Enzymatic desymmetrization of meso cis,cis-2,4,6-substituted tetrahydropyrans

Article abstract of DOI:10.1016/S0957-4166(98)00460-1

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.

Full text of DOI:10.1016/S0957-4166(98)00460-1

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

4286
R. Chênevert et al. / Tetrahedron: Asymmetry 9 (1998) 4285–4288
Scheme 1. Reagents: (a) EtOH, H2SO4, reflux; (b) H2O, H2, Rh/Al2O3; (c) TBDMSCl, CH2Cl2, pyridine, DMAP or MOMCl,
CH2Cl2; (d) NaBH4, Et2O, 0°C to rt; (e) pyridine, Ac2O, DMAP, rt
stereoselective but the yields in monoacetates were moderate, indicating that the monoacetates were
also substrates. The starting material was completely converted into the monoacetates 10 and 11 and the
corresponding diacetates. The enantiomeric composition was measured by 19F NMR (282 MHz) analysis
of the corresponding (+)-α-methoxy-α-trifluoromethyl-α-phenyl acetate (MTPA, Mosher’s ester).
Table 1
Enzymatic acylation of diols by Candida antartica lipasea at room temperature
The enzymatic hydrolysis of diacetates 8 and 9 was performed in phosphate buffer (pH 7.0) in
the presence of Candida antarctica lipase and Triton X-100 as surfactant, at room temperature. The
hydrolysis was sluggish and incomplete in the absence of a surfactant. In general, the transesterification
of meso diols and the hydrolysis of the corresponding meso diesters are complementary and give the
opposite enantiomers. As expected, monoesters (2S,4R,6R)-10 and (2S,4R,6R)-11 were obtained in fair
yields and high enantioselectivity (Table 2).
The absolute configuration of monoesters 10 and 11 was determined by correlation with compound 15
of known absolute configuration.6 A sample of compound 10 was transformed into 15 by simple protec-
ting group manipulation in four steps (Scheme 2): protection of the 6-OH group as a p-methoxybenzyl
ether (10 -→ 12); deprotection of the 4-O-t-butyldimethylsilyl group by tetrabutylammonium fluoride

R. Chênevert et al. / Tetrahedron: Asymmetry 9 (1998) 4285–4288
4287
Table 2
Enzymatic hydrolysis of diacetates by Candida antartica lipasea at room temperature in pH 7 buffer
with Triton X-100
(12 -→ 13); protection of the 4-OH group as a benzyl ether (13 -→ 14); and deprotection of the 6-O-PMB
group by DDQ (14 -→ 15).
Scheme 2. Reagents: (a) p-Methoxybenzyl 2,2,2-trichloroacetamidate, Et2O, TfOH; (b) n-Bu4NF, THF, rt; (c) benzyl
2,2,2-trichloroacetamidate, TfOH, cyclohexane–CH2Cl2, rt; (d) DDQ, CH2Cl2–H2O, rt
Similarly, a sample of 11 was transformed into 15 in four steps (Scheme 3): protection of the 6-OH
group as a triphenylsilyl ether (11 -→ 16); deprotection of the 4-O-methoxymethyl group by Me3SiBr
(16 -→ 17); protection of the 4-OH group as a benzyl ether (17 -→ 18); and deprotection of the 6-OTPS
group by tetrabutylammonium fluoride.
Scheme 3. Reagents: (a) TPSCl, CH2Cl2, pyridine, DMAP, 0°C to rt; (b) Me3SiBr, CH2Cl2, −25°C to 0°C; (c) benzyl
2,2,2-trichloroacetamide, TfOH, cyclohexane–CH2Cl2, rt; (d) n-Bu4NF, THF, rt
The current report complements the work of Hoffmann et al.5,6 in several ways: (1) tetrahydropyrans
were prepared by a new method; (2) high enantioselectivity was obtained using a different enzyme; and

4288
R. Chênevert et al. / Tetrahedron: Asymmetry 9 (1998) 4285–4288
(3) both hydrolysis and acylation reactions were highly enantioselective in contrast to previous work in
which only hydrolysis gave good results. The enzymatic desymmetrization of meso compounds is an
efficient approach for the synthesis of enantiomerically pure compounds.7
Acknowledgements
We acknowledge the financial support of this work by the Natural Sciences and Engineering Research
Council of Canada (NSERC). D.G. thanks NSERC and Y.S.R. thanks ‘Le Fonds pour la Formation de
Chercheurs et l’Aide à la Recherche, Québec (FCAR)’ for postgraduate scholarships.
References
1. Norcross, R. D.; Paterson, I. Chem. Rev. 1995, 95, 2041.
2. Boivin, T. L. B. Tetrahedron 1987, 43, 3309.
3. Pettit, G. R.; Leet, J. E.; Herald, C. L.; Kamano, Y.; Boetlner, F. E.; Baczynskyj, L.; Nieman, R. A. J. Org. Chem. 1987,
52, 2854.
4. Searle, P. A.; Molinski, T. F.; Brzezinski, L. J.; Leahy, J. W. J. Am. Chem. Soc. 1996, 118, 9422.
5. Lampe, T. F. J.; Hoffmann, H. M. R. Tetrahedron Lett. 1996, 37, 7695.
6. Lampe, T. F. J.; Hoffmann, H. M. R.; Bornscheuer, V. T. Tetrahedron: Asymmetry 1996, 7, 2889.
7. Schoffers, E.; Golebiowspy, A.; Johnson, C. R. Tetrahedron 1996, 52, 3769.