C O M M U N I C A T I O N S
Table 1. Ru-Catalyzed Cycloisomerizationa
erinacine A (2),4c this asymmetric route also constitutes a formal
synthesis of this natural product as well. A full account of our efforts
will be published in due course.
entry
substrate
yield (15
+
16) %
15/16 ratio
1
2
3
14a
14b
14c
62 (and 30% 17a)
1.2:1c
1.5:1c
6.7:1c
60b
55b
Acknowledgment. We thank the National Institutes of Health
and the National Science Foundation for their generous support of
our program. Mass spectra were provided by the Mass Spectrometry
Facility, University of California, San Francisco, supported by the
NIH Division of Research Resources. We are grateful to Prof. H.
Kawagishi for sharing the NMR spectra of (+)-allocyathin B2.
a All reactions were performed with 20 mol % CpRu(CH3CN)3PF6 and
100 mol % DMF in 2-butanone (0.1 M) at room temperature for 2 h. b Yields
of 17b and 17c were not determined. c Ratio was determined after isolation.
Both geometrical isomers were obtained as single diastereomers.
a
Scheme 4. Synthesis of (+)-Allocyathin B2
Supporting Information Available: Full experimental procedures
and characterization data (PDF). This material is available free of charge
References
(1) (a) Ayer, W. A.; Lee, S. P. Can. J. Chem. 1979, 57, 3332-3337. (b)
Allbutt, A. D.; Ayer, W. A.; Brodie, H. J.; Johri, B. N.; Taube, H. Can.
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a (a) PhS(O)CH2CN, piperidine, 75%; (b) 10% Pd/C, H2, 83%; (c)
DIBAL-H; (d) KOH, MeOH, 60 °C, 51% from 21.
that tert-butyl ester 14c gave the highest selectivity as the most
relief was achieved in this case.
Since Z-isomer 16 is not suitable for the subsequent cyclization
to form the seven-membered ring, we faced the challenge to further
increase the ratio of compound 15. If the rationale shown in Scheme
3 holds true, we reasoned that by increasing the size of the ester
we might be able to attenuate the strain and thus promote the double
bond isomerization. Indeed, we observed a drastic improvement in
the ratio of compound 15 by changing methyl ester to tert-butyl
ester without compromising the conversion and the diastereose-
lectivity (Table 1). Eventually compound 15c was obtained in 48%
yield as a single diastereomer.
With a viable route to compound 15c in hand, a hydroxylative
Knoevenagel reaction (PhS(O)CH2CN, piperidine) was carried out
to extend the carbon chain and introduce the R-hydroxyl group.14
Instead of the corresponding alcohol, lactone 20 was obtained in
good yield and with excellent diastereoselectivity (dr > 20:1,
Scheme 4).15 By taking advantage of the unique conformation of
compound 20, the C12-C13 double bond was selectively hydro-
genated (10% Pd/C, H2) to generate compound 21 in satisfactory
yield.
At this point, we turned our attention to the construction of the
final seven-membered ring through an intramolecular aldol con-
densation. Toward this end, compound 21 was partially reduced to
aldehyde 3 and subjected to a variety of aldol conditions. Eventually,
we found that aldehyde 3 participates in a base-mediated cyclization
to afford (+)-allocyathin B2 (1) in satisfactory yield (Scheme 4).4a,16
The spectroscopic properties of synthetic (+)-allocyanthin B2 were
in full agreement with those reported in the literature.4
(2) Kawagishi, H.; Shimada, A.; Shirai, R.; Okamoto, K.; Ojima, F.; Sakamoto,
H.; Ishiguro, Y.; Furukawa, S. Tetrahedron Lett. 1994, 35, 1569-1572.
(3) Synthesis of cyathin core: (a) Wright, D. L.; Whitehead, C. R. Org. Prep.
Proced. Int. 2000, 32, 307-320. (b) Wender, P. A.; Bi, F. C.; Brodney,
M. A.; Gosselin, F. Org. Lett. 2001, 3, 2105-2108. (c) Tekeda, K.;
Nakane, D.; Tekeda, M. Org. Lett. 2000, 2, 1903-1905. (d) Thominiaux,
C.; Chiaroni, A.; Desmaele, D. Tetrahedron Lett. 2002, 43, 4107-4110.
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(b) Snider, B. B.; Vo, N. H.; O’Neil, S. V. J. Org. Chem. 1998, 63, 4732-
4340. (c) Snider, B. B.; Vo, N. H.; O’Neil, S. V.; Foxman, B. M. J. Am.
Chem. Soc. 1996, 118, 7644-7645. Snider and co-workers also completed
the synthesis of (+)-erinacine A from racemic allocyathin B2 by resolution.
(5) (a) Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999, 121, 6759-
6760. (b) Trost, B. M.; Schroeder, G. M.; Kristensen, J. Angew. Chem.,
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(6) Trost, B. M.; Pissot-Soldermann, C.; Chen, I.; Schroeder, G. M. J. Am.
Chem. Soc. 2004, 126, 4480-4481.
(7) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979-982.
(8) Corey, E. J.; Kang, M.; Desai, M. C.; Ghosh, A. K.; Houpis, I. N. J. Am.
Chem. Soc. 1988, 110, 649-651.
(9) Nesnas, N.; Rando, R. R.; Nakanishi, K. Tetrahedron 2002, 58, 6577-
6584.
(10) (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc. 1980,
102, 3298-3299. (b) Negishi, E.; Swanson, D. R.; Rousset, C. J. J. Org.
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5025-5036.
(12) The relative stereochemistry was established by comparison with the cis
series, which was prepared independently and will be reported in due
course.
(13) For complete double bond isomerization in the formation of seven-
membered rings from 1,7-enynes, see refs 11b and 11d.
(14) (a) Ono, T.; Tamaoka, T.; Yuasa, Y.; Matsuda, T.; Nokami, J.; Waka-
bayashi, S. J. Am. Chem. Soc. 1984, 106, 7890-7893. (b) Nokami, J.;
Mandai, T.; Imakura, Y.; Nishiuchi, K.; Kawada, M.; Wakabayashi, S.
Tetrahedron Lett. 1981, 22, 4489-4490. (c) Trost, B. M.; Mallert, S.
Tetrahedron Lett. 1993, 34, 8025-8028.
(15) The relative stereochemistry of the C14 oxygen-bearing stereocenter was
assigned by comparison of the final product with the natural material.
(16) Ho, P.-T. Tetrahedron Lett. 1978, 19, 1623-1626.
In conclusion, the first enantioselective synthesis of (+)-
allocyathin B2 was accomplished in 16 steps from 2-methylcyclo-
pentanone highlighting a Pd-catalyzed enolate AAA reaction, a
diastereoselective Ru-catalyzed cycloisomerization, and a unique
hydroxylative Knoevenagel reaction. The unusual olefin isomer-
ization in the Ru-catalyzed cycloisomerization was investigated and
exploited for the synthesis. Since glycosidation of 1 produces
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