Enantioselectivities were modest, as expected. Subsequent debromination of 2e, following the procedure described earlier gave 5e in 83% isolated yield. Subsequent ring-closing metathesis resulted in 1-methyl-2-cyclopentenol 8a, in 40% yield, the moderate yield being solely due to its extreme volatility. Ring-closing of its congener 2f gave 8b in high yield.

Ph

HO

Ph

O

Br Br1a

5 mol%CuBr.SMe2

−78 oC, overnight

CH2=CH(CH2)2MgBr

5e (83%)2e (62%, ee 52%) 8a (40%)

OH6 mol% (S, RFe)-L

Ph

HO HG' IIDCM

r.t., 2 h

Ph Ph

HOPh Ph

O

Me Me1c 2f (65%, ee 44%) 8b (82%)

OHPh

HG' IIDCMr.t., 2 h

5 mol%CuBr.SMe2

−78 oC, overnight

CH2=CH(CH2)2MgBr

tBuLiEt2O

−78 oC, 0.5 h

6 mol% (S, RFe)-L

tBuOMe

tBuOMe

Scheme 3. Synthesis of 2-cyclopenten-1-ols 8

In order to determine the absolute configuration of this class of tertiary alcohols and ethers, we decided to prepare the corresponding α-hydroxy acids 9a-b from 2a-b and 2g (Table 4). This would lead to known, well-described compounds and in itself, this approach might serve as an alternative route to chiral enantioenriched α,α-disubstituted acids which are important building blocks in natural product synthesis and normally prepared from chiral pool precursors. Hydroxy acid 9a and 9b were obtained from 2a and 2b in good yield by ozonolysis in acetone. The sign of their optical rotation, in comparison with the literature data, showed unambiguously that the (S,RFe) enantiomer of ligand L produces the opposite stereochemistry for R1 = Me than for R1 = Ph, though both products are assigned the R configuration due to application of the CIP-rules. In the case of 2g, ozonolysis was followed by a bromoform reaction which provided 9b in low yield. For this substrate holds that the (S,RFe) enantiomer of L provides the same stereochemistry as for 2b (in both cases R1

32


is Ph), although the product (that is, the product of the 1,2 addition reaction, not the compound in Table 4) is designated S due to the CIP-rules.[23]

R1

X

HO

i. ozoneiii. NaOH(aq),then HCl(aq)

R1

HO

HOOC

Ph

HO

HOOC

2 9

9 yield (%)R1 / X (2)

Me / Br (2a)

Ph / Br (2b)

9a

9b

75

86

HO

HOOC

config. (2)

Ph / Me (2g) Ph

HO

HOOC9b

16

Acetone

iia. Br2, NaOH (4 M),

a Reactions ii is only for the synthesis of 9b from 2g.

Dioxane, 0 oC

−78 oC

R

S

R

Table 4. Synthesis of α-hydroxy acids 9

2.4 Conclusions

In summary, we have developed a novel approach for the enantioselective synthesis of chiral dihydrofurans with a tertiary oxygen-containing stereocenter and of tertiary cyclopentenols. Based on the catalytic asymmetric 1,2-addition of Grignard reagents, combined with a Sonogashira coupling/cyclization approach, or an alkylation followed by ring-closing metathesis, different kinds of dihydrofurans were prepared efficiently. With their absolute stereochemistry being established, the obtained compounds are versatile building blocks both for natural product synthesis and pharmaceuticals.

2.5 Experimental Section General remarks: 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded with CDCl3 as solvent. Chemical shifts were determined relative to the residual solvent peaks (CHCl3, δ = 7.26 ppm for 1H NMR, δ = 77.0 ppm for 13C NMR). The following abbreviations are used to indicate signal multiplicity: s, singlet; d, doublet; t, triplet; q, quartet; qi, quintet; m, multiplet; br, broad. Enantiomeric excesses were determined by chiral HPLC in comparison with racemic products. Racemic products were obtained by the same procedure as used for the enantioselective 1,2-addition, but omitting the ligand and CuBr•SMe2 (5 mol%) and

33

Chapter 2

only using Grignard reagent (1.2 eq) at 0 oC in Et2O. Regioselectivities were determined by 1H NMR. Optical rotations were measured with a 10 cm cell (c given in g/100 mL) at 20 °C. Thin-layer chromatography (TLC) was performed on TLC Silica gel. Flash chromatography was performed on silica gel. Mass spectra were obtained from high resolution (ESI+ or APCI+) mass spectrometer. Copper salt was purchased and used without further purification. All starting materials, Copper salt, ligand (S, RFe)-L and iBuMgBr (2 M in Et2O) were purchased and used without further purification. All Grignard reagents were prepared from the corresponding alkyl bromides and Mg activated with I2 in Et2O. For the stereochemistry of α-bromo enones 1, to our surprise, we could not find a rigorous proof of the stereochemistry of the so-obtained bromo enones in literature, despite the fact that these compounds have been reported several times. In this study the stereochemistry is determined unambiguously a posteriori. Upon catalytic asymmetric 1,2-addition using the bromo enones as substrate, the products are identical to the corresponding products obtained in the uncatalyzed addition with the same Grignard reagent, used to prepare the racemic reference material, so isomerisation during the Grignard addition can be excluded. After debromination of the resulting tertiary alcohols with tBuLi (vide infra), 1H-NMR clearly shows the presence of an E-carbon-carbon double bond. This determines the stereochemistry of the starting bromo enones being as shown. 1a-c: Starting materials were prepared following literature procedures[17]. General procedure for the preparation of α-brominated enones: To a suspension of oxone (100 mmol) in dichloromethane (250 mL) and water (50 mL) was added portion-wise sodium bromide (100 mmol) over 10 min at 0 oC, and the resulting mixture was stirred for an additional 30 min. Then the enone (50 mmol) was added over 20 min and stirred overnight, allowing the reaction to warm to room temperature. The mixture was poured into water and extracted with dichloromethane. The combined organic phases were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in dry dichloromethane (100 mL) and the solution was treated with dry triethylamine (60 mmol) added dropwise via syringe over 10 min under nitrogen. After the addition was complete, the mixture was left stirring under nitrogen at room temperature for an additional 16 h. Then the mixture was washed with HCl (aq, 2 M) and brine, dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatograpgy on silica gel (pentane/EtOAc = 60 : 1) to afford the α-bromo-enone as a light yellow oil.

34


Ph

ONaBr, oxone

DCM:H2O = 3:1Et3N

CH2Cl2Ph

O

Br

Ph O

Br+

1a S10 oC to r.t.

(Z)-3-Bromo-4-phenyl-3-buten-2-one (1a). 1a: yield 60%. 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1 H), 7.87–7.85 (m, 2 H), 7.44-7.43 (m, 3 H), 2.59 (s, 3 H); (E)-3-Bromo-4-phenyl-3-buten-2-one (S1). S1: yield 14%. 1H NMR (400 MHz, CDCl3) δ 7.35-7.34 (m, 3 H), 7.33 (s, 1 H), 7.27-7.34 (m, 2 H), 2.27 (s, 3 H).

Ph Ph

ONaBr, oxone

DCM:H2O = 3:1Et3N

CH2Cl2Ph Ph

O

Br

Ph

Ph

O

Br

+1b0 oC to r.t. S2

(Z)-2-Bromo-1,3-diphenyl-2-propen-1-one (1b). 1c: yield 78%. 1H NMR (400 MHz, CDCl3) δ 7.86-7.80 (m, 4 H), 7.70 (s, 1 H), 7.62-7.58 (m, 1 H), 7.49 (t, J = 7.6 Hz, 2 H), 7.45-7.42 (m, 3 H). (E)-2-Bromo-1,3-diphenyl-2-propen-1-one (S2). S2: yield 7%. 1H NMR (400 MHz, CDCl3) δ 8.01-7.97 (m, 2 H), 7.57-7.53 (m, 1 H), 7.45-7.40 (m, 2 H), 7.38 (s, 1 H), 7.19-7.16 (m, 5 H).

Grignard reagent

R1

HO R2

R1

O

X X

5 mol% CuBr.SMe2


1 2

6 mol% (S, RFe)-L

General procedure for the copper-catalysed 1,2-addition of Grignard reagents: A Schlenk tube equipped with septum and stirring bar was charged with CuBr·SMe2 (11.3 mg, 0.055 mmol, 5 mol%) and ligand (S, RFe)-L (39.2 mg, 0.066 mmol, 6 mol%). Under nitrogen, dry tBuOMe (8 mL) was added and the solution was stirred at room temperature for 15 min. Then the corresponding enone (1.10 mmol, in 5 mL tBuOMe) was added and the resulting solution was cooled to –78 oC. The corresponding Grignard reagent (1.32 mmol, 1.2 eq in Et2O) was diluted with tBuOMe (2 mL) and added to the reaction mixture over 3 h. The mixture was left to stir overnight at –78 oC. The reaction was quenched by the addition of MeOH and saturated aqueous NH4Cl and the mixture was warmed to room temperature, diluted with Et2O and the layers were separated. The aqueous layer was extracted with Et2O and the combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatograghy on silica gel (pentane/Et2O = 20 : 1) to afford alcohol 2.

HO

Br

35

Chapter 2

(R)-(Z)-2-Bromo-3,5-dimethyl-1-phenyl-1-hexen-3-ol (2a). Light yellow oil (265 mg, 85%). 86% ee determined by HPLC (Chiral AS-H column, heptane/iPrOH 90:10, 40 °C, 210 nm). Retention time: tmajor = 23.6 and tminor = 22.5 min. [α]D

20 = +10.0 (c 1.04, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.56-7.54 (m, 2 H), 7.39-7.35 (m, 2 H), 7.32-7.28 (m, 1 H), 7.24 (s, 1 H), 2.01 (br s, 1 H), 1.89 (dd, J = 14.0, 5.6 Hz, 1 H), 1.84-1.78 (m, 1 H), 1.65 (dd, J = 14.0, 6.0 Hz, 1 H), 1.58 (s, 3 H), 1.00 (2 x d, J = 6.4 Hz, 6 H); 13C NMR (100 MHz, CDCl3) δ 136.2, 134.7, 129.0, 128.1, 127.7, 126.3, 77.6, 49.1, 28.8, 24.5, 24.2.

HO

Br

(R)-(Z)-2-Bromo-5-methyl-1,3-diphenyl-1-hexen-3-ol (2b). Light yellow oil (239 mg, 63%). 98% ee determined by HPLC (Chiral OD-H column, heptane/iPrOH 99:1, 40 °C, 230 nm). Retention time: tmajor = 21.9 and tminor = 20.8 min. [α]20

D = –7.8 (c 0.49, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 7.6 Hz, 2 H), 7.56 (d, J = 7.6 Hz, 2 H), 7.43-7.32 (m, 7 H), 2.60 (s, 1 H), 2.23 (dd, J = 14.4, 5.6 Hz, 1 H), 2.14-2.09 (m, 1 H), 1.91-1.84 (m, 1 H), 1.08 (d, J = 6.8 Hz, 3 H), 0.89 (d, J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 144.4, 135.9, 134.9, 129.2, 128.3, 128.2, 128.0, 127.5, 126.0, 81.0, 48.0, 24.7, 24.5; HRMS (APCI) calcd. for C19H20Br [M – OH]+ 327.0743, found 327.0740.

HO

Br

(R)-(Z)-2-Bromo-5-ethyl-3-methyl-1-phenyl-1-hepten-3-ol (2c). Light yellow oil (281 mg, 82%). 94% ee determined by HPLC (Chiral AS-H column, heptane/iPrOH 90:10, 40 °C, 210 nm). Retention time: tmajor = 16.0 and tminor = 17.6 min. [α]20

D = +14.1 (c 1.05, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.2 Hz, 2 H), 7.39-7.35 (m, 2 H), 7.32-7.28 (m, 1 H), 7.22 (s, 1 H), 1.98 (br s, 1 H), 1.87-1.83 (m, 1 H), 1.69-1.64 (m, 1 H), 1.59 (s, 3 H), 1.46-1.35 (m, 5 H), 0.90-0.86 (m, 6 H); 13C NMR (100 MHz, CDCl3) δ 136.3, 135.0, 129.0, 128.1, 127.6, 126.3, 77.6, 43.8, 36.4, 28.6, 26.5, 10.8; HRMS (ESI): calcd for C16H22Br [M – OH]+ 293.0905, found: 293.0879.

HO

Br

Cy

36


(R)-(Z)-3-Bromo-1-cyclohexyl-2-methyl-4-phenyl-3-buten-2-ol (2d). Light yellow oil (249 mg, 70%). 75% ee determined by HPLC (Chiral AD-H column, heptane/iPrOH 98:2, 40 °C, 250 nm). Retention time: tmajor = 25.1 and tminor = 23.9 min. [α]20

D = +12.2 (c 0.64, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 7.2 Hz, 2 H), 7.41-7.38 (m, 2 H), 7.34-7.30 (m, 1 H), 7.27 (s, 1 H), 2.18 (s, 1 H), 1.91-1.83 (m, 3 H), 1.74-1.65 (m, 4 H), 1.61 (s, 3 H), 1.56-1.49 (m, 1 H), 1.35-1.17 (m, 3 H), 1.13-1.03 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ 136.4, 134.9, 129.1, 128.1, 127.7, 126.3, 77.7, 48.0, 34.9, 34.7, 33.9, 28.8, 26.5, 26.3; HRMS (ESI) calcd. for C17H22Br [M – OH]+ 305.0899, found 305.0901.

HO

Br

(R)-(Z)-2-Bromo-3-methyl-1-phenyl-1,6-heptadien-3-ol (2e). Light yellow oil (191 mg, 62%). 52% ee determined by HPLC (Chiral AD-H column, heptane/iPrOH 98:2, 40 °C, 260 nm). Retention time: tmajor = 15.9 and tminor = 14.1 min. [α]D

20 = +4.8 (c 0.58, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 7.9 Hz, 2 H), 7.45-7.27 (m, 3 H), 7.21 (s, 1 H), 5.88 (m, 1 H), 5.19-4.83 (m, 2 H), 2.21-2.10 (m, 3 H), 2.10-1.98 (m, 1 H), 1.82 (m, 1 H), 1.57 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 138.4, 136.1, 133.7, 129.0, 128.1, 127.8, 126.8, 115.1, 77.3, 39.7, 28.4, 27.9; HRMS (ESI): calcd for C14H16Br [M – OH]+ 263.0436, found: 263.0431.

HO

(S)-(E)-2-methyl-1,3-diphenyl-1,6-heptadien-3-ol (2f). Light yellow oil (199 mg, 65%). 44% ee determined by HPLC (Chiral AD-H column, heptane/iPrOH 98:2, 40 °C, 250 nm). Retention time: tmajor = 30.6 and tminor = 27.8 min. [α]20

D = –19.4 (c 0.95, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.6 Hz, 2 H), 7.38-7.22 (m, 8 H), 6.91 (s, 1 H), 5.97-5.87 (m, 1 H), 5.07 (d, J = 17.2 Hz, 1 H), 5.00 (d, J = 10.4 Hz, 1 H), 2.31-2.10 (m, 4 H), 1.97 (s, 1 H), 1.67 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 145.1, 141.7, 138.9, 138.1, 129.1, 128.2, 128.1, 127.1, 126.4, 125.9, 124.8, 114.8, 79.6, 38.0, 28.2, 15.1; HRMS (APCI) calcd. for C20H21 [M – OH]+ 261.1638, found 261.1639.

HO

(S)-(E)-2,5-Dimethyl-1,3-diphenyl-1-hexen-3-ol (2g). Light yellow oil (188 mg, 61%). 37% ee determined by HPLC (Chiral OD-H column, heptane/iPrOH 98:2,

37

Chapter 2

40 °C, 250 nm). Retention time: tmajor = 14.1 and tminor = 14.5 min. [α]20D = –16.3 (c

0.32, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.43-7.38 (m, 2 H), 7.25-7.08 (m, 8 H), 6.81 (s, 1 H), 2.03 (dd, J = 14.4, 5.6 Hz, 1 H), 1.93 (dd, J = 14.4, 5.6 Hz, 1 H), 1.75-1.70 (m, 2 H), 1.55 (d, J = 0.8 Hz, 3 H), 0.91 (d, J = 6.8 Hz, 3 H), 0.80 (d, J = 6.4 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 145.9, 142.4, 138.3, 129.1, 128.16, 128.11, 126.9, 126.3, 125.9, 124.4, 80.1, 47.2, 24.84, 24.83, 24.2, 15.4; HRMS (ESI) calcd. for C20H23 [M – OH]+ 263.1794, found 263.1800.

PhenylacetyleneCuI, Pd(PPh3)2Cl2, H2O

Et3N, 80 oC

Ph R1

HO R2

Ph

R1

HO R2

Br

2 3 General procedure for the Pd-catalyzed synthesis of enynes[18]: To a solution of 2 (0.50 mmol) in Et3N (5 mL) was added Pd(PPh3)2Cl2 (17.5 mg, 0.025 mmol, 5 mol%), CuI (9.5 mg, 0.050 mmol, 10 mol%), phenylacetylene (0.082 mL, 0.75 mmol, 1.5 eq) and H2O (0.045 mL, 2.5 mmol, 5 eq), and the resulting mixture was stirred at 80 oC. The solvent was evaporated under reduced pressure after the starting material had been consumed and the residue was diluted with Et2O and washed with saturated aqueous NH4Cl. The organic layer was separated, and the aqueous layer was extracted with Et2O. The combined organic layers were dried over Na2SO4, concentrated in vacuo, and the residue was purified by column chromatography on silica gel (pentane/Et2O = 12 : 1) to afford enyne 3.

HO

(R)-3-[(E)-benzylidene]-4,6-dimethyl-1-phenyl-1-heptyn-4-ol (3a). Light brown oil (134 mg, 88%). [α]20

D = +24.2 (c 0.48, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.0 Hz, 2 H), 7.51-7.49 (m, 2 H), 7.42-7.37 (m, 5 H), 7.32-7.29 (m, 1 H), 7.10 (s, 1 H), 1.99 (dd, J = 14.0, 5.6 Hz, 1 H), 1.92-1.86 (m, 1 H), 1.81 (br s, 1 H), 1.74-1.69 (m, 1 H), 1.60 (s, 3 H), 1.04-1.00 (m, 6 H); 13C NMR (100 MHz, CDCl3) δ 136.5, 131.8, 131.3, 128.9, 128.5, 128.4, 128.2, 128.0, 126.3, 123.4, 97.5, 88.1, 76.5, 50.1, 29.6, 24.6, 24.52, 24.50; HRMS (ESI) calcd. for C22H23 [M – OH]+ 287.1794, found 287.1795.

38


Ph

HO

(R)-3-[(E)-Benzylidene]-6-methyl-1,4-diphenyl-1-heptyn-4-ol (3b). Light brown oil (147 mg, 80%). [α]20

D = +28.0 (c 1.18, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.82-7.80 (m, 2 H), 7.55-7.52 (m, 2 H), 7.28-7.12 (m, 11 H), 7.05 (s, 1 H), 2.31 (dd, J = 14.4, 5.6 Hz, 1 H), 2.20 (br s, 1 H), 2.04 (dd, J = 14.4, 5.6 Hz, 1 H), 1.86-1.79 (m, 1 H), 0.96 (d, J = 6.8 Hz, 3 H), 0.86 (d, J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 145.9, 136.4, 132.9, 131.3, 129.0, 128.50, 128.46, 128.43, 128.22, 128.21, 128.1, 127.1, 125.9, 123.3, 98.1, 88.2, 79.5, 48.5, 24.9, 24.8, 24.5; HRMS (ESI) calcd. for C27H25 [M – OH]+ 349.1951, found 349.1948.

HO

(R)-3-[(E)-benzylidene]-6-ethyl-4-methyl-1-phenyl-1-octyn-4-ol (3c).[12c] Light brown oil (152 mg, 92%). [α]D

20 = +51.6 (c 1.80, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.02-7.84 (m, 2 H), 7.59-7.26 (m, 8 H), 7.07 (s, 1 H), 2.06-1.88 (m, 2 H), 1.78 (s, 1 H), 1.60 (s, 3 H), 1.54-1.28 (m, 5 H), 0.88 (t, J = 7.2 Hz, 3 H), 0.72 (t, J = 7.1 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 136.6, 131.8, 131.3, 129.2, 128.9, 128.44, 128.37, 128.2, 128.1, 127.9, 123.4, 97.4, 88.2, 76.5, 44.7, 36.3, 29.3, 26.9, 10.8; HRMS (ESI): calcd for C24H27 [M – OH]+ 315.2113, found: 315.2107.

HOCy

(R)-3-[(E)-benzylidene]-1-cyclohexyl-2-methyl-5-phenyl-4-pentyn-2-ol (3d). Light brown oil (145 mg, 84%). [α]20

D = +37.6 (c 1.20, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.84-7.82 (m, 2 H), 7.40-7.38 (m, 2 H), 7.32-7.25 (m, 5 H), 7.23-7.22 (m, 1 H), 6.98 (s, 1 H), 1.88-1.83 (m, 1 H), 1.75 (d, J = 12.4 Hz, 2 H), 1.67 (s, 1 H), 1.62-1.56 (m, 3 H), 1.53 (d, J = 1.2 Hz, 1 H), 1.49 (s, 3 H), 1.18-1.08 (m, 3 H), 1.07-0.92 (m, 3 H); 13C NMR (100 MHz, CDCl3) δ 136.6, 131.7, 131.3, 129.2, 128.8,

39

Chapter 2

128.43, 128.37, 128.2, 127.9, 123.4, 97.4, 88.1, 76.5, 48.9, 35.2, 34.8, 33.8, 29.5, 26.4, 26.3; HRMS (ESI) calcd. for C25H27 [M – OH]+ 327.2107, found 327.2107.

R1

HO R2

tBuOKDMSO, 60 oC

OR1R2

3 4

General procedure for cyclization of the enyne[14a, 19]:To a solution of 3 (0.25 mmol) in DMSO (4.0 mL) was added tBuOK (31 mg, 0.275 mmol, 1.1 eq) and the resulting mixture was stirred at 60 oC for 1 h. The mixture was poured into water (50 mL) and extracted with Et2O. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (pentane) to afford 4.

O

(R)-3-[(E)-Benzylidene]-2-isobutyl-2-methyl-5-phenyl-2,3-dihydrofuran (4a). Yellow oil (61 mg, 80%). [α]20

D = +27.6 (c 2.05, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.63 (dd, J = 8.4, 1.6 Hz, 2 H), 7.32-7.24 (m, 7 H), 7.10-7.05 (m, 1 H), 6.55 (s, 1 H), 5.62 (s, 1 H), 1.81-1.71 (m, 2 H), 1.62-1.57 (m, 1 H), 1.41 (s, 3 H), 0.86 (dd, J = 11.2, 6.4 Hz, 6 H); 13C NMR (100 MHz, CDCl3) δ 163.0, 150.5, 139.1, 130.8, 129.3, 128.49, 128.45, 127.5, 125.7, 125.5, 111.6, 98.7, 91.9, 50.1, 28.2, 24.6, 24.5, 24.3; HRMS (APCI) calcd. for C22H25O [M + H]+ 305.1900, found 305.1905.

O

Ph

(Z/E = 5/1)

4b. Yellow oil (75 mg, 82%, Z/E = 5/1). [α]20D = +41.1 (c 0.94, CHCl3); HRMS (ESI)

calcd. for C27H27O [M + H]+ 367.2056, found 367.2055; (R)-3-[(E)-Benzylidene]-2-isobutyl-1,5-diphenyl-2,3-dihydrofuran [4b(E)]. 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 7.2, 1.2 Hz, 2 H), 7.59-7.57 (m, 2 H), 40


7.49-7.37 (m, 10 H), 7.22-7.18 (m, 1 H), 6.73 (s, 1 H), 6.00 (s, 1 H), 2.39-2.34 (m, 1 H), 2.18-2.12 (m, 1 H), 2.02-1.96 (m, 1 H), 1.08-1.06 (m, 3 H), 1.02 (dd, J = 6.8, 1.6 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 163.2, 149.5, 144.3, 138.7, 130.4, 129.5, 128.6, 128.5, 128.4, 127.8, 127.3, 125.8, 125.5, 124.8, 114.3, 98.9, 94.1, 49.4, 29.8, 24.9, 24.6. (R)-3-[(Z)-Benzylidene]-2-isobutyl-1,5-diphenyl-2,3-dihydrofuran [4b(Z)]. 1H NMR (400 MHz, CDCl3) δ 7.70-7.68 (m, 0.40H), 7.63-7.61 (m, 0.40 H), 7.49-7.37 (m, 0.20 H), 7.33-7.29 (m, 1.00 H), 7.12-7.11 (m, 0.60 H), 6.95-6.93 (m, 0.40 H), 6.61 (s, 0.20 H), 6.27 (s, 0.20 H), 2.39-2.34 (m, 0.40 H), 2.02-1.96 (m, 0.20 H), 1.08-1.02 (m, 1.20 H); 13C NMR (100 MHz, CDCl3) δ 160.0, 148.9, 143.6, 137.1, 130.5, 129.1, 128.5, 128.0, 127.8, 126.4, 125.9, 125.6, 117.2, 105.9, 93.5, 42.9, 29.4, 25.0, 24.9.

