Synthesis of 6-aza-bicyclo[3,2,1]octan-3-ones via vinylogous imide photochemistry: An approach to the synthesis of the hetisine alkaloids [4]

Full text of DOI:10.1021/ja010542w

J. Am. Chem. Soc. 2001, 123, 7429-7430
7429
Scheme 1
Synthesis of 6-Aza-bicyclo[3,2,1]octan-3-ones via
Vinylogous Imide Photochemistry: An Approach to
the Synthesis of the Hetisine Alkaloids
Young-Shin Kwak and Jeffrey D. Winkler*
Department of Chemistry
The UniVersity of PennsylVania
Philadelphia, PennsylVania 19104
ReceiVed February 28, 2001
ReVised Manuscript ReceiVed May 25, 2001
We have demonstrated that the intramolecular photocycload-
dition of vinylogous amides (1,6-dienes) 1 leads, upon retro-
Mannich fragmentation of 2 and isomeric Mannich closure of
the derived ketoiminium 3, to the synthesis of perhydroindoles
4, as outlined in Scheme 1.1 The utility of this methodology for
the synthesis of nitrogen-containing ring systems is underscored
by the successful application of this methodology to the syntheses
of mesembrine,2 vindorosine,3 and manzamine A.4 We have
recently examined the photocycloaddition of the corresponding
1,5-dienes, that is, 5, and we report herein that these substrates
lead to a general synthesis of azabicyclo[3,2,1]octanones, 8, via
the “crossed” photoadduct, 6. The widespread distribution of the
azabicyclo[3,2,1]octanone ring system in molecules of nature, that
is, sarain A, 9,5 securinine, 10,6 and hetisine, 11,7 and the
importance of this ring system in medicinal chemistry for the
development of analgesics8 and muscarinic antagonists9 suggests
that the photochemistry of 5 should be of comparable utility to
that of 1.
Scheme 2
Scheme 3
The synthesis of 5 and its conversion to 8 is outlined in Scheme
2. Michael addition of allylamine to 3-butynone gave vinylogous
amide 12, which on reaction with di-tert-butyl-carbonate in the
presence of DMAP gave the photosubstrate 5 in 85% yield over
two steps. It is interesting to note that direct irradiation of 12 did
not produce the desired photoadduct, the amine analogue of 6, a
result that is consistent with the work of Swindell.10 This
difference in photoreactivity can be attributed to the importance
of sp2 character of the nitrogen in the photocycloaddition, an
indication of the subtle balance in vinylogous amide photochem-
(1) Winkler, J.; Mazur, C.; Liotta, F. Chem. ReV. 1995, 95, 2003-2020.
(2) Winkler, J.; Muller, C.; Scott, R. J. Am. Chem. Soc. 1988, 110, 4831-
4832.
(3) Winkler, J.; Scott, R.; Williard, P. J. Am. Chem. Soc. 1990, 112, 8971-
8975.
(4) Winkler, J.; Axten, J. J. Am. Chem. Soc. 1998, 120, 6425-6426.
(5) (a) Sung, M. J.; Lee, H. I.; Chong, Y.; Cha, J. K. Org. Lett. 1999, 1,
2017. (b) Jaroch, S.; Matsuoka, R. T.; Overman, L. E. Tetrahedron Lett. 1999,
40, 8719. (c) Irie, O.; Samizu, K.; Henry, J. R.; Weinreb, S. M. J. Org. Chem.
1999, 64, 587-595. (d) Denhart, D. J.; Griffith, D. A.; Heathcock, C. H. J.
Org. Chem. 1998, 63, 9616-9617
(6) For recent publications of syntheses of securinine, see: (a) Honda, T.;
Namiki, H.; Kudoh, M.; Watanabe, N.; Nagase, H.; Mizutani, H. Tetrahedron
Lett. 2000, 41, 5927-5930. (b) Han, G.; LaPorte, M. G.; Folmer, J. J.; Werner,
K. M. J. Org. Chem. 2000, 645, 6293-6306.
istry, as nitrogen protection is not needed for the photocycload-
dition of 1 (Scheme 1).
(7) For synthetic studies of hetisine, see: Van der Baan, J. L.; Bickelhaupt,
F. Recl. TraV. Chim. Pays-Bas. 1975, 94, 109-12.
Irradiation of 5 (0.01 M in MeCN, Pyrex filter, 450-W Hanovia
medium-pressure lamp) led to the bicyclic photoadduct 6 in 87%
yield. The formation of the crossed photoadduct is consistent with
the “rule of five” observed in the intramolecular photocycload-
dition of 1,5-dienes.11 Exposure of 6 to refluxing ethanol led to
the retro-Mannich fragmentation product 7, which on reaction
with catalytic PPTS gave the Mannich product 8 in 87% yield.
Having established the viability of this approach for the construc-
(8) (a) Takeda, M.; Inoue, H.; Noguchi, K.; Honma, Y.; Kawamori, M.;
Tsukamoto, G.; Yamawaki, y.; Saito, S. Chem. Pharm. Bull. 1976, 24,
1514-1520. (b) Takeda, M.; Inoue, H.; Noguchi, K.; Honma, Y.; Kawamori,
M.; Tsukamoto, G.; Yamawaki, y.; Saito, S. Chem. Pharm. Bull. 1976, 24,
2-1007.
(9) (a) Carroll, F.; Abraham, P.; Parham, K.; Griffith, R.; Ahmad, A.;
Richard, M.; Padilla, F.; Witkin, J.; Chiang, P. J. Med. Chem. 1987, 30, 805-
809. (b) Triggle, D. J.; Kwon, Y. W.; Abraham, P.; Pitner, J. B.; Mascarella,
S. W.; Carroll, F. I. J. Med. Chem. 1991, 34, 3164-3171. (c) Carroll, F. I.;
Abraham, P.; Mascarella, S. W.; Singh, P.; Moreland, C. G.; Sanker, S. S.;
Kwon, Y. W.; Triggle, D. J. J. Med. Chem. 1991, 34, 1436-1440.
(10) Swindell, C. S.; Patel, B. P.; deSolms, S. J. J. Org. Chem. 1987, 52,
2346-2355
(11) (a) Crimmins, M. Chem. ReV. 1988, 88, 1453. (b) Crimmins, M.;
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10.1021/ja010542w CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/06/2001

