ORGANIC
LETTERS
1999
Vol. 1, No. 7
1051-1052
Stereoselective Synthesis of
2-Isocyanoallopupukeanane
Tse-Lok Ho* and Liang-Rern Kung
Department of Applied Chemistry, National Chiao Tung UniVersity,
Hsinchu, Taiwan, Republic of China
Received July 22, 1999
ABSTRACT
A stereoselective synthesis of 2-isocyanoallopupukeanane (3) in ca. 5% overall yield features an intramolecular Diels−Alder reaction to establish
a bridged cyclopentane ring to the existing bicyclo[3.2.1]octane unit.
The pupukeananes constitute a novel family of marine
sesquiterpenoids. These isonitriles are subdivided into three
classes according to their carbon skeletons as represented
by the isocyanopupukeananes [e.g., 2-isocyanopupukeanane
(1a)1 and 9-isocyanopupukeanane (1b)2], 9-isocyanoneopu-
pukeanane (2),3 and 2-isocyanoallopupukeanane (3),4 re-
spectively (Figure 1). Some, if not all, of these substances
are implicated in delicate and interesting ecological interac-
tions between sponges and nudibranch mollusks. The mol-
lusks acquire such sponge metabolites as defense weapons
against predators.
The novel structures of the isocyanopupukeananes have
attracted much attention from synthetic chemists. Thus,
synthetic approaches to both 1a and 1b were reported in
1979, and formal syntheses of the latter which terminated at
9-pupukeanone have also appeared in the literature.5 On the
other hand, to our best knowledge, 2-isocyanoallopu-
pukeanane 3, which possesses a different skeleton, had not
yet been synthesized. We now wish to disclose our efforts
in this direction.
Our synthesis started from the Diels-Alder adduct of
cyclopentadiene and methyl acrylate. Methylation gave
predominantly endo ester 4 (endo:exo 13:1) which was
converted to lactone 5 by a phase transfer reaction6 (CHBr3,
KOH, Bu3N; KOH; H+) in 56% yield. Reaction of 5 with
MeMgI/CuI-Me2S at -40 °C apparently proceeded via an
SN2′ pathway, leading to acid 6 (81%). Next, we commenced
a homologation reaction sequence: (1) LAH reduction, to
7a, 98%; (2) tosylation, to 7b, 98%; (3) cyanide displace-
ment, to 8, 99%; (4) DIBAL reduction, to 9, 95%; (5) Wittig
reaction, to 10, 77%.
Initially with the chloro analogue of 10, we attempted an
intramolecular ene reaction (eq 1) but failed to generate the
(1) Hagadone, M. R.; Scheuer, P. J.; Holm, A. J. Am. Chem. Soc. 1984,
106, 2447.
(2) Burreson, B. J.; Scheuer, P. J.; Finer, J.; Clardy, J. J. Am. Chem.
Soc. 1975, 97, 4763.
(3) Karuso, P.; Poiner, A.; Scheuer, P. J. J. Org. Chem. 1989, 54, 2095.
(4) Fusetani, N.; Wolstenholme, H. J.; Matsunaga, S. Tetrahedron Lett.
1991, 32, 7291.
(5) 2-Isocyanopupukeanane: Corey, E. J.; Ishiguro, M. Tetrahedron Lett.
1979, 2745. 9-Isocyanopupukeanane: Corey, E. J.; Behforouz, M.; Ishiguro,
M. J. Am. Chem. Soc. 1979, 101, 1608. Yamamoto, H.; Sham, H. L. J.
Am. Chem. Soc. 1979, 101, 1609. Formal syntheses of 2: Schiehser, G.
A.; White, J. D. J. Org. Chem. 1980, 45, 1864. Piers, E.; Winter, M. Liebigs
Ann. Chem. 1982, 973. Hsieh, S.-L., Chiu, C.-T.; Chang, N. C. J. Org.
Chem. 1989, 54, 3820.
desired tricycle.7 Actually, it was our inability to induce Cl/
Li exchange that caused us to investigate the bromo series.
The conversion of 10 to enone 11 by treatment with t-BuLi
and then with N-methoxy-N-methylacetamide8 was ac-
(6) Isagawa, K.; Kimura, Y.; Kwon, S. J. Org. Chem. 1974, 39, 3171.
(7) Chein, R.-J. M.Sc. Thesis, National Chiao Tung University, 1996.
(8) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
10.1021/ol990181d CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/15/1999