Synthesis of (S)-α-tocotrienol via an enzymatic desymmetrization of an achiral chroman derivative

Article abstract of DOI:10.1016/S0040-4039(02)01865-8

The stereoselective acylation of an achiral chromandimethanol derivative by vinyl acetate in the presence of Candida antarctica lipase in organic media gave the corresponding (S)-monoester in high enantiomeric purity (ee=98%). (S)-α-Tocotrienol was synthe

Full text of DOI:10.1016/S0040-4039(02)01865-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7971–7973
Synthesis of (S)-a-tocotrienol via an enzymatic desymmetrization
of an achiral chroman derivative
Robert Cheˆnevert* and Gabriel Courchesne
De´partement de Chimie, Faculte´ des Sciences et de Ge´nie, Universite´ Laval, Que´bec, Canada, G1K 7P4
Received 12 July 2002; accepted 26 August 2002
Abstract—The stereoselective acylation of an achiral chromandimethanol derivative by vinyl acetate in the presence of Candida
antarctica lipase in organic media gave the corresponding (S)-monoester in high enantiomeric purity (ee=98%). (S)-a-Tocotrienol
was synthesized in 19% overall yield over six steps from this (S)-monoester. © 2002 Elsevier Science Ltd. All rights reserved.
Vitamin E occurs naturally in eight main isoforms: a, b,
and d-tocopherols and four corresponding
Tocotrienols are found in high concentration in palm
oil and rice bran and in lower concentrations in several
other natural sources (soybeans, barley, wheat germ).6
Tocotrienols inhibit cholesterol biosynthesis by post-
transcriptional suppression of b-hydroxy-b-methyl-glut-
aryl-coenzyme A reductase activity.6–8 Also, toco-
trienols are effective antioxidants and inhibit the oxida-
tion of low density lipoproteins associated with coro-
nary heart disease. In addition, they have been shown
to have anticarcinogenic and neuroprotective proper-
ties.9,10 Saucy et al. reported a stereoselective synthesis
of a-tocotrienol via fractional crystallization of an
intermediate acid with (S)-a-methylbenzyl amine
g
tocotrienols1 (Fig. 1). The a, b, g and d-homologues are
determined by the methylation patterns of the common
chromanol moiety. Tocotrienols differ from toco-
pherols by possessing a farnesyl (three double bonds)
rather than a phytyl (saturated) side chain. Natural
tocotrienols have the (2R),3%-trans,7%-trans configura-
tion. The chiral chromanol subunit is found in several
other natural products such as polyalthidin,2 cysto-
seirol,3 and garcinoic acid.4 This structural element is
also found in synthetic bioactive compounds such as
the antidiabetic drug troglitazone.5
Figure 1. Vitamin E main isoforms.
Keywords: a-tocotrienol; desymmetrization; lipase; asymmetric synthesis.
* Corresponding author. Fax: 418-656-7916; tel.: 418-656-3283; e-mail: robert.chenevert@chm.ulaval.ca
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01865-8

