activity against gram-positive bacteria, poor activity against
gram-negative bacteria, and observed hemolytic activity
against human red blood cells.4 This hemolytic property
precludes the use of guanacastepene A as an antibiotic, but
nonetheless guanacastepene A represents a novel lead
structure for antibiotic development.
We believed that this novel constitutional group selectivity
could be showcased in the synthesis of guanacastepene A.
Retrosynthetic disassembly of guanacastepene A (1) leads
to compound 4 containing the carbocyclic skeleton and all
the necessary functionality for the conversion to guanacaste-
pene A (Scheme 1). The 4-alkylidene cyclopentenone 4 could
The novel carbon skeleton of guanacastepene A and its
highly functionalized upper half make it a challenging and
attractive synthetic target. Not surprisingly, synthetic studies
have been reported by a number of groups.5 Danishefsky
and co-workers recently reported the first total synthesis of
guanacastepene A,5m,n and shortly thereafter Snider’s group
reported a formal total synthesis.5ï Both of these approaches
involved a strategy that begins with the construction of the
five-membered ring followed by sequential annulations of
the seven- and six-membered rings, i.e., an A f AB f ABC
approach. A conceptually novel route to guanacastepene A
was suggested by the recent demonstration in our group
showing that an intramolecular allenic Pauson-Khand reac-
tion can be used to form seven-membered rings.6 In this
report, we were able to control the constitutional group
selectivity of the reaction by simply altering the reaction
conditions. In all cases examined, when rhodium biscarbonyl
chloride dimer [Rh(CO)2Cl]2 was used as a catalyst to effect
the allenic Pauson-Khand reaction, the cyclization occurred
exclusively with the distal double bond of the allene,
independent of the substitution pattern of the allene. This
was the case even when the tether length was increased by
one methylene unit. As can be seen in eq 1, when alkynyl
allenes 2a-c were subjected to 5 mol % [Rh(CO)2Cl]2, they
gave only the fused bicyclic ring systems 3a-c.
Scheme 1. Retrosynthetic Analysis
in turn be obtained from alkynyl allene 5 using the allenic
Pauson-Khand strategy depicted above in eq 1. This
Pauson-Khand-based approach to guanacastepene A is
especially attractive since the preparation of allenyne 5 could
take advantage of one of many efficient and stereoselective
syntheses of cyclohexenones in the literature. In addition, it
is predicted that the stereocenters that are introduced after
the Pauson-Khand reaction can all be set in a stereoselective
manner relative to the existing stereocenters in the cyclo-
hexenone. For these reasons, we chose cyclohexenone 6 as
our desired starting material. The primary considerations for
the assembly of 5 from 6 are the appropriately timed
introduction of the quaternary center and the potentially
sensitive allene group.
Preparation of compound 5 is ideally suited for the
vinylogous ester-1,3-dicarbonyl transposition developed by
Stork et al.7 that was later modified by Smith to include a
hydroxymethyl group on the cyclohexenone ring.8 Our
synthesis was initiated using Smith’s enone 7 (Scheme 2).8
Introduction of the required alkyne functionality was ac-
complished via an alkylation of the enolate of enone 7 using
LDA and iodide 8.9 Unfortunately, the conversion of 7 to
11 was a low-yielding reaction (30-40%).10 Alternative
bases such as KHMDS, NaHMDS were used, in addition to
varying the amount of alkynyl iodide 8, with no measurable
increase in the yield of the alkylation product 11. The order
(3) Brady, S. F.; Bondi, S. M.; Clardy, J. J. Am. Chem. Soc. 2001, 123,
9900.
(4) Singh, M. P.; Janso, J. E.; Luckman, S. W.; Brady, S. F.; Clardy, J.;
Greenstein, M.; Maiese, W. M. J. Antibiot. 2000, 53, 256.
(5) (a) Dudley, G. B.; Danishefsky, S. J. Org. Lett. 2001, 3, 2399. (b)
Dudley, G. B.; Tan, D. S.; Kim, G.; Tanski, J. M.; Danishefsky, S. J.
Tetrahedron Lett. 2001, 42, 6789. (c) Magnus, P.; Waring, M. J.; Ollivier,
C.; Lynch, V. Tetrahedron Lett. 2001, 42, 4947. (d) Snider, B. B.; Shi, B.
Tetrahedron Lett. 2001, 42, 9123. (e) Snider, B. B.; Hawryluk, N. A. Org.
Lett. 2001, 3, 569. (f) Dudley, G. B.; Danishefsky, S. J.; Sukenick, G.
Tetrahedron Lett. 2002, 43, 5605; Mehta, G.; Umarye, J. D. Org. Lett. 2002,
4, 1063. (g) Mehta, G.; Umarye, J. D.; Gagliardini, V. Tetrahedron Lett.
2002, 43, 6975. (h) Shipe, W. D.; Sorensen, E. J. Org. Lett. 2002, 4, 2063.
(i) Nguyen, T. M.; Lee, D. Tetrahedron Lett. 2002, 43, 4033. (j) Nguyen,
T. M.; Seifert, R. J.; Mowrey, D. R.; Lee, D. Org. Lett. 2002, 4, 3959. (k)
Nakazaki, A.; Sharma, U.; Tius, M. A. Org. Lett. 2002, 4, 3363. (l) Boyer,
F. D.; Hanna, I. Tetrahedron Lett. 2002, 43, 7469. (m) Tan, D. S.; Dudley,
G. B.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2002, 41, 2185. (n) Lin,
S.; Dudley, G. B.; Tan, D. S.; Danishefsky, S. J. Angew. Chem., Int. Ed.
2002, 41, 2188. (o) Shi, B.; Hawryluk, N. A.; Snider, B. B. J. Org. Chem.
2003, 68, 1030. (p) Mehta, G.; Umarye, J. D.; Srinivas, K. Tetrahedron
Lett. 2003, 44, 4233. (q) Xiaohui, D.; Chu, H. V.; Kwon, O. Org. Lett.
2003, 5, 1923.
(6) Brummond, K. M.; Chen, H.; Fisher, K. D.; Kerekes, A. D.; Rickards,
B.; Sill, P. C.; Geib, S. J. Org. Lett. 2002, 11, 1931. Narasaka published a
similar result as a single example during our investigations into the scope
of this reaction. Kobayashi, T. Koga, Y.; Narasaka, K. J. Organomet. Chem.
2001, 624, 73. Another group has reported the formation of bicyclo[5.3.0]-
dec-1,7-dien-9-ones from allenes via rhodium(I) catalysis. Mukai, C.;
Nomura, I.; Yamanishi, K.; Hanaoka, M. Org. Lett. 2002, 4, 1755.
(7) Stork, G.; Danheiser, R. L. J. Org. Chem. 1973, 38, 1775.
(8) Smith, A. B., III; Dorsey, B. D.; Ohba, M.; Lupo, A. T., Jr.; Malamas,
M. S. J. Org. Chem. 1988, 53, 4314.
3492
Org. Lett., Vol. 5, No. 19, 2003