Novel entry to the tricyclic core of stemofoline and didehydrostemofoline

Article abstract of DOI:10.1016/j.tetlet.2010.10.038

A novel approach to the tricyclic core of the Stemona alkaloids stemofoline and didehydrostemofoline has been discovered that features an intramolecular (3+2) dipolar cycloaddition of an unactivated carbon-carbon double bond with an azomethine ylide; the azomethine ylide was generated by an unprecedented reaction that occurred during a Swern oxidation of an α-(N-cyanomethyl)- β-hydroxy ester. In separate experiments, the efficacy of introducing the requisite oxygen functionality at C(8) and the 1-butenyl side chain at C(3) was established.

Full text of DOI:10.1016/j.tetlet.2010.10.038

Tetrahedron Letters 52 (2011) 2048–2050
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel entry to the tricyclic core of stemofoline and didehydrostemofoline
⇑
Jochen Dietz, Stephen F. Martin
Department of Chemistry and Biochemistry, The University of Texas, Austin, TX 78712, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel approach to the tricyclic core of the Stemona alkaloids stemofoline and didehydrostemofoline has
been discovered that features an intramolecular (3+2) dipolar cycloaddition of an unactivated carbon–
carbon double bond with an azomethine ylide; the azomethine ylide was generated by an unprecedented
Received 9 September 2010
Revised 30 September 2010
Accepted 6 October 2010
Available online 15 October 2010
reaction that occurred during a Swern oxidation of an
a-(N-cyanomethyl)-b-hydroxy ester. In separate
experiments, the efficacy of introducing the requisite oxygen functionality at C(8) and the 1-butenyl side
chain at C(3) was established.
Dedicated to my friend and colleague Harry
Wasserman on the occassion of his 90th
birthday.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Azomethine ylide
Dipolar cycloaddition
Alkaloid synthesis
Remote functionalization
The roots and leaves of the Stemonacea species have been used
extensively in traditional oriental medicine as insecticides and to
treat respiratory diseases and parasitic infestation.1 Stemofoline
(1) was the first alkaloid isolated from Stemona japonica,2 and dide-
hydrostemofoline (2), which was originally named asparagamine A
because the plant from which it was isolated was erroneously
thought to be Asparagus racemosus, was reported afterward.3,4
Isostemofoline and isodidehydrostemofoline, the 11,12-E isomers
of 1 and 2, respectively, have also been isolated.5 Both 1 and 2
exhibit powerful insecticidal activity as insect acetylcholine recep-
tor antagonists.4,6 Moreover, 2 exhibits nanomolar activity against
different human carcinoma cell lines and possesses potent in vivo
anti-oxytocin activity.3b,7 These structurally intricate and biologi-
cally interesting targets have attracted considerable interest from
the synthetic community.8 However, the only total syntheses that
have been recorded for alkaloids of this family are of ( )-isostemof-
oline by Kende9 and of racemic 2 and ( )-isodidehydrostemofoline
by Overman.10
requisite lactone ring. A variety of options were then envisioned
for converting 3 into the targeted alkaloids. We now report the de-
tails of some of our work in this area that has led to the discovery
of a novel reaction to generate azomethine ylides and the successful
preparation of the functionalized tricyclic core of 1 and 2.
Inasmuch as we ultimately wished to complete enantioselective
syntheses of 1 and 2, we were attracted to a general entry to chiral
pyrrolidines that had been developed by Davis.13 However, in the
interest of establishing the underlying efficacy of our plan, we
elected to perform some preliminary experiments using racemic
intermediates. In the event, benzenesulfinyl amide (7) was con-
densed with 4-pentenal (8), which was freshly prepared by Swern
oxidation of 4-pentenol, in the presence of Ti(OEt)4 to give the sul-
finyl amine 9 in 92% yield (Scheme 2). When 9 was allowed to react
with an excess of the enolate of methyl acetate, a tandem Mannich/
cross-Claisen reaction ensued to provide the keto ester 10 in 52%
yield. Although the dianion of methyl acetoacetate also reacted
with 9 to give 10, the yields were lower. Because Davis had shown
that N-sulfinyl groups were incompatible with the impending
cyclization,13a the N-sulfinyl group was replaced with an N-Boc
group in 87% overall yield. Reaction of 11 with 4-carbo-
xybenzenesulfonyl azide (4-CBSA) gave the intermediate diazo
compound 12 that underwent facile Rh-catalyzed cyclization to
give the protected pyrrolidine 13 in 84% overall yield.
In developing an approach to 1 and 2, we were intrigued by the
possibility of forming the tricyclic core embodied in 4 by a (3+2)
dipolar cycloaddition involving an azomethine ylide 5 that might
be generated in situ by silver ion promoted decyanation and depro-
tonation of the chiral amino nitrile 6 (Scheme 1).11 The subsequent
transformation of 4 into the advanced intermediate 3 would then re-
quire a remote functionalization12 followed by introduction of the
We soon discovered that removal of the N-Boc protecting group
from 13 gave an unstable intermediate keto ester that could not be
further manipulated. Accordingly, we modified our plan and re-
duced the keto function in 13 and immediately transformed the
intermediate alcohol into 14 by sequential removal of the N-Boc
⇑
Corresponding author. Tel.: +1 512 471 3915; fax: +1 512 471 4180.
E-mail address: sfmartin@mail.utexas.edu (S.F. Martin).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.038