O

(R)-3-[(E)-Benzylidene]-2-(2-ethyl-butyl)-2-methyl-5-phenyl-2,3-dihydrofuran (4c).[12c] Yellow oil (76 mg, 91%). [α]D

20 = +37.7 (c 0.90, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.82-7.65 (m, 2 H), 7.37 (m, 7 H), 7.17 (t, J = 7.1 Hz, 1 H), 6.64 (s, 1 H), 5.73 (s, 1 H), 1.76 (m, 2 H), 1.50 (s, 3 H), 1.42-1.24 (m, 5 H), 0.80 (t, J = 7.1 Hz, 6 H); 13C NMR (100 MHz, CDCl3) δ 163.0, 150.5, 139.1, 130.7, 129.3, 128.5, 128.4, 127.5, 125.7, 125.4, 111.6, 98.7, 92.0, 44.5, 36.4, 28.1, 26.8, 26.5, 10.9.

OCy

(R)-3-[(E)-Benzylidene]-2-cyclohexyl-2-methyl-5-phenyl-2,3-dihydrofuran (4d). Yellow oil (62 mg, 72%). [α]20

D = +41.4 (c 1.07, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 6.8 Hz, 2 H), 7.32-7.24 (m, 7 H), 7.08 (t, J = 7.2 Hz, 1 H), 6.54 (s, 1 H), 5.62 (s, 1 H), 1.77-1.71 (m, 1 H), 1.68 (d, J = 5.6 Hz, 1 H), 1.65-1.60 (m, 1 H), 1.58-1.49 (m, 4 H), 1.40 (s, 3 H), 1.18-0.88 (m, 6 H); 13C NMR (100 MHz, CDCl3) δ 163.0, 150.7, 139.1, 130.8, 129.3, 128.50, 128.45, 127.5, 125.7, 125.5, 111.6, 98.6, 91.9, 48.8, 34.8, 34.7, 33.9, 28.1, 26.44, 26.39; HRMS (ESI) calcd. for C25H29O [M + H]+ 345.2213, found 345.2211.

41

Chapter 2

R1

HO R2

BrtBuLi

Et2O, −78 oCR1

HO R2

2 5

General procedure for the preparation of α,β-unsaturated alcohols[20]: To a solution of 2 (0.55 mmol) in Et2O (5.0 mL) was slowly added a solution of tBuLi (1.65 mmol, 3.0 eq, 1.7 M in pentane) under nitrogen at –78 oC, and the resulting mixture was stirred at this temperature for 30 min. Then the reaction was quenched with MeOH and saturated aqueous NH4Cl, and the mixture was warmed to room temperature, diluted with Et2O and the layers were separated. The aqueous layer was extracted with Et2O and the combined organic phase was dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (pentane/Et2O = 20 : 1) to afford alcohol 5.

HO

(R)-(E)-3,5-Dimethyl-1-phenyl-1-hexen-3-ol (5a). Light yellow oil (94 mg, 84%). [α]20

D = +32.4 (c 0.53, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 7.6 Hz, 2 H), 7.35-7.31 (m, 2 H), 7.24 (t, J = 7.2 Hz, 1 H), 6.61(d, J = 16.0 Hz, 1 H), 6.31 (d, J = 16.0 Hz, 1 H), 1.84-1.79 (m, 1 H), 1.62 (br s, 1 H), 1.59 (d, J = 6.0 Hz, 2 H), 1.40 (s, 3 H), 1.00-0.96 (m, 6 H); 13C NMR (100 MHz, CDCl3) δ 137.3, 137.2, 128.6, 127.3, 126.5, 126.4, 73.7, 51.6, 29.2, 24.63, 24.59, 24.45; HRMS (ESI) calcd. for C14H19 [M – OH]+ 187.1481, found 187.1480.

HO

(S)-(E)-5-methyl-1,3-diphenyl-1-hexen-3-ol (5b). Light yellow oil (127 mg, 87%). [α]20

D = +18.8 (c 0.49, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.6 Hz, 2 H), 7.44-7.25 (m, 8 H), 6.70 (d, J = 16.0 Hz, 1 H), 6.60 (d, J = 16.0 Hz, 1 H), 2.06-2.01 (m, 1 H), 2.01 (br s, 1 H), 1.95 (dd, J = 14.4, 6.0 Hz, 1 H), 1.84-1.78 (m, 1 H), 1.00 (d, J = 6.8 Hz, 3 H), 0.90 (d, J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 146.3, 137.0, 136.6, 128.6, 128.3, 127.5, 127.4, 126.8, 126.6, 125.5, 77.5, 51.3, 24.6, 24.3; HRMS (APCI) calcd. for C19H21 [M – OH]+ 249.1638, found 249.1634.

HO

42


(R)-(E)-5-Ethyl-3-methyl-1-phenyl-1-hepten-3-ol (5c). Light yellow oil (105 mg, 82%). [α]20

D = +38.7 (c 0.45, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 7.2 Hz, 2 H), 7.35-7.31 (m, 2 H), 7.25-7.22 (m, 1 H), 6.60 (d, J = 16.0 Hz, 1 H), 6.30 (d, J = 16.0 Hz, 1 H), 1.61-1.58 (m, 3 H), 1.42 (s, 3 H), 1.42-1.34 (m, 5 H), 0.89-0.83 (m, 6 H); 13C NMR (100 MHz, CDCl3) δ 137.3, 137.2, 128.6, 127.3, 126.5, 126.4, 73.8, 46.3, 36.3, 29.0, 27.0, 26.9, 10.8; HRMS (ESI) calcd. for C16H23 [M – OH]+ 215.1794, found 215.1793.

HO

(R)-(E)-3-methyl-1-phenyl-1,6-heptadien-3-ol (5e). Light yellow oil (92 mg, 83%). [α]20

D = +9.1 (c 1.95, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.40-7.22 (m, 5 H), 6.60 (d, J = 16.0 Hz, 1 H), 6.28 (d, J = 16.0 Hz, 1 H), 5.91-5.81 (m, 1 H), 5.05 (d, J = 17.6 Hz, 1 H), 4.97 (d, J = 10.4 Hz, 1 H), 2.20-2.14 (m, 2 H), 1.76-1.72 (m, 3 H), 1.41 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 138.8, 136.9, 136.4, 128.6, 127.4, 127.3, 126.4, 114.6, 73.3, 41.7, 28.6, 28.4; HRMS (ESI) calcd. for C14H17 [M – OH]+ 185.1325, found 185.1322.

Allyl BromideNaH, HMPATHF, reflux

R1

AllylO R2

R1

HO R2

5 6

General procedure for the allylation of the α,β-unsaturated tertiairy alcohols[21]: To a solution of 5 (0.35 mmol) in dry THF (5.0 mL) was added NaH (21.0 mg, 0.53 mmol, 1.5 eq, 60% oil dispersion) under nitrogen, and the resulting mixture was stirred under reflux for 2 h. Then HMPA (0.18 mL, 1.05 mmol, 3.0 eq) was added to the mixture followed by allyl bromide (0.046 mL, 0.53 mmol, 1.5 eq). After the addition, the mixture was stirred under reflux for another 2 h. The reaction mixture was allowed to cool to room temperature, quenched with 2 M aqueous HCl, and extracted with Et2O. The combined organic phases were washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatograghy on silica gel (pentane/Et2O = 100 : 1) to afford diene 6.

O

(R)-(E)-3-Allyloxy-3,5-dimethyl-1-phenyl-1-hexene (6a). Light yellow oil (80 mg, 93%). [α]20

D = –15.4 (c 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 7.2 43

Chapter 2

Hz, 2 H), 7.35-7.31 (m, 2 H), 7.26-7.22 (m, 1 H), 6.50 (d, J = 16.4 Hz, 1 H), 6.20 (d, J = 16.4 Hz, 1 H), 5.99-5.89 (m, 1 H), 5.33-5.28 (m, 1 H), 5.14-5.10 (m, 1 H), 3.91 (d, J = 5.2 Hz, 2 H), 1.87-1.80 (m, 1 H), 1.63-1.60 (m, 2 H), 1.41 (s, 3 H), 0.98-0.96 (2 x d J = 2.2 Hz, 6 H); 13C NMR (100 MHz, CDCl3) δ 137.1, 136.1, 135.5, 129.0, 128.6, 127.4, 126.4, 115.4, 78.0, 63.5, 49.7, 24.7, 24.6, 24.1, 22.9; HRMS (ESI) calcd. for C14H19 [M – OAllyl]+ 187.1481, found 187.1480.

O

(S)-(E)-3-allyloxy-5-methyl-1,3-diphenyl-1-hexene (6b). Light yellow oil (104 mg, 97%). [α]20

D = –5.5 (c 0.66, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 7.2 Hz, 2 H), 7.46 (d, J = 7.6 Hz, 2 H), 7.41-7.35 (m, 4 H), 7.32-7.26 (m, 2 H), 6.75 (d, J = 16.4 Hz, 1 H), 6.42 (d, J = 16.4 Hz, 1 H), 6.09-5.97 (m, 1 H), 5.44 (dd, J = 17.2, 1.2 Hz, 1 H), 5.21 (d, J = 10.8 Hz, 1 H), 3.94-3.86 (m, 2 H), 2.13-2.02 (m, 2 H), 1.80-1.72 (m, 1 H), 0.91 (dd, J = 50.0, 6.4 Hz, 6 H); 13C NMR (100 MHz, CDCl3) δ 143.9, 137.1, 135.6, 134.2, 129.5, 128.6, 128.1, 127.6, 126.9, 126.5, 115.3, 81.8, 63.9, 46.5, 24.5, 24.4, 23.8; HRMS (APCI) calcd. for C19H21 [M – OAllyl]+ 249.1638, found 249.1639.

O

(R)-(E)-3-Allyloxy-5-ethyl-3-methyl-1-phenyl-1-heptene (6c). Light yellow oil (80 mg, 84%). [α]20

D = –24.1 (c 0.49, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 7.2 Hz, 2 H), 7.36-7.33 (m, 2 H), 7.27-7.24 (m, 1 H), 6.50 (d, J = 16.4 Hz, 1 H), 6.21 (d, J = 16.4 Hz, 1 H), 5.99-5.92 (m, 1 H), 5.35-5.30 (m, 1 H), 5.14 (dd, J = 10.4, 1.6 Hz, 1 H), 3.93 (d, J = 5.2 Hz, 2 H), 1.64-1.62 (m, 2 H), 1.42 (s, 3 H), 1.42-1.36 (m, 4 H), 1.29 (s, 1 H), 0.89-0.83 (m, 6 H); 13C NMR (100 MHz, CDCl3) δ 137.1, 136.2, 135.4, 129.2, 128.6, 127.4, 126.4, 115.2, 78.3, 63.6, 45.0, 36.0, 26.9, 26.8, 22.5, 10.82, 10.76; HRMS (ESI) calcd. for C16H23 [M – OAllyl]+ 215.1794, found 215.1795.

R1

R'O R2

Hoveyda-Grubbs' II O

R1

R2

CH2Cl2, r.t.6 or 5e or 2f 7 or 8R' = Allyl or H

General procedure for the ring-closing metathesis of the dienes[22]: To a solution of diene (0.29 mmol) in dichloromethane (5 mL) was added Hoveyda-Grubbs’ II catalyst (9.4 mg, 0.015 mmol, 0.05 eq) and the resulting mixture was stirred under

44


nitrogen at room temperature for 2 h. Then the mixture was concentrated in vacuo, and the crude product was purified by column chromatography (pentane/Et2O = 200 : 1) to afford five-membered ring 7 or 8.

O

(R)-2-Isobutyl-2-methyl-2,5-dihydro-furan (7a). Colorless oil (35 mg, 85%). [α]20

D

= –7.5 (c 1.13, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.71 (d, J = 6.0 Hz, 1 H), 5.64-5.63 (m, 1 H), 4.58-4.51 (m, 2 H), 1.63-1.55 (m, 1 H), 1.50-1.37 (m, 2 H), 1.19 (s, 3 H), 0.84-0.81 (m, 6 H); 13C NMR (100 MHz, CDCl3) δ 134.4, 124.9, 90.4, 74.1, 49.4, 34.1, 24.6, 24.4, 24.3; HRMS (ESI) calcd. for C9H17O [M + H]+ 141.1274, found 141.1276.

O

(S)-2-Isobutyl-2-phenyl-2,5-dihydro-furan (7b). Colorless oil (53 mg, 90%). [α]20D

= –94.0 (c 1.08, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 7.6 Hz, 2 H), 7.35-7.32 (m, 2 H), 7.26-7.21 (m, 1 H), 6.04-6.02 (m, 1 H), 5.86 (d, J = 6.0 Hz, 1 H), 4.82-4.78 (m, 1 H), 4.73-4.69 (m, 1 H), 1.89 (dd, J = 14.4, 5.6 Hz, 1 H), 1.80 (dd, J = 14.4, 6.0 Hz, 1 H), 1.73-1.67 (m, 1 H), 0.94 (d, J = 6.8 Hz, 3 H), 0.88 (d, J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 146.5, 133.4, 128.2, 126.4, 125.2, 124.7, 93.8, 74.7, 50.1, 24.6, 24.32, 24.29; HRMS (APCI) calcd. for C14H19O [M + H]+ 203.1430, found 203.1427.

O

(R)-2-(2-Ethyl-butyl)-2-methyl-2,5-dihydro-furan (7c). Colorless oil (40 mg, 82%). [α]20

D = –5.7 (c 0.53, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.78 (d, J = 6.4 Hz, 1 H), 5.69 (d, J = 6.4 Hz, 1 H), 4.64-4.57 (m, 2 H), 1.57-1.52 (m, 1 H), 1.45 (dd, J = 14.4, 4.8 Hz, 1 H), 1.39-1.25 (m, 5 H), 1.26 (s, 3 H), 0.85-0.79 (m, 6 H); 13C NMR (100 MHz, CDCl3) δ 134.4, 125.0, 90.5, 74.3, 44.0, 36.7, 27.1, 26.8, 26.7, 10.82, 10.80; HRMS (ESI) calcd. for C11H21O [M + H]+ 169.1587, found 169.1583.

OH (R)-1-Methyl-2-cyclopenten-1-ol (8a)[15]. Colorless oil (11 mg, 40%)*. [α]20

D = +16.8 (c 0.25, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.83-5.81 (m, 1 H), 5.70-5.69 (m, 1 H), 2.51-2.45 (m, 1 H), 2.35-2.29 (m, 1 H), 1.98-1.89 (m, 2 H), 1.68 (br s, 1 H), 1.38 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 137.9, 132.7, 83.4, 39.7, 31.1, 27.4; HRMS (ESI) calcd. for C6H9 [M – OH]+ 81.0699, found 81.0695.

45

Chapter 2

* This reaction gave full conversion to the desired product, but the yield was diminished due to its volatility.

OH

(S)-2-Methyl-1-phenyl-2-cyclopenten-1-ol (8b). Colorless oil (44 mg, 87%). [α]20D

= +33.2 (c 0.85, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.32-7.24 (m, 4 H), 7.18-7.15 (m, 1 H), 5.63 (d, J = 1.6 Hz, 1 H), 2.44-2.37 (m, 1 H), 2.33-2.25 (m, 2 H), 2.20-2.12 (m, 1 H), 1.86 (s, 1 H), 1.48-1.47 (m, 3 H); 13C NMR (100 MHz, CDCl3) δ 146.0, 144.0, 128.7, 128.1, 126.5, 124.8, 87.9, 43.4, 29.4, 11.9; HRMS (ESI) calcd. for C12H13 [M – OH]+ 157.1012, found 157.1008. α-hydroxy acids 9: 9a-b and S9c were prepared from 2a-b and 2g following the literature procedure,[24] and S9c afforded 9b following the procedure of literature[23c]. The absolute configurations of 9a-b were based on specific rotations reported in literatures.[23a, 23b]

R1

Br

HO i. ozoneacetone, −78 oCii. NaOH (aq)iii. HCl (aq)

R1

HO

HOOC2 9

To a stirred solution of 2 (0.28 mmol) in acetone (7 mL) at –78 oC a stream of ozone was bubbled until a blue color persisted in the solution. Subsequently, nitrogen was bubbled through the solution until the blue color had disappeared. Dimethyl sulfide (0.5 mL) and water (1 mL) were added and the mixture was allowed to stir at room temperature for 1 h. The solvent was evaporated and the residue was extracted with ether. For the products of 2a-b, the combined organic phases were extracted with 5% NaOHaq, and the combined alkaline phases were acidified with 10% HCl. The resulted solution was extracted with ether. The combined organic phases were dried over MgSO4 and evaporated to afford 9a-b as colorless crystals. For the products of 2g, the combined organic phases were dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography (pentane/Et2O = 50 : 1) to afford S9c as a colorless oil.

HO

HOOC

(R)-2-Hydroxy-2,4-dimethyl-pentanoic acid (9a). yield 75%. [α]20D = –10.4 (c 0.56,

CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.83 – 1.75 (m, 2 H), 1.69 – 1.66 (m, 1 H), 46


1.47 (s, 3 H), 0.96 (d, J = 5.2 Hz), 0.89 (d, J = 5.6 Hz); 13C NMR (100 MHz, CDCl3) δ 180.0, 72.0, 45.6, 24.9, 21.8, 21.7, 20.5.

HO

HOOC

(R)-2-Hydroxy-4-methyl-2-phenyl-pentanoic acid (9b). yield 86%. [α]20D = –10.0

(c 1.16, CHCl3), [α]20D –72.4 (c 1.16, EtOH); 1H NMR (400 MHz, CDCl3) δ 7.29 -

7.27 (m, 2 H), 7.01 – 6.92 (m, 3 H), 1.81 – 1.68 (m, 2 H), 1.50 (s, 1 H), 0.61 (d, J = 8.0 Hz, 3 H), 0.56 (d, J = 4.0 Hz). The absolute configuration was based on specific rotation reported in the literature: 9b [α]22

D = –16.7 (c 0.83, EtOH).

HOO

(R)-3-Hydroxy-5-methyl-3-phenyl-2-hexanone (S9c). Colorless oil (46 mg, 79%). [α]20

D = –16.9 (c 0.43, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.42-7.39 (m, 2 H), 7.30-7.26 (m, 2 H), 7.23-7.19 (m, 1 H), 4.46 (s, 1 H), 2.13-2.06 (m, 2 H), 2.04 (s, 3 H), 1.79-1.72 (m, 1 H), 0.90-0.85 (m, 6 H); 13C NMR (100 MHz, CDCl3) δ 209.9, 141.7, 128.5, 127.8, 126.1, 82.8, 44.9, 24.6, 24.2, 23.8, 23.7; HRMS (ESI) calcd. for C13H17O [M – OH]+ 189.1274, found 189.1268.

PhO

HO Br2, NaOH (4 M)Dioxane

0 oC HOOC Ph

HO

S9c 9b To a solution of S9c (40 mg, 0.19 mmol) in dioxane (3 mL) was added NaOH (10 mL, 4 M). The resulting suspension was stirred vigorously at 0 oC while bromine (0.030 mL, 0.57 mmol) was added slowly. The resulting mixture was stirred for another 5 min after the addition was finished. Then the mixture was washed with ether. The aqueous layer was acidified with 1 M HCl and extracted with ether. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The residue was further purified by chromatography on silica gel (EtOAc : pentane = 6 : 1/ 1% AcOH) to afford 9b (8 mg, 20 %) which showed to be identical to the ozonolysis product of 2b. [α]20

D = –7.8 (c 0.25, CHCl3). 2.6 References

[1] a) B. M. Fraga, Nat. Prod. Rep. 1992, 9, 217-241; b) A. T. Merritt, S. V. Ley, Nat. Prod. Rep.

1992, 9, 243-287; c) B. M. Trost, M. R. Machacek, B. D. Faulk, J. Am. Chem. Soc. 2006, 128,

6745-6754; d) M. M. Faul, B. E. Huff, Chem. Rev. 2000, 100, 2407-2473; e) E. J. Kang, E. 47

Chapter 2

Lee, Chem. Rev. 2005, 105, 4348-4378; f) Y. J. Shang, K. Ju, X. W. He, J. S. Hu, S. Y. Yu,

M. Zhang, K. S. Liao, L. F. Wang, P. Zhang, J. Org. Chem. 2010, 75, 5743-5745.

[2] C. M. Horiuchi, J. W. Medlin, Langmuir 2010, 26, 13320-13332.

[3] a) J. R. Monnier, J. W. Medlin, Y. J. Kuo, Appl. Catal. a-Gen. 2000, 194, 463-474; b) F.

Billes, H. Bohlig, M. Ackermann, M. Kudra, J. Mol. Struc-Theochem. 2004, 672, 1-16.

[4] A. L. Hall, R. G. Fayter, Jr., US Patent 1985, 4, 522, 950.

[5] a) N. O. Brace, J. Am. Chem. Soc. 1955, 77, 4157-4158; b) F. Ozawa, A. Kubo, T. Hayashi, J.

Am. Chem. Soc. 1991, 113, 1417-1419; c) Y. Yamamoto, R. Takuma, T. Hotta, K. Yamashita,

J. Org. Chem. 2009, 74, 4324-4328.

[6] a) H. C. Shen, Tetrahedron 2008, 64, 3885-3903; b) N. T. Patil, Y. Yamamoto, Chem. Rev.

2008, 108, 3395-3442.

[7] B. M. Trost, H. C. Shen, L. Dong, J. P. Surivet, C. Sylvain, J. Am. Chem. Soc. 2004, 126,

11966-11983.

[8] K. Asano, S. Matsubara, J. Am. Chem. Soc. 2011, 133, 16711-16713.

[9] a) S. Hatakeyama, K. Sakurai, H. Numata, N. Ochi, S. Takano, J. Am. Chem. Soc. 1988, 110,

5201-5203; b) T. W. Funk, Org. Lett. 2009, 11, 4998-5001.

[10] S. E. Denmark, M. T. Burk, Org. Lett. 2012, 14, 256-259.

[11] a) D. S. La, J. B. Alexander, D. R. Cefalo, D. D. Graf, A. H. Hoveyda, R. R. Schrock, J. Am.

Chem. Soc. 1998, 120, 9720-9721; b) T. W. Funk, J. M. Berlin, R. H. Grubbs, J. Am. Chem.

Soc. 2006, 128, 1840-1846.

[12] a) A. V. R. Madduri, S. R. Harutyunyan, A. J. Minnaard, Angew. Chem. Int. Ed. 2012, 51,

3164-3167; b) A. V. R. Madduri, A. J. Minnaard, S. R. Harutyunyan, Chem. Commun. 2012,

48, 1478-1480; c) A. V. R. Madduri, A. J. Minnaard, S. R. Harutyunyan, Org. Biomol. Chem.

2012, 10, 2878-2884.

[13] An alternative approach uses the stereospecific conversion of secondary alcohols into tertiary

alcohols, see: A. P. Pulis, V. K. Aggarwal, J. Am. Chem. Soc. 2012, 134, 7570-7574.

[14] a) S. Takano, Y. Iwabuchi, K. Ogasawara, J. Chem. Soc. Chem. Comm. 1989, 1371-1372; b)

R. Guo, K.-N. Li, L.-Z. Gong, Org. Biomol. Chem. 2013, 11, 6707-6712; c) B. Alcaide, P.

Almendros, T. Martínez del Campo, M. R. Torres, J. Org. Chem. 2013, 78, 8956-8965; d)

Z.-Y. Han, D.-F. Chen, Y.-Y. Wang, R. Guo, P.-S. Wang, C. Wang, L.-Z. Gong, J. Am.

Chem. Soc. 2012, 134, 6532-6535; e) A. S. K. Hashmi, M. Ghanbari, M. Rudolph, F.

Rominger, Chem. Eur. J. 2012, 18, 8113-8119; f) R. Kotikalapudi, K. C. Kumara Swamy,


[15] I. C. Chiu, H. Kohn, J. Org. Chem. 1983, 48, 2857-2866.

