An expeditious total synthesis of (±)-stenine

Article abstract of DOI:10.1021/ja055629m

(±)-Stenine was synthesized in eight steps from a known ketophosphonate reagent. The key step was an exo-selective Diels-Alder/intramolecular Schmidt domino reaction that afforded three of the four rings and four stereocenters in a single reaction. Copyright

Full text of DOI:10.1021/ja055629m

Published on Web 10/22/2005
An Expeditious Total Synthesis of (()-Stenine
Yibin Zeng and Jeffrey Aub e´ *
Department of Medicinal Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe, Malott Hall, Room 4070,
Lawrence, Kansas 66045-7852
Received August 17, 2005; E-mail: jaube@ku.edu
The development of rapid and efficient routes to complex natural
product skeleta serves both target- and diversity-oriented synthetic
chemistry. The Stemona alkaloids provide attractive targets for both
kinds of research due to the diversity of structures found in this
family of alkaloids and the range of biological activities associated
Scheme 1
1
with this class. Stenine (1), in particular, has provided researchers
with a synthetic challenge that has been met in the racemic manifold
2
3
4
by Hart, Padwa, and, in a formal synthesis, this laboratory.
Enantioselective syntheses of this target were recorded nearly
5
6
simultaneously by Wipf and Morimoto. The difficulty of this
target, which features a central cyclohexane fused to three other
rings and bearing a stereogenic center at every carbon, is evinced
by the fact that these syntheses required 16-33 steps and provided
the target in overall yields of 0.9-7.2%.
Our interest in this alkaloid and its congeners was recently
reinforced by reports that neostenine, a stereoisomer of stenine,
Scheme 2
7
has antitussive activity comparable to that of codeine. Clearly, the
existing methodology available for the total synthesis of these
compounds would not be sufficient for the procurement of sufficient
quantities for detailed biological evaluation or the synthesis of
analogues. In this paper, we describe a new approach to the
synthesis of Stemona alkaloids that has strong potential for the
practical solution of both of these issues.
Our original approach to stenine was based on the premise that
the BCD ring system could be obtained through an intramolecular
Schmidt reaction on a ketone that would itself arise from an
intramolecular Diels-Alder reaction of the triene shown in Scheme
1. We quickly learned that both the Diels-Alder and Schmidt
reactions could be carried out in the same pot upon treatment with
a Lewis acid, but that the reaction was poorly regio- and stereo-
selective. Thus, compound a was only available in 43% yield at
best. Other issues were the number of steps needed to provide the
“
starting” triene (about 12) and the utilization of Hart’s iodolac-
tonization/radical allylation sequence to install the ethyl group. This
sequence has the virtues of stereocontrol and relative efficiency,
but nonetheless requires three steps for the removal of the terminal
methylene carbon to afford the requisite ethyl substituent.
Subsequently, we have investigated domino reactions that
combine an intermolecular Diels-Alder reaction with a Schmidt
facile preparation of the diene component and the direct, early
incorporation of the ethyl group. On the other hand, the stereo-
chemical outcome of the sequence was uncertain; the expected
endo-selectivity would afford an intermediate corresponding to the
epi-ethyl version of neostenine 2, whereas an exo-Diels-Alder
would lead to natural stenine stereochemistry. In this paper, we
show that both outcomes can be effected through choice of Lewis
acid and present a very short (nine-step) synthesis of (()-stenine.
The known9 Horner-Wadsworth-Emmons reagent 3 was
prepared in 99% yield from commercially available dimethyl
methylphosphonate and butyryl chloride (Scheme 2). Olefination
8
reaction. This sequence is featured in an alternative retrosynthetic
analysis shown at the bottom of Scheme 1. Application of a different
Diels-Alder disconnection to that used previously and subsequent
Schmidt reaction would afford a ketone b that would only require
butyrolactone attachment. This route would involve a much more
