J . Org. Chem. 2001, 66, 7751-7756
7751
A Syn th etic Ap p r oa ch to th e Stem on a Alk a loid s
Mira M. Hinman and Clayton H. Heathcock*
Center for New Directions in Organic Synthesis, Department of Chemistry, University of California,
Berkeley, California 94720
heathcock@cchem.berkeley.edu
Received J une 22, 2001
This paper describes our work developing a strategy for the construction of the typical core structure
of the Stemona alkaloids. The approach is to control the relative stereochemistry of the groups on
the core 1-azabicyclo[5.3.0]decane ring system by a [3,3] sigmatropic rearrangement of an
acylimmonium ion followed by selective reduction. After optimization, this reaction sequence afforded
the desired diastereomer in 62% yield. Further efforts were directed toward elaboration of the
characteristic butyrolactone substituent.
Sch em e 1
The Stemona alkaloids have generated considerable
interest in recent years. They are from the Stemonaceae
family, which has two genera, Stemona and Croomia.
Several alkaloids have been isolated from the roots of
these plants; representative examples are croomine (1),1
stemotinine (2),2 and parvistemonine (3).3 Common to all
of the Stemona alkaloids is the central 1-azabicyclo[5.3.0]-
decane ring system. Another common feature is the
R-methyl-γ-lactone, although the stereochemistry at the
methyl position varies. Their unusual structures have
intrigued chemists and inspired several total syntheses
of Stemona alkaloids.4-7
outlined for a model compound in Scheme 1. An inter-
mediate such as immonium ion 4 might undergo stereo-
controlled aza-Cope rearrangement to provide immonium
ion 5, which should undergo stereoselective reduction
from the less hindered face to effectuate control of three
stereocenters on the 1-azabicyclo[5.3.0]decane skeleton
(C6, C7, and C10). Furthermore, if the angular allyl
group in 4 is suitably substituted at the terminal position,
we might be able to control the configuration at C11.
We began our investigation with a very simple model
system to explore the feasibility of the aza-Cope strategy.
Since we planned to install the nitrogen by a Beckmann
rearrangement, the synthesis of ketone 9 was our initial
goal. Use of Stork’s method8 allowed the cyclohexylimine
of cyclohexanone to be deprotonated and alkylated with
bromoacetal 7 to give ketone 8 in 65% yield (Scheme 2).
Ketone 8 was converted once again into its cyclohexyl-
imine, which was metalated by sec-butyllithium and the
resulting metalloenamine alkylated with allyl bromide
to obtain ketone 9 in 80% yield.9 Unfortunately, it was
not possible to combine these two alkylations and avoid
cleavage of the first imine. Nonetheless, this reaction
sequence provided a convenient synthesis of ketone 9.
With ketone 9 in hand, our next task was to install
the nitrogen and attempt the aza-Cope reaction. Treat-
ment of ketone 9 with hydroxylamine hydrochloride and
sodium acetate in methanol for 20 h at room temperature
provided the corresponding oxime in 99% yield. The
oxime was treated with p-toluenesulfonyl chloride (TsCl)
and catalytic N,N-(dimethylamino)pyridine (DMAP) in
In this article, we report the results of a study to
develop a strategy for construction of the typical core
structure of this family of alkaloids. Our approach is
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(7) For a recent review, see: Pilli, R. A.; Ferreira de Oliveira, M. C.
Nat. Prod. Rep. 2000, 17, 117-27.
(8) Stork, G.; Dowd, S. R. J . Am. Chem. Soc. 1963, 85, 2178-80.
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10.1021/jo0106391 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/25/2001