[16] a) D. Bek, H. Balcar, N. Zilkova, A. Zukal, M. Horacek, J. Cejka, Acs. Catal. 2011, 1,

709-718; b) H. A. Meylemans, R. L. Quintana, B. R. Goldsmith, B. G. Harvey,

Chemsuschem 2011, 4, 465-469.

48


[17] a) J. C. Banks, D. Van Mele, C. G. Frost, Tetrahedron Lett. 2006, 47, 2863-2866; b) S.-M.

Lu, C. Bolm, Angew. Chem. Int. Edit. 2008, 47, 8920-8923; c) J. A. Murphy, K. A. Scott, R.

S. Sinclair, C. G. Martin, A. R. Kennedy, N. Lewis, J. Chem. Soc. Perkin Trans 1. 2000,

2395-2408.

[18] J. Y. Yang, C. Y. Wang, X. Xie, H. F. Li, E. D. Li, Y. Z. Li, Org. Biomol. Chem. 2011, 9,

1342-1346.

[19] A. Funayama, T. Satoh, M. Miura, J. Am. Chem. Soc. 2005, 127, 15354-15355.

[20] V. G. Nenajdenko, K. I. Smolko, E. S. Balenkova, Tetrahedron: Asymmetr 2001, 12,

1259-1266.

[21] J. M. Reuter, R. G. Salomon, J. Org. Chem. 1977, 42, 3360-3364.

[22] B. C. Maity, V. M. Swamy, A. Sarkar, Tetrahedron Lett. 2001, 42, 4373-4376.

[23] a) D. Basavaiah, S. Pandiaraju, M. Bakthadoss, K. Muthukumaran, Tetrahedron: Asymmetr

1996, 7, 997-1000; b) F. Effenberger, B. Horsch, F. Weingart, T. Ziegler, S. Kuhner,

Tetrahedron Lett. 1991, 32, 2605-2608; c) G. A. Moniz, J. L. Wood, J. Am. Chem. Soc. 2001,

123, 5095-5097.

[24] T. Satoh, K. Onda, K. Yamakawa, J. Org. Chem. 1991, 56, 4129-4134.

49

Chapter 2

50

Chapter 3

Total Synthesis of (R,R,R)-γ-Tocopherol through Cu-Catalyzed

Asymmetric 1,2-Addition In this chapter, the total synthesis of (R, R, R)-γ-tocopherol is described. Starting from 2,3-dimethylhydroquinone and phytol, (R, R, R)-γ-tocopherol was synthesized in 36% yield over 12 steps (longest linear sequence), based on the copper (I) catalysed 1,2-addition of Grignard reagents to ketones. Parts of this chapter have been published: Z. Wu, S. R. Harutyunyan, A. J. Minnaard, Chem. Eur. J. 2014, 20, 14250-14255.

Chapter 3

3.1 Introduction Vitamins are essential food ingredients for humans and in feed for animal

husbandry. The most important fat-soluble antioxidant, vitamin E, was first reported about one century ago,[1] and is of particular industrial interest as a food and feed additive.[2] Although formally vitamin E comprises a family of tocopherols and tocotrienols with a chroman core (Figure 1), in practice the term is synonymous with α-tocopherol or its acetate as it is by far the most dominant member.[2a, 3] All-rac-α-tocopherol is produced on a scale of more than 30,000 ton per year.[4] To meet this huge demand of vitamin E, the industrial synthesis is accomplished by the condensation of trimethylhydroquinone (9) and chemically produced isophytol 10. (Scheme 1)[5]

HOR1

R2 O

R1 R2 tocopherol

-Me -Me

-Me

-Me-H

-H-H -H

α- (1)β- (2)γ- (3)δ- (4)

HOR1

R2 O

Tocopherols 1-4

R1 R2 tocotrienol

-Me -Me

-Me

-Me-H

-H-H -H

α- (5)β- (6)γ- (7)δ- (8)Tocotrienols 5-8

1

23

456

78

1

23

456

87

Figure 1. Vitamin E

The naturally occurring (R,R,R)-tocopherols are biologically the most active,[3, 6] and in particular the stereochemistry at C2 is important.[7] Consequently, the asymmetric synthesis of 1, and especially the stereoselective synthesis of the chroman core,[8] has been the topic of intense research, which has been discussed in several reviews.[9] A selection of the more recent approaches in asymmetric catalysis is depicted in Scheme 2.[10] A very recent shoot of this tree is the application of the Ni-catalyzed conjugate addition of methyl organometallics to a 2-alkyl-4-chromenone core providing the racemic product unfortunately. Later, the high (2R)-stereoselectivity was achieved by the same group via an asymmetric 1,4-addition of AlMe3 to the activated 2-substituted chromenone in the presence of a chiral Cu(I)-phosphoramidite complex as a catalyst.[11]

γ-Tocopherol is another major member of the vitamin E family and the main

52

Total Synthesis of (R,R,R)-γ-Tocopherol

vitamin E in US diet. Although α-tocopherol has the highest vitamin E activity,[7] γ-tocopherol has an unsubstituted aromatic position and therefore can trap electrophilic mutagens, such as nitronium ions,[12] more efficiently.[13] This has elicited further research focused on γ-tocopherol.[14]

HO

OH HO

Trimethylquinone 9 Isophytol 10

cat.

(all-rac)-α-tocopherol

+HO

O

Scheme 1. Synthesis of all-rac-α-tocopherol

BnO

OH

O

O

BnOO

Tietze et al., 2007

EtOH2CO

OCH2OEt

OO

O

HO

OH

Breit et al, 2007OH

MeO

RO

O

MeO

R

OH

Woggon et al, 2008

MeO

O

OHC

R O

MeO

R

Woggon et al, 2010

MeO

OH

CHOR

OHC

O

MeOO OH

R

Woggon et al, 2008

O

OHORO

O O

HO

OR

O

Barrier et al, 1990

Scheme 2. Recently reported strategies on the stereoselective construction of the 2R-chroman core in the synthesis of 1[15]

Compared to α-tocopherol, synthesis efforts on (R,R,R)-γ-tocopherol 3 have been

particularly scarce, and the first total synthesis of γ-tocopherol was reported in 1994 with a copper mediated coupling methodology.[9a, 9d][16] In 1997, Habicher et al. prepared γ-tocopherol by photodecarboxylation of γ-tocopherol-5-carboxylic acid, in turn derived from α-tocopherol.[17] Based on this aryl demethylation approach of α-tocopherol, Salvadori et al. reported the preparation of labeled and unlabeled (R,R,R)-γ-tocopherol 3.[18] No catalytic asymmetric synthesis of 3 has been reported. 3.2 Retrosynthetic strategy for (R,R,R)-γ-tocopherol 3

In 2012, we reported the enantioselective 1,2-addition of Grignard reagents to α,β-unsaturated ketones applying a copper/Josiphos-type catalyst (Scheme 3).[19] This

53

Chapter 3

leads to chiral enantioenriched tertiary allylic alcohols, and in Chapter 2 is described that we established their absolute configuration.[20]

(CH3)2CHCH2MgBr

HOO

X X

5 mol% CuBr•SMe2


X = Br, Me

Fe

L1

6 mol% L1Cy2P

Ph2P

94% yield, 90% ee

Scheme 3. An example of the asymmetric Cu-catalyzed 1,2-addition of Grignard reagents to enones

We realized that this catalytic asymmetric 1,2-addition could function as a cornerstone for a novel, relatively straightforward approach to tocopherols and tocotrienols provided the subsequent ring closure to the chroman nucleus would be racemization-free. This requires either a strictly SN2-type nucleophilic substitution of the tertiary alcohol by the aromatic hydroxyl group, or an aromatic alkoxylation reaction. The latter, proceeding via an oxidation-reduction pathway of the hydroquinone, had been discovered and studied in depth already by Cohen et al. and does not lead to erosion of e.e.,[21] (Scheme 4) as confirmed by subsequent studies.[10c,

22] Based on these two key steps, a retrosynthesis was designed allowing full freedom both in the substitution pattern (α, β, γ, δ)- of the aromatic ring and in the chain leading to tocopherols and tocotrienols.

HO

OHHO R

O

OHO R

H+

O

HO

R

TraceO2

O

O

OH Rredox

ox.

A B

CD

A

Scheme 4. Mechanism of the cyclization leading to vitamin E

Aiming at γ-tocopherol, in the synthesis direction ketone 13 should be accessible

from commercially available 2,3-dimethyl hydroquinone 15. As the copper-catalyzed 54


asymmetric Grignard addition requires both an unsaturation and an α-substituent flanking the carbonyl group, subsequent steps should lead to 12 (Scheme 5). We showed already that after the 1,2-addition, the auxiliary Br is readily removed via Li halogen exchange followed by protonation. Also reduction of the alkene was not expected complicated provided hydrogenolysis of the hydroxyl group could be suppressed. For the actual copper-catalyzed asymmetric 1,2-addition, the current method would have to be advanced. Substrates containing heavily substituted phenyl groups had not been studied in this reaction and therefore the influence of these substitutions on the chemo-, regio-, and enantioselectivity was not known. Moreover, the required Grignard reagent 14 is a long chain with the nearest branch at the δ-position, whereas in the current catalyst system high e.e.’s were obtained solely with β-branched Grignard reagents such as iso-butylmagnesium bromide (see Scheme 3). Although efficient catalytic strategies for the asymmetric synthesis of so-called saturated polyisoprenoids have been developed both by Pfaltz et al.[23] and by us,[24] readily available natural (R,R)-phytol was chosen in this case as the precursor of the chain.[25]

HO

O

Tocopherol 3

HO

OHOH

OMe

OMe

Br

O

BrMg 14

11

13

+

OMe

OMe

HO

Br

acid catalyzed cyclization

Cu(I)-catalyzed 1,2-addition

12 Scheme 5. Retrosynthesis of (R,R,R)-γ-tocopherol 3

3.3 Results and discussion

The synthesis of 13 is summarized in Scheme 6. An attempted formylation of 15 according to Skattebøl et al. (with paraformaldehyde, MgCl2 and triethylamine)[26] did not provide the desired aldehyde; not unexpected as this reaction has not been reported with hydroquinones as substrate. Therefore, 16 was prepared in quantitative yield.[27] A direct formylation of 16 turned out to be very difficult as well. Duff reaction (hexamine and TFA) with 16 has been reported[28] to afford 18 in 44% yield, a result that was reproduced but not improved. Vilsmeier-Haack reaction (phosphoryl chloride and DMF),[29] Rieche formylation (titanium tetrachloride and dichloromethyl methyl ether),[30] and also ortholithiation with nBuLi/TMEDA followed by reaction

55

Chapter 3

with DMF[31] did not provide significant amounts of 18. In an alternative approach, using the conditions reported by Fukuyama et al., 16 was first brominated,[32] followed by bromo lithium exchange and reaction with DMF.[33] This led after optimization to 18 in an excellent yield from 16. Then, 18 was transformed into enone 19 by aldol condensation with acetone in 96% yield.[34] Subsequent dibromination/HBr elimination furnished α-enone 13 in 80% yield over two steps.[20,

35]

OH

OH

15OMe

OMe

16

OMe

OMe

Br

17

OMe

OMe

O

18

OMe

OMe

O

19

OMe

OMe20

OBr

Br

OMe

OMe13

O

Br

a b c d

e f

Scheme 6. Synthesis of 13: a) MeI, NaH, DMF, 0 ºC to r.t., 3 h; b) NBS, CH2Cl2, reflux, overnight, 93% over two steps; c) nBuLi, DMF, THF, –78 ºC, 0.5 h, 92%; d) acetone, NaOH, EtOH, r.t., 10 min, 96%; e) NaBr, oxone, CH2Cl2/H2O, 0 ºC to r.t., overnight; f) Et3N, THF, reflux, overnight, 80% over two steps.

The preparation of Grignard reagent 14 started from phytol 21 which already contains two chiral centers with the desired absolute configuration (Scheme 7). Ozonolysis of phytol led to ketone 22,[36] which was followed by Baeyer-Villiger oxidation according to the procedure of Pratt and Porter et al. to give 23.[37] After hydrolysis of the acetate, 24 was isolated in 92% yield over 3 steps. Bromination gave the desired 25 in 76% yield from 24.[38] This bromide was converted into its corresponding Grignard reagent 14 as an ≈ 1.5 M solution in ether.

With both 13 and 14 in hand, the copper catalyzed asymmetric 1,2-addition was studied. Applying the established conditions (Scheme 3) and Grignard reagent 14, tertiary alcohol 26 was obtained in very good yield. The diastereoselectivity however (as the Grignard reagent itself is chiral enantiopure, the stereoselectivity in the formed chiral center is expressed as d.e.), was only 42% (Table 1, entry 1). Screening various solvents, e.g. diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, and cyclopentyl methyl ether, as well as applying a prolonged addition time, or portion-wise addition of 13 and 14 did not improve this result. To benchmark the obtained 42% d.e., the asymmetric addition of isobutylmagnesium bromide to 13 was carried out as well, 56


which provided 27 in a rewarding 87% e.e. (entry 2). This strongly suggested that the moderate d.e. in the case of 26 is not due to the substitution pattern of the phenyl ring but due to the structure of the Grignard reagent 14. That there are boundaries at the substitution pattern on the aromatic ring of the substrate became clear in a parallel study. When the methyl protecting groups in 13 were replaced by tertbutyldimethylsilyl groups leading to enone 28, this substrate did not react under standard 1,2-addition conditions (entry 3). Also 29 was prepared as the precursor for (R,R,R)-α-tocopherol 1, but the product of the addition of 14, 30, was almost racemic (entry 4).

HO21

O

O

O

22

23 24

HO

Br

25

BrMg

14

a b

c d

e

Scheme 7. Synthesis of 14: a) Ozone, CH2Cl2/MeOH, –78 ºC; b) (CF3CO)2O, Na2CO3

.1.5 H2O2, CH2Cl2, r.t., 2 d; c) LiOH, THF/MeOH/H2O, r.t., 2 h; 92% over three steps; d) NBS, PPh3, CH2Cl2, 0 ºC, 2 h, 76%; e) Mg, Et2O.

These studies forced a re-evaluation of the applied chiral ligand, rev-Josiphos L1. In the development of the catalytic asymmetric 1,2-addition of Grignard reagents we had already experienced that L1 was unique in its chiral induction. Both closely related ligands such as the parent Josiphos, and unrelated ligands such as BINAP, and phosphoramidites performed badly. These studies were carried out with iso-butylmagnesium bromide as the nucleophile.

We therefore studied various chiral ligands, including the commercial ligands L2-4 and L8-9 and the ligands L5-7 prepared for this purpose,[39][40] in combination with Grignard reagent 14. Most ligands performed less well compared to rev-Josiphos L1 (entry 5-10). Josiphos-type ligand L8, being an exception, afforded a virtually identical d.e. as L1 (entry 11). L8 bears a sterically demanding di-tert-butyl phosphine group in combination with the Josiphos-like arrangement of a di-alkyl phosphine on the ethyl branch and a diarylphosphine on the ferrocene ring. In our experience, the enantioselectivity of the copper catalyzed 1,2-addition profits from rev-Josiphos type ligands, that is, a di-alkyl phosphine on the ferrocene and a diarylphosphine ethyl branch. Following this idea, we studied commercial ligand L9.

57

Chapter 3

Table 1. Investigations on the Cu-catalyzed 1,2-addition.

OR1

OR1

O

Br

5 mol% CuBr.SMe2

TBME−78oC, overnight

OR1

OR1

HO R3

Br

=[b] C16H33*

Ph2P

tBu2P

Fe

FeCy2P

Ph2P

L1

L8

Cy2P

tBu2P

Fe

L3

L9

L2 L4

neopentyl2P

Ph2P

Fe

L7L6

L5

R2 R2

R3MgBr

Entry R1 R2 R3 Ligands d.e./e.e.[a]

Me H C16H33*[b] L1 42

Me H (CH3)2CHCH2 L1 87

TBS H C16H33* -

Me Me L1 7C16H33*

Me H C16H33* L8 43

Me H C16H33* L2 36

Me H C16H33* L3 7

Me H C16H33* L4 12

Me H C16H33* L5 racemic

Me H C16H33* L6 racemic

Me H C16H33* L9 73

Me H C16H33* L7 26

1

2

3

4

5

6

7

8

9

10

11

12

Ketone 1,2-Adduct

13

13

13

13

13

13

13

13

13

13

28

29

26

27

-

30

26

26

26

26

26

26

26

26

L1

Cy2P

(o-tolyl)2P

Fe

Cy2P

(3,5-(CF3)2C6H3)2P

Fe Fe

PPh2

PtBu2

Fe

PCy2

PCy2 Fe

PtBu2

P(pCF3C6H4)2

[a] d.e./e.e. is not related to the absolute configuration of the 1,2-addition products.

6 mol% ligands

To our delight, a significant improvement of the diastereoselectivity to 73% was observed in the 1,2-addition of Grignard reagent 14 to 13 (entry 12). So, the 3 rev-Josiphos-type ligands L7, L1, and L8, gave us a clear hint to increase the d.e. in the 1,2-addition of 14 to 13, by increasing the steric bulk at the ferrocene phosphorus substituent of rev-Josiphos type ligands. This lured us into an attempt to prepare 58


several new rev-Josiphos type ligands with sterically very hindered phosphorus substituents on position 2 of the ferrocenyl ring (Figure 2). A considerable effort was invested in the preparation of L1-type ligands with R = EtMe2C, Et3C, iPrMe2C, and adamantyl according to literature procedures for related ligands.[41] However, the coupling of the R2PCl reagent with the ortho-lithiated ferrocene invariably failed, probably due to this (desired) steric hindrance. Ligand L7 was accessible via this method but afforded a low d.e. in the subsequent 1,2-addition, probably because the steric bulk was not directly positioned at the phosphorus center. Therefore we had to conclude that 73% d.e. was the maximum achievable stereoselectivity at present.

R2P

Ph2P

Fesubstituents biggerthan a tert-butyl group

R =

Figure 2. Designed rev-Josiphos type ligands.

With the most optimal ligand L9, we produced the key chiral tertiary alcohol 26 in 73% d.e. and 93% yield (Scheme 8, the appropriate enantiomer of L9 was chosen based on Chapter 2, which turned out to be correct, vide infra). Straightforward debromination of 26 with tBuLi at –78 ºC for 0.5 h afforded 31 in 91% yield.[42] Reduction of the double bond in 31 turned out to be a showcase for flavine-catalyzed diimide reduction.[43] Heterogeneous transition metal catalysts, e.g. Pd/C,[44] Pt/C, PtO2,[45] and Pd/C/NaOAc,[10c] in combination with H2 invariably provided the hydrogenolysis product, and also the recently disclosed diimide reduction with FeCl3 as the catalyst suffered from hydrogenolysis.[46] Flavine-catalyzed double bond reduction of 31 afforded 32 as the only product in 90% yield.[47] To prepare for the ringclosing step, 32 was oxidized to the corresponding quinone by treatment with cerium(IV)ammonium nitrate, followed by subsequent reduction to afford hydroquinone 11. Finally, acid-catalyzed and oxygen-induced cyclization of 11 provided the desired (R,R,R)-γ-tocopherol 3 in 72% yield over three steps.[22b, 22c] The synthetic material was identical in all aspects (1H- and 13C-NMR, mass analysis) with the reported data.[48]

59

Chapter 3

OMe

OMe13

O

Br

OMe

OMe

HO

Br

26

OMe

OMe

HO

31

MeO

OHMeO

γ-Tocopherol 3

32

HO

O

a b

c dHO

OHOH

11

e

Scheme 8. Synthesis of (R,R,R)-γ-tocopherol. a) 14, CuBr⋅SMe2, L9, TBME, –78 ºC, overnight, 93%; b) tBuLi, Et2O, –78 ºC, 0.5 h, 91%; c) flavin catalyst, O2, N2H4⋅H2O, EtOH, r.t., overnight; 90%; d) i. Ce(NH4)2(NO3)6, THF/H2O, 0 ºC, 0.5 h; ii. Na2S2O4, acetone/H2O, r.t., 0.5 h; e) p-TSA, toluene, 60 ºC, 5 min, 72% over three steps.

3.4 Conclusion In summary, we developed an efficient synthesis of (R,R,R)-γ-tocopherol based on

copper catalyzed asymmetric 1,2-addition. Starting from commercially available 2,3-dimethyl hydroquinone and natural phytol, (R,R,R)-γ-tocopherol was prepared in 12 steps (longest linear sequence), 36% overall yield and 73% d.e. at the C2 chiral center. The synthesis is not misplaced in the current collection of catalytic asymmetric approaches to the tocopherols, as the route is straightforward, in particular in its introduction of chirality at C2, and its use of readily available building blocks. An important finding is that the catalyst system used for the asymmetric addition of a complex Grignard reagent could be considerably optimized in terms of stereoselectivity. This means that the scope of Grignard reagents suitable for this reaction has been enlarged and invites to further study this direction. Inherently the method is very versatile as Grignard reagents are readily prepared from alkyl bromides.

3.5 Experimental section General remarks: 1H-NMR and 13C-NMR spectra were recorded on a Varian AMX400 (400 and 100 MHz, respectively) with CDCl3 as solvent. Chemical shifts were determined relative to the residual solvent peaks (CHCl3, δ = 7.26 ppm for 1H NMR, δ = 77.0 ppm for 13C-NMR). The following abbreviations are used to indicate signal multiplicity: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad. Enantiomeric excesses were determined by chiral HPLC using a Shimadzu LC-20AD HPLC 60


equipped with a Shimadzu SPD-M20A diode array detector and columns (Chiralpak AD-H and OD-H) provided by Daicel corporation, in comparison with the corresponding enantiomers and racemic mixtures. Racemic products were obtained by the same procedure as used for the enantioselective 1,2-addition, but omitting the ligand and CuBr•SMe2 and only using Grignard reagent (1.2 eq) at 0 °C in Et2O. Regioselectivities were determined by 1H-NMR. Optical rotations were measured on a Schmidt + Haensch polarimeter (Polartronic MH8) with a 10 cm cell (c given in g/100 mL) at 20 °C. Thin-layer chromatography (TLC) was performed on Merck TLC Silica gel 60 Kieselguhr F254. Flash chromatography was performed on silica gel Merck Type 9385 230-400 mesh. Mass spectra were recorded on an LTQ Orbitrap XL (ESI+ or APCI+). Copper salts were purchased from Aldrich, and used without further purification. All starting materials and ligands were purchased from Aldrich. All Grignard reagents were prepared from the corresponding alkyl bromides and Mg activated with I2 in Et2O.

OH

OH

15

MeI, NaHDMF

O

O

16 1,4-Dimethoxy-2,3-dimethylbenzene (16). To a suspension of NaH (60% in mineral oil, 8.69 g, 217 mmol) in DMF (150 mL) was added 2,3-dimethylhydroquinone (10.0 g, 72.4 mmol). The mixture was stirred for 10 min and then cooled to 0 ºC. Subsequently, MeI (10.4 mL, 167 mmol) was added dropwise at 0 ºC. The resulting mixture was stirred at 0 ºC for 30 min and 3 h at room temperature. Then the mixture was poured into 500 mL water and filtered. The obtained wet solid was dissolved in Et2O and the organic phase was separated, dried over MgSO4 and concentrated in vacuo. The crude product was used for the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 6.66 (s, 2 H), 3.78 (s, 6 H), 2.17 (s, 6 H).

O

O

16

NBS

DCMreflux, overnight

O

O

Br

17 (93% over two steps) 2,5-Dimethoxy-3,4-dimethylbromobenzene (17). To a solution of 16 (crude product from the previous step) in dry CH2Cl2 (50 mL) was added NBS (13.3 g, 74.6 mmol). The mixture was stirred at reflux for 6 h. The mixture was allowed to cool down and washed with saturated Na2SO3 (aq). The organic phase was dried over MgSO4,

61

Chapter 3

filtered and evaporated in vacuo. The crude product was purified by chromatography on silica gel (pentane/EtOAc = 50 : 1) to afford 17 (16.5 g, 93%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 6.87 (s, 1 H), 3.78 (s, 3 H), 3.73 (s, 3 H), 2.24 (s, 3 H), 2.09 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 154.1, 149.0, 132.4, 126.0, 113.3, 112.3, 60.5, 55.9, 13.3, 12.1; HRMS (ESI) calcd. for C10H14

81BrO2 [M + H]+ 247.0151, found 247.0169.