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R. Cheˆne6ert, G. Courchesne / Tetrahedron Letters 43 (2002) 7971–7973
as a resolving agent.11 A few syntheses of racemic
lutions have been developed for the asymmetric synthe-
sis of related heterocyclic compounds.18–24
a-tocotrienol have been reported.12–14
We report here the enzymatic desymmetrization of
achiral chromanedimethanol 1 and the use of the corre-
sponding enantiomerically enriched monoester 2 in the
synthesis of (S)-a-tocotrienol.
Monoester (S)-2 was treated with two equivalents of
mesyl chloride in the presence of triethylamine to give
dimesylate (R)-4 in 87% yield (Scheme 2). Reduction of
(R)-4 with NaBH4 in DMSO provided chromanol (R)-5
in 82% yield. Selective benzylation of the phenol func-
tion (NaH, benzyl bromide, THF, 80%) afforded (R)-6.
The enantiomeric purity of (R)-6 was further checked
by 19F NMR analysis of the MTPA derivative (ee]
98%). This procedure proved that there is complete
retention of configuration in the previous steps. The
absolute configuration of (R)-6 was determined by its
transformation (Swern’s oxidation, 97% yield) into
known chroman-2-carboxaldehyde (R)-7 ([h]2D3 − 13.5 (c
1.21, CHCl3); lit.21 [h]D −10.9 (c 0.39, CHCl3) for R
configuration; lit.25 [h]D 12.78 (c 5, CHCl3) for S
configuration.
Triol 1 was first prepared according to the procedure
reported by Oku et al.15 A modified procedure using
tributyl[(methoxymethoxy)methyl]-stannane16
as
a
hydroxymethyl anion equivalent gave a better overall
yield. Next, we did some screening to find enzymes
which are able to distinguish the enantiotopic groups of
compound 1. Of the enzymes and conditions studied,17
the esterification of triol 1 with vinyl acetate in the
presence of Candida antarctica lipase in Et2O (Scheme 1)
gave enantiomerically pure (ee]98%) monoester 2 (60%
yield) and the corresponding achiral diester 3 (27%).
Replacement of ether by acetonitrile provided a better
yield of monoester 2 (2, yield=87%; 3, yield=12%) but
a lower enantiomeric excess (ee=90%). Diester 3 is
easily recovered and recycled by chemical hydrolysis of
the ester groups. The enantiomeric composition of 2 was
determined by reaction with (+)-a-methoxy-a-trifluoro-
methyl-a-phenylacetic acid in the presence of 1-[3-
The coupling of chromanol (R)-6 with the farnesyl side
chain was accomplished using the reaction sequence
depicted in Scheme 3. The anion of sulfone 926,27 gener-
ated by treatment with butyllithium in the presence of
hexamethylphosphoramide (HMPA) was subjected to
alkylation with the triflate (R)-8 to give the coupling
product (R)-10 as a mixture of diastereoisomers in 60%
yield. Reductive cleavage of (R)-10 provided a-
tocotrienol (S)-11 in 83% yield. The spectroscopic and
physical data of synthetic (S)-a-tocotrienol were identi-
cal to those reported in the literature.11–14,28,29
(dimethylamino)propyl]-3-ethyl-carbodiimide
hydro-
chloride (EDC) and dimethylaminopyridine (DMAP),
followed by 19F NMR (282 MHz) analysis of the
resulting diastereomeric esters (MTPA, Mosher’s ester).
A variety of strategies based on enzymatic kinetic reso-
Scheme 1. Reagents and conditions: (a) Candida antarctica lipase, vinyl acetate, Et2O, 2 h.
Scheme 2. Reagents and conditions: (a) MsCl, Et3N, CH2Cl2, 87%; (b) NaBH4, DMSO, 82%; (c) NaH, BnBr, THF, 80%; (d)
(COCl)2, DMSO, Et3N, CH2Cl2, −78°C, 97%.

R. Cheˆne6ert, G. Courchesne / Tetrahedron Letters 43 (2002) 7971–7973
7973
Scheme 3. Reagents and conditions: (a) Tf2O, Et3N, CH2Cl2, −10°C, 65%; (b) BuLi, THF/HMPA, −78°C, 60%; (c) Li, EtNH2,
Et2O, −78°C, 83%.
Acknowledgements
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1983, 31, 4341–4345.
The authors would like to thank the Natural Sciences
and Engineering Research Council of Canada
(NSERC) for financial support and a postgraduate
scholarship to G.C.
14. Pearce, B. C.; Parker, R. A.; Deason, M. E.; Qureshi, A.
A.; Wright, J. J. K. J. Med. Chem. 1992, 35, 3595–3606.
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A. J. Am. Chem. Soc. 1987, 109, 527–532.
16. Danheiser, R. L.; Romines, K. R.; Koyama, H.; Gee, S.
K.; Johnson, C. R.; Medich, J. R. Org. Synth. 1992, 71,
133–139.
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Penicillium sp., Rhizopus niveus, Mucor sp., Rhizopus sp.,
Aspergillus niger, porcine pancreas, and pig liver esterase
failed to give enantioselective acylation.
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