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SCHEME 1. Lactam Cyclization Strategy Using Gold Catalysis
Expedient Pyrrolizidine Synthesis by Propargylsilane
Addition to N-Acyliminium Ions followed by Gold-
Catalyzed r-Allenyl Amide Cyclization
Arjen C. Breman, Jan Dijkink, Jan H. van Maarseveen, Sape
S. Kinderman,* and Henk Hiemstra*
Van’t Hoff Institute for Molecular Sciences, University of
Amsterdam, Nieuwe Achtergracht 129, 1018 WS Amsterdam,
The Netherlands
substrates to cyclize in such an approach, leaving the remain-
ing double bond in the product amenable for further func-
tionalization.
Our group has ample experience in the formation of R-
allenyl lactams like 2, through N-acyliminium-type additions
of propargylsilanes to alkoxylactams (3),7,8 and we wished to
explore a cyclization strategy of such lactams to arrive at
bicyclic alkaloid building blocks in only a few steps. Espe-
cially the field of gold-catalyzed cyclizations caught our
attention.9 Lewis-acidic gold catalysts are capable of activat-
ing double and triple bonds toward nucleophilic acttack,
even in the presence of other polar substituents. On the basis
of the initial work of the groups of Krause and Lee,10,11 gold
catalysis seemed a suitable solution also for cycloamidations
of R-allenyl lactams like 2.12 Krause showed that linear
allenic amides like 4 could be cyclized using 2 mol % AuCl3
in dichloromethane at room temperature to give dihydro-
pyrrolidine 5 (Scheme 2).10
s.s.kinderman@uva.nl; h.hiemstra@uva.nl
Received July 1, 2009
For allenyl azetidinones 6 (R=alkyl, aryl), the group of
Lee reported successful gold-catalyzed cyclization to give
bicycle 7 in good yields ranging from 65 to 85%.11 Besides
these gold-catalyzed examples, silver salts were shown to
cyclize certain R-allenylazetidinones (6, R=H, Me) to give 7,
but in general requiring high catalyst loadings.13 Alterna-
tively, PtCl2-catalyzed cyclizations of unsubstituted R-alle-
nylazetidinones 6 were reported to be successful for R=H,
alkyl, or aryl.14 With oxygen-containing substituents present
on the allene, yields dropped dramatically.
Our study toward the intended sequence of N-acyliminium
ion additions of propargylsilanes, followed by the gold-
catalyzed allenyl lactam cyclization, started with the synth-
esis of R-allenyl lactam substrates 19-31 (Scheme 3).
A
reaction sequence, involving the addition of
(substituted) propargylsilanes to lactam-derived N-acyli-
minium ions followed by gold-catalyzed cyclization of the
resulting R-allenyl amide, is applied in expedient synth-
eses of pyrrolizidine alkaloids heliotridine and ent-retro-
necine in five steps from (S)-malic acid.
Pyrrolizidine and indolizidine alkaloids are well-studied
synthetic targets.1 Several members display interesting bio-
logical properties, and short synthetic approaches to these
drug-like compounds are therefore desirable.2 Many strate-
gies start with one functionalized ring after which the bicyclic
framework 1 (Scheme 1) is constructed using nucleophilic
substitution by nitrogen,1 through iminium ion cyclization,3
ring-closing metathesis,4 or other transition metal mediated
cyclizations.5,6 R-Allenyl lactams (2) would be interesting
(7) (a) Hiemstra, H.; Fortgens, H. P.; Speckamp, W. N. Tetrahedron Lett.
1984, 25, 3115. (b) Karstens, W. F. J.; Klomp, D.; Rutjes, F. P. J. T.;
Hiemstra, H. Tetrahedron 2001, 57, 5123.
(8) (a) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817.
(b) Yazici, A.; Pyne, S. G. Synthesis 2009, 339.
€
(1) (a) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139. (b) Liddell, J. R. Nat.
Prod. Rep. 2002, 19, 773.
(2) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In Alkaloids: Chemical
and Biological Perspectives; Pelletier, S. W., Ed.; Pergamon: New York, 1999;
Vol. 13, pp 1-161.
(9) For reviews on gold catalysis, see: (a) Hoffmann-Roder, A.; Krause,
N. Org. Biomol. Chem. 2005, 3, 387. (b) Widenhoefer, R. A.; Han, X. Eur. J.
Org. Chem. 2006, 4555. (c) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180.
(d) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351.
(10) (a) Morita, N.; Krause, N. Org. Lett. 2004, 6, 4121. (b) Morita, N.;
Krause, N. Eur. J. Org. Chem. 2006, 4634.
(3) (a) For a recent example, see: Meyers, E. L.; de Vries, J. G.; Aggarwal,
V. K. Angew. Chem., Int. Ed. 2007, 46, 1893. (b) Remuson, R. Beilstein J. Org.
Chem. 2007, 3, no. 32 and references cited.
(11) Lee, P. H.; Kim, H.; Lee, K.; Kim, M.; Noh, K.; Kim, H.; Seomoon,
D. Angew. Chem., Int. Ed. 2005, 44, 1840.
€
(4) (a) Martin, S. F.; Chen, H.-J.; Courtney, A. K.; Liao, Y.; Patzel, M.;
(12) For other examples of gold- and silver-catalyzed hydroaminations of
linear allenes, see: (a) Patil, N. T.; Lutete, L. M.; Nishina, N.; Yamamoto, Y.
Tetrahedron Lett. 2006, 47, 4749. (b) Mitasev, B.; Brummond, K. M. Synlett
2006, 3100. (c) Widenhoefer, R. A.; Han, X. Eur. J. Org. Chem. 2006, 4555.
(d) Lalonde, R. L.; Sherry, B. D.; Kang, E. J.; Toste, F. D. J. Am. Chem. Soc.
2007, 129, 2452. (e) Zhang, Z.; Bender, C. F.; Widenhoefer, R. A. Org. Lett.
2007, 9, 2887.
Ramser, M. N.; Wagman, A. S. Tetrahedron 1996, 52, 7251. (b) Phillips, A. J.;
Abell, A. D. Aldrichimica Acta 1999, 32, 75.
€
(5) Palladium-catalyzed examples: (a) Andersson, P. G.; Backvall, J. E.
J. Am. Chem. Soc. 1992, 114, 8696. (b) Karstens, W. F. J.; Rutjes, F. P. J. T.;
Hiemstra, H. Tetrahedron Lett. 1997, 38, 6275. For a review see: (c) Zimmer,
R.; Dinesh, C. U.; Nandanan, E.; Khan, F. A. Chem. Rev. 2000, 100, 3067.
ꢀ
(6) For an overview of silver-catalyzed examples, see: Alvarez-Corral,
~
M.; Munoz-Dorado, M.; Rodrıguez-Garcıa, I. Chem. Rev. 2008, 108, 3174.
(13) Prasad, J. S.; Liebeskind, L. S. Tetrahedron Lett. 1988, 29, 4253.
(14) Jiang, B.; Tian, H. Tetrahedron Lett. 2007, 48, 7942.
DOI: 10.1021/jo901393y Published on Web 07/17/2009
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J. Org. Chem. 2009, 74, 6327–6330 6327
2009 American Chemical Society