Asymmetric synthesis of homochiral Baylis-Hillman products employing (R)-N-methyl-N-α-methylbenzyl amide

Article abstract of DOI:10.1016/S0957-4166(00)00224-X

The conjugate addition of (R)-N-methyl-N-α-methylbenzyl amide to tert-butyl cinnamate followed by an asymmetric aldol reaction and subsequent N-oxidation/Cope elimination affords β-substituted homochiral Baylis-Hillman products in good yield. Copyright (C

Full text of DOI:10.1016/S0957-4166(00)00224-X

Tetrahedron: Asymmetry 11 (2000) 2437±2441
Asymmetric synthesis of homochiral Baylis±Hillman products
employing (R)-N-methyl-N-a-methylbenzyl amide
Stephen G. Davies,* Christian A. P. Smethurst, Andrew D. Smith and G. Darren Smyth
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QY, UK
Received 22 May 2000; accepted 1 June 2000
Abstract
The conjugate addition of (R)-N-methyl-N-a-methylbenzyl amide to tert-butyl cinnamate followed by an
asymmetric aldol reaction and subsequent N-oxidation/Cope elimination a€ords b-substituted homochiral
Baylis±Hillman products in good yield. # 2000 Elsevier Science Ltd. All rights reserved.
The Baylis±Hillman reaction involves the condensation of an aldehyde and an acrylate ester,
catalysed by the presence of a tertiary amine to a€ord a-methylene-b-hydroxy-esters.1 These
compounds have proven to be useful synthetic intermediates,2 and have been shown to serve as
useful synthons for stereoselective synthesis.3 Various attempts have been made to develop an
asymmetric version of this reaction to a€ord allylic alcohols in enantiomerically enriched form.4
For example, Brzezinski et al. have reported an asymmetric Baylis±Hillman reaction which utilises
Oppolzer's sultam auxiliary to generate adducts in >99% e.e.5 This methodology is limited,
however, to aldehydes unbranched at the a-position. Barrett et al. have probed the use of a chiral
pyrrolizidine in promoting the coupling of vinyl ketones with aromatic aldehydes with poor to
moderate levels of asymmetric induction (21±47% e.e.).6 Similar levels of selectivity were also
observed when using (S)-BINAP as a catalyst for the reaction of pyrimidine-5-carbaldehydes and
acrylate esters.7 All of these approaches are limited, however, to the use of acrylate derived systems,
and we wish to address this structural limitation by developing methodology applicable to a
wider range of substrates. We report herein on a protocol based on the diastereoselective conjugate
addition of lithium amides to a,b-unsaturated esters,8 which may be employed as a synthetic
equivalent of an asymmetric Baylis±Hillman reaction.
We have previously demonstrated that b-amino ester 1 derived from conjugate addition of (R)-
N-methyl-N-a-methylbenzyl amide 2 to tert-butyl (E,E)-hexa-2,4-dienoate 3 readily undergoes
Cope elimination via N-oxide 4 when treated with MCPBA in CHCl3 (Scheme 1).9
* Corresponding author. E-mail: steve.davies@chemistry.ox.ac.uk
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00224-X

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Scheme 1. Reagents and conditions: (i) 1.6 equiv. (R)-2, THF, ^78ꢀC; then NH4Cl (aq); (ii) MCPBA, CHCl3, rt
We wished to exploit this facile elimination process for the development of an asymmetric
Baylis±Hillman reaction. It was proposed that this could be achieved via a three-step strategy
involving the conjugate addition of lithium amide 2 to a Michael acceptor; an asymmetric aldol
reaction and ®nally subsequent N-oxidation/Cope elimination. Accordingly, conjugate addition
of lithium amide (R)-2 to tert-butyl cinnamate 5 gave b-amino ester 6 in 88% d.e. and in excellent
yield (Scheme 2).
Scheme 2. Reagents and conditions: (i) 1.6 equiv. (R)-2, THF, ^78ꢀC; then NH4Cl (aq)
Puri®cation to homogeneity of b-amino ester 6 proved problematic since repeated chroma-
tography did not enhance the diastereomeric excess from 88% and therefore the minor diastereo-
isomer remained as an impurity in the product. The con®guration of the new stereogenic centre at
C(3) of 6 was assigned as (S). This assignment is based on the transition state model previously
developed for the addition of this class of lithium amide to Michael acceptors, which demon-
strated that the facial selectivity for these conjugate additions is controlled by the stereogenic
centre of the a-methylbenzyl fragment of the lithium amide.10 This assignment was con®rmed
by comparison with authentic ent-6 which was prepared from the known b-amino ester 7
according to the protocol described in Scheme 3. Therefore, conjugate addition of (S)-N-allyl-N-
a-methylbenzyl amide 8 to tert-butyl cinnamate 5 gave b-amino ester 7 which was deallylated
with Wilkinson's catalyst to give monoprotected b-amino ester 8.11 Subsequent treatment of 8
with MeI gave ent-6.
Scheme 3. Reagents and conditions: (i) 1.6 equiv. (S)-8, THF, ^78ꢀC; then NH4Cl (aq); (ii) (PPh3)3RhCl, MeCN/H2O
(5:1), Á; (iii) MeI, neat, rt