O

O

Br

17

O

O

OnBuLi, DMFTHF

−78 oC, 0.5 h

18 (92%) 2,5-Dimethoxy-3,4-dimethylbenzaldehyde (18). To a solution of 17 (15.0 g, 61.2 mmol) in dry THF (80 mL) was added nBuLi (36.7 mL, 91.8 mmol, 2.5 M in hexanes) at – 78 ºC. To the resulting mixture was added DMF (23.7 mL, 306 mmol) slowly while maintaining the internal temperature below – 60 ºC. The reaction was allowed to warm to rt, quenched with water, and concentrated under reduced pressure. The residue was diluted with Et2O, and washed with saturated NaHCO3 (aq), and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (pentane/Et2O = 8 : 1) to afford 18 (10.9 g, 92%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.33 (s, 1 H), 7.14 (s, 1 H), 3.84 (s, 3 H), 3.81 (s, 3 H), 2.24 (s, 3 H), 2.21 (s, 3 H).

O

O

O

18

NaOH (1.25 M)10 eq acetone

O

O

O

19

r.t., 10 minEtOH

(E)-4-(2,5-Dimethoxy-3,4-dimethylphenyl)-3-buten-2-one (19). To a solution of 18 (5.28 g, 27.2 mmol) and acetone (19.2 mL) in EtOH (48 mL) was added 1.25 M NaOH (aq, 96 mL). The mixture was stirred at rt for 15 min and then diluted with water (200 mL). The reaction mixture was subsequently neutralized with 2 M HCl (aq). EtOH was evaporated under vacuum and the water phase was extracted with Et2O. The combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The crude product was purified by chromatography on silica gel (pentane/Et2O = 4 : 1) to afford 19 (6.12 g, 96%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 16.4 Hz, 1 H), 6.87 (s, 1 H), 6.68 (d, J = 16.4 Hz, 1 H), 3.81 (s, 3 H), 3.69 (s, 3 H), 2.40 (s, 3 H), 2.22 (s, 3 H), 2.16 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 198.9, 154.0, 152.1, 139.0, 131.6, 130.6, 127.2, 124.6,

62


105.1, 62.1, 55.7, 27.0, 12.6, 12.5; HRMS (ESI) calcd. for C14H19O3 [M + H]+

235.1329, found 235.1319.

O

O

O

19

O

O

20

OBr

Br

O

O

13 (80%)

O

BrNaBr, Oxone

DCM : H2O = 5 :10 oC to r.t.

Et3N OOO

Br13-E

+THFreflux, overnight

Et3NTHF

Reflux

(Z)-3-Bromo-4-(2,5-dimethoxy-3,4-dimethylphenyl)-3-buten-2-one (13). To a suspension of oxone (32.1 g, 52.5 mmol) in dichloromethane (150 mL) and water (30 mL) was added portion-wise sodium bromide (5.38 g, 52.2 mmol) over 10 min at 0 ºC, and the resulting mixture was stirred for an additional 30 min. Then, enone 19 (6.12 g, 26.1 mmol) was added as the solid, portion-wise over 20 min and the mixture was stirred overnight, allowing the reaction to warm to rt. The mixture was poured into water and extracted with dichloromethane. The combined organic phases were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The residue 20 was dissolved in dry THF (150 mL) and the solution was treated with dry triethylamine (10 mL, 72 mmol) added dropwise via syringe over 10 min under nitrogen. The mixture was stirred under nitrogen at reflux for an additional 16 h. Then the mixture was washed with HCl (aq, 2 M) and brine, dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (pentane/EtOAc = 30 : 1) to afford the α-bromo-enone 13 as a brown solid and (E)-3-Bromo-4-(2,5-dimethoxy-3,4-dimethylphenyl)-3-buten-2-one (13-E) as a yellow oil. 13-E was subsequently treated under the conditions mentioned above for the conversion of 20 into 13 and this afforded an additional crop of 13. In total, 6.54 g of 13 was obtained in an overall yield of 80%. 13: 1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1 H), 7.61 (s, 1 H), 3.84 (s, 3 H), 3.68 (s, 3 H), 2.61 (s, 3 H), 2.24 (s, 3 H), 2.18 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 192.6, 153.3, 152.1, 136.7, 131.0, 130.6, 124.2, 123.9, 108.4, 62.2, 55.8, 26.7, 12.59, 12.57, ; HRMS (APCI) calcd. for C14H18O3

79Br [M + H]+ 313.0434, found 313.0430. 13-E: 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1 H), 6.53 (s, 1 H), 3.74 (s, 3 H), 3.62 (s, 3 H), 2.26 (s, 3 H), 2.19 (s, 3 H), 2.13 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 197.1, 153.6, 149.8, 134.0, 131.5, 128.8, 125.3, 121.3, 108.5, 61.0, 55.7, 28.6, 12.6, 12.4; HRMS (APCI) calcd. for C14H18O3

79Br [M + H]+

313.0434, found 313.0431.

63

Chapter 3

OH

OH

33

MeI, NaHDMF

O

O

34

NBSDCM

reflux, overnight

O

O

Br

35 (88% over two steps)

O

O

OnBuLi, DMFTHF

−20 oC, 0.5 h

36 (90%)


O

O

O

37 (99%)

r.t., 10 minEtOH

O

O

38

OBr

Br

O

O

29 (36%)

O

BrNaBr, oxone

DCM : H2O = 5 :10 oC to r.t., overnight

KOAcEtOH

reflux, overnight

0 oC to r.t., 3 h

OH

OH

33

MeI, NaHDMF

O

O

34 1,4-Dimethoxy-2,3,5-trimethylbenzene (34) was prepared starting from 2,3,5-trimethylhydroquinone 33 following a procedure similar to that for 16. 1H NMR (400 MHz, CDCl3) δ 6.53 (s, 1 H), 3.78 (s, 3 H), 3.66 (s, 3 H), 2.28 (s, 3 H), 2.21 (s, 3 H), 2.12 (s, 3 H); HRMS (ESI) calcd. for C11H17O2 [M + H]+ 181.1223, found 181.1222.

O

O

34

NBSDCM

reflux, overnight

O

O

Br

35 (88% over two steps) 2,5-Dimethoxy-3,4,6-trimethylbromobenzene (35). 35 was prepared from 34 in 88% yield over two steps following a procedure similar to that for 17. 1H NMR (400 MHz, CDCl3) δ 3.74 (s, 3 H), 3.65 (s, 3 H), 2.35 (s, 3 H), 2.22 (s, 3 H), 2.17 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 153.3, 151.5, 129.9, 129.5, 129.4, 117.6, 60.3, 60.2, 16.5, 13.3, 12.8; HRMS (APCI) calcd. for C11H16

79BrO2 [M + H]+ 259.0328, found 259.0328.

O

O

Br

35

O

O

OnBuLi, DMFTHF

−20 oC, 0.5 h

36 (90%) 2,5-Dimethoxy-3,4,6-trimethylbenzaldehyde (36). 36 was prepared from 35 in 90% yield following a procedure similar to that for 18 except for the reaction temperature 64


which was –20 ºC. 1H NMR (400 MHz, CDCl3) δ 10.47 (s, 1 H), 3.76 (s, 3 H), 3.64 (s, 3 H), 2.48 (s, 3 H), 2.26 (s, 3 H), 2.20 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 192.8, 159.0, 153.5, 138.4, 131.0, 129.0, 126.1, 63.2, 60.2, 13.6, 12.8, 12.0; HRMS (APCI) calcd. for C12H17O3 [M + H]+ 209.1172, found 209.1172.

O

O

O

36


O

O

O

37 (99%)

r.t., 10 minEtOH

(E)-4-(2,5-Dimethoxy-3,4,6-trimethylphenyl)-3-buten-2-one (37) was prepared from 36 in 99% yield following a procedure similar to that for 19. 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 16.4 Hz, 1 H), 6.79 (d, J = 16.4 Hz, 1 H), 3.64 (s, 3 H), 3.60 (s, 3 H), 2.37 (s, 3 H), 2.32 (s, 3 H), 2.21 (s, 3 H), 2.18 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 199.1, 153.9, 153.3, 138.6, 133.0, 131.6, 128.9, 128.8, 125.6, 60.3, 60.2, 27.6, 13.4, 13.2, 12.5; HRMS (APCI) calcd. for C15H21O3 [M + H]+ 249.1485, found 249.1484.

O

O

O

37

O

O

38

OBr

Br

O

O

29 (36%)

O

BrNaBr, OxoneDCM : H2O = 5 :1

0 oC to r.t., overnight

KOAcEtOH

reflux, overnight

(Z)-3-Bromo-4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-3-buten-2-one (29). Dibromide 38 was prepared from 37 following a procedure similar to that for 20. Subsequently, 38 was dissolved in EtOH and 2 eq of KOAc was added. The resulting mixture was refluxed overnight and concentrated in vacuo. The residue was dissolved in CH2Cl2 and washed with brine. The organic layer was dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (pentane/Et2O = 8 : 1) to afford α-bromo-enone 29 in 36% yield as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1 H), 3.67 (s, 3 H), 3.58 (s, 3 H), 2.61 (s, 3 H), 2.22 (s, 3 H), 2.18 (s, 3 H), 2.15 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 192.2, 153.4, 151.1, 140.1, 131.8, 129.6, 128.4, 127.3, 126.7, 60.9, 60.1, 26.9, 13.3, 12.9, 12.4; HRMS (APCI) calcd. for C15H20O3

79Br [M + H]+ 327.0590, found 327.0587.

65

Chapter 3

O

O

O

OH

OH

O

3918

BBr3CH2Cl2

−78 oC to r.t., 3 h

DBU, TBSClDCM

r.t., 10 min

OTBS

OTBS

O

40

Ph3P=CHCOCH3PhMe

reflux, 2 d

OTBS

OTBS41

O OTBS

OTBS28

O OTBS

OTBS28-E

O

NaBr, OxoneDCM

Et3NTHF

reflux, 24 h

+

0 oC to r.t., overnightBr

Br

O

O

O

OH

OH

O

3918

BBr3CH2Cl2

−78 oC to r.t., 3 h

2,5-Dihydroxy-3,4-dimethylbenzaldehyde (39). To a solution of 18 (500 mg, 2.57 mmol) in CH2Cl2 (25 mL) was added BBr3 (2 mL, 21 mmol) slowly at –78 oC. The resulting mixture was warmed to rt, stirred for 3 h, and quenched with cold water. The organic layer was separated and the aqueous phase was extracted with CH2Cl2. The combined organic phases were washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (pentane/Et2O = 2 : 1) to afford 39 (423 mg, 99%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 11.00 (s, 1 H), 9.72 (s, 1 H), 6.78 (s, 1 H), 4.76 (s, 1 H), 2.25 (s, 3 H), 2.20 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 195.5, 154.4, 146.6, 135.3, 126.6, 117.4, 114.4, 13.1, 11.3; HRMS (APCI) calcd. for C9H11O3 [M + H]+ 167.0703, found 167.0703.

OH

OH

O

39

DBU, TBSClDCM

r.t., 10 min

OTBS

OTBS

O

40

2,5-Bis(tert-butyldimethylsiloxy)-3,4-dimethylbenzaldehyde (40). To a solution of 39 (402 mg, 2.42 mmol) in CH2Cl2 (10 mL) were added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.91 mL, 6.05 mmol) and tert-butyldimethylchlorosilane (802 mg, 5.32 mmol) at rt. The resulting mixture was stirred for 10 min at that temperature, and then washed with water, 0.1 M HCl (aq), saturated NaHCO3 (aq) and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on 66


silica gel (pentane/Et2O = 30 : 1) to afford 40 (945 mg, 99%) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1 H), 7.07 (s, 1 H), 2.18 (s, 3 H), 2.14 (s, 3 H), 1.06 (s, 9 H), 1.01 (s, 9 H), 0.22 (s, 6 H), 0.12 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 190.0, 151.0, 148.4, 137.6, 130.3, 125.5, 113.0, 25.84, 25.77, 18.5, 18.2, 14.1, 13.8, -4.1, -4.3; HRMS (ESI) calcd. for C21H39O3Si2 [M + H]+ 395.2432, found 395.2433.

OTBS

OTBS

O

40

Ph3P=CHCOCH3PhMe

reflux, 2 d

OTBS

OTBS41

O

(E)-4-(2,5-Bis(tert-butyldimethylsiloxy)-3,4-dimethylphenyl)-3-buten-2-one (41). A solution of 40 (873 mg, 2.21 mmol) and l-(triphenylphosphoranylidene)-2-propanone (1.06 g, 3.32 mmol) in toluene was stirred and heated to reflux for 2 d. The resulting mixture was filtered through a silica gel pad and the filter cake washed with Et2O. The combined solvents were evaporated in vacuo and the residue was further purified by column chromatography on silica gel (pentane/Et2O = 20 : 1) to afford 41 (627 mg, 65%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 16.4 Hz, 1 H), 6.86 (s, 1 H), 6.46 (d, J = 16.4 Hz, 1 H), 2.37 (s, 3 H), 2.14 (s, 3 H), 2.12 (s, 3 H), 1.08 (s, 9 H), 1.02 (s, 9 H), 0.21 (s, 6 H), 0.11 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 198.8, 148.2, 147.1, 140.8, 133.0, 129.7, 125.7, 123.2, 112.8, 26.7, 25.9, 25.8, 18.5, 18.2, 14.4, 13.8, -3.6, -4.2; HRMS (ESI) calcd. for C24H43O3Si2 [M + H]+ 435.2745, found 435.2744.

OTBS

OTBS41

O OTBS

OTBS28

O OTBS

OTBS28-E

O

NaBr, OxoneDCM

Et3NTHF

reflux, 24 h

+

0 oC to r.t., overnightBr

Br

(Z)-3-Bromo-4-(2,5-bis(tert-butyldimethylsiloxy)-3,4-dimethylphenyl)-3-buten-2-one (28). 28 (36%) was prepared from 41 together with 9% of 28-E following a procedure similar to that for 13. 28: 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1 H), 7.46 (s, 1 H), 2.56 (s, 3 H), 2.16 (s, 3 H), 2.14 (s, 3 H), 1.05 (s, 9 H), 1.02 (s, 9 H), 0.24 (s, 6 H), 0.07 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 192.8, 147.5, 147.0, 138.4, 132.7, 129.1, 122.9, 122.5, 115.7, 26.8, 25.9, 25.8, 18.4, 18.3, 14.3, 13.7, -3.7, -4.3; HRMS (ESI) calcd. for C24H42O3Si2

79Br [M + H]+ 513.1850, found 513.1848; (28-E) 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 1 H), 6.45 (s, 1 H), 2.30 (s, 3 H), 2.110 (s, 3 H), 2.108 (s, 3 H), 1.05 (s, 9 H), 1.00 (s, 9 H), 0.17 (s, 6 H), 0.14 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 197.0, 147.8, 145.2, 136.2, 131.1, 129.4, 123.9, 119.7, 116.0, 28.9,

67

Chapter 3

26.0, 25.8, 18.5, 18.2, 14.3, 13.6, -3.5, -4.4; HRMS (ESI) calcd. for C24H42O3Si279Br

[M + H]+ 513.1850, found 513.1847.

HO21

OOzone

DCM/MeOH−78 oC 22

(6R, 10R)-6,10,14-Trimethylpentadecan-2-one (22). Through a stirred solution of phytol 21 (the natural R,R-isomer, 10.7 g, 36.0 mmol, ≥ 97%, purchased from Sigma-Aldrich) in MeOH (20 mL) and CH2Cl2 (110 mL) at –78 oC was bubbled ozone over 1 h until a blue color persisted in the solution. Subsequently, nitrogen was bubbled through the solution until the blue color disappeared. Me2S (20 mL) was added dropwise and the mixture was stirred at rt for 2 h. Volatiles were removed under reduced pressure and the residue was divided between water and Et2O. The organic phase was separated, washed with brine, dried over MgSO4, and concentrated in vacuo. The obtained crude product 22 was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 2.40 (t, J = 8.0 Hz, 2 H), 2.13 (s, 3 H), 1.57-1.49 (m, 2 H), 1.38-1.04 (m, 17 H), 0.87-0.83 (m, 12 H).

OO

O22 23

TFAANa2CO3

•1.5H2O2DCMr.t., 2 d

(4R,8R)-4,8,12-Trimethyltridecyl acetate (23). To a mixture of 22 from last step and sodium percarbonate (90 g, 576 mmol) in CH2Cl2 (600 mL) was added trifluoroacetic anhydride (20 mL, 143 mmol). The resulting mixture was stirred vigorously at rt for 48 h, and subsequently filtered over a Celite pad. The filtrate was neutralized by washing with saturated NaHCO3 (aq), and the layers were separated. The aqueous layer was back-extracted with Et2O and the combined organic phases were dried over MgSO4, filtered and evaporated in vacuo. The obtained crude product 23 was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 4.04 (t, J = 8.0 Hz, 2 H), 2.04 (s, 3H), 1.62-1.04 (m, 19 H), 0.87-0.83 (m, 12 H).

O

O 23 24 (92% over 3 steps)

LiOHTHF/MeOH/H2O

HOr.t., 2 h

(4R, 8R)-4,8,12-Trimethyltridecan-1-ol (24). To a solution of 23 from last step in a

68


mixture of THF (150 mL), MeOH (150 mL) and water (75 mL) was added LiOH (1.12 g, 46.8 mmol). The mixture was stirred at rt for 2 h. Then the mixture was neutralized with HCl (1 M) and the organic solvents were removed in vacuo. The aqueous layer was extracted with Et2O and the combined organic phases were dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (pentane/EtOAc = 20 : 1) to afford alcohol 24 (8.03 g, 92% over 3 steps) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 3.63 (t, J = 6.4 Hz, 2 H), 1.61-1.04 (m, 19 H), 0.88-0.83 (m, 12 H).

24

HO Br

25 (76%)

NBS, PPh3DCM

0 oC, 2 h

(4R,8R)-1-Bromo-4,8,12-trimethyltridecane (25). To a solution of 24 (2.11 g, 8.7 mmol) and PPh3 (2.74 g, 10.4 mmol) in CH2Cl2 (20 mL) was added N-bromosuccinimide (1.75 g, 9.8 mmol, 1.1 eq) at 0 oC over 10 min. The reaction was stirred for 2 h and concentrated in vacuo. To the solid/liquid residue was added hexane (20 mL), solids were removed by filtration and washed with hexane. The concentrated filtrate was purified by chromatography on silica gel (hexane) to afford 25 (2.03 g, 76%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 3.39 (dt, J = 6.8 Hz, 1.2 Hz, 2 H), 1.92-1.81 (m, 2 H), 1.56-1.04 (m, 17 H), 0.88-0.84 (m, 12 H).

Br

25

BrMg

14 (1.47 M in Et2O)

Mg, I2Et2O

(4R,8R)-4,8,12-Trimethyltridecanylmagnesium bromide (14). A Schlenk tube equipped with stirring bar was charged with magnesium turnings (190 mg, 7.9 mmol) and a crystal of iodine. The tube was heated until the iodine had decolorized and after cooling back to rt, 2 mL of dry Et2O was added and the resulting suspension was stirred under nitrogen. 25 (2.01 g, 6.6 mmol) was dissolved in Et2O (2.4 mL) and added to the Schlenk tube at 0 oC at such a rate that the suspension maintained a gentle reflux. The mixture was subsequently allowed to come to rt and was stirred for 2 h to afford 14. The concentration was determined to be 1.47 M by a titration with menthol using 1,10-phenanthroline as an indicator.

69

Chapter 3

O

O13

O

BrCuBr-SMe2, L9

TBME−78 oC, overnight

14O

O

HO

Br

26 (3R, 7R,11R)-(Z)-2-Bromo-3,7,11,15-tetramethyl-1-(2,5-dimethoxy-3,4-dimethyl phenyl)-hexadecen-3-ol (26) A Schlenk tube equipped with septum and stirring bar was charged with CuBr·SMe2 (16.4 mg, 0.080 mmol, 5 mol%) and ligand L9 (52.1 mg, 0.096 mmol, 6 mol%). Under nitrogen, dry tBuOMe (8 mL) was added and the solution was stirred at rt for 15 min. Then 13 (500 mg, 1.60 mmol, in 5 mL tBuOMe) was added and the resulting solution was cooled to –78 oC. The corresponding Grignard reagent 14 (1.30 mL, 1.92 mmol, 1.47 M in Et2O) was diluted with tBuOMe (2 mL) and added to the reaction mixture over 3 h with a syringe pump. Stirring was continued overnight at –78 oC. The reaction was quenched by the addition of MeOH and saturated aqueous NH4Cl before the mixture was warmed to rt. Et2O was added to the mixture and the organic layer was separated. The aqueous layer was extracted with Et2O and the combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (pentane/EtOAc = 20 : 1) to afford alcohol 26 (803 mg, 93%) as a light yellow oil. According to chiral HPLC (OD-H column, heptane/i-PrOH 98:2, 40 °C, 256 nm) the d.e. was 73%. Retention time: tmajor = 23.1 and tminor = 30.6 min. [α]20

D = +3.9 (c 0.93, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.27 (s, 1 H), 7.05 (s, 1 H), 3.82 (s, 3 H), 3.63 (s, 3 H), 2.22 (s, 3 H), 2.16 (s, 3 H), 2.14 (brs, 1 H), 1.92-1.70 (m, 2 H), 1.59 (s, 3 H), 1.56-1.50 (m, 1 H), 1.44-1.04 (m, 18 H), 0.88-0.84 (m, 12 H); 13C NMR (100 MHz, CDCl3) δ 153.1, 150.3, 135.20, 130.5, 126.8, 126.7, 123.4, 109.4, 77.1, 61.2, 55.9, 41.4, 39.4, 37.44, 37.40, 37.3, 37.2, 32.8, 32.7, 28.0, 27.5, 24.8, 24.5, 22.7, 22.6, 21.5, 19.74, 19.67, 12.5, 12.2; HRMS (APCI) calcd. for C30H50

81BrO2 [M - OH]+ 523.2974, found 523.2958.

O

O

HO

Br

26

tBuLi

O

O

HO

31

−78 oC, 0.5 hEt2O

(3R,7R,11R)-(E)-3,7,11,15-tetramethyl-1-(2,5-dimethoxy-3,4-dimethylphenyl)-hexadecen-3-ol (31) To a solution of 26 (300 mg, 0.56 mmol) in Et2O was slowly added a solution of tBuLi (0.82 mL, 1.40 mmol, 1.7 M in pentane) under nitrogen at –78 oC, and the resulting mixture was stirred at this temperature for 30 min. Then the reaction 70


was quenched with MeOH and saturated aqueous NH4Cl. The mixture was warmed to rt and diluted with Et2O. The organic layer was separated. The aqueous layer was extracted with Et2O and the combined organic phases were dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (pentane/EtOAc = 15 : 1) to afford alcohol 31 (235 mg, 91%) as a light yellow oil. [α]20

D = +7.5 (c 0.64, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.84 (d, J = 16.0 Hz, 1 H), 6.79 (s, 1 H), 6.26 (d, J = 16.0 Hz, 1 H), 3.82 (s, 3 H), 3.65 (s, 3 H), 2.21 (s, 3 H), 2.14 (s, 3 H), 1.66-1.61 (m, 3 H), 1.56-1.49 (m, 1 H), 1.44-1.05 (m, 18 H), 1.41 (s, 3 H), 0.88-0.83 (m, 12 H); 13C NMR (100 MHz, CDCl3) δ 153.9, 150.0, 137.0, 131.0, 127.2, 126.2, 122.3, 105.2, 73.4, 61.0, 55.8, 43.2, 39.4, 37.6, 37.42, 37.38, 37.3, 32.79, 32.77, 28.2, 28.0, 24.8, 24.5, 22.7, 22.6, 21.6, 19.73, 19.65, 12.5, 12.1; HRMS (APCI) calcd. for C30H51O2 [M - OH]+ 443.3884, found 443.3869.