7430 J. Am. Chem. Soc., Vol. 123, No. 30, 2001
Communications to the Editor
tion of the azabicyclooctane ring system, we turned our attention
to the construction of 13, the tricyclic core of 14, the carbon
skeleton of the hetisine alkaloids.
18B. Mannich closure of 18A then leads to the observed product,
19. The stereochemical relationships in 19 could be unambigu-
ously established by X-ray crystallographic analysis of 20 (Ar )
p-BrPh, mp 172 °C (dichloromethane), which was prepared from
19 via TFA-mediated Boc removal, p-bromobenzamide formation,
and tosylhydrazone formation.
The syntheses of 8 (Scheme 2) and 19 (Scheme 3) in excellent
overall yields underscore the efficiency of this new photochemical
sequence. The application of this methodology to the synthesis
of the hetisine alkaloids is currently underway in our laboratory,
and our progress will be reported in due course.
Reduction of amide 1512 with DIBAL-H to the corresponding
amine, followed by reaction with butynone and di-tert-butyl-
dicarbonate, led to the formation of photosubstrate 16 in 75%
yield (one-pot reaction). Irradiation of 16 (6 µM in MeCN, Pyrex
filter, 450-W Hanovia medium-pressure lamp) led to the formation
of the tricyclic photoadduct 17 in 86% yield, which was obtained
as a mixture of epimers, presumably at the acetyl-bearing carbon.
While the presence of the Boc-protecting group complicated the
1H NMR spectrum of 17, we found that exposure of 17 to
refluxing ethanol lead to formation of 18 in excellent yield, in
which the relative stereochemical relationship in the photoadduct
is no longer present. Exposure of 18 to catalytic PPTS gave 19
in 84% yield, which embodies the tricyclic core of the hetisine
alkaloids.
Acknowledgment. Support from the National Institutes of Health
(CA40250), Glaxo-Smith Kline, Dupont Pharmaceutics, and Merck is
gratefully acknowledged. We thank Dr. Pat Carroll for the determination
of the X-ray crystal structure of 20.
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
The stereoselective formation of 19 can be attributed to kinetic
protonation from the sterically less hindered convex face of 18,
which would lead to the formation of ketoiminium 18A and not
(12) Klein, J. Tetrahedron 1964, 20, 465-479.
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