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J. AM. CHEM. SOC. 2005, 127, 15712-15713
10.1021/ja055629m CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
Scheme 4
This work demonstrates the utility of the Diels-Alder/Schmidt
reaction sequence for complex synthesis. The brevity of the route,
in particular, the four-step preparation of tricyclic compounds 7a
and 7b, suggests that it will be amenable to an analogue program
based on total synthesis. Experiments in this direction are underway.
of aldehyde 4 (itself known10 and made in a single step from
acrylaldehyde and hydrazoic acid) afforded an enone that was
readily converted to the corresponding trimethylsilyloxy diene.
Acknowledgment. We thank the National Institute of General
Medical Sciences (GM-49093) for financial support, David Vander
Velde and Sarah Neuenswander for NMR help, Ben Neuenswander
for HPLC-MS, and Douglas Powell for X-ray crystallography.
4
Treatment of the latter with cyclohexenone and SnCl afforded a
ca. 3:1 ratio of Diels-Alder/Schmidt adducts 7a and 7b, with the
former compoundsfrom an exo-selective Diels-Alder steps
predominating. Presumably, exo-selectivity predominates because
the endo alternative encounters significant steric encumbrance
between one of the γ protons with the incoming nucleophilic silyl
enol ether.11 This stereostructure was supported by NOE studies,
an X-ray structure of a later intermediate, and by the eventual
conversion of 7a to stenine.
Supporting Information Available: Experimental details and
characterization data for new compounds, including the X-ray structure
of 9. This material is available free of charge via the Internet at http://
pubs.acs.org.
References
The completion of the synthesis is shown in Scheme 3. All of
the additional stereocenters were generated by highly selective
substrate-directed reactions: an axially directed alkylation and
reduction afforded compounds 8 and 9 (an X-ray of this compound
was performed to verify the structure; see Supporting Information),
respectively. The completion of the synthesis followed known
procedures. Thus, alkylation proceeded smoothly to give the known
lactam 10. Conversion of 10 to stenine required selective lactam
carbonyl reduction, which was accomplished as previously re-
(1) The Stemona alkaloids have been associated with insecticidal, anthelmintic,
antitussive, and various neurochemical effects, although mechanisms have
rarely been identified. For reviews, see: (a) Edwards, O. E. Alkaloids
(Academic Press) 1967, 9, 545-551. (b) G o¨ tz, M.; Strunz, G. M. In
Alkaloids; Wiesner, K., Ed.; Butterworth: London, 1973; Vol. 9, pp 143-
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(
(
(
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,3,5
The spectra of the natural product thus prepared fully
(
(
matched those literature values. Overall, the total synthesis was
accomplished in only eight steps from known 3 (or nine steps from
commercially available reagents) and 14% overall yield.
The value of this general strategy to the synthesis of neostenine
and other congeners would be enhanced by access to the endo-
Diels-Alder adduct 7b or its synthetic equivalent. In preliminary
work, we have shown that this can be accomplished in two ways
1
1106-11112. This group has also extended their general approach to
encompass several more complex analogues of stenine as well: (b) Wipf,
P.; Spencer, S. R. J. Am. Chem. Soc. 2005, 127, 225-235.
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2
003, 69, 914-920.
(
8) Zeng, Y.; Reddy, D. S.; Hirt, E.; Aub e´ , J. Org. Lett. 2004, 6, 4993-
(
Scheme 4). In one experiment, we reacted 6 with BF
3
2
•OEt ,
4995.
(
9) Khatri, N. A.; Schmitthenner, H. F.; Shringarpure, J.; Weinreb, S. M. J.
Am. Chem. Soc. 1981, 103, 6387-6393.
which afforded exclusively endo material in modest yield. Alter-
natively, we have previously shown that a diene lacking the terminal
ethyl group gave better yields of a moderately endo-selective
reaction.8
(10) Ma, Y. Heteroatom Chem. 2002, 13, 307-309.
(
11) Ge, M.; Stoltz, B. M.; Corey, E. J. Org. Lett. 2000, 2, 1927-1929.
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