O

O

HO

31

Flavin, O2H2N-NH2

O

OHO

32

EtOHr.t., overnight

(3R,7R,11R)-(E)-3,7,11,15-tetramethyl-1-(2,5-dimethoxy-3,4-dimethylphenyl)-hexadecan-3-ol (32) To a vigorously stirring solution of 31 (155 mg, 0.34 mmol) in EtOH (5 mL) was added a solution of flavin catalyst (206 mg, 0.51 mmol) in EtOH (0.50 mL) and hydrazine hydrate (0.33 mL, 6.8 mmol) over 10 min under an atmosphere of oxygen. The resulting mixture was stirred overnight. Subsequently CH2Cl2 was added and the mixture was washed with water. The organic phase was dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (pentane/Et2O = 5 : 1) to afford alcohol 32 (142 mg, 90%) as a colorless oil. [α]20

D = +2.7 (c 0.67, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.54 (s, 1 H), 3.79 (s, 3 H), 3.68 (s, 3 H), 2.69-2.65 (m, 2 H), 2.21 (s, 3 H), 2.12 (s, 3 H), 1.78-1.73 (m, 2 H), 1.54-1.49 (m, 4 H), 1.44-1.05 (m, 18 H), 1.25 (s, 3 H), 0.88-0.84 (m, 12 H); 13C NMR (100 MHz, CDCl3) δ 153.7, 150.2, 132.5, 130.8, 124.1, 109.2, 72.7, 60.9, 55.8, 43.2, 42.4, 39.4, 37.8, 37.44, 37.40, 37.3, 32.81, 32.79, 28.0, 26.9, 24.9, 24.8, 24.5, 22.7, 22.6, 21.5, 19.74, 19.67, 12.8, 11.9; HRMS (APCI) calcd. for C30H53O2 [M - OH]+ 445.4040, found 445.4030. O

OHOγ-Tocopherol 332

HO

O

CANTHF/H2O = 3/1

0 oC, 30 min

Na2S2O4acetone/H2Or.t., 30 min

pTSAtoluene

60 oC, 5 min

71

Chapter 3

γ-Tocopherol To a solution of 32 (45 mg, 0.097 mmol) in CH3CN (3 mL) was added a solution of cerium (IV) ammonium nitrate (159 mg, 0.29 mmol) in CH3CN/H2O (3 mL/3 mL) at 0 oC. The resulting mixture was stirred at this temperature for 2 h and subsequently CH2Cl2 (15 mL) was added. The organic layer was separated and the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried over MgSO4, filtered and evaporated in vacuo. The crude product was dissolved in acetone (20 mL) without further purification, and an aqueous solution of Na2S2O4 (1.15 g in 10 mL water) was added. The mixture was stirred at rt for 30 min, and then extracted with CH2Cl2. The combined organic phases were dried over MgSO4, filtered and evaporated in vacuo. The crude product was immediately dissolved in dry toluene (10 mL), and the resulting solution heated to 65 oC followed by addition of p-toluenesulfonic acid monohydrate (5 mg). The mixture was stirred at this temperature for 30 min, and was then concentrated in vacuo. The residue was purified by column chromatography on silica gel (pentane/Et2O = 10 : 1) to afford γ-tocopherol (29 mg, 72%) as a brown oil. [α]20

D = +1.8 (c 1.44, CHCl3); [α]20D =

+1.5 (c 1.18, EtOH); 1H NMR (400 MHz, CDCl3) δ 6.37 (s, 1 H), 4.25 (br s, 1 H), 2.69-2.65 (m, 2 H), 2.14 (s, 3 H), 2.12 (s, 3 H), 1.78-1.69 (m, 2 H), 1.58-1.50 (m, 3 H), 1.47-1.04 (m, 18 H), 1.25 (s, 3 H), 0.88-0.84 (m, 12 H); 13C NMR (100 MHz, CDCl3) δ 146.2, 145.7, 125.8, 121.6, 118.3, 112.1, 75.5, 40.1, 39.4, 37.6, 37.5, 37.4, 37.3, 32.8, 32.7, 31.3, 28.0, 24.8, 24.4, 24.1, 22.7, 22.6, 22.3, 21.0, 19.74, 19.68, 11.90, 11.86; HRMS (ESI) calcd. for C28H48O2 [M] 416.3649, found 416.3640; C28H49O2 [M + H]+ 417.3682, found 417.3677. 1H NMR and 13C NMR are identical to the disclosed data in the literature.

O

O29

O

BrCuBr-SMe2, L1


14O

O

HO

Br

30 (3R,7R,11R)-(Z)-2-Bromo-3,7,11,15-tetramethyl-1-(2,5-dimethoxy-3,4,6-trimethylphenyl)-hexadecen-3-ol (30). 30 was prepared from 29 in 21% yield according to the procedure for the preparation of 26 and meanwhile 37% of starting material was recycled. 1H NMR (400 MHz, CDCl3) δ 7.07 (s, 1 H), 3.67 (s, 3 H), 3.61 (s, 3 H), 2.21 (s, 3 H), 2.18 (s, 3 H), 2.15 (s, 3 H), 1.94-1.85 (m, 1 H), 1.77-1.69 (m, 1 H), 1.58 (s, 3 H), 1.54-1.49 (m, 1 H), 1.43-1.08 (m, 19 H), 0.88-0.84 (m, 12 H); 13C NMR (100 MHz, CDCl3) δ 153.1, 151.5, 130.1, 129.3, 128.0, 127.2, 124.3, 76.9, 60.5, 60.1, 41.4, 72


39.4, 37.43, 37.38, 37.3, 37.2, 32.79, 32.77, 28.0, 27.7, 24.8, 24.5, 22.7, 22.6, 21.3, 19.74, 19.67, 13.1, 12.8, 12.5; HRMS (ESI) calcd. for C31H53O3

79BrNa [M + Na]+

575.3070, found 575.3065.

O

O13

O

BrCuBr

.SMe2, L1


O

O

HO

Br

27

iso-butylmagnesium bromide

(R)-(Z)-2-Bromo-3,5-dimethyl-1-(2,5-dimethoxy-3,4-dimethylphenyl)-1-hexen-3-ol (27). 27 was prepared from 13 in 90% yield following a procedure similar to that for 26. According to chiral HPLC (OD-H column, heptane/i-PrOH 98:2, 40 °C, 256 nm) the ee was 87%. Retention time: tmajor = 27.6 and tminor = 34.8 min; 1H NMR (400 MHz, CDCl3) δ 7.33 (s, 1 H), 7.06 (s, 1 H), 3.82 (s, 3 H), 3.63 (s, 3 H), 2.22 (s, 3 H), 2.17 (br s, 1 H), 2.16 (s, 3 H), 1.90-1.80 (m, 2 H), 1.70-1.65 (m, 1 H), 1.60 (s, 3 H), 1.04-0.99 (m, 6 H); 13C NMR (100 MHz, CDCl3) δ 153.1, 150.4, 135.4, 130.5, 126.8, 126.7, 123.1, 109.4, 77.6, 61.1, 55.9, 49.1, 28.7, 24.6, 24.5, 24.3, 12.5, 12.2; C18H26O2

79Br [M - OH]+ 353.1111, found 353.1105.

Me3CCH2Cl Me3CCH2MgCl PCl3Et2OMg neopentyl2PCl

Et2O Bisneopentylphosphorus chloride. 4.5 mL of neopentyl chloride and 1.05 g of magnesium were used to prepare neopentylmagnesium chloride in 18 mL of diethyl ether. The resulting Grignard reagent was cooled down to 0 oC and 0.88 mL of PCl3 was added slowly. After heating at reflux for 4 h, the mixture was stirred overnight at rt. The solvent was removed in vacuo, and the residue was used for the next step immediately.

Me2N

Fe

sec-BuLi

Et2Oreflux, 2.5 h

Me2N

Feneopentyl2P

42 43

neopentyl2PCl

(S)-N,N-Dimethyl-1-[(R)-2-(dineopentylphosphino)ferrocenyl]ethylamine (43). To a solution of (S)-(−)-N,N-dimethyl-1-ferrocenylethylamine 42 (0.10 mL, 0.48 mmol)

73

Chapter 3

in Et2O (4 mL) was added sec-BuLi (1.4 M in cyclohexane, 0.45 mL) at rt. The resulting mixture was stirred for 2 h at rt and the freshly made bisneopentyl phosphorus chloride (0.60 g, >>2 eq.) was added. The mixture was heated under reflux for 2.5 h and subsequently cooled down to 0 oC. Saturated NaHCO3 (aq) was added slowly, and the organic layer was separated. The aqueous layer was extracted with toluene. The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. The residue was partly purified by quick column chromatography on silica gel (CH2Cl2/MeOH = 10 : 1) and the obtained crude product 43 (147 mg) was used directly for the next step.

Me2N

Feneopentyl2P

43

neopentyl2P

Ph2P

Fe

Ph2PHHOAc

90 oC, 3 h

L7

(S)-1-[(R)-2-(Dineopentylphosphino)ferrocenyl]ethyldiphenylphosphine (L7). To a solution of 43 (147 mg) in anhydrous and degassed acetic acid was added diphenylphosphine (0.06 mL, 0.34 mmol). The resulted mixture was stirred for 3 h at 80 oC. The acetic acid was removed in vacuo and the residue was partly purified by quick column chromatography on silica gel (CH2Cl2/MeOH = 10 : 1). The obtained crude product (103 mg) was dissolved in CH2Cl2 and CuBr⋅SMe2 (31 mg) was added portion-wise to get a clear solution. The solvent was removed in vacuo. The residue was recrystallized in cyclohexane and afforded L7 (72 mg, 21% from 42) as an orange powder. 1H NMR (400 MHz, CDCl3) δ 7.60-7.56 (m, 2 H), 7.40-7.29 (m, 4 H), 7.20-7.17 (m, 4 H), 4.39 (s, 1 H), 4.21 (s, 5 H), 4.13 (s, 1 H), 3.90 (s, 1 H), 3.50-3.44 (m, 1 H), 2.33-2.19 (m, 4 H), 1.49 (t, J = 8.0 Hz, 3 H), 1.22 (s, 9 H), 1.18 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 135.1, 135.0, 132.6, 132.5, 130.3 (d), 129.3, 128.8, 128.7, 128.1, 128.0, 72.8 (d), 70.5 (d), 69.0, 67.2 (d), 50.8 (d), 42.3 (t), 32.1 (d), 31.6 (m), 14.3; 31P NMR (133 MHz, CDCl3) δ -8.27 (d, J = 146.3 Hz), -46.33 (d, J = 146.4 Hz); HRMS (APCI) calcd. for C34H34CuFeP2 [M - Br]+ 633.1558, found 633.1560.

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74


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78

Chapter 4

A Protecting Group-free Synthesis of the Colorado Potato

Beetle Pheromone In this chapter, a novel synthesis of the aggregation pheromone of the Colorado potato beetle, Leptinotarsa decemlineata, is described. Based on a Sharpless asymmetric epoxidation in combination with a chemoselective alcohol oxidation using catalytic [(neocuproine)PdOAc]2OTf2, the pheromone was synthesized in 3 steps, 80% yield and 86% ee from geraniol. Parts of this chapter have been published: Z. Wu, M. Jäger, J. Buter, A. J. Minnaard, Beilstein J. Org. Chem. 2013, 9, 2374–2377.

Chapter 4

4.1 Introduction The Colorado potato beetle Leptinotarsa decemlineata, a worldwide pest causing

considerable damage in the US annually, has developed resistance to more than 25 insecticides[1-4]. For crop protection, currently several insecticides are used such as the neonicotinoids imidacloprid, thiamethoxam and thiachloprid[1,5], albeit these are expensive and moreover resistance lies in wait[6]. From the standpoint of environmental protection and economics, it is important to reduce the use of insecticides controlling the Colorado potato beetle, and an attractive alternative is to use a pheromone management strategy. An important finding in this connection was the isolation of the male produced aggregation pheromone by Dickens and Oliver et al. in 2002[7], which was subsequently identified as (S)-1,3-dihydroxy-3,7-dimethyl-6-octen-2-one 1 (Figure 1)[8]. (S)-1 is attractive for both male and female Leptinotarsa decemlineata while (R)-1 is inactive or inhibitory, as was demonstrated by the inactivity of the racemate[7]. Since then, (S)-1 has been synthesized by the groups of Oliver[8], Mori[9], and Chauhan[10] respectively, and the first field evaluation of synthetic (S)-1 in a trap crop pest management strategy showed its practical utility[1].

OOH

OH

Figure 1: (S)-1,3-dihydroxy-3,7-dimethyl-6-octen-2-one 1

The commercial enantioselective production of chiral pheromones of many pest insects is hampered by prohibitively high costs. The selective introduction of stereocenters and the number of steps are the main reasons. In 2002, Oliver described the first synthesis of both enantiomers of 1 from (R)- and (S)-linalool, and also the synthesis of its racemate from geraniol, to establish the absolute configuration. Although the approach is elegant, (S)-linalool required for natural (S)-1 is not commercially available. In 2005, Mori employing lipase-catalyzed kinetic resolution of (±)-2,3-epoxynerol as the key step, synthesized both (S)- and (R)-1 in gram quantities with high ee. In Chauhan’s work, Grignard reaction, oxidation and stereoselective methylation using organometallic reagents are the key steps, affording (S)-1 in high enantiomeric purity and in gram quantities. In all these approaches, however, protection of the primary hydroxyl group of the 1,2,3-triol substructure is required for the selective oxidation of the secondary alcohol at C-2. 80

A protecting group-free synthesis of the Colorado potato beetle pheromone

4.2 Synthetic strategy for (S)-1,3-dihydroxy-3,7-dimethyl-6-octen-2-one 1 In 2010, Waymouth reported the chemoselective, catalytic oxidation of glycerol to dihydroxyacetone (Scheme 1) using catalytic [(neocuproine)PdOAc]2OTf2 2 in the presence of either benzoquinone or air as the terminal oxidant[11]. More recently, the transformation of unprotected vicinal polyols to α-hydroxy ketones was achieved by regio- and chemoselective oxidation using catalyst 2[12]. In the group, we use this method for the catalytic regioselective oxidation of glycosides (Scheme 1)[13] and expected that the approach might also be applicable in the synthesis of (S)-1. Triol 3, with vicinal primary, secondary, and tertiary hydroxyl groups should be a suitable substrate for chemoselective oxidation with catalytic 2, enabling a protecting group-free synthesis of the Colorado potato beetle pheromone (Scheme 2). An additional challenge was the presence of an alkene in the substrate, as the orthogonality of 2-catalyzed alcohol oxidations with alkenes had not been studied.

HO OHOH 5 mol% 2

3 eq benzoquinoneDMSO or CH3CN, rt HO OH

O

OHOHO

OHOMe

OH

OHOOH

OMe

OH

O

benzoquinonecat. 2,

N NPd

O O

N NPd

O O

2+

2-OTf

2 Scheme 1: Selective oxidation of glycerol[14] and methyl α-D-glucopyranoside

OH

OH

OHOH

OH

O

(3S)-3 (S)-1 Scheme 2: chemoselective oxidation in a synthetic approach to(S)-1

In our approach, Sharpless asymmetric epoxidation of readily available geraniol or

nerol[15-17] followed by stereospecific ring-opening with water would lead to the desired triol 3. Subsequently, regioselective oxidation of 3 would provide (S)-1 in a concise 3 step route. The resulting synthesis would be interesting for commercial application, and in addition for synthesis in general because the oxidation pattern in 1 occurs more widespread in natural products and pharmaceuticals such as in cortisol

81

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(hydrocortisone).

4.3 Results and Disscussion The synthesis of (S)-1 is summarized in Scheme 3. The choice for either geraniol or

nerol should have been based on the stereoselectivity of the Sharpless epoxidation. For both reactions, however, varying enantioselectivities had been reported, so both substrates were studied. According to the published procedure, upon treatment of freshly distilled geraniol (Scheme 3) with tert-butylhydroperoxide in the presence of D-(–)-diisopropyl tartrate (DIPT) and Ti(OiPr)4 in dry CH2Cl2 at –10 to –23 oC for 2 h, the desired epoxide (2R, 3R)-4 was obtained in 93% yield and 88% ee. The ee was determined by HPLC analysis of its corresponding TBDPS ether. This result compares well with the ones reported in the literature: 77 - 95% yield and 81 - 95% ee[16-20]. According to Sharpless et al.[17], 5 mol% of Ti(OiPr)4 and 7.5 mol% of DIPT were used, so at least 20% excess of tartrate ester in order to obtain the maximum enantiomeric excess. The use of freshly distilled DIPT and Ti(OiPr)4 was important to obtain consistently 88% ee. With epoxide (2R, 3R)-4 at hand, an acid-catalyzed ring-opening reaction was carried out using HClO4 in THF/water at room temperature[21]. In the process of ring-opening, close to quantitative inversion of configuration at C-3 took place[22,23], a result which was confirmed as determination of the ee of both substrate and product shows a slight drop in ee from 88% to 86%. Triol (2R, 3S)-3 was obtained from (2R, 3R)-4 in high yield by this regio- and stereoselective ring-opening reaction. Subsequently, (2R, 3S)-3 was converted into (S)-1 by treatment with 0.5 mol% of catalyst 2 and benzoquinone in CH3CN/water at room temperature. The reaction turned out to be very selective for the secondary alcohol and neither oxidation of the primary alcohol nor of the alkene was observed. (S)-1 was obtained in 91% yield and both the 1H-NMR and the 13C-NMR spectrum coincided with those reported in the literature[8,9].

OH a OHO

b OHOH

OHOH

OH

Oc

Geraniol (2R, 3R)-4 (2R, 3S)-3 (S)-1

Scheme 3: Synthesis of (S)-1 from geraniol. Reagents and conditions: a) D-(–)-diisopropyl tartrate, Ti(OiPr)4, tert-butylhydroperoxide, CH2Cl2, 4Å MS, –10 to –23 oC, 2 h, 93%, 94:6 e.r.; b) HClO4 (70%), THF/water, r.t., 30 min, 94%; c) 0.5 mol% 2, p-benzoquinone, CH3CN/water, r.t., overnight, 91%. 82


Starting from nerol, Sharpless asymmetric epoxidation afforded the epoxide (2S, 3R)-4 in a disappointing 74% ee, a result which is nevertheless in the range of the reported values: 70 – 94%[24-29] (Scheme 4). Applying the same ring-opening reaction to epoxide (2S, 3R)-4, triol (2S, 3S)-3 was obtained in high yield but a 6% loss in enantiomeric excess was observed. Considering these disappointing results using nerol as the starting material, oxidation to (S)-1 was not performed.

a

O

b OHOH

OH

Nerol (2S, 3R)-4 (2S, 3S)-3

OH OH

Scheme 4: asymmetric epoxidation and ringopening starting from nerol. Reagents and conditions: a) L-(+)-diisopropyl tartrate, Ti(OiPr)4, tert-butylhydroperoxide, CH2Cl2, 4Å MS, –10 to –23 oC, 2 h, 89%, 87:13 e.r.; b) HClO4 (70%), THF/H2O, r.t., 30 min, 92%. 4.4 Conclusion In summary, we have developed an efficient synthesis of the aggregation pheromone of the Colorado potato beetle (S)-1,3-dihydroxy-3,7-dimethyl-6-octen-2-one 1. Combining Sharpless asymmetric epoxidation, stereoselective epoxide ring-opening and catalytic chemoselective alcohol oxidation with [(neocuproine)PdOAc]2OTf2 2, (S)-1 was synthesized in 80% overall yield and 86% ee over 3 steps from geraniol. Nerol turned out to be less suitable as starting material as its asymmetric epoxidation provided lower ee. It has been shown that (S)-1 with an ee of 92% is as active as enantiopure (S)-1 (99% ee), therefore it might be safe to conclude that the currently obtained 86% ee suffices. In addition, it has been shown that the palladium-catalyzed alcohol oxidation according to Waymouth is orthogonal to a trisubstituted alkene, an observation of direct relevance for further natural product synthesis. 4.5 Experimental section General remarks: 1H-NMR and 13C-NMR spectra were recorded on a Varian AMX400 (400 and 100 MHz, respectively) with CDCl3 as solvent. Chemical shifts were determined relative to the residual solvent peaks (CHCl3, δ = 7.19 ppm for 1H-NMR, δ = 77.0 ppm for 13C-NMR). The following abbreviations are used to indicate signal multiplicity: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad. Enantiomeric

83

Chapter 4

excesses were determined by chiral HPLC using a Shimadzu LC-20AD HPLC equipped with a Shimadzu SPD-M20A diode array detector and columns (Chiralpak AD-H and OD-H) provided by Daicel corporation, in comparison with the corresponding enantiomers and racemic mixtures. (2S,3S)-2,3-Epoxygeraniol was obtained by the same procedure as used for (2R,3R)-2,3-epoxygeraniol, but using L-(+)-diethyl tartrate. (2R,3S)-2,3-Epoxynerol was obtained by the same procedure as used for (2S,3R)-2,3-epoxynerol, but using D-(–)-diisopropyl tartrate (DIPT). Optical rotations were measured on a Schmidt + Haensch polarimeter (Polartronic MH8) with a 10 cm cell (c given in g/100 mL) at approx. 20 °C. Thin-layer chromatography (TLC) was performed on Merck TLC Silica gel 60 Kieselguhr F254. Flash chromatography was performed on silica gel Merck Type 9385 230-400 mesh. Geraniol, nerol, D-(–)-diisopropyl tartrate (DIPT), L-(+)-DIPT, titanium tetraisopropoxide and tert-butyl hydroperoxide solution (TBHP) (5~6 M in decane) were purchased from Aldrich. Geraniol, nerol, D-(–)-DIPT, L-(+)-DIPT and titanium tetraisopropoxide were purified by Kugelrohr distillation. The catalyst [(2,9-dimethyl-1,10-phenanthroline)-Pd(µ-OAc)]2(OTf)2 was made according to the literature procedure.[14] 4 Ǻ molecular sieves (MS) were dried at 130 oC for 2 d in an oven and heated by a heat gun under vacuum before use.

OHO

(2R, 3R)-2,3-Epoxygeraniol (4). To 20 ml of dry CH2Cl2 containing 4 Ǻ molecular sieves (2.0 g) were added D-(–)-DIPT (228 mg, 0.97 mmol) and titanium tetraisopropoxide (184 mg, 0.65 mmol) successively at –10 oC under nitrogen. After having added TBHP (3.5 mL, 5~6 M in decane) slowly, the resulted mixture was stirred for an additional 30 min. Then the mixture was cooled to –23 oC by a Cryostat and freshly distilled geraniol (2.0 g, 13.0 mmol) was added over 0.5 h keeping the inner temperature below –20 oC . The mixture was stirred at –23 oC for an additional 2.5 h, and was then quenched with water (2 mL). The mixture was vigorously stirred for 30 min while allowing to warm to rt. After adding aq. NaOH (1.2 mL, 3 M), the mixture was stirred for another 30 min at rt and then filtered over a Büchner funnel under suction. The filtrate was stirred vigorously with 10% aqueous citric acid (6 mL) for 1 h at rt. The organic layer was separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by Kugelrohr distillation (120 – 122 oC, 2 torr) to afford epoxide (2R,3R)-4 (2.05 g, 93%) as a colorless oil. [α]20

D = +2.3 (c 84


1.32, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.04-5.00 (m, 1 H), 3.76 (d, J = 12.0 Hz, 1 H), 3.61 (dd, J = 12.0, 6.4 Hz, 1 H), 2.91 (dd, J = 6.8, 4.4 Hz, 1 H), 2.02 (q, J = 7.6 Hz, 2 H), 1.84 (br s, 1 H), 1.65-1.54 (m, 1 H), 1.62 (s, 3 H), 1.54 (s, 3 H), 1.44-1.37 (m, 1 H), 1.23 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 132.1, 123.3, 62.9, 61.4, 61.2, 38.5, 25.6, 23.7, 17.6, 16.7.

OTBDPSO

(2R, 3R)-1-tert-Butyldiphenylsilyloxy-2,3-epoxy-3,7-dimethyl-6-octene (5). To a stirred solution of (2R,3R)-4 (87 mg, 0.51 mmol) in CH2Cl2 (2 mL) were added imidazole (43 mg, 0.63 mmol) and TBDPSCl (0.15 mL, 0.58 mmol) successively at rt. After 5 min, 5 mL of saturated aq. NH4Cl and 5 mL of CH2Cl2 were added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (pentane/Et2O = 50/1) to afford (2R,3R)-5 (188 mg, 90%) as a colorless oil. According to HPLC (Chiral OD-H column, heptane/i-PrOH 99.9:0.1, 40 °C, 225 nm) the ee was 88%. Retention time: tmajor = 23.9 and tminor = 20.4 min. [α]20

D = +9.7 (c 1.17, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.62-7.60 (m, 4 H), 7.36-7.29 (m, 6 H), 5.02 (t, J = 7.2 Hz, 1 H), 3.73 (dd, J = 11.2, 5.2 Hz, 1 H), 3.66 (dd, J = 11.2, 5.2 Hz, 1 H), 2.92 (t, J = 5.2 Hz, 1 H), 1.99 (q, J = 7.6 Hz, 2 H), 1.60-1.32 (m, 2 H), 1.60 (s, 3 H), 1.53 (s, 3 H), 1.06-0.99 (m, 12 H); 13C NMR (100 MHz, CDCl3) δ 135.6, 135.5, 133.5, 133.3, 132.0, 129.7, 127.8, 127.70, 127.69, 123.5, 62.90, 62.86, 60.5, 38.5, 26.8, 25.7, 23.8, 19.2, 17.6, 16.7; HRMS (C26H37O2Si, APCI): calcd. 409.2557, found 409.2556.

