Enantioselective synthesis of (-)-α-conhydrine via cyclic sulfate methodology

Article abstract of DOI:10.1016/S0040-4039(03)00031-5

An asymmetric synthesis of (-)-α-conhydrine is described using the Sharpless asymmetric dihydroxylation and the regiospecific nucleophilic opening of a cyclic sulfate as the key steps.

Full text of DOI:10.1016/S0040-4039(03)00031-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1957–1958
Enantioselective synthesis of (−)-a-conhydrine via cyclic sulfate
methodology
SubbaRao V. Kandula and Pradeep Kumar*
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India
Received 5 December 2002; accepted 20 December 2002
Abstract—An asymmetric synthesis of (−)-a-conhydrine is described using the Sharpless asymmetric dihydroxylation and the
regiospecific nucleophilic opening of a cyclic sulfate as the key steps. © 2003 Elsevier Science Ltd. All rights reserved.
Alkaloid mimics with a nitrogen in the ring, including
naturally occurring and synthetic monocyclic and
bicyclic derivatives, constitute a realm of important
functional molecules which have drawn considerable
attention by virtue of their potent and varied biological
activities.1 Conhydrine is one of the poisonous alka-
loids of the hemlock, Conium maculatum whose extracts
were used in the ancient Greece for the execution of
criminals.2 Various methods for the synthesis of a- and
b-conhydrine (Fig. 1) have been documented in the
literature. While a number of auxiliary-supported syn-
theses or chiral pool approaches have been reported for
unnatural b-conhydrine,3 less attention has been paid to
the enantioselective synthesis of a-conhydrine.
Recently, the structural assignment of (−)-a-conhydrine
and its first asymmetric synthesis based on RAMP/
SAMP hydrazone methodology were reported.4 Sur-
prisingly, there has been no report in the literature
about the asymmetric synthesis of conhydrine employ-
ing the Sharpless asymmetric dihydroxylation proce-
dure. As part of our research program aimed at
developing enantioselective syntheses of naturally
occurring lactones5a,b and amino alcohols,5c–f the
Sharpless asymmetric dihydroxylation and subsequent
transformation of the diols formed via cyclic sulfites/
sulfates were envisioned as powerful tools offering con-
siderable opportunities for synthetic manipulations.
Herein we report a new and highly enantioselective
synthesis of (−)-a-conhydrine employing the Sharpless
asymmetric dihydroxylation as the source of chirality.
The synthesis of (−)-a-conhydrine 1 commences from
propionaldehyde 3, a readily available starting material
as illustrated in Scheme 1. Thus, treatment of 3 with
(methoxycarbonylmethylene)triphenylphosphorane in
benzene under reflux conditions gave the Wittig
product 4 in 85% yield. The dihydroxylation of 4 with
osmium tetroxide and potassium ferricyanide as co-oxi-
dant in the presence of (DHQ)2PHAL as chiral ligand
under the Sharpless asymmetric dihydroxylation (SAD)
conditions6 gave the diol 5 in 88% yield with 95% ee,
having [h]2D0 −5.5 (c 1.0, CHCl3) [lit.7 [h]2D0 −5.9 (c 0.35,
CHCl3)]. The diol 5 was then treated with thionyl
chloride and triethylamine to give the cyclic sulfite
which was further oxidized using NaIO4 and a catalytic
amount of ruthenium trichloride to furnish the corre-
sponding cyclic sulfate 68 in excellent yield. The essen-
tial feature of our synthetic strategy shown in Scheme 1
was based on the presumption that the nucleophilic
opening of the cyclic sulfate 6 would occur in a
regiospecific manner at the a-carbon atom.
Figure 1.
Indeed the cyclic sulfate 6 reacted with NaN3 with
apparent complete selectivity for attack at the C-2,
* Corresponding author. Tel.: +91-20-5893300, ext. 2050; fax: +91-20-
5893614; e-mail: tripathi@dalton.ncl.res.in
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(03)00031-5

1958
S. V. Kandula, P. Kumar / Tetrahedron Letters 44 (2003) 1957–1958
Acknowledgements
S.V.K. thanks CSIR, New Delhi for financial assis-
tance. We are grateful to Dr. M. K. Gurjar for his
support and encouragement. This is NCL communica-
tion No. 6638.
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Scheme 1. Reagents and conditions: (a) Ph3PꢀCHCOOMe,
benzene, reflux,
2 h, 85%; (b) (DHQ)2PHAL, OsO4,
CH3SO2NH2, K3Fe(CN)6, K2CO3, t-BuOH:H2O (1:1), 24 h,
0°C, 88%; (c) (i) SOCl2, Et3N, 15 min, (ii) RuCl3/NaIO4, 1 h,
88%; (d) NaN3, acetone, 1 h, 20% aq. H2SO4, ether, 10 h,
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In conclusion, we have demonstrated that the enan-
tioselective synthesis of (−)-a-conhydrine can be accom-
plished by the Sharpless asymmetric dihydroxylation
and regiospecific nucleophilic opening of the corre-
sponding cyclic sulfate. To the best of our knowledge,
this is the first asymmetric synthesis of (−)-a-conhy-
drine using Sharpless asymmetric dihydroxylation as
the source of chirality. The synthetic strategy described
has significant potential for further extension to the
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