syn-Selective boron mediated aldol condensations for the asymmetric synthesis of β-hydroxy-α-amino acids

Article abstract of DOI:10.1016/S0040-4039(00)00734-6

Imidazolidinone-bound glycine enolate derivatives have been shown to undergo aldol condensation with aromatic and aliphatic aldehydes in good yields and with excellent stereocontrol (62-84%, 93-95% d.e.). Removal of the pendant imidazolidinone auxiliary and hydrogenolysis affords the β-hydroxy- α-amino acid derivatives. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00734-6

Tetrahedron Letters 41 (2000) 5963±5966
syn-Selective boron mediated aldol condensations for the
asymmetric synthesis of b-hydroxy-a-amino acids
S. Caddick,a,* N. J. Parra and M. C. Pritchardb
aCentre for Biomolecular Design and Drug Development, School of Chemistry, Physics and Environmental Sciences,
University of Sussex, Falmer, Brighton BN1 9QJ, UK
bParke-Davis NRC, Forvie Site, Robinsons Way, Cambridge CB2 2QB, UK
Received 23 March 2000; accepted 4 May 2000
Abstract
Imidazolidinone-bound glycine enolate derivatives have been shown to undergo aldol condensation with
aromatic and aliphatic aldehydes in good yields and with excellent stereocontrol (62±84%, 93±95% d.e.).
Removal of the pendant imidazolidinone auxiliary and hydrogenolysis a€ords the b-hydroxy-a-amino acid
derivatives. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: aldol; b-hydroxy-a-amino acids; glycine enolates; boron; imidazolidinone; asymmetric synthesis.
a-Amino-b-hydroxyacid derivatives have been shown to act e€ectively in enzymatic inhibition1
and are important precursors to many b-lactam antibiotics.2 Reports in the literature for the
formation of these compounds have focused primarily on racemic syntheses,3 with only a few
reports addressing the enantioselective preparation of the anti- and syn-aldol diastereomers.4
Herein we wish to report boron-mediated aldol condensations of a dibenzylated glycine enolate
derivative for the enantioselective preparation of syn b-hydroxy-a-amino acids.5
The protected glycine template (3) was prepared from the commercially available imidazolidinone
(1) via acylation to the a-bromo-amide (2), followed by nucleophilic displacement with dibenzyl-
amine (Scheme 1).
Scheme 1. Reagents and conditions: (a) BrCOCH2Br, 2,6-lutidine, ^30ꢀC, CH2Cl2, 99%; (b) (PhCH2)2NH, THF, 74%
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00734-6

5964
The 9-BBN vinyloxyborane of (3) reacts in a highly diastereoselective fashion with aromatic
and aliphatic aldehydes to produce the syn-aldol derivatives (4a±9a) (Scheme 2). Selected results
obtained for the aldol condensation with the chiral glycine derivative (3) and a range of aldehydes
is provided in Table 1.
Scheme 2. Reagents and conditions: (c) 9-BBNOTf, Et3N, CH2Cl2, 0ꢀC, 1 h, then RCHO, 2 h, pH7 (phosphate bu€er),
MeOH, H2O2 (aq), 0ꢀC, 1h.
Table 1
Aldol products derived from (3)
Figure 1. Molecular structure of 5a, 20(R), 30(S)

5965
Absolute stereochemical assignments are 0m0 ade on the analogous 1H NMR chemical shifts and
coupling constants6 of H20 and H30 to the 4 -methoxy derivatives (5a) and (5b) both having been
con®rmed by X-ray crystal data (Figs. 1 and 2).
Figure 2. Molecular structure of 5b, 20(S), 30(R)
Assuming (Z)-boron enolate generation under the reaction conditions, the stereoselectivity
observed for the 9-BBN enolates can be explained by invoking a chair-like transition state. The
chiral auxiliary adopts a conformation in which the dipole±dipole repulsion between the two
oxygen atoms of the enolate is minimized, thus hindering approach of the aldehyde from the a-face
(Fig. 3).7
Figure 3.
Removal of the imidazolidinone auxiliary,8 exempli®ed in the formation of (14), followed by
hydrogenation using Pearlmanns catalyst9 a€orded the corresponding b-hydroxy-a-amino acid
derivative (15) in high yield, with no observed epimerization (Scheme 3).10
Scheme 3. Reagents and conditions: (d) NaOMe, MeOH, 77%; (e) Pd(OH)2/C, H2, MeOH, 96%

5966
In conclusion, the imidazolidinone derivative (3) o€ers a new and practical chiral glycine enolate
equivalent. The simplicity of the experimental procedures, the excellent levels of optical purity
obtained and the uniformity of the chemical yields make this an attractive procedure for the
preparation of b-hydroxy-a-amino acid derivatives.
Acknowledgements
We thank the EPSRC and Parke-Davis for ®nancial support. We also thank GlaxoWellcome,
AstraZeneca, and SmithKline Beecham for additional support. We gratefully acknowledge the
contributions of the EPSRC mass spectrometry service, Swansea (UK), Dr. P. B. Hitchcock, Dr.
A. Abdul-Sada and Dr. A. G. Avent (Sussex).
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