OHOH

OH

(2R, 3S)-3,7-Dimethyl-6-octene-1,2,3-triol (3). To a solution of (2R,3R)-4 (200 mg, 1.17 mmol) in THF (5.4 mL) was added dropwise a solution of HClO4 (0.07 mL, 70%) in H2O (1 mL) at rt. The resulting mixture was stirred for an additional 30 min at rt. Then ethyl acetate (10 mL) and water (3 mL) were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The crude product (2R,3S)-3 (206 mg, 94%) was obtained as a colorless oil,

85

Chapter 4

sufficiently pure for the next step. [α]20D = +5.7 (c 1.02, CHCl3); 1H NMR (400 MHz,

CDCl3) δ 5.04-5.01 (m, 1 H), 3.70-3.61 (m, 5 H), 3.41 (dd, J = 6.4, 3.2 Hz, 1 H), 2.05-1.93 (m, 2 H), 1.61 (s, 3 H), 1.56-1.49 (m, 1 H), 1.54 (s, 3 H), 1.34-1.26 (m, 1 H), 1.14 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 131.9, 124.1, 76.9, 74.5, 63.1, 37.7, 25.6, 23.2, 22.1, 17.6.

OTBDPSOH

OH

(2R, 3S)-1-tert-Butyldiphenylsilyloxy-3,7-dimethyl-6-octene-2,3-diol (6). To a stirred solution of (2R,3S)-3 (50 mg, 0.27 mmol) in CH2Cl2 (2 mL) were added imidazole (23 mg, 0.34 mmol) and TBDPSCl (0.08 mL, 0.31 mmol) successively at rt. After 5 min, 5 mL of saturated aq. NH4Cl and 5 mL of CH2Cl2 were added to the reaction mixture. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (pentane/Et2O = 3/1) to afford (2R,3S)-6 (92 mg, 80%) as a colorless oil. According to HPLC (Chiral AD-H column, heptane/i-PrOH 99:1, 40 °C, 230 nm) the ee was 86%. Retention time: tmajor = 31.5 and tminor = 37.1 min. [α]20

D = -1.8 (c 0.68, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.61-7.58 (m, 4 H), 7.38-7.29 (m, 6 H), 4.97 (t, J = 7.2 Hz, 1 H), 3.77-3.71 (m, 2 H), 3.43-3.40 (m, 1 H), 2.68 (br s, 2 H), 2.03-1.97 (m, 1 H), 1.90-1.83 (m, 1 H), 1.59 (s, 3 H), 1.51-1.45 (m, 1 H), 1.48 (s, 3 H), 1.30-1.24 (m, 1 H), 1.11 (s, 3 H), 0.99 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 135.55, 135.52, 132.7, 132.6, 131.7, 130.0, 127.873, 127.865, 124.3, 75.8, 73.9, 64.9, 38.1, 26.9, 25.7, 23.2, 22.1, 19.2, 17.6; HRMS (C26H38O3SiNa, APCI): calcd. 449.2482, found 449.2477.

OHOH

O

(S)-1,3-Dihydroxy-3,7-dimethyl-6-octen-2-one (1). To a suspension of 3 (200 mg, 1.06 mmol) and p-benzoquinone (346 mg, 3.20 mmol) in CH3CN/H2O (5 mL/0.5 mL) was added [(2,9-dimethyl-1,10-phenanthroline)-Pd(µ-OAc)]2(OTf)2 (5.6 mg, 0.0054 mmol). The resulting mixture was stirred overnight at rt and subsequently filtered over a silica pad. The pad was washed with ethyl acetate and the combined filtrate was concentrated in vacuo. The residue was purified by column 86


chromatography on silica gel (pentane/EtOAc = 3/1) to afford 1 (180 mg, 91%) as a colorless oil. [α]20

D = +1.6 (c 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ 4.97 (t, J = 7.2 Hz, 1 H), 4.42 (br t, J = 21.6 Hz, 2 H), 2.89 (br s, 2 H), 2.07-1.98 (m, 1 H), 1.88-1.78 (m, 1 H), 1.76-1.63 (m, 2 H), 1.60 (s, 3 H), 1.52 (s, 3 H), 1.30 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 214.1, 133.3, 122.9, 78.5, 64.6, 39.9, 26.1, 25.6, 22.2, 17.7.

O

OH

(2S, 3R)-2,3-Epoxynerol (4). (2S,3R)-4 was prepared from nerol following a procedure similar to that for geraniol to (2R,3R)-4. [α]20

D = -13.0 (c 1.03, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.02 (tt, J = 7.2, 1.2 Hz, 1 H), 3.74 (d, J = 12.0 Hz, 1 H), 3.60-3.55 (m, 1 H), 2.90 (dd, J = 7.2, 4.4 Hz, 1 H), 2.45 (br d, J = 32.0 Hz, 1 H), 2.08-1.99 (m, 2 H), 1.62 (s, 3 H), 1.62-1.57 (m, 1 H), 1.54 (s, 3 H), 1.45-1.37 (m, 1 H), 1.27 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 132.4, 123.3, 64.4, 61.5, 61.2, 33.1, 25.6, 24.1, 22.1, 17.6.

O

OTBDPS

(2S, 3R)-1-tert-Butyldiphenylsilyloxy-2,3-epoxy-3,7-dimethyl-6-octene (5). (2S,3R)-5 was prepared from (2S,3R)-4 following a procedure similar to that for (2R,3R)-4 to (2R,3R)-5. According to HPLC (Chiral OD-H column, heptane/i-PrOH 99.9:0.1, 40 °C, 230 nm) the ee was 74%. Retention time: tmajor = 31.4 and tminor = 24.7 min. [α]20

D = -7.4 (c 0.76, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.61-7.58 (m, 4 H), 7.37-7.32 (m, 6 H), 5.00-4.96 (m, 1 H), 3.81 (dd, J = 8.8, 2.4 Hz, 1 H), 3.74-3.67 (m, 2 H), 2.04 (q, J = 8.4 Hz, 2 H), 1.79-1.65 (m, 2 H), 1.60 (s, 3 H), 1.52 (s, 3 H), 1.40 (s, 3 H), 1.00 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 135.5, 132.9, 132.8 132.2, 129.92, 129.89, 127.8, 123.3, 77.4, 75.5, 64.3, 40.3, 26.8, 25.64, 25.56, 23.0, 19.2, 17.6. HRMS (C26H36O2SiNa, APCI): calcd. 431.2377, found 431.2372.

OHOH

OH

(2S, 3S)-3,7-Dimethyl-6-octene-1,2,3-triol (3). (2S,3S)-3 was prepared from

87

Chapter 4

(2S,3R)-4 following a procedure similar to that for (2R,3R)-4 to (2R,3S)-3. [α]20D =

-1.1 (c 1.09, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.06-5.02 (m, 1 H), 3.68-3.66 (m, 2 H), 3.46-3.44 (m, 1 H), 2.84 (br s, 3 H), 1.99 (apparent q, J = 8.0 Hz, 2 H), 1.61 (s, 3 H), 1.55 (s, 3 H), 1.52-1.50 (m, 1 H), 1.25-1.23 (m, 1 H), 1.10 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 132.0, 124.1, 75.6, 74.5, 63.3, 39.1, 25.7, 22.2, 22.1, 17.6; HRMS (C10H21O3, APCI): calcd. 189.1485, found 189.1484.

OTBDPSOH

OH

(2S, 3S)-1-tert-Butyldiphenylsilyloxy-3,7-dimethyl-6-octene-2,3-diol (6). (2S,3S)-6 was prepared from (2S,3S)-3 following a procedure similar to that for (2R,3S)-3 to (2R,3S)-6. According to HPLC (Chiral AD-H column, heptane/i-PrOH 99:1, 40 °C, 230 nm) the ee was 68%. Retention time: tmajor = 26.7 and tminor = 20.7 min. [α]20

D = -7.2 (c 1.09, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.61-7.59 (m, 4 H), 7.38-7.31 (m, 6 H), 5.03-5.00 (m 1 H), 3.76-3.68 (m, 2 H), 3.46-3.43 (m, 1 H), 1.94 (dd, J = 17.2, 6.8 Hz, 2 H), 1.60 (s, 3 H), 1.52 (s, 3 H), 1.49-1.43 (m, 2 H), 1.02 (s, 3 H), 1.00 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 135.53, 135.50, 132.7, 132.6, 131.6, 130.0, 127.9, 127.8, 124.3, 75.0, 73.6, 65.0, 39.0, 26.8, 25.7, 22.21, 22.17, 19.2, 17.6; HRMS (C26H38O3SiNa, APCI): calcd. 449.2482, found 449.2478.

88


(S)-16 Synthetic (S)-1

CDCl3 500 MHz

δH (J)

CDCl3 400 MHz

δH (J)

Assignments

1

2

3

3-Me

4

5

6

7-Me

7-Me

4.50 (d, 4.9 Hz)4.48 (d, 4.9 Hz)

-

-

1.37 (s)

1.79 (br ddd, 14, 9.8, 6.1 Hz)1.71 (br ddd, 14, 10, 5.8 Hz)

2.09 (br dt, 14, 6.4 Hz)1.90 (br dt, 14, 6.4 Hz)

5.04 (br t, 6.4 Hz)

1.58 (s)

1.67 (s)

1.30 (s)

-

-

1.76-1.63 (m)

2.07-1.98 (m)1.88-1.78 (m)

1.60 (s)

1.52 (s)

4.97 (t, 7.2 Hz)

4.42 (br t, 21.6 Hz)

1H NMR data for (S)-1,3-Dihydroxy-3,7-dimethyl-6-octen-2-one (1)

-OH 2.90-2.95 (m) 2.89 (br s)

(S)-17

CDCl3 500 MHz

δH (J)

4.51 (d, 19.7 Hz)4.47 (d, 19.7 Hz)

-

-

1.37 (s)

1.79 (br ddd, 14.1, 9.7, 6.0 Hz)1.71 (br ddd, 14.1, 9.7, 6.0 Hz)

2.08 (m)1.89 (m)

5.04 (tm, 7.2, 1.4 Hz)

1.58 (br s)

1.66 (m)

2.94 (br s)

In our studies, the chemical shift of residual CHCl3 was set to 7.19 ppm whereas in the literature this was 7.26 ppm. Therefore the values of synthetic 1 are consistently 0.07 ppm lower.

89

Chapter 4

(S)-16 Synthetic (S)-1

CDCl3 125 MHz

δH (J)

CDCl3 100 MHz

δH (J)

Assignments

1

2

3

3-Me

4

5

6

7-Me (E)

7-Me (Z)

64.6

214.2

78.4

39.9

122.9

26.0

17.7

78.5

214.1

39.9

22.2

26.1

133.3

122.9

64.6

13C NMR data for (S)-1,3-Dihydroxy-3,7-dimethyl-6-octen-2-one (1)

7 133.2

25.6

(S)-17

CDCl3 125 MHz

δH (J)

64.65

214.15

78.47

17.66

39.92

22.16

122.95

133.32

26.13

25.63

17.6

22.1

25.6

4.6 References

[1] Kuhar, T. P.; Mori, K.; Dickens, J. C. Agr. Forest. Entomol. 2006, 8, 77-81.

[2] Roush, R. T.; Hoy, C. W.; Ferro, D. N.; Tingey, W. M. J. Econ. Entomol. 1990, 83, 315-319.

[3] Ioannidis, P. M.; Grafius, E.; Whalon, M. E. J. Econ. Entomol. 1991, 84, 1417-1423.

[4] Grafius, E. J. Econ. Entomol. 1997, 90, 1144-1151.

[5] Połeć, I. Pestycydy/Pesticides 2010, 1-4, 33-41.

[6] Olson, E. R.; Dively, G. P.; Nelson, J. O. J. Econ. Entomol. 2000, 93, 447-458.

[7] Dickens, J. C.; Oliver, J. E.; Hollister, B.; Davis, J. C.; Klun, J. A. J. Exp. Biol. 2002, 205,

1925-1933.

[8] Oliver, J. E.; Dickens, J. C.; Glass, T. E. Tetrahedron Lett. 2002, 43, 2641-2643.

[9] Tashiro, T.; Mori, K. Tetrahedron-Asymm. 2005, 16, 1801-1806.

[10] Babu, B. N.; Chauhan, K. R. Tetrahedron Lett. 2009, 50, 66-67.

[11] Painter, R. M.; Pearson, D. M.; Waymouth, R. M. Angew. Chem. Int. Ed. 2010, 49,

9456-9459.

[12] Chung, K.; Banik, S. M.; De Crisci, A. G.; Pearson, D. M.; Blake, T. R.; Olsson, J. V.; Ingram,

A. J.; Zare, R. N.; Waymouth, R. M. J. Am. Chem. Soc. 2013, 135, 7593-7602.

[13] Jäger, M.; Hartmann, M.; de Vries, J. G.; Minnaard, A. J. Angew. Chem. Int. Ed. 2013, 52,

90


7809 –7812.

[14] Conley, N. R.; Labios, L. A.; Pearson, D. M.; McCrory, C. C. L.; Waymouth, R. M.

Organometallics 2007, 26, 5447-5453.

[15] Hashimoto, M.; Harigaya, H.; Yanagiya, M.; Shirahama, H. J. Org. Chem. 1991, 56,

2299-2311.

[16] Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974-5976.

[17] Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am.

Chem. Soc. 1987, 109, 5765-5780.

[18] Nacro, K.; Baltas, M.; Escudier, J. M.; Gorrichon, L. Tetrahedron 1996, 52, 9047-9056.

[19] Molawi, K.; Delpont, N.; Echavarren, A. M. Angew. Chem. Int. Ed. 2010, 49, 3517-3519.

[20] Mohapatra, D. K.; Pramanik, C.; Chorghade, M. S.; Gurjar, M. K. Eur. J. Org. Chem. 2007,

5059-5063.

[21] Gonzalez, I. C.; Forsyth, C. J. J. Am. Chem. Soc. 2000, 122, 9099-9108.

[22] Hanson, R. M. Tetrahedron Lett. 1984, 25, 3783-3786.

[23] Corey, E. J.; Ha, D. C. Tetrahedron Lett. 1988, 29, 3171-3174.

[24] Kolb, M.; Vanhijfte, L.; Ireland, R. E. Tetrahedron Lett. 1988, 29, 6769-6772.

[25] Marshall, J. A.; Trometer, J. D.; Cleary, D. G. Tetrahedron 1989, 45, 391-402.

[26] Vanhijfte, L.; Kolb, M. Tetrahedron 1992, 48, 6393-6402.

[27] Ray, N. C.; Raveendranath, P. C.; Spencer, T. A. Tetrahedron 1992, 48, 9427-9432.

[28] Mori, N.; Kuwahara, Y.; Kurosa, K. Bio-org. Med. Chem 1996, 4, 289-295.

[29] Underwood, B. S.; Tanuwidjaja, J.; Ng, S. S.; Jamison, T. F. Tetrahedron 2013, 69,

5205-5220.

91

Chapter 4

92

Chapter 5

Contributions to A Total Synthesis of Phorbasin B In this chapter, efforts toward to the synthesis of phorbasin B are described. The skeleton of cyclohexenone with all needed three chiral centers was synthesized successfully.

Chapter 5

5.1 Introduction In 1994, the group of Kashman reported the isolation of four chlorinated

phenylpyrrolyloxazoles, phorbazoles A-D, as first in class metabolites from sponges of the genus Phorbas.[1] Embodying an unprecedented chlorinated pyrrole moiety, these compounds represented a new class of marine alkaloids. One year later, two new potent cytostatic macrolides, phorboxazoles A and B, were isolated from the same species by Searle and Molinski.[2] The phorbazoles and the phorboxazoles were the only two accounts on isolation in the early stages of the research on Phorbas species until the discovery of the phorbasins. In 2000, Vuong and Capon isolated a novel unstable polyene diterpene from a southern Australian Phorbas species and named the compound phorbasin A[3] (Figure 1). In their ongoing investigations into the chemistry of southern Australian marine sponges they found another two phorbasin family members, phorbasin B and C, which displayed growth inhibitory activity against the Gram positive bacteria Staphylococcus aureus and Micrococcus luteus.[4] Recently, additional phorbasin members have been obtained, and studies have shown that this class of diterpenes possesses a range of specific cytotoxic properties.[5]

O OH

HO

phorbasin A

OH

O

OR

HHO

phorbasin B: R = Hphorbasin C: R = Ac

S

N

O

OR

HHO

H

O

H

OHH

OH

OO

*

*

phorbasin E: R = Hphorbasin F: R = Ac

OOH

H

OHOH

"carvotacetone" skeleton

11

Figure 1. Phorbasins and related structures

5.2 The reported synthesis of phorbasin C

Structurally, the phorbasins are related to the terrestrial carvotacetone monoterpenes and carvone itself. Initially, the absolute stereochemistry of phorbasin B and C was depicted as in Figure 1 whereas the relative stereochemistry at C11 was not defined. In 2009, Micalizio completed the first total synthesis of (+)-phorbasin C and elucidated its structure[6] (Scheme 1). Starting from the chiral diene 1, they furnished the stereodefined diol 2. A subsequent, rather spectacular, titanium-mediated

94

Contributions to a total synthesis of phorbasin B

reductive cross-coupling of 2 with TMS-propyne via a formal metallo-[3,3] rearrangement (A) afforded 1,4-diene 3 with exquisite selectivity after protonation of alkoxide B. 3 was further functionalized to vinyl iodide 7, the substrate for a subsequent Suzuki cross-coupling. In order to determine the stereochemistry at C11, the skeleton of the target molecule was assembled by Suzuki cross-coupling of 7 with both 8S and 8R, in turn prepared from 11R/11S by repetitive oxidation and olefination in several steps, to give compounds 9 and 10. This synthesis completed the structure elucidation of phorbasin C as ent-10.

OH

O

OH

HHO

BrOH

HO1) 2,2-DMP, pTSA2) OsO4, NMO

3) Bu3SnH, AIBN65% OH

HO

OO

TMS-propyne

c-C5H9MgCl, Et2O

then add to thebis-lithium alkoxide of 2

1 2−78 oC to r.t.

O

OH

O

OTi

TMS

Men(L)

M

TMS

Ti(L)n-1OO

OO H

M

TMS

HO

OO H

A B

3

H+

47%

1) VO(acac)2, TBHP, toluene, 50oC (63%)2) (COCl)2, DMSO, Et3N, CH2Cl23) Ph3P=CH2, THF, 0 to 5 oC (79%)

TMSO

O

O

H

H

H

4

1) Pd(PPh3)4, AcOH, THF2) Ac2O, pyr, DMAP, CH2Cl2

90%

TMSO

O H

5

AcOOAc

1) NIS, CH3CN (77%)2) TFA, H2O, THF3) IBX, DMSO (75%)

IH

6

AcOOAc

OOH

Sc(OTf)3MeOH, H2O

80%

IH

7

HOOAc

OOH

Pd(PPh3)4, Tl2CO3

THF, H2O

BO

O

H

9

HOOAc

OOH

H

HOOAc

OOH

8S

10

8S

8R

63%

67%

ent-10

phorbasin C[α]22

D −131 (c 0.18, MeOH) (lit. value)

[α]22D +124 (c 0.18, MeOH)

OH

OTHP

11R

Ti(OiPr)4

Scheme 1. Total synthesis of (+)-phorbasin C

5.3 Retrosynthesis of phorbasin B

In 2013, Y. Huang in our institute developed a novel catalytic asymmetric aproach to skipped dienes with a methyl-branched central stereocenter, using copper-catalyzed asymmetric allylic alkylation of diene bromides[7] (Scheme 2). This system affords excellent regio- and enantioselectivity with a reasonable substrate scope. We realized that this method can provide a concise way to the synthesis of the side chain of the phorbasins, which encouraged us to design a novel approach to phorbasin B.

95

Chapter 5

R1 BrR3

R2

R1R3

R2

R1

R2

R3

+

CuBr.SMe2 5 mol%

12

13 6 mol%MeMgBr 1.2 eq

CH2Cl2−80 oC, overnight

14 15

14/15 up to 97:3, ee up to 99%

PPh2Ph2P NMe2

Fe

13R1= Ph, aryl, ester, TBSOCH2 or HR2 = H, Me or ester

R3 = H or Me

Scheme 2. Copper-catalyzed asymmetric allylic alkylation of diene bromides

Based on this idea, we retrosynthetically disconnected phorbasin B to substituted

2-cyclohexen-1-one 20 and 1,4-diene 21 (Figure 2), in the synthetic direction to be joined via a crosss-methathesis reaction. In an initial synthetic approach in our department, Huang made a considerable effort towards the synthesis of ent-21 via a chiral TADDOL-titanium complex-catalyzed asymmetric Diels-Alder reaction[8] of vinyl borate 16 and a dienol acetate 17 (Scheme 3).[9] However, this Diels-Alder reaction was unsuccessful, and enforced the design of an alternative synthetic route.

B NO

O

O

O

O

O

O

O

O OHOHPh

PhPh

Ph Ph

18 (5 mol%)iPrO2TiCl2 (5 mol%)4Å MS, toluene/PE

B

OAc

N

O

O

O

O

O

+

18

OPG

O

OPG

HOPG

ent-21

16 17 19

Scheme 3. Huang’s attempt on the synthesis of ent-21 via D-A reaction.

In this new approach, we planned to prepare the 1,3-diene part of 21 by extending

the hydroxymethyl group in 22. Compound 22, in turn, is a Rubottom/Baylis-Hillman product of cyclohexenone 23 (Figure 3). Compound 23 was expected to be the product of the intramolecular aldol condensation of keto-aldehyde 24, in turn derived, after functional group transformation, from the Evans aldol reaction product 25.

96


OPG

OOH

OPG

HOPG

OOPG

OPG

H O

OOPG

OPG OHOH

22 23 24 25

OH

O

OH

HHO

OPG

O

OPG

HOPG

+

phorbasin B 2120

Figure 2. Retrosynthesis of phorbasin B

5.4. Results and discussion

The synthesis commenced with the preparation of chiral oxazolidinone 29 (Scheme 4). Acyl chloride 27 was treated with deprotonated (4S)-(-)-isopropyl-2-oxazolidinone 28 to give 29 in 87% yield.[10] The Evans aldol reaction of 29 and aldehyde 30, followed by an oxidative cleavage of the resulting borinate ester with H2O2 in methanol/aqueous phosphate buffer of pH 7[11] furnished the two desired chiral centers of product 32 as diastereomers (d.r. 82:18). The use of a phosphate buffer was essential to avoid elimination to the aldol condensation product. Then, reduction of 32 by LiBH4 in THF/MeOH afforded a diastereomeric mixture of diol 25 in 90% yield. The protection of diol 25 was accomplished by acetal formation. Catalyzed by pyridinium p-toluenesulfonate, 25 reacted with benzaldehyde dimethyl acetal at room temperature[12] to give 33, together with a small amount of inseparable impurities but fortunately as one diastereomer because trans-25 did not react. Therefore the product was used as such in the next step. The Wacker oxidation of 33 with oxygen and PdCl2/Cu(OAc)2 in AcNMe2/water at room temperature[13] afforded ketone 34 in a disappointing 38% yield over two steps from 25. The internal alkene of 34 was cleaved by ozonolysis and a subsequent intramolecular aldol condensation[14] of keto-aldehyde 24 resulted in the desired cyclohexenone 23 in 52% yield over two steps from 34.

97

Chapter 5

OH

O

Cl

O

oxalyl chloride NaH

O NH

O

O N

O O nBu2BOTf, DIPEADCM, 0 oC

−78 oC, 3 h, then r.t., overnight

H

O

O N

O O OBBu2

MeOH, H2O2pH~7 buffer

r.t., 1 h

O N

O O OH OH OH

LiBH4THF-MeOH

0 oC, 2 h

PPTS, PhCH(OMe)2DCM

O O

Ph

PdCl2, Cu(OAc)2AcNMe2/H2O

O2O3

DCM, −78 oC

O O

O

Ph

O O

O

O

Ph

O O

O

Ph

1. DBU, DCM

2. MsCl,Et3N DCM

26 27 29 (87%)

31 32 (78%) 25 (90%)

33 34 (38%) 24 23 (52%)

30DMF

0 oC to r.t., 1 h THF0 oC to r.t., overnight

r.t., overnight

r.t., 2 d

r.t., overnight

r.t., 0.5 h

28

Scheme 4. Synthesis of cyclohexenone 23

To furnish the stereoselective α-hydroxylation of ketone 23 by Rubottom oxidation,

initially triethylsilyl enol ether 35 was synthesized in 78% yield by treating 23 with TESOTf and Et3N in CH2Cl2 (Scheme 5).[15] Unfortunately, in the subsequent oxidation both dimethyl dioxirane (DMDO)[16] and m-CPBA[17] solely produced epoxide 36 in moderate yields without formation of the expected Rubbotom reaction product 38. In the 1H-NMR and 13C-NMR of 36, no diastereomer of 36 was detected. In the epoxidaton of silyl enol ether 35, DMDO and m-CPBA attacked the opposite side of the [1,3]dioxinyl ring exclusively owing to the steric hindrance. To get to 38, the TES group was removed to afford α-hydroxy ketone 37 after rearrangement[17] and the newly generated hydroxyl group was re-protected by treatment of 37 with TBSCl and imidazole in DMF at room temperature. Although 38 was synthesized this way successfully, the route is rather inefficient due to the low yields and the number of steps.