S. G. Davies et al. / Tetrahedron: Asymmetry 11 (2000) 2437±2441
2439
b-Amino ester 6 (d.e. 88%) was then subjected to an asymmetric aldol reaction, whereby
deprotonation with LDA followed by transmetallation with trimethyl borate a€orded a boron
enolate which reacted with either acetaldehyde or benzaldehyde to a€ord the desired aldol products
9 and 10 in good d.e.12 The major diastereoisomeric aldol product in each case could be easily
puri®ed to homogeneity by ¯ash chromatography at this stage (Scheme 4).
Scheme 4. Reagents and conditions: (i) 3 equiv. LDA, THF, ^78ꢀC; (ii) B(OMe)3, THF, ^78ꢀC; (iii) MeCHO or
PhCHO, THF, ^78ꢀC.y Yield refers to isolated yield of pure major diastereomer.
In order to establish the absolute stereochemistry of the two new stereogenic centres formed in
the aldol reaction, 9 and 10 were converted into the acetonides 11 and 12, respectively, via a
protocol involving reduction with lithium aluminium hydride in THF and treatment of the
resulting diol 13 and 14 with dimethoxypropane and CSA in acetone (Scheme 5).
Scheme 5. Reagents and conditions: (i) LiAlH4, THF, rt; (ii) (MeO)2CMe2, CSA, acetone, Á
1H NMR spectroscopic analysis of acetonides 11 and 12 con®rmed the relative stereo-
chemistries of the newly formed stereogenic centres of the aldol products 9 and 10. The absolute
con®gurations of these centres follow from the known stereochemistry of substrate 6 and the
established stereochemical bias observed for aldol reactions of (E)-b-amino ester enolates.13
Treatment of 9 with MCPBA in CHCl3 resulted in N-oxidation and Cope elimination to a€ord
1
the Baylis±Hillman adduct 15 as a single diastereoisomeric product in 74% yield. H NMR
spectroscopic analysis via NOE di€erence experiments was indicative of the (E) geometry of the
double bond. This assignment is consistent with the well-documented syn-elimination of N-oxides

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S. G. Davies et al. / Tetrahedron: Asymmetry 11 (2000) 2437±2441
during Cope elimination and follows from the known stereochemistry of aldol product 9.14
Similar treatment of 10 a€orded its Baylis±Hillman product 16 also as a single diastereoisomer in
57% yield. Authentic scalemic samples of 15 and 16 were obtained for comparative purposes via
repetition of this three stage protocol using a 2:1 (R):(S) mixture of lithium N-methyl-N-a-
methylbenzyl amide 2 in the initial conjugate addition. This enabled the enantiomeric excess of 15
and 16 to be determined as >99% e.e. via chiral HPLC analysis using a Chiralpak OD stationary
phase (Scheme 6).
Scheme 6. Reagents and conditions: (i) 2 equiv. MCPBA, CHCl3, rt
In conclusion, we have demonstrated that (R)-N-methyl-N-a-methylbenzyl amide 2 is an ecient
chiral auxiliary for the asymmetric synthesis of homochiral Baylis±Hillman products. Our novel
synthetic approach involves conjugate addition of lithium amide 2 to tert-butyl cinnamate to
a€ord b-amino ester 6, reaction of the boron enolate of 6 with either acetaldehyde or benzalde-
hyde and subsequent N-oxidation/Cope elimination to a€ord the desired homochiral Baylis±
Hillman products 15 and 16. Importantly, deploying the enantiomer of lithium amide (R)-2 in the
initial conjugate addition step will allow simple access to ent-Baylis±Hillman products. The
extension of this methodology to a,b-unsaturated acceptors other than cinnamate esters is currently
under investigation.
Acknowledgements
We are indebted to Oxford Asymmetry International plc and the EPSRC for funding
(C.A.P.S.).
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