Concise Formal Synthesis of (-)-Peduncularine via Ring-Closing Metathesis

Article abstract of DOI:10.1021/ol0354066

Equation presented. A synthesis of the 6-aza[3.2.1]bicyclooctene (-)-2 has been completed by a short sequence of reactions that required only six operations from (S)-malic acid and featured a novel ring-closing metathesis to form the bridged bicyclic ring. Because 2 was previously converted into (-)-peduncularine (1), its preparation constitutes a formal enantioselective synthesis of 1.

Full text of DOI:10.1021/ol0354066

ORGANIC
LETTERS
2003
Vol. 5, No. 19
3523-3525
Concise Formal Synthesis of
(−)-Peduncularine via Ring-Closing
Metathesis
David G. Washburn, Richard W. Heidebrecht, Jr., and Stephen F. Martin*
Department of Chemistry and Biochemistry, The UniVersity of Texas,
Austin, Texas 78712
sfmartin@mail.utexas.edu
Received July 26, 2003
ABSTRACT
A synthesis of the 6-aza[3.2.1]bicyclooctene (−)-2 has been completed by a short sequence of reactions that required only six operations from
(S)-malic acid and featured a novel ring-closing metathesis to form the bridged bicyclic ring. Because 2 was previously converted into (−)-
peduncularine (1), its preparation constitutes a formal enantioselective synthesis of 1.
(-)-Peduncularine (1) is the principal alkaloid in the
Tasmanian shrub Aristotelia peduncularis,1 from which a
number of structurally related alkaloids have also been
isolated.2 Interest in peduncularine has been stimulated by
the combination of its anticancer activity and the presence
of an unusual 6-azabicyclo[3.2.1]oct-3-ene subunit that is
believed to be biosynthetically derived from tryptamine and
a rearranged geranyl fragment. The first total synthesis of
(-)-peduncularine was reported by Hiemstra and Speckamp
in 1989.3 A key intermediate in this synthesis was the bicyclic
lactam 2, which has been subsequently prepared in racemic
form by Weinreb.4 Moreover, the ketone corresponding to
2 has been prepared in racemic form independently by the
groups of Rigby5 and Woerpel.6 In a nice extension of his
original work, Woerpel has recently completed a total
synthesis of racemic 1 in which a solution to the problem of
controlling the stereochemistry at C(7) of the natural product
is described.7
Our retrosynthetic analysis of peduncularine (1) was
inspired by our longstanding interest in applying ring-closing
metatheses (RCM) reactions to problems in alkaloid syn-
thesis.8,9 We focused our initial efforts upon the enantio-
selective synthesis of the 6-azabicyclo[3.2.1]octene 2, en-
visioning that it would be accessible via a RCM of the
pyrrolidinone derivative 4 (Scheme 1). A significant feature
of this approach is that it also allows for the possible
stereoselective introduction of an indole side chain, or a
precursor thereof, onto 4 leading to 3. This strategy thus
offers an alternative tactic for controlling the stereochemistry
(1) (a) Bick, I. R. C.; Bremner, J. B.; Preston, N. W.; Calder, I. C. J.
Chem. Soc., Chem. Commun. 1971, 1155-1156. (b) Ros, H.-P.; Kyburz,
R.; Preston, N. W.; Gallagher, R. T.; Bick, I. R. C.; Hesse, M. HelV. Chim.
Acta 1979, 62, 481-487.
(5) Rigby, J. H.; Meyer, J. H. Synlett 1999, S1, 860-862.
(6) Roberson, C. W.; Woerpel, K. A. Org. Lett. 2000, 2, 621-623.
(7) Roberson, C. W.; Woerpel, K. A. J. Am. Chem. Soc. 2002, 124,
11342-11348.
(8) For recent reviews of RCM in synthesis, see: (a) Schuster, M.;
Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2037-2056. (b) Grubbs,
R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. (c) Wright, D. L. Curr.
Org. Chem. 1999, 3, 211-240. (d) Fu¨rstner, A. Angew. Chem., Int. Ed.
2000, 39, 3012-3043.
(2) Bick, I. R. C.; Hai, M. A. In The Alkaloids; Brossi, A., Ed.; Academic
Press: New York, 1985; Vol. 24, pp 113-151.
(3) Klaver, W. J.; Hiemstra, H.; Speckamp, W. N. J. Am. Chem. Soc.
1989, 111, 2588-2595.
(4) Lin, X.; Stien, D.; Weinreb, S. M. Tetrahedron Lett. 2000, 41, 2333-
2337.
10.1021/ol0354066 CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/20/2003