98


TESOTf, Et3NO O

OTES

Ph

O O

O

Ph

23 35 (78%)

DMDOCH3CN/DME

O O

OTES

Ph

O

TBAFDCM, rt

O O

O

Ph

HO

36 (49%) 37 (77%)

O O

O

Ph

TBSO

38 (quant.)

ImidazoleDMF, rt

TBSCl

0oC to r.t., 0.5 h r.t. 2 hDCM

Scheme 5. Synthesis 38 from 23 by Rubottom oxidation

In a later stage of the research, we found that tert-butyldimethylsilyl enol ether 39

is a more suitable substrate for Rubottom reaction. 39 was prepared from 23 in 81% yield following a similar procedure as for 35 (Scheme 6). Oxidation of 39 with m-CPBA gave the desired rearrangement product 38 as well as a substantial amount of the corresponding deprotected product 37. An improved yield of 38 was obtained by treating 39 with DMDO in a mixture of acetone/CH2Cl2/water at room temperature.[18] Employing these conditions, 38 was synthesized in a satisfying 64% yield together with 12% of 37 in one step from 39.

O O

OTBS

Ph

O O

O

Ph

23 39 (81%)

O O

O

Ph

HO

37

O O

O

Ph

TBSO

38

TBSOTf mCPBADCM

+

Acetone/DCM/H2 O

O O

O

Ph

38 (64%)

TBSO

O O

O

Ph

HO

+

37 (12%)

DMDO0 oC to r.t., 0.5 h

Et3Nr.t., 0.5 h r.t., 0.5 h

Scheme 6. An improved Rubottom oxidation to provide 38

In the next step, we planned to introduce a hydroxymethyl group at C7 via

Baylis-Hillman reaction. This reaction is initiated by conjugate addition of a suitable nucleophile, commonly used are dimethylamino pyridine (DMAP)[19] and 1,4-diazabicyclo[2.2.2]octane. (DABCO).[20] The resulting enolate subsequently reacts with, in our case, formaldehyde and elimination of DMAP or DABCO then

99

Chapter 5

provides the product. The conjugate addition of the nucleophile should on the one hand be favorable, to provide a sufficient concentration of the enolate, but on the other hand not suffer from direct addition of the nucleophile to the aldehyde and be reversible. These constraints have provided the Baylis-Hillman reaction with a dubious reputation in organic synthesis and long reaction times are often required. This was confirmed in the initial attempts, as 38 did not react with formaldehyde even over weeks (Table 1). To accelerate the Baylis-Hillman reaction, Ito and Iguchi in 2005 reported[21] the use of tributylphosphine and Me2PhP in the reaction of 2-cyclopenten-1-one and 2-cyclohexen-1-one with aldehydes, and this provided the corresponding Baylis-Hillman products within a short time and in good yields (Scheme 7). The authors observed that the rate of the reaction was strongly dependent on the solvent and the optimal solvent combination in their hands was a mixture of MeOH, CHCl3, and water. With this catalytic system, the Baylis-Hillman reaction of 38 with formaldehyde (37% in H2O) indeed afforded the desired primary alcohol 40 as the major product and 1,4-adduct 41 as a minor side product, the latter which unfortunately became the major product upon scale up. To suppress the formation of 41, the use of CHCl3 as the sole solvent (together with the water coming with the aqueous formaldehyde) was examined, which turned out to be very successful. Finally, employing this optimized system, 40 was obtained in 53% yield in a 2 d reaction with no 41 observed (Scheme 8). The primary alcohol of 41 was subsequently protected with a TBS-group to afford 42 in 94% yield.

O O

OH37% HCHO in H2O

5 mol% Bu3PMeOH-CHCl3r.t., 2 h

82%

Scheme 7. The Baylis-Hillman reaction according to Ito and Iguchi

100


O O

O

Ph

38

TBSO37% HCHO

O O

O

Ph

40

TBSOOH

DMAP

DABCO

solvents

THF

THF

results

N.R.

N.R.

time

21d

14d

Bu3P CHCl3-MeOH overnight 40 (major) + 41 (minor)

O O

O

Ph

41

TBSO

OMe

Bu3P CHCl3-MeOH overnight 40 (minor) + 41 (major)

Bu3P CHCl3 overnight 40

nucleophilic catalyst

solvents, r.t.

entry

1

2

3

4*

5

* scale-up

nucleophilic catalyst

Table 1. Investigation of the Baylis-Hillman reaction of 38 with formaldehyde

O O

O

Ph

38

TBSO r.t., 2d

O O

O

Ph

40 (53%)

TBSOOH

Bu3P, 37% HCHOCHCl3

TBSCl, ImidazoleDCMr.t., 2 h

O O

O

Ph

42 (94%)

TBSOOTBS

ongoing

OH OPG

OTBSO

OTBS

22 Scheme 8. Synthesis of 42

The next step in the synthesis is the planned deprotection of the acetal in 42,

preferably leaving a benzyl protecting group on the secondary alcohol. This however, turned out to be very difficult and we were not able to provide a satisfying protocol. Various conditions reported for the regioselective reductive ringopening, e.g. DIBAL,[22] BH3⋅THF in combination with Cu(OTf)2,[23] Pd(OH)2/C and H2, EtSH/Zn(OTf)2,[24] PDC/tBuOOH,[25] and TES/TFA,[26] were examined, but the desired product 22 was never observed and side products often appeared due to further reduction or deprotection of the TBS-protected alcohol. As the available time was consumed, the synthesis of phorbasin B was not further pursued from this point. 5.5 Conclusion

In summary, the three chiral centers in the cyclohexenone fragment of phorbasin B have been constructed efficiently via Evans aldol reaction and Rubottom oxidation. Wacker oxidation afforded the carbonyl group for phorbasin B while the subsequent ozonolysis and intramolecular aldol condensation resulted in the desired

101

Chapter 5

cyclohexenone. Given the recent advances in the Wacker oxidation, the overall yield in this sequence might well be improved. Employing an optimized Baylis-Hillman reaction, hydroxymethylation of the cyclohexenone fragment was achieved successfully. Although a yield of 53%, might seem modest, the added complexity to the molecule in combination with a carbon-carbon bond formation compensates for the moderate yield.

As the selective deprotection of 42 is apparently not achievable, full deprotection of 42 under acidic conditions followed by selective protection/deprotection of the resulting hydroxyl groups might well bring a solution. An alternative could be the use of a more readily removable protecting group, for example a p-methoxy benzyl group that can be oxidatively cleaved.

Once the primary alcohol 22 is obtained, further functionalization to furnish the side chain of phorbasin B is envisioned through oxidation (to 43), alkynylation (to 44), Zr-catalyzed methylalumination/iodination (45) and finally Suzuki cross-coupling (to provide 21). In the final stages, metathesis of fragment 21 and the 1,4-diene 20 is planned to afford the natural product phorbasin B (Scheme 9).

O OPG

OGPO

43

OPG

OPG

OGPO

OPG

44

OPG

OGPO

OPG

45

IOPG

OGPO

OPG

21

O O

O

Ph

42

TBSOOTBS

OH OPG

OGPO

OPG

22

OH

O

OH

HHO

phorbasin B Scheme 9. The planning for the remaining steps in the synthesis of phorbasin B

5.6 Experimental section General remarks: 1H-NMR and 13C-NMR spectra were recorded on a Varian AMX400 (400 and 100 MHz, respectively) with CDCl3 as solvent. Chemical shifts were determined relative to the residual solvent peaks (CHCl3, δ = 7.26 ppm for 1H-NMR, δ = 77.0 ppm for 13C-NMR). The following abbreviations are used to indicate signal multiplicity: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad. Optical rotations were measured on a Schmidt + Haensch polarimeter (Polartronic MH8) with a 10 cm cell (c given in g/100 mL) at rt, with equals approximately 20 degrees. Thin-layer chromatography (TLC) was performed on Merck TLC Silica gel 60 Kieselguhr F254. Flash chromatography was performed on silica gel Merck Type 9385 230-400 mesh. All starting materials and chemical reagents were purchased from Aldrich, Acros and 102


TCI.

O N

O O

(S)-4-(1-Methylethyl)-3-(1-oxo-4-pentenyl)-2-oxazolidinone (29).[10] To a stirred mixture of 4-pentenoic acid 26 (9.3 mL, 91 mmol) and a few drops of DMF, oxalyl chloride (8.2 mL, 91 mmol) was slowly added at 0 oC. The reaction mixture was allowed to warm to rt and stirred for 1 h to afford 4-pentenoyl chloride 27. To a stirred solution of (4S)-(-)-isopropyl-2-oxazolidinone 28 (10.0 g, 77.4 mmol) in dry THF (100 mL) was added NaH (3.7 g, 93 mmol, as a 60% dispersion in mineral oil) at 0 oC under nitrogen. The resulting mixture was stirred for 1 h and then was added 27 drop-wise. The reaction mixture was allowed to warm to rt and stirred overnight. Subsequently, the reaction was quenched by the addition of saturated NH4Cl (aq) and the organic layer was separated. The aqueous layer was extracted with Et2O and the combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (pentane : Et2O = 3 : 1) to afford 29 (14.2 g, 87%) as a colorless oil. [α]20

D = +823 (c 1.20, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.86-5.76 (m, 1 H), 5.07-4.94 (m, 2 H), 4.41-4.37 (m, 1 H), 4.26-4.15 (m, 2 H), 3.09-3.01 (m, 1 H), 2.98-2.88 (m, 1 H), 2.42-2.29 (m, 3 H), 0.87 (dt, J = 7.2 Hz, 2.8 Hz, 3 H), 0.83 (dt, J = 7.2 Hz, 2.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 172.4, 154.0, 136.7, 115.5, 63.4, 58.3, 34.7, 28.34, 28.29, 17.9, 14.6; HRMS (ESI) calcd. for C11H18NO3 [M + H]+ 212.1281, found 212.1273.

O N

O O OH

(S)-4-(1-Methylethyl)-3-((2S,3R)-2-allyl-3-hydroxy-5-methyl-1-oxo-4-hexenyl)-2-oxazolidinone (32). To a solution of 29 (14.2 g, 67 mmol) in dry CH2Cl2 (120 mL) was added dibutylboron triflate (74 mL, 74 mmol, 1 M in CH2Cl2) at 0 oC under nitrogen. The resulting solution was stirred for 15 min at 0 oC and then DIPEA (14.0 mL, 80.5 mmol) was added. The reaction mixture was stirred for an additional 1.5 h before cooling down to –78 oC. Then 3-methyl-2-butenal 30 (6.8 mL, 71 mmol) was added and the reaction mixture was stirred for 3 h before warming to rt. The resulting solution was stirred overnight at rt and quenched with phosphate buffer of pH 7. Then

103

Chapter 5

a mixture of methanol / 30% aqueous H2O2 (150 mL, v/v = 2/1) was added to the mixture and the organic layer was separated after stirring vigorously for 1 h. The aqueous layer was extracted with CH2Cl2 and the combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated in vacuo.[11] The residue was purified by column chromatography on silica gel (pentane : CH2Cl2 = 3 : 1) to afford 32 (15.5 g, 78%) as white solid. [α]20

D = +43 (c 0.89, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.85-5.75 (m, 1 H), 5.24 (dt, J = 8.8 Hz, 1.2 Hz, 1 H), 5.05 (dd, J = 16.8 Hz, 1.2 Hz, 1 H), 4.97 (d, J = 10.4 Hz, 1 H), 4.57 (dd, J = 8.8 Hz, 6.0 Hz, 1 H), 4.43-4.40 (m, 1 H), 4.30-4.25 (m, 1 H), 4.22-4.14 (m, 2 H), 2.52-2.43 (m, 3 H), 2.29-2.25 (m, 1 H), 1.70 (d, J = 0.8 Hz, 3 H), 1.65 (d, J = 0.8 Hz, 3 H), 0.87 (d, J = 6.8 Hz, 3 H), 0.82 (d, J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 174.3, 154.1, 136.9, 135.3, 124.1, 116.9, 69.3, 63.1, 58.7, 47.7, 32.8, 28.3, 25.9, 18.4, 18.0, 14.6; HRMS (ESI) calcd. for C16H24NO3 [M - OH]+ 278.1751, found 278.1740. OH OH

(2R,3R)-2-Allyl-5-methylhex-4-ene-1,3-diol (25). To a solution of 32 (15.2 g, 51.5 mmol) in MeOH/THF (80 mL/80 mL) was added LiBH4 (2.24 g, 103 mmol) at 0 oC. The reaction mixture was stirred for 2 h at rt and quenched with saturated NH4Cl (aq). The solution was extracted with Et2O and the combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (pentane : Et2O = 1 : 1) to afford 25 (7.9 g, 90%) as white solid. [α]20

D = +9 (c 0.30, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.87-5.77 (m, 1 H), 5.36-5.33 (m, 1 H), 5.09-5.01 (m, 2 H), 4.57 (dd, J = 9.2 Hz, 4.4 Hz, 1 H), 3.77 (dd, J = 11.2 Hz, 7.2 Hz, 1 H), 3.67 (dd, J = 11.2 Hz, 4.4 Hz, 1 H), 2.27-1.96 (m, 5 H), 1.76 (d, J = 1.2 Hz, 3 H), 1.69 (d, J = 1.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 136.9, 136.7, 124.4, 116.3, 71.2, 64.0, 45.2, 31.4, 26.0, 18.4; HRMS (APCI) calcd. for C11H17O [M - OH]+ 153.1274, found 153.1273.

O O

Ph

(4R,5R)-5-Allyl-4-(2-methylprop-1-en-1-yl)-2-phenyl-1,3-dioxane (33). To a solution of 25 (7.90 g, 46.4 mmol) in CH2Cl2 (100 mL) was added pyridinium p-toluenesulfonate (0.58 g, 2.3 mmol) and benzaldehyde dimethyl acetal (7.3 mL, 49 104


mmol) at rt. The resulted mixture was stirred overnight and quenched with Et3N.[12] The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (pentane : Et2O = 30 : 1) to afford impure 33 (10 g) and starting material (1.4 g). The obtained 33 was used for the next step without further purification. [α]20

D = +9.6 (c 1.36, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.52-7.49 (m, 2 H), 7.38-7.30 (m, 3 H), 5.88-5.78 (m, 1 H), 5.60 (s, 1 H), 5.37 (dt, J = 8.0 Hz, 1.2 Hz, 1 H), 5.15 (dd, J = 16.8 Hz, 1.2 Hz, 1 H), 5.08 (d, J = 10.0 Hz, 1 H), 4.78 (dd, J = 8.0 Hz, 2.4 Hz, 1 H), 4.24(dd, J = 11.6 Hz, 1.2 Hz, 1 H), 4.00 (dq, J = 11.6 Hz, 1.2 Hz, 1 H), 2.68-2.59 (m, 1 H), 2.44-2.38 (m, 1 H), 1.76 (s, 3 H), 1.72 (s, 3 H), 1.48 (dt, J = 10.8 Hz, 1.2 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 138.7, 137.3, 135.3, 128.8, 128.3, 126.2, 123.3, 116.7, 102.2, 77.7, 69.4, 38.1, 29.2, 25.9, 18.6; HRMS (APCI) calcd. for C17H23O2 [M + H]+ 259.1693, found 259.1693.

O O

O

Ph

(4R,5R)-4-(2-Methylprop-1-en-1-yl)-5-(2-oxopropyl)-2-phenyl-1,3-dioxane (34) To a solution of 33 (7.7 g from the previous step) in AcNMe2/water (7 : 1, 160 mL) was added PdCl2 (528 mg, 3.0 mmol) and Cu(OAc)2⋅H2O (1.19 g, 6.0 mmol) and the reaction flask was equipped with a balloon filled with oxygen. The reaction mixture was stirred for 2 d at rt and subsequently diluted with ether. The organic layer was separated and the aqueous layer was extracted with ether. The combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated in vacuo.[13] The residue was purified by column chromatography on silica gel (pentane : ether = 3 : 1) to afford 34 (3.33 g, 38% over two steps) as a colorless oil. [α]20

D = +3.4 (c 2.07, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.51-7.48 (m, 2 H), 7.39-7.33 (m, 3 H), 5.58 (s, 1 H), 5.22 (dt, J = 7.2 Hz, 1.2 Hz, 1 H), 4.74 (dd, J = 7.2 Hz, 2.4 Hz, 1 H), 4.09 (d, J = 1.6 Hz, 2 H), 3.07 (dd, J = 18.8 Hz, 9.6 Hz, 1 H), 2.75 (dd, J = 18.4 Hz, 3.2 Hz, 1 H), 2.19 (s, 3 H), 2.16-2.13 (m, 1 H), 1.74 (s, 3 H), 1.70 (d, J = 1.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 208.3, 138.5, 136.2, 128.9, 128.3, 126.0, 122.8, 101.9, 77.4, 71.0, 39.5, 33.5, 30.6, 25.8, 18.7; HRMS (ESI) calcd. for C17H22O3Na [M + Na]+ 259.1693, found 259.1693.

105

Chapter 5

O O

O

O

Ph

(4S,5R)-4-Carbaldehyde-5-(2-oxopropyl)-2-phenyl-1,3-dioxane (24) Through a stirred solution of 34 (3.32 g, 12.1 mmol) in CH2Cl2 (30 mL) at –78 oC was bubbled ozone during 1 h until a blue color persisted. Subsequently, nitrogen was bubbled through the solution until the blue color had disappeared. Me2S (5 mL) was added dropwise and the mixture was stirred at rt for 2 h. Volatiles were removed under reduced pressure and the residue (crude 24) was used in the next step without further purification.

O O

O

Ph

(4aR,8aR)-2-Phenyl-4a,5-dihydro-4H-benzo[d][1,3]dioxin-6(8aH)-one (23) To a solution of 24 (from the previous step) in CH2Cl2 (80 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.8 mL, 12 mmol) at rt. The resulted mixture was stirred overnight followed by addition of MsCl (2.8 mL, 36 mmol) and Et3N (15 mL, 109 mmol). The reaction mixture was stirred for another 0.5 h and quenched with saturated NH4Cl (aq). The organic layer was separated and the aqueous layer was extracted with ether. The combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated in vacuo.[14] The residue was purified by column chromatography on silica gel (pentane : ether = 1 : 1) to afford 23 (1.44 g, 52% over two steps) as a yellow oil. [α]20

D = -158 (c 0.85, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.51-7.48 (m, 2 H), 7.40-7.35 (m, 3 H), 6.93 (dd, J = 10.0 Hz, 5.6 Hz, 1 H), 6.19 (d, J = 10.0 Hz, 1 H), 5.60 (s, 1 H), 4.56 (dd, J = 5.6 Hz, 2.8 Hz, 1 H), 4.24 (dd, J = 12.0 Hz, 3.2 Hz, 1 H), 4.08 (d, J = 12.0 Hz, 1 H), 3.23 (dd, J = 16.4 Hz, 13.6 Hz, 1 H), 2.45 (dd, J = 16.4 Hz, 4.0 Hz, 1 H), 2.08 (dd, J = 13.6 Hz, 4.0 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 199.7, 142.7, 137.7, 132.7, 129.2, 128.4, 126.1, 101.9, 70.6, 70.0, 37.1, 32.6; HRMS (ESI) calcd. for C14H15O3 [M + H]+ 231.1016, found 231.1007.

106


O O

OTES

Ph

Triethyl(((4aR,8aR)-2-phenyl-4a,8a-dihydro-4H-benzo[d][1,3]dioxin-6-yl)oxy)silane (35) To a solution of 23 (203 mg, 0.88 mmol) in CH2Cl2 (10 mL) were added Et3N (0.15 mL, 1.06 mmol) and TESOTf (0.24 mL, 1.06 mmol) at 0 oC. The resulting mixture was warmed to rt and stirred for 0.5 h. The reaction was quenched with saturated NH4Cl (aq) and the organic layer was separated. The aqueous layer was extracted with ether and the combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated in vacuo.[15] The residue was purified by column chromatography on silica gel (pentane : ether = 15 : 1) to afford 35 (236 mg, 78%) as a colorless oil. [α]20

D = -178 (c 0.64, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.46-7.43 (m, 2 H), 7.33-7.31 (m, 3 H), 6.10 (dd, J = 9.6 Hz, 2.0 Hz, 1 H), 6.02 (d, J = 9.6 Hz, 5.6 Hz, 1 H), 5.47 (s, 1 H), 5.07 (t, J = 1.2 Hz, 1 H), 4.31 (td, J = 5.2 Hz, 1.2 Hz, 1 H), 4.242-4.235 (m, 2 H), 2.35 (t, J = 2.0 Hz, 1 H), 1.02 (t, J = 8.0 Hz, 9 H), 0.74 (q, J = 8.0 Hz, 6 H); 13C NMR (100 MHz, CDCl3) δ 148.6, 138.5, 131.4, 128.9, 128.2, 126.3, 124.2, 106.8, 100.5, 70.7, 69.4, 34.8, 6.7, 4.9; HRMS (ESI) calcd. for C20H29O3Si [M + H]+ 345.1881, found 345.1875.

O O

OTES

Ph

O Triethyl(((1aS,3aR,7aR,7bS)-5-phenyl-3a,7,7a,7b-tetrahydro-1aH-oxireno[2',3':3,4]benzo[1,2-d][1,3]dioxin-1a-yl)oxy)silane (36) To a solution of 35 (82 mg, 0.24 mmol) in CH3CN/DME (dimethoxyethane) (3 mL, 2 : 1) were added Bu4NHSO4 (3.9 mg, 0.012 mmol), acetone (0.64 mL, 8.7 mmol) and 0.1 M K2CO3 (0.58 mL). Oxone (533 mg, 0.87 mmol in 2.3 mL 4 × 10-4 M EDTA solution) and K2CO3 (533 mg, 3.86 mmol in 2.3 mL H2O) were added separately by syringe pump over 1.5 h at rt. The reaction mixture was stirred for 2 h and subsequently extracted with ether. The combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated in vacuo.[16] The residue was purified by column chromatography on silica gel (pentane : ether = 5 : 1) to afford 36 (42 mg, 49%) as a colorless oil. [α]20

D = -149 (c 0.50, CHCl3);1H NMR (400 MHz, CDCl3) δ 7.50-7.48 (m, 2 H), 7.40-7.36 (m, 3 H), 6.81 (dd, J = 9.6 Hz, 5.2 Hz, 1 H), 6.14 (d, J = 9.6 Hz, 1 H), 5.63 (s, 1 H), 4.91 (d, J =

107

Chapter 5

12.0 Hz, 1 H), 4.69 (dd, J = 5.2 Hz, 2.8 Hz, 1 H), 4.62 (d, J = 12.0 Hz, 1 H), 4.02 (dd, J = 12.0 Hz, 2.8 Hz, 1 H), 1.97 (d, J = 11.2 Hz, 1 H), 1.02 (t, J = 8.0 Hz, 9 H), 0.78-0.71 (m, 6 H); 13C NMR (100 MHz, CDCl3) δ 199.5, 141.4, 137.8, 131.3, 129.2, 128.4, 126.1, 102.4, 72.2, 71.2, 66.9, 40.3, 6.8, 4.9; HRMS (ESI) calcd. for C20H29O4Si [M + H]+ 361.1830, found 361.1825.

O O

OTBS

Ph

tert-Butyldimethyl(((4aR,8aR)-2-phenyl-4a,8a-dihydro-4H-benzo[d][1,3]dioxin-6-yl)oxy)silane (39) 39 was prepared from 23 in 81% yield based on recovered starting material according to a procedure for the preparation of 35. [α]20

D = -165 (c 0.33, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.45-7.43 (m, 2 H), 7.35-7.30 (m, 3 H), 6.07 (dd, J = 10.0 Hz, 1.6 Hz, 1 H), 6.01 (dd, J = 10.0 Hz, 5.2 Hz, 1 H), 5.47 (s, 1 H), 5.06 (s, 1 H), 4.33-4.30 (m, 1 H), 4.242-4.238 (m, 2 H), 2.35 (s, 1 H), 0.96 (s, 9 H), 0.21 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 148.7, 138.5, 131.5, 128.9, 128.2, 126.3, 124.2, 107.1, 100.5, 70.7, 69.4, 34.8, 25.7, 18.1, -4.4, -4.5; HRMS (ESI) calcd. for C20H29O3Si [M + H]+ 345.1881, found 345.1883.

