Asymmetric functionalization of a chiral non-racemic oxazolidine ester enolate. A new route towards the preparation of quaternary serine esters

Article abstract of DOI:10.1016/S0040-4039(00)00026-5

A new route towards the preparation of enantiomerically pure quaternary serine esters is described. The key step involves the diastereoselective functionalization of an oxazolidine ester enolate having an exocyclic chiral appendage. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00026-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1737–1740
Asymmetric functionalization of a chiral non-racemic oxazolidine
ester enolate. A new route towards the preparation of quaternary
serine esters
Valérie Alezra,a Martine Bonin,a Angèle Chiaroni,b Laurent Micouin,a Claude Riche b and
Henri-Philippe Husson a,∗
aLaboratoire de Chimie Thérapeutique associé au CNRS et à l’Université René Descartes (UMR 8638), Faculté des Sciences
Pharmaceutiques et Biologiques, 4 Avenue de l’Observatoire, 75270 Paris cedex 06, France
bInstitut de Chimie des Substances Naturelles, Avenue de la Terrasse, F-91198 Gif-sur-Yvette, France
Received 25 November 1999; accepted 23 December 1999
Abstract
A new route towards the preparation of enantiomerically pure quaternary serine esters is described. The key
step involves the diastereoselective functionalization of an oxazolidine ester enolate having an exocyclic chiral
appendage. © 2000 Elsevier Science Ltd. All rights reserved.
The asymmetric synthesis of α-substituted serines has been of major interest in recent years.1 Such
amino acids can be encountered as a part of the bioactive natural products,2 and can also be precursors
of various α,α-disubstituted amino acids.3
Several synthetic strategies have been developed in the preparation of these derivatives. Among them,
one of the classical approaches is the application of the Seebach’s SRS principle (self-regeneration of
stereocentres) starting from oxazolidine 1 (Fig. 1).4 In this approach, the original chirality of serine is
transferred to a temporary centre of chirality, which will control the diastereoselective formation of the
quaternary centre. The nature of the nitrogen-protective group was reported to have a strong influence on
the course of the reaction, the N-formyl derivative leading to the most stable lithium enolate. However,
a very efficient aldol reaction was reported by Corey and Li in the lactacystin synthesis, using N-benzyl
oxazolidine 2 as starting material.5 We therefore decided to investigate the alkylation of oxazolidine 3,
including a ‘chiral N-benzyl’-protective group, in order to study the chirality transfer in such a system
having an exocyclic chiral appendage.
∗
Corresponding author. Tel: +33 (0)1 53 73 97 54; fax +33 (0)1 43 29 14 03; e-mail: husson@pharmacie.univ-paris5.fr (H.-P.
Husson)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00026-5
tetl 16306

1738
Fig. 1.
Compound 3 can be efficiently prepared as a 1/1 diastereomeric mixture in three steps on a multigram
scale, as depicted in Scheme 1. The key step is the oxazolidine ring system formation through a 3+2
dipolar cycloaddition with paraformaldehyde.6
Scheme 1. Reagents and conditions: (a) (i) KH, THF; (ii) MeI, 77%; (b) BrCH2CO2tBu, K2CO3, MeCN, 73%; (c) (CH2O)n
toluene, ∆, 87%
After optimization, potassium hexamethylsilylamide proved to be the most convenient base for enolate
generation. Contrary to what was reported with oxazolidines 1 and 2, no additive (HMPA, DMPU or
LiBr) was required to improve the yields by lowering competitive β-elimination rate.7
The reactivity of the potassium enolate was then investigated with several electrophiles. Best results
were obtained with iodide as a leaving group for alkylating reagents. The use of chlorinated or brominated
derivatives led to the same product, but in a lower yield. In all cases, the reaction proved to be highly
stereoselective (Table 1).8
Table 1
In some cases, compounds 7 were not very stable, and the crude reaction mixture was directly
submitted to acidic hydrolysis to furnish amino esters 8. Selective oxazolidine cleavage needed careful
optimization because of the presence of acid sensitive quaternary t-butyl ester. If needed, minor diastereo-
mer could be discarded at this stage by column chromatography and/or crystallization.

1739
Hydrolysis of compound 7e did not lead to 8 but to lactone 9 (Scheme 2). The low overall yield, caused
by the presence of acidic protons in the electrophile, is still to be optimized.
Scheme 2.
An alternative protective group transformation, based on the reactivity of oxazolidines as potential
iminiums, was performed on compound 7b, leading to N-benzyl amino ester 10 (Scheme 2).
The absolute configuration of the newly created asymmetric centre was determined by X-ray analysis
of the crystalline methyl derivative 8a (Fig. 2).9 Alkylation occurred on the Si face of the transient enolate.
Fig. 2.
Finally, compounds 8a and 8c were deprotected by hydrogenolysis to give 11a and 11c in 79 and 89%
yield, respectively (Scheme 3).
Scheme 3.
In conclusion, oxazolidine 3 proved to be a suitable tool for the elaboration of enantiopure α-
substituted serine esters. Formation of the quaternary centre proceeds efficiently, in good yield and with
good diastereoselectivity. Applications of this method to the synthesis of natural products as well as aldol
reactions are currently under investigation and will be reported in due course.
Acknowledgements
One of us (V.A.) thanks the MENRT for a grant.
References
1. Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry 1998, 9, 3517–3599.