J. Dietz, S. F. Martin / Tetrahedron Letters 52 (2011) 2048–2050
2049
Scheme 4.
give 6, which might undergo reaction with an electrophilic species
present during the Swern oxidation to give an intermediate of the
general form 17. Loss of either HCl or of a proton and dimethyl sul-
fide would furnish 18. The formation of 18 from 6 under these con-
ditions is unprecedented and merits further investigation as a
novel entry to azomethine ylides.
Scheme 1.
We then explored several tactics for introducing the requisite
functionality at C(8) of 15 by remote functionalization. Toward this
objective, the ketone moiety of 15 was stereoselectively reduced
with NaBH4 to give 19 (Scheme 5). Irradiation of a solution of 19
in the presence of iodobenzene diacetate and iodine under condi-
tions developed by Suaréz gave 20 in 85% yield.15 The formation
of the iodo ether in this process is also unusual and appears to arise
from two consecutive hydrogen-abstraction/iodination steps. In a
parallel study, we discovered that an oxygen atom may be intro-
duced at C(8) of 19 via a Barton reaction in the presence of oxygen
to give the nitrate ester 21.16 The structures of both, 20 and 21,
were unequivocally proven by X-ray crystallography.14
Scheme 2.
Scheme 5.
Scheme 3.
group and cyanomethylation (Scheme 3). We then envisioned that
oxidation of the alcohol function in 14 would give 6 that would
then be transformed into the tricyclic adduct 4 according to the
plan outlined in Scheme 1. However, initial attempts to oxidize
14 under a variety of conditions afforded complex mixtures of
unidentifiable products. Surprisingly, when 14 was subjected to
oxidation under Swern conditions, we obtained a mixture (ca.
5:1) of 15 and 16. After separation of these two compounds by
chromatography, 15 was isolated in 62% yield; the structures of
15 and 16 were confirmed by X-ray crystallography.14
The unexpected formation of a mixture of 15 and 16 upon
Swern oxidation of 14 is consistent with the generation and cycli-
zation of the azomethine ylide 18 (Scheme 4). A plausible mecha-
nism for the formation of 18 might involve initial oxidation of 14 to
Scheme 6.

2050
J. Dietz, S. F. Martin / Tetrahedron Letters 52 (2011) 2048–2050
Having established several viable tactics to introduce an oxygen
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.10.038.
function at C(8), we then turned our attention toward removing
the undesired cyano group. In order to set the stage for this effort,
the ester group was first transformed into the butenyl side chain at
C(3) required for the synthesis of didehydrostemofoline (2). In the
event, the alcohol moiety in 19 was first protected as a TES ether by
reaction with TES–OTf to give 22 in 95% yield (Scheme 6). Chemo-
selective reduction of the ester moiety to the primary alcohol fol-
lowed by Swern oxidation gave the aldehyde 23 in 60% overall
yield. Stereoselective olefination of 23 with the anion generated
from 24 by the Julia-Kocienski protocol delivered 25.17 Unfortu-
nately, we have been unable to effect the reductive decyanation
of 25 to give 26 under a number of standard conditions.
In summary, we have developed a novel entry to the tricyclic
core of the Stemona alkaloids stemofoline and didehydrostemofo-
line. The approach features the intramolecular (3+2) dipolar cyclo-
addition of an unactivated carbon–carbon double bond with an
azomethine ylide; the azomethine ylide was generated by an
unprecedented reaction that occurred during a Swern oxidation
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We thank the National Institutes of Health (GM 25439 and
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Supplementary data
Supplementary data (experimental procedures and character-
ization data for all new compounds are provided) associated with