rated.7 Triethylamine-promoted opening of epoxide 8 by
thiophenol afforded the homopropargyl alcohol 9. Depro-
tection of the p-methoxybenzyl group with DDQ8 and
subsequent reduction of the resulting propargyl alcohol
Th e Su lfin yl Moiety a s a n In ter n a l
Nu cleop h ile. 2. Ster eoselective Syn th esis of
(-)-Ga la n tin ic Acid via 1,3-Asym m etr ic
In d u ction †
9
10 with LiAlH4 afforded trans allyl alcohol 11, which
Sadagopan Raghavan* and S. Ramakrishna Reddy
was protected as its silyl ether 12. Oxidation of sulfide
12 with NaIO4 yielded an equimolar, inseparable
mixture of sulfoxides 5 (Scheme 2).
10
Organic Division I, Indian Institute of Chemical
Technology, Hyderabad 500 007, India
Treatment of the epimeric mixture of sulfoxides 5 with
N-bromosuccinimide (NBS) in the presence of water in
toluene as the solvent afforded bromohydrin 13 as an
inseparable mixture of epimeric sulfoxides. Oxidation of
13 with m-CPBA yielded sulfone 14, which revealed a
single set of signals in its 1H NMR spectrum, proving
unambiguously the isomeric nature of 13 as an outcome
of the sulfur chirality. The structure of bromohydrin 13
was proven by transforming 14 into acetonide 17 employ-
ing a straightforward sequence of reactions (Scheme 3).
Thus di-deprotection of the silyl ether followed by selec-
tive monoprotection of the primary hydroxy group of triol
15 as its tert-butyldiphenylsilyl (TBDPS) ether and
reaction of resulting diol 16 with 2,2-dimethoxypropane
(2,2-DMP) in the presence of catalytic amounts of cam-
phor-10-sulfonic acid (CSA) afforded acetonide 17. The
13C spectrum of 17 revealed signals for the methyl group
at δ 19.5, 29.3 and for the quaternary carbon at δ 99.3,
indicating a 1,3-syn disposition of the hydroxy groups.11
The anti disposition of the bromine and hydroxy groups
is expected from an overall trans addition of the electro-
phile and nucleophile across the face of the double bond.12
The formation of 13 from 5 can be rationalized by
bromonium ion attack on the olefin followed by intramo-
lecular nucleophilic attack by the sulfinyl group in a 6-exo
fashion to yield the sulfoxonium salt and finally hydroly-
sis13 (Figure 1). The observed stereoselectivity can be
explained by the difference in the energies of diastereo-
meric intermediates I and III (II not being preferred for
purush101@yahoo.com
Received December 21, 2002
Abstr a ct: A stereoselective synthesis of (-)-galantinic acid
is disclosed. The key steps include hydrolytic kinetic resolu-
tion of a racemic epoxide and regio- and stereoselective
heterofunctionalization of an olefin, using a pendant sulfinyl
group as the nucleophile. The participation of the sulfinyl
group was unambiguously proven by conducting the reaction
in the presence of H218O.
(-)-Galantinic acid (1), a nonproteinogenic amino acid,
is a constituent of the peptide antibiotic galantin I, which
was isolated from the culture broth of Bacillus pulvifa-
ciens.1 Galantinic acid was isolated from galantin I by
chemical degradation and was originally assigned the
structure 2. The structure of galantin I and galantinic
acid were revised by Ohfune and co-workers, who also
reported the first synthesis of galantinic acid.2a,b Galan-
tinic acid has attracted the attention of synthetic chem-
ists due to its interesting biological activity and unique
structure. The syntheses of galantinic acid reported to
date2 employ chiral pool starting materials (L-serine and
D-ribonolactone); the 1,2-asymmetric induction in the
vicinal amino alcohol formation and/or 1,3-asymmetric
induction in the diol formation, however, needs to be
improved. In connection with our interest in the use of
the sulfinyl moiety as an intramolecular nucleophile,3 we
envisaged (Scheme 1, retrosynthetic analysis) the syn-
thesis of galantinic acid from â-hydroxy-δ,ꢀ-unsaturated
sulfoxide (5). Galantinic acid can be elaborated from
epoxide 3 by a one-carbon homologation by cyanide ion
opening followed by hydrolysis. The epoxide can be
elaborated from sulfoxide 4, the synthesis of which can
be traced to olefin 5. Sulfoxide 5 can be readily elaborated
from epoxide 6.
(4) (a) Tokunaga, M.; Larrow, J . F.; Kakiuchi, F.; J acobsen, E. N.
Science 1997, 277, 936. (b) Ready, J . M.; J acobsen, E. N. J . Am. Chem.
Soc. 2001, 123, 2687. (c) Breinbauer, R.; J acobsen, E. N. Angew. Chem.,
Intl. Ed. 2000, 39, 3604.
(5) The racemic epoxide 6 was readily prepared in two high-yielding
steps: (i) reaction of propargyl ether with epichlorohydrin, using
Yamaguchi protocol, and (ii) treatment of the resulting chloro alcohol
with K2CO3 in CH3CN.
Herein we report the details of our investigation that
culminated in a stereoselective synthesis of a protected
derivative of galantinic acid. Hydrolytic kinetic resolu-
tion4 of the racemic epoxide 65 with (S,S)-salen Co(III)-
OAc catalyst afforded optically pure epoxide 86 in 42.5%
yield along with diol 7 (49%) which were readily sepa-
(6) The alcohol 9 was transformed into its mandelate ester by
reaction with (S)-R-methoxy mandelic acid and found to be homoge-
neous by comparing it with the ester prepared from racemic 9. The
absolute configurations of the product were determined by application
of the models for the HKR reaction and by total synthesis.
(7) Attempted kinetic resolution of the epoxide 6, using 0.55 equiv
of PhSH in the presence of (R,R)-salen Co(III)OAc catalyst, afforded
only racemic product 9.
† IICT Communication No. 021017.
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Matsurra, S. J . J . Antibiot. 1975, 28, 122.
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Sakai, N.; Ohfune, Y. J . Am. Chem. Soc. 1992, 114, 998. (c) Ikota, N.
Heterocycles 1991, 31, 521. (d) Kumar, J . S. R.; Datta, A. Tetrahedron
Lett. 1999, 40, 1381. (e) Kiyooka, S.; Goh, K.; Nakamura, Y.; Takesue,
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Campagne, J .-M. Tetrahedron Lett. 2001, 42, 4467.
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Kumar, Ch.; Varma, A. K.; Nangia, A. J . Org. Chem. 2002, 67, 5838.
(b) Raghavan, S.; Rasheed, M. A.; J oseph, S. C.; Rajender, A. J . Chem.
Soc., Chem. Commun. 1999, 1845.
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10.1021/jo026892y CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/18/2003
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J . Org. Chem. 2003, 68, 5754-5757