1740
2. (a) Fujita, T.; Inoue, K.; Yamamoto, S.; Ikumoto, T.; Sazaki, S.; Toyama, R.; Chiba, K.; Hoshino, Y.; Okumoto, T. J.
Antibiotics 1994, 47, 208–215. (b) Fujita, T.; Inoue, K.; Yamamoto, S.; Ikumoto, T.; Sazaki, S.; Toyama, R.; Chiba, K.;
Hoshino, Y.; Okumoto, T. J. Antibiotics 1994, 47, 216–224. (c) Kawatsu, M.; Yamashita, T.; Ishizuka, M.; Takeuchi, T. J.
Antibiotics 1995, 48, 222–225. (d) Horn, W. S.; Smith, J. L.; Bills, G. F.; Raghoobar, S. L.; Helms, G. L.; Kurtz, M. B.;
Marrinan, J. A.; Frommer, B. R.; Thornton, R. A.; Mandala, S. M. J. Antibiotics 1992, 45, 1692–1696.
3. Boulton, L. T.; Stock, H. T.; Raphy, J.; Horwell, D. C. J. Chem. Soc., Perkin Trans. 1 1999, 1421–1429.
4. (a) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2708–2748. (b) Seebach, D.; Aebi, J. D.;
Tetrahedron Lett. 1984, 25, 2545–2548. (c) Seebach, D.; Aebi, J. D.; Gander-Coquoz, M.; Naef, R. Helv. Chim. Acta 1987,
70, 1194–1216.
5. For a recent review, see: Corey, E. J.; Li, W.-D. Z. Chem. Pharm. Bull. 1999, 47, 1–10.
6. Bureau, R.; Mortier, J.; Joucla, M. Bull. Soc. Chim. Fr. 1993, 130, 584–596. Toluene has to be degassed prior to reflux to
avoid formation of ca. 10% N-methylation.
7. For a general discussion on β-elimination with oxazolidine esters, see Ref. 4a.
8. Typical procedure: To a solution of the diastereomeric mixture of oxazolidine 3 (200 mg, 0.65 mmol) in dry THF (5 mL)
at −78°C under argon atmosphere was added KHMDS (0.5 M in toluene, 2.60 mL, 1.30 mmol) by cannula. After 0.5 h,
iodomethane (122 µL, 1.95 mmol) was added. The reaction mixture was stirred at −78°C for 2.5 h and then quenched with
saturated NH4Cl aqueous solution (5 mL). The mixture was allowed to warm to room temperature and diluted with Et2O (5
mL). The aqueous layer was separated and extracted twice with CH2Cl2, and the combined organic phases were dried over
MgSO4, filtered and concentrated. The crude product (205 mg) was dissolved in a mixture of MeOH (2.5 mL) and H2O (5
mL). An aqueous solution of HCl (1 M) was added until pH=2. The reaction was stirred for 6 h at room temperature and
quenched with saturated K2CO3 solution until pH=8. After addition of Et2O (5 mL), the aqueous layer was separated and
extracted with two 10 mL portions of CH2Cl2; the combined organic phases were dried over MgSO4, filtered and concentrated.
The crude mixture was purified by flash chromatography on silica gel (cyclohexane:AcOEt, 80:20) to give the pure compound
8a (126 mg, 0.41 mmol, 63% overall yield).
9. Compound 8a. Small colourless crystal (0.20×0.30×0.30 mm) recrystallized from heptane. C17H27NO4, Mw=309.40,
mp=104°C. Orthorhombic system, space group P212121, Z=4, a=10.668 (5), b=12.397 (6), c=13.436 (6) Å, V=1777(1) Å3,
dc=1.157 g cm−3, F(000)=672, λ (CuKα)=1.5418 Å, µ=0.66 mm−1; 1858 diffractometric data measured (Nonius CAD-4
diffractometer), 1858 unique, of which 1482 considered as observed with I≥2.0σ(I); absorption ignored. The structure was
solved by direct methods using the SHELXS86 program and refined by full-matrix least-squares based upon unique Fo2 with
the SHELXL93 program. Refinement converged to R1(F)=0.0708 (for the 1482 observed Fo) and wR2(F2)=0.2078 (for all the
1858 data with goodness-of-fit S=1.079). In the final difference map, the residual electron density was found to be between
−0.33 and 0.28 eÅ−3. Lists of the fractional atomic coordinates, thermal parameters, distances, bond and torsion angles have
been deposited at the Cambridge Crystallographic Data Centre, UK, as Supplementary Material (CIF file).