Scheme 1
Scheme 2
at C(7). The key intermediate 4 would be derived from the
known imide 5, prepared in a one-pot operation from (S)-
malic acid.3 We describe the reduction of this plan to practice.
The known imide 5 was first converted into the ethoxy
aminal 6 by regioselective hydride reduction to give the
ethoxy aminal 6. Although 6 could be reacted with various
vinyl organometallic reagents, the yield of the desired adduct
was low, so we investigated other leaving groups. Inspired
by the work of Ley,10 we converted 6 into the sulfone 7 by
reaction with freshly prepared benzenesulfinic acid; the
quality of this reagent was essential to the success of the
reaction. When 7 was allowed to react with vinylmagnesium
bromide in the presence of ZnCl2 followed by workup with
concentrated sulfuric acid, a separable mixture (ca. 4:1) of
epimeric vinyl pyrrolidinones was obtained from which the
desired 8 was isolated in 65% yield. It then remained to
introduce the allyl group by stereoselective alkylation of 8.
Indeed, when a homogeneous solution of the dianion of 8
was treated with allyl bromide, the desired product 9 was
formed as a single diastereomer in 71% yield, thereby setting
the stage for the key RCM reaction.
experiment where the TMS ether 12 was found to cyclize
smoothly in the presence of 10 to give 13 (Scheme 3). It is
perhaps instructive to consider a possible cause for the lack
of the observed reactivity of 9 toward 10, even though such
reasoning is presently speculative. On the basis of steric
considerations, 10 would likely react preferentially with the
less hindered allylic carbon-carbon double bond of 9. If
the proximal hydroxy group then coordinated with the
ruthenium ion as in 14, the complex could then be locked in
a conformation that would be unreactive toward further
metathesis because of the relative orientation of the carbene
and the pendant vinyl group.
Although this synthesis of 13 provided an effective
solution to the problem associated with the lack of reactivity
Initial experiments to effect the RCM of 9 using the first
generation Grubbs catalyst 1011 under a variety of conditions
were unsuccessful. This result was rather surprising because
10 has been shown to be tolerant to the presence of free
hydroxyl groups, although there are scattered reports of
problems with this catalyst.12 That the hydroxyl group was
indeed the source of the problem was confirmed in a separate
Scheme 3
(9) For some leading references, see: (a) Martin, S. F.; Liao, Y.; Wong,
Y.; Rein, T. Tetrahedron Lett. 1994, 35, 691-694. (b) Martin, S. F.; Chen,
H.-J.; Courtney, A. K.; Liao, Y.; Pa¨tzel, M.; Ramser, M. N.; Wagman, A.
S. Tetrahedron 1996, 52, 7251-7264. (c) Fellows, I. M.; Kaelin, D. E.;
Martin, S. F. J. Am. Chem. Soc. 2000, 122, 10781-10787. (d) Lee, K. L.;
Goh, J. B.; Martin, S. F. Tetrahedron Lett. 2001, 42, 1635-1638. (e)
Humphrey, J. M.; Liao, Y.; Ali, A.; Rein, T.; Wong, Y.-L.; Chen, H.-J.;
Courtney, A. K.; Martin, S. F. J. Am. Chem. Soc. 2002, 124, 8584-8592.
(f) Deiters, A.; Martin, S. F. Org. Lett. 2002, 4, 3243-3245. (g) Neipp, C.
E.; Martin, S. F. Tetrahedron Lett. 2002, 43, 1779-1782.
(10) Brown, D. S.; Charreau, P.; Hansson, T.; Ley, S. V. Tetrahedron
1991, 47, 1311-3128.
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Org. Lett., Vol. 5, No. 19, 2003

of 9 toward 10, the requirement to protect the hydroxyl group
on 9 added steps and hence was not appealing. We then
turned to the second generation Grubbs’ catalyst 11, which
is substantially more reactive and less Lewis acidic than 10.13
In the event, we discovered that reaction of 9 with 11
delivered (-)-2 in nearly quantitative yield (Scheme 2). This
material exhibited 1H and 13C NMR spectral, MS, and TLC
properties virtually identical to those obtained for a sample
of racemic 2.14 The [R]D of our synthetic (-)-2 was -79.5°
(c 0.6, CHCl3), whereas the literature value was -126° (c
1.02, CHCl3).3 However, Mosher ester analysis using racemic
2 confirmed that our (-)-2 was >98% enantiomerically pure.
We have thus completed a concise formal synthesis of (-)-
peduncularine (1) by preparing the key intermediate (-)-2
in only four operations and 36% overall yield from the
known aminal 6. This synthesis of 2 illustrates the potential
of RCM for the facile synthesis of alkaloids containing
bridged azabicylic rings. Further applications of RCM to
alkaloid synthesis are the subjects of current investigations,
the results of which will be disclosed in due course.
Acknowledgment. We thank the National Institutes of
Health, the Robert A. Welch Foundation, Pfizer, Inc., and
Merck Research Laboratories for their generous support of
this research. D.G.W. is also grateful to the American Cancer
Society for a Postdoctoral Fellowship. We also thank Mr.
Christopher L. Franklin for technical assistance.
(11) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100-110.
(12) (a) Maughon, B. R.; Grubbs, R. H. Macromolecules 1997, 30, 3459-
3469. (b) Ackermann, L.; Tom, D. E.; Fu¨rstner, A. Tetrahedron 2000, 56,
2195-2202. (c) Rodriguez, J. R.; Castedo, L.; Mascarenas, J. L. Org. Lett.
2000, 2, 3209-3212.
(13) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953-956. (b) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem.
Soc. 2001, 123, 6543-6554.
(14) We thank Professor Steven M. Weinreb (The Pennsylvania State
University) for an authentic sample of racemic 2.
Supporting Information Available: Copies of 1H NMR
spectra of 2, 7-9, and the Mosher esters of (-)-2 and
racemic 2, as well as experimental procedures and analytical
data for compounds 2, 7-9, and the Mosher esters of 2. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0354066
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