Diastereoselective protonation of enolates of chiral Schiff bases

Article abstract of DOI:10.1016/S0957-4166(98)00133-5

Diastereoselective protonation of potassium enolates of chiral Schiff bases prepared from racemic α-amino esters and 2-hydroxypinan-3-one afforded, after mild cleavage of the imine function, optically active α- amino esters.

Full text of DOI:10.1016/S0957-4166(98)00133-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1493–1495
Diastereoselective protonation of enolates of chiral Schiff bases
∗
Mohamed Tabcheh, Christel Guibourdenche, Louis Pappalardo, Marie-Louise Roumestant
and Philippe Viallefont
UMR 5810, Laboratoire des Aminoacides, Peptides et Protéines, Université Montpellier I et 2 Place E. Bataillon,
34095 Montpellier Cédex 5, France
Received 23 March 1998; accepted 27 March 1998
Abstract
Diastereoselective protonation of potassium enolates of chiral Schiff bases prepared from racemic α-amino
esters and 2-hydroxypinan-3-one afforded, after mild cleavage of the imine function, optically active α-amino
esters. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Much effort has been devoted to the synthesis of α-amino acids in enantiomerically pure form, and
this subject has been covered by several general reviews.1 Amongst the different methods reported in
these reviews, asymmetric protonation of enolates is rarely reported; however it is a very efficient method
since it permits the conversion of a racemic compound into the desired enantiomer.
–3
4
Duhamel et al. have centred their research on the deprotonation of Schiff bases of racemic α-amino
esters with lithium amides, followed by enantioselective reprotonation of the intermediate prochiral eno-
late to give optically active products. The reactions can be carried out using simple achiral lithium amide
bases, followed by addition of a homochiral proton source (tartrate derivative). However, better results5
have been obtained by using a combination of homochiral lithium amide bases, for the deprotonation and
6
an optically active acid for the reprotonation (70% ee). A similar result was obtained using LHMDS as
the base for deprotonation and adding the more basic chiral secondary amine to the so-formed enolate
prior to reprotonation.
Equilibration of Schiff’s bases derived from α-amino acids and a chiral carbonyl component via their
7
Cu-chelates followed by hydrolysis, results in moderate enantioselectivity (22–53% ee).
8
In our laboratory, Daunis et al. used a polyacrylic resin with pendant chirality as the chiral auxiliary.
The prochiral ester enolate, reversibly linked to the polymer chain via a Schiff base, is surrounded by
∗
Corresponding author. E-mail: roumestant@crit.univ-montp2.fr
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00133-5

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M. Tabcheh et al. / Tetrahedron: Asymmetry 9 (1998) 1493–1495
chiral pendants allowing supramolecular asymmetric induction to occur. Enantioselective protonation
depends on the initial configuration of the supported amino acid. Alanine was obtained in 90% ee by
repetitive asymmetric protonation.
2. Results
We have developed an efficient method for the synthesis of enantiomerically pure mono and disubsti-
9
10
11
tuted α-amino acids, imino acids and functionalized amino acids by diastereoselective alkylation of
chiral Schiff bases 1 prepared from 2-hydroxypinan-3-one12 and α-amino esters. This method has also
13
been extended to the asymmetric synthesis of α-aminophosphonic acids and constituents of natural
14
15
12b
products: HC toxine leucinostatine. This chiral auxiliary, first used by Yamada, was then adopted
16–18
by other teams.
We report here on the use of this readily available chiral auxiliary in the diastereoselective protonation
of Schiff bases 1. For deprotonation several bases have been tested (LDA, Li HMDS, t-BuOK, KHMDS),
but t-BuOK was most suitable among the bases examined. Protonation was attempted by different proton
sources (H O, CH CO H, NH Cl/H O, etc); the best results were obtained using a saturated solution of
2
3
2
4
2
NH Cl. The results are reported in Table 1.
4
Table 1
Protonation of enolates of chiral Schiff bases
The Schiff bases were easily cleaved using citric and/or a very mild agent: boric acid. Starting from
-hydroxypinan-3-one of (S)-chirality, (R)-amino esters were obtained.
2
In a typical procedure, the Schiff base 1 (1 mmol) was dissolved in dry THF (20 ml) at −78°C
under argon, freshly sublimed t-BuOK (2 equiv.) was added and the mixture was stirred for 0.5 h at
this temperature. The mixture was quenched with a saturated solution of NH Cl and extracted with
4
ether. The organic phase was dried (MgSO ), the solvent evaporated, and the residue was analyzed
4
1
(
diastereomeric excesses were determined by H NMR in C D and also by HPLC). For R=CH Ph, when
6
6
2
the temperature was raised to −50°C, a transesterification reaction occurred but only one diastereomer
was detected. Diastereoisomers of Schiff bases 2a, 2b, 2c were separated by column chromatography.
The major isomers and the imines 2d, 2e were treated with a 15% citric acid solution or boric acid to
yield the amino esters 3.
This work will now be extended to non-natural α-amino esters in order to determine the scope and
limitations of this method.

M. Tabcheh et al. / Tetrahedron: Asymmetry 9 (1998) 1493–1495
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