O O

O

Ph

38 (64%)

TBSO

O O

O

Ph

HO

+

37 (12%) (4aR,5S,8aR)-5-((tert-Butyldimethylsilyl)oxy)-2-phenyl-4a,5-dihydro-4H-benzo[d][1,3]dioxin-6(8aH)-one (38) To a solution of 39 (1.0 g, 2.9 mmol) in CH2Cl2/acetone (38 mL, 1 : 1) were added 18-crown-6 (77 mg, 0.29 mmol) and NaHCO3 (1.16 g, 13.8 mmol in 15 mL water). The resulting mixture was cooled to 0 oC followed by addition of oxone (2.10 g, 3.42 mmol in 10 mL H2O). The reaction mixture was warmed to rt and stirred for 2 h before quenching with saturated Na2S2O3 (aq) and NaHCO3 (aq). The mixture was subsequently extracted with CH2Cl2 and the combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated in vacuo.[18] The residue was purified by column chromatography on silica gel (pentane : ether = 5 : 1 to 1 : 1) to afford 38 (664 mg, 64%) and 37 (85 mg, 12%) as colorless oils. 38: [α]20

D = -182 (c 0.94, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.50-7.48 (m, 2 H), 7.40-7.36 (m, 3 H), 6.81 (dd, J = 10.0 Hz, 5.2 Hz, 1 H), 6.14 (d, J = 10.0 Hz, 1 H), 5.63 (s, 1 H),

108


4.90 (d, J = 11.6 Hz, 1 H), 4.70 (dd, J = 5.6 Hz, 3.2 Hz, 1 H), 4.65 (d, J = 12.0 Hz, 1 H), 4.02 (dd, J = 12.0 Hz, 2.4 Hz, 1 H), 1.99 (ddd, J = 11.6 Hz, 2.4 Hz, 2.0 Hz, 1 H), 0.98 (s, 9 H), 0.23 (s, 3 H), 0.14 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 199.5, 141.4, 137.8, 131.3, 129.2, 128.4, 126.1, 102.3, 72.3, 71.4, 66.8, 40.3, 25.9, 18.6, -4.3, -5.6; HRMS (ESI) calcd. for C20H28O4SiNa [M + Na]+ 383.1649, found 383.1644. (4aS,5S,8aR)-5-Hydroxy-2-phenyl-4a,5-dihydro-4H-benzo[d][1,3]dioxin-6(8aH)-one (37): [α]20

D = -138 (c 1.15, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.52-7.50 (m, 2 H), 7.41-7.36 (m, 3 H), 6.95 (dd, J = 10.0 Hz, 5.6 Hz, 1 H), 6.28 (d, J = 10.0 Hz, 1 H), 5.64 (s, 1 H), 4.87 (d, J = 12.0 Hz, 1 H), 4.71-4.67 (m, 2 H), 4.00 (dd, J = 12.4 Hz, 2.8 Hz, 1 H), 3.48 (br s, 1 H), 1.91-1.87 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 200.7, 143.8, 137.6, 129.6, 129.2, 128.3, 126.1, 102.2, 71.4, 69.4, 66.8, 39.7; HRMS (ESI) calcd. for C14H15O4 [M + H]+ 247.0965, found 247.0958.

O O

O

Ph

TBSOOH

(4aR,5S,8aR)-5-((tert-Butyldimethylsilyl)oxy)-7-(hydroxymethyl)-2-phenyl-4a,5-dihydro-4H-benzo[d][1,3]dioxin-6(8aH)-one (40). To a solution of 38 (210 mg, 0.58 mmol) in CHCl3 (4 mL) were added formaldehyde (0.10 mL, 1.3 mmol, 37% in water) and Bu3P (0.05 mL, 0.20 mmol) at rt.[21] The reaction mixture was stirred at room temperature for 2 d (in case the reaction ceased, more Bu3P was added) and purified directly by column chromatography on silica gel (pentane : ether = 1 : 1) to afford 40 (120 mg, 53%) as a colorless oil. [α]20

D = -135 (c 0.54, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.50-7.47 (m, 2 H), 7.41-7.35 (m, 3 H), 6.79 (d, J = 5.6 Hz, 1 H), 5.64 (s, 1 H), 4.91 (d, J = 11.6 Hz, 1 H), 4.74 (dd, J = 5.6 Hz, 3.2 Hz, 1 H), 4.62 (d, J = 12.0 Hz, 1 H), 4.41 (d, J = 14.4 Hz, 1 H), 4.24 (d, J = 14.4 Hz, 1 H), 4.02 (dd, J = 12.0 Hz, 2.8 Hz, 1 H), 2.01 (ddd, J = 11.6 Hz, 2.8 Hz, 2.0 Hz, 1 H), 0.98 (s, 9 H), 0.22 (s, 3 H), 0.14 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 200.6, 140.3, 137.8, 136.9, 129.2, 128.4, 126.1, 102.3, 71.7, 71.3, 66.9, 61.1, 40.3, 25.9, 18.5, -4.3, -5.5; HRMS (ESI) calcd. for C21H30O5SiNa [M + Na]+ 413.1755, found 413.1750.

O O

O

Ph

TBSOOTBS

(4aR,5S,8aR)-5-((tert-Butyldimethylsilyl)oxy)-7-(((tert-butyldimethylsilyl)oxy)met

109

Chapter 5

hyl)-2-phenyl-4a,5-dihydro-4H-benzo[d][1,3]dioxin-6(8aH)-one (41). To a solution of 40 (325 mg, 0.83 mmol) in CH2Cl2 (8 mL) were added imidazole (68 mg, 1.0 mmol) and TBSCl (138 mg, 0.92 mmol). The resulted mixture was stirred for 2 h at rt and quenched with water. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (pentane : ether = 20 : 1) to afford 41 (394 mg, 94%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.51-7.49 (m, 2 H), 7.41-7.35 (m, 3 H), 6.87 (d, J = 6.0 Hz, 1 H), 5.64 (s, 1 H), 4.90 (d, J = 11.6 Hz, 1 H), 4.74 (t, J = 2.8 Hz, 1 H), 4.62 (d, J = 12.0 Hz, 1 H), 4.49 (dt, J = 16.4 Hz, 2.0 Hz, 1 H), 4.29 (dd, J = 16.4 Hz, 2.0 Hz, 1 H), 4.01 (dd, J = 12.4 Hz, 2.8 Hz, 1 H), 1.99 (ddd, J = 11.6 Hz, 2.4 Hz, 2.0 Hz, 1 H), 0.98 (s, 9 H), 0.90 (s, 9 H), 0.22 (s, 3 H), 0.13 (s, 3 H), 0.60 (d, J = 1.2 Hz, 6 H); 13C NMR (100 MHz, CDCl3) δ 199.5, 141.1, 137.9, 135.0, 129.2, 128.4, 126.2, 102.3, 71.8, 71.3, 67.0, 59.6, 40.5, 25.9, 18.6, 18.3, -4.3, -5.49, -5.50, -5.6; HRMS (ESI) calcd. for C27H45O5Si2 [M + H]+ 505.2800, found 505.2791. 5.7 References [1] A. Rudi, Z. Stein, S. Green, I. Goldberg, Y. Kashman, Y. Benayahu, M. Schleyer,


[2] P. A. Searle, T. F. Molinski, J. Am. Chem. Soc. 1995, 117, 8126-8131.

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Sim, J.-R. Rho, Chem. Pharm. Bull. 2008, 56, 1198-1200.

[6] T. K. Macklin, G. C. Micalizio, J. Am. Chem. Soc. 2009, 131, 1392-1393.

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3309-3311.

[8] I. Yamamoto, K. Narasaka, Bull. Chem. Soc. Jpn. 1994, 67, 3327-3333.

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ISBN 978-90-367-6343-1 (book) 978-90-367-6432-4 (electronic).

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[12] J. Xie, Y. Ma, D. A. Horne, Tetrahedron 2011, 67, 7485-7501.

[13] F. Yokokawa, T. Asano, T. Shioiri, Tetrahedron 2001, 57, 6311-6327.

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Ōmura, Tetrahedron Lett. 2007, 48, 5297-5300.

[15] T. C. Henninger, M. Sabat, R. J. Sundberg, Tetrahedron 1996, 52, 14403-14418.

[16] M. Frohn, Z.-X. Wang, Y. Shi, J. Org. Chem. 1998, 63, 6425-6426.

[17] S. Katsumura, A. Kimura, S. Isoe, Tetrahedron 1989, 45, 1337-1346.

[18] A. J. Minnaard, PhD Dissertation, University of Wageningen, 1997, ISBN 90-5485-668-8.

[19] N. Kotoku, Y. Sumii, M. Kobayashi, Org. Lett. 2011, 13, 3514-3517.

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Chapter 5

112

English Summary

English Summary

Enantioselective synthesis of natural products containing tertiary alcohols and contributions to a total synthesis of phorbasin B

Chiral tertiary alcohols and ethers are ubiquitous in natural products and pharmaceutical compounds. The recently developed copper catalyzed enantioselective

1,2-addition of alkyl Grignard reagents to α-methyl-α,β-unsaturated ketones affords a new access to these compounds. This thesis describes the application of this methodology in the asymmetric synthesis of dihydrofurans and cyclopentenols and in

the total synthesis of (R,R,R)-γ-tocopherol. The second part of this thesis describes a novel protecting group-free synthesis of the Colorado potato beetle pheromone, also equipped with a chiral tertiary alcohol, and efforts towards the total synthesis of phorbasin B.

R1

HO R2

R1

O

X XCuBr.SMe2, L

tBuOMe, −78 oC

R2MgBr

O

R1

R2Ph

Ph

O

R1

R2

R1 = Me, Ph; R2 = alkyl, alkenyl.

X = Br, Me

OH

R1

X

Figure 1. Catalytic asymmetric synthesis of dihydrofurans and cyclopentenols with quaternary

stereocenters

In chapter 2, a novel approach for the enantioselective synthesis of chiral

dihydrofurans with a quaternary oxygen-containing stereocenter and of tertiary cyclopentenols is described (Figure 1). Based on the catalytic asymmetric 1,2-addition of Grignard reagents, combined with a Sonogashira coupling/cyclization approach, or an alkylation followed by ring-closing metathesis, different kinds of dihydrofurans were prepared efficiently. With their absolute stereochemistry being established, the obtained compounds are versatile building blocks both for natural product synthesis and pharmaceuticals.

114

English Summary

OMe

OMe

O

Br OMe

OMe

HO

Br

γ-Tocopherol (36%, 73% de)

HO

O

BrMg

+

1,2-addition

Figure 2. Total synthesis of (R,R,R)-γ-tocopherol through Cu-catalyzed asymmetric 1,2-addition

In chapter 3, an efficient synthesis of (R,R,R)-γ-tocopherol based on copper catalyzed asymmetric 1,2-addition is described (Figure 2). Starting from commercially available 2,3-dimethyl hydroquinone and natural phytol,

(R,R,R)-γ-tocopherol was prepared in 12 steps (longest linear sequence), 36% overall yield and 73% d.e. at the C2 chiral center. The synthesis is not misplaced in the current collection of catalytic asymmetric approaches to the tocopherols, as the route is straightforward, in particular in its introduction of chirality at C2, and its use of readily available building blocks. An important additional finding is that the catalyst system used for the asymmetric addition of a complex Grignard reagent could be considerably optimized in terms of stereoselectivity.

OOHH

GGeerraanniiooll

OOHH

OOHH

OO

CCoolloorraaddoo ppoottaattoo bbeeeettllee pphheerroommoonnee

33 sstteeppss,, 8800%% yyiieelldd,, 8866%% eeee

Figure 3. A protecting group-free synthesis of the Colorado potato beetle pheromone starting from

geraniol

In chapter 4, an efficient synthesis of the aggregation pheromone of the Colorado

potato beetle (S)-1,3-dihydroxy-3,7-dimethyl-6-octen-2-one is described (Figure 3). Combining Sharpless asymmetric epoxidation, stereoselective epoxide ring-opening and catalytic chemoselective alcohol oxidation with [(neocuproine)PdOAc]2OTf2, the Colorado potato beetle pheromone was synthesized in 80% overall yield and 86% ee over 3 steps from geraniol. Nerol turned out to be less suitable as starting material as its asymmetric epoxidation provided lower ee. In addition, it has been shown that the

115

English Summary

palladium-catalyzed alcohol oxidation according to Waymouth is orthogonal to a trisubstituted alkene, an observation of direct relevance for further natural product synthesis.

OH

O

OH

HHO

phorbasin B Figure 4. Structure of phorbasin B

In chapter 5, efforts toward the synthesis of phorbasin B (Figure 4) are described.

In the current work, three chiral centers in the cyclohexenone fragment of phorbasin B have been constructed efficiently via Evans aldol reaction and Rubottom oxidation. Wacker oxidation provided the carbonyl group in phorbasin B while subsequent ozonolysis and intramolecular aldol condensation resulted in the desired cyclohexenone. Employing an optimized Baylis-Hillman reaction, hydroxymethylation of the cyclohexenone fragment was achieved successfully. The selective deprotection of an acetal turned out to be very difficult and is currently the pit stop in this synthesis.

116

Nederlandse Samenvatting


De enantioselectieve synthese van tertiaire alcohol bevattende natuurproducten en een bijdrage aan de totaalsynthese van phorbasin B

Chirale tertiaire alcoholen en ethers zijn alomtegenwoordig in natuurproducten en farmaceutische stoffen. De recent ontwikkelde koper gekatalyseerde enantioselectieve

1,2-additie van alkyl-Grignard reagentia aan α-methyl-α,β-onverzadigde ketonen, verschaft een nieuwe toegankelijkheid tot dit soort stoffen. Dit proefschrift beschrijft de toepassing van deze methodologie in de asymmetrische synthese van

dihydrofuranen en cyclopentolen en in de totaalsynthese van (R,R,R)-γ-tocoferol. Het tweede deel van deze dissertatie beschrijft een nieuwe beschermgroepvrije synthese van het aggregatieferomoon van de coloradokever, bevattende een tertiair alcohol, en pogingen tot de totaalsynthese van phorbasin B.

R1

HO R2

R1

O

X XCuBr.SMe2, L

tBuOMe, −78 oC

R2MgBr

O

R1

R2Ph

Ph

O

R1

R2

R1 = Me, Ph; R2 = alkyl, alkenyl.

X = Br, Me

OH

R1

X

Figuur 1. Katalytische asymmetrische synthese van dihydrofuranen en cyclopentolen met

quaternaire stereocentra

In hoofdstuk 2 is een nieuwe benadering van de enantioselectieve synthese van tertiair zuurstof bevattende chirale dihydrofuranen en cyclopentolen beschreven (Figuur 1). Gebaseerd op de asymmetrische 1,2-additie van Grignard reagentia, gecombineerd met een Sonogashira koppeling/ringsluiting, of alkylering gevolgd door een ringsluitingsmetathesereactie, zijn verscheidende dihydrofuranen efficiënt geproduceerd. Met de absolute stereochemie bepaald vormen de stoffen veelzijdige bouwstenen voor de synthese van zowel natuurstoffen als farmaceutisch interessante stoffen.

118


OMe

OMe

O

Br OMe

OMe

HO

Br

γ-Tocopherol (36%, 73% de)

HO

O

BrMg

+

1,2-addition

Figuur 2. De totaalsynthese van (R,R,R)-γ-tocoferol door middel van een Cu-gekatalyseerde

asymmetrische 1,2-additie

In hoofdstuk 3 is een efficiënte synthese van (R,R,R)-γ-tocoferol, gebaseerd op de koper gekatalyseerde asymmetrische 1,2-additie beschreven (Figuur 2). Startend vanuit commercieel verkrijgbaar 2,3-dimethyl hydroquinon en de natuurstof fytol is

(R,R,R)-γ-tocoferol gemaakt in 12 stappen (langste lineaire sequentie), in 36% totale opbrengst en 73% d.e. op het C2 chirale centrum. De synthese is geen uitbijter in de huidige collectie van asymmetrisch katalytische benaderingen van de tocoferolen. Dit aangezien de route recht-toe-recht-aan is, vooral in de introductie van de enantioselectiviteit op C2, en gebruikt maakt van makkelijk verkrijgbare bouwstenen. Een belangrijke vondst is dat de stereoselectiviteit significant verbeterd kon worden voor de asymmetrische additie van een complex Grignard reagens.

Geraniol Colorado potato beetle pheromone

3 steps, 80% yield, 86% ee

OHO

OHOH

Figuur 3. Een beschermgroepvrije synthese van het feromoon van de coloradokever, vanuit

geraniol.

In hoofdstuk 4 wordt de efficiënte synthese van (S)-1,3-dihydroxy-3,7-dimethyl-6-octen-2-non, het aggregatieferomoon van de coloradokever, beschreven (Figuur 3). Door combinatie van de Sharpless asymmetrische epoxidatie, stereoselectieve ringopening en een katalytische chemoselectieve alcohol oxidatie met [(neocuproine)PdOAc]2OTf2, is het feromoon gemaakt in een totaalopbrengst van 80%, en 86% ee (enantiomere overmaat) in

119


slechts drie stappen uit geraniol. Het isomeer nerol bleek een minder goed startmateriaal aangezien de asymmetrische epoxidatie een lage ee gaf. Daarnaast is voor het eerst gedemonstreerd dat de palladium gekatalyseerde alcohol oxidatie volgens Waymouth orthogonaal is met een (trigesubstitueerd) alkeen, een observatie belangrijk voor het gebruik in natuurstofsynthese.

OH

O

OH

HHO

phorbasin B Figuur 4. De structuur van phorbasin B

In hoofdstuk 5 staan de pogingen tot een synthese van phorbasin B beschreven. In

het huidige werk zijn drie stereocentra in het cyclohexenon fragment van phorbasin B efficiënt geïnstalleerd middels een Evans aldolreactie en een Rubottom oxidatie. Een Wacker oxidatie gaf de carbonyl group in phorbasine B, waarna ozonolyse en een intramoleculaire aldolcondensatie resulteert in het gewenste cyclohexenonfragment. Door toepassing van een geoptimaliseerde Baylis-Hillman reactie is de hydroxymethylering van het cyclohexenon succesvol uitgevoerd. De selectieve ontscherming van een acetal bleek erg moeilijk en is momenteel het eindpunt van de synthese.

120

Acknowledgements

Acknowledgements

September 21th, 2010, a new beginning of my life! After 24 hours’ travel I arrived in Groningen with my wife, a totally different world, at least for us. That was a fresh morning, just after a rain. Everything could not be cleaner. Clear sky, a quiet river, sunshine fell on the roads, and “a few people” on the square outside of the central station, this was first impression I got of Groningen.

If the time went back to half a year earlier, you would see a Chinese guy trying his best to

communicate with Prof. dr. ir. Adriaan J Minnaard via a phone-call in a SIOC laboratory. Probably, that was the first time when Prof. Minnaard felt English is not so universal. Fortunately, Adri offered me this PhD position regardless of my “difficult” English, which opened a new chapter of my life. Thank you so much, Adri, for giving me an opportunity to experience something different. At that moment, I did not expect I would stay in Groningen for such a long time since now it’s already the fifth year and maybe another two more years will follow. During the last four years’ study under your supervision, I learnt not only the chemistry, but also responsibility and patience from you. And more importantly, I found the research could be enjoyable as you have never pushed me on making progress in a short period. Self-motivation leads to more results rather than pressure from outside. Adri, I also want to thank you for all your help and care on my daily life. You always encourage me to face the difficulties and give me advices to solve problems in both research and life. You are a good mentor and friend!

I would like to acknowledge the members of the reading committee, Prof. dr. Henk Hiemstra,

Prof. dr. Gonzalo Blay and Prof. dr. Gerard Roelfes for reading and approving this thesis.

I express my sincere thanks to Anna, Martin, Syuzi and Ashoka for all your suggestions and help on my projects. Ebe, Monique and Theodora, thank you very much for all the technical help.

Miriam, I am very grateful to you for picking me up on my first arrival and helping me out with the housing problems. Before I saw my first room in Groningen, I really did not know one empty room could be so empty, nothing at all! Without your help, my wife and I would not know how to go through the first week.

Milon, we stayed in the same office as well as the same lab for more than three years. In these

days, we shared a lot of thoughts, happiness and also frustrations. You let me know so many things in India. My dear friend, I wish you great success in your future career.

Jeffrey, you are a great neighbor in the lab. It is very nice for you being in the left fumehood of

mine as I could always find the needed glassware in your drawers. Your enthusiasm on chemistry impressed me, and thank you for your suggestions on my projects and nice Dutch translation for the summary of this thesis. I am very happy to have two published papers together with you. Oh, almost forgot, thanks to you and Dorus, I knew the song of “who let the dogs out, Wu, Wu, Wu……”. And Dorus, thank you very much for giving me so much fun in the lab.

I want to express my gratitude to Cati for your encouragement in my first year’s study, Niek for

your help on dealing with so many Dutch things, Bea, Leticia and Ana for your Spanish language training, Peter for letting me know the broken-feeling on my body after a gym exercise, Manuel

122

Acknowledgements

for affording the catalyst in the synthesis of Colorado potato beetle pheromone, and Yange for the efforts on the total synthesis of phorbasin B and all the help on my beginning in Groningen.

Tao and Wenjun, you were the only support I had when Annie was born in Martini Ziekenhuis

on 15th of October, 2015. One day is short, but that day was very long for me. Thanks so much for being with me and helping us on that important moment in my life. Shuo, Jingyi and Yun, you gave me so much supports during the first month after Annie’s born. Without your help it would be very difficult to get through that period. I really appreciate all the help you afforded.

I also want to thank all the group members: Santi, Danny, Adi, Felix, Tiziana, Kiran, Blijke,

Hylke, Jasmin, Jelle, Jerre, Edwin, Nick, Jonas, Patrick, Steven, Vasu, Arne, Mannathan, Vijay, Zuzanna, Yagiz, Paul, Jonas, Judy, Gongbao, as well as some people from Stratingh institute: Wiktor, Wim, Claudia, Maria, Francesca, Jiawei, Rik, Suresh, for all nice your help and supports.

The life in Groningen always gives me so much happiness because of you, the Chinese

community: Xiaoyan&Lili, Bin, Jianwei, Depeng, Jiajia, Yang, Jiawen&Beibei, Zheng&Qian, Kai&Juanjuan, Lifei&Qinhong, Jun&Pei, Tiancai&Yang, Qing&Zhuojun, Wei, Jing&Jiaying, Chao, Hongyan, Qiuyan, Jin&Zhen, Zhiyuan, Guowei, Tao, Jiquan, Yi&Ting, Zheng, Wenqiang, and all my Chinese friends in Groningen.

Leaving so far away from my parents, I can only share my happiness and surprises with them

via phone-calls or video-chats. My dear parents, I am very grateful to your constant support, and I am really sorry for leaving you farther and farther in the past ten years. And I always feel sorry to take your most important people so far away from you, my dear parents-in-law and sister-in-law (Keling, as you wished, your name appeared in my thesis, but sorry for being just in the acknowledgement), thank you so much for giving me a beautiful wife and a good partner in my life. Now I am also a father, which makes me understand better how much you miss us.

父母的思念远胜于儿女，以至于每次离家都不忍直视父母的眼神，那眼神里有太多的不舍和期盼。有了

双方父母这么多年的支持，我们两个从大学一路走到现在，并在去年有了我们可爱的女儿。为人父，为人

母之后，才明白了什么是“父母”。在此感谢双方父母的无私奉献！

Lei, my dearest, thank you so much for accompanying me for so many years and all the

contributions to our family. Last year, you gave me the most precious gift in my entire life, Annie! Since then, home is where you and Annie are! I wish you great success in your PhD study, and you will be always beautiful in my life, just as your name, a young flower. Annie (俣佟), my little sweet heart, you already bring me so much happiness even if you can only communicate with me with “blablabla…”, smile and your rhythmical crying. Thank you for letting me be a father. Witnessing your grow-up will be the happiest part in my life. Happiness and health will be always with you, my biggest wish for you.

人生匆匆，不觉已五载。几年的格村生活，自己收获了一份平静，平静的生活，平静的心态。如能有幸，

祝愿自己的将来一如当下，平平静静……

—— 写给 30 岁的自己

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