TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 4285–4288
Enzymatic desymmetrization of meso cis,cis-2,4,6-substituted
tetrahydropyrans
Robert Chênevert,∗ Daniel Goupil, Yannick Stéphane Rose and Emmanuelle Bédard
Département de chimie, Faculté des sciences et de génie, Université Laval, Québec (Qc), Canada G1K 7P4
Received 29 September 1998; accepted 27 October 1998
Abstract
The stereoselective acylation of meso-tetrahydropyrans 6 and 7 by enol esters (vinyl acetate or isopropenyl
acetate) in the presence of Candida antarctica lipase in organic media gave the corresponding (2R,4S,6S)-
monoesters 10 and 11 in high enantiomeric purity. The hydrolysis of the corresponding diacetate derivatives 8
and 9 in the presence of the same enzyme provided the opposite enantiomers, (2S,4R,6R)-monoesters 10 and 11.
© 1998 Elsevier Science Ltd. All rights reserved.
The cis-2,6-substituted tetrahydropyran ring system is found in many bioactive natural products1,2
such as phorboxazoles3 and bryostatins.4 Synthetic interest in these compounds stems mainly from their
biological activities, and in particular, their potential as antineoplastic agents. Recently, Hoffmann et al.
reported the enzymatic desymmetrization of 2,4,6-trifunctionalized tetrahydropyrans in studies directed
towards the synthesis of bryostatins.5,6 This report describes new desymmetrizations of tetrahydropyrans.
The substrates were prepared as outlined in Scheme 1. Esterification of chelidonic acid 1 gave diester
2 in 80% yield. Catalytic hydrogenation of 2 over rhodium on alumina gave hydroxy-diester 3 in
quantitative yield. Evidence for the stereochemical outcome of the hydrogenation reaction rested on
1H NMR studies. The chemical shifts and coupling constants for H2, H4 and H6 were consistent with
an axial configuration and supported the meso cis,cis stereochemistry of compound 3. Protection of the
alcohol as the tert-butyldimethylsilyl (TBS) ether or the methoxymethyl (MOM) ether provided diesters
4 (80% yield) and 5 (84% yield). Reduction of 4 and 5 with LiAlH4 gave the diols 6 (95% yield) and 7
(80% yield). Diols 6 and 7 were acetylated by acetic anhydride in pyridine in the presence of DMAP to
give meso diacetates 8 (96% yield) and 9 (95% yield).
Diols 6 and 7 were subjected to enzyme-catalyzed esterification by treatment with Candida antarctica
lipase (CAL) in vinyl or isopropenyl acetate (solvent and acyl donor) to give optically active esters
(2R,4S,6S)-10 and (2R,4S,6S)-11 (Table 1). The reactions were monitored by TLC analysis and ter-
minated when all the diol was consumed. The reaction in the presence of CAL was fast and highly
∗
Corresponding author. E-mail: robert.chenevert@chm.ulaval.ca
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00460-1