considered as a potential lead compound in the development
of new antibacterial agents. Because of this, in combination
with the novel carbon skeleton, guanacastepenes have stimu-
lated significant synthetic activity in a number of research
groups.6-10 In 2002, Danishefsky and co-workers reported6
the first total synthesis of racemic guanacastepene (()-1,
which was followed by a formal total synthesis by the
research group of Snider.7 In addition, in the last three years
several leading research groups have reported novel ap-
proaches (mostly racemic) to AB, BC, and ABC ring systems
of guanacastepenes.8 In the context of enantioselective
synthesis of guanacastepenes, Lee and co-workers described
the enantiospecific construction of the tricyclic ring system
of guanacastepenes starting from (S)-verbenone and (S)-
citronellyl bromide.9 Very recently, Trauner and co-workers
disclosed10 their asymmetric approach to BC ring system of
guanacastepene employing a intramolecular rhodium car-
benoid insertion methodology, which prompted us to report
our efforts toward the enantiospecific construction of gua-
nacastepenes. Herein, we wish to describe enantiospecific
approaches to the construction of BC and AB ring systems
of guanacastepenes from a common intermediate and exten-
sion of the strategy for the enantiospecific construction of
BC and AB ring systems of the marine diterpene rameswar-
alide (2), another therapeutically important lead molecule.
To begin, we have developed a short and efficient
enantiospecific approach to the BC ring system of guana-
castepenes. Our strategy is based on the identification of the
isopropenyl group of the readily available monoterpene (R)-
Scheme 1
carvone (3) as a masked hydroxy group.11 A ring closing
metathesis (RCM)12 reaction has been contemplated as the
key step for the construction of seven membered B-ring of
guanacastepenes as depicted in Scheme 1 (side chains with
m ) 2 and n ) 1 were opted for convenience).13 It is worth
noting that the strategy is suitable for the generation of either
enantiomeric form of the BC ring system of guanacastepenes
by controlling the stereochemistry at the C-6 position of 6,6-
dialkylcarvone. The synthetic sequence is depicted in Scheme
(1) (a) Brady, S. F.; Singh, M. P.; Janso, J. E.; Clardy, J. J. Am. Chem.
Soc. 2000, 122, 2116. (b) Brady, S. F.; Bondi, S. M.; Clardy, J. J. Am.
Chem. Soc. 2001, 123, 9900.
(2) Singh, M. P.; Janso, J. E.; Luckman, S. W.; Brady, S. F.; Clardy, J.;
Greenstein, M.; Maiese, W. M. J. Antibiot. 2000, 53, 256.
(3) According to systematic nomenclature (von Baeyer system), the
tricyclic 5-7-6 ring system present in guanacastepenes is tricyclo[8.4.0.03,7]-
tetradecane. However, it is not clear to us why a different numbering (based
on tricyclo[9.3.0.03,8]tetradecane) was given for guanacastepenes. In this
paper, we follow the systematic numbering with the two quaternary ring
junction carbons numbered as 7 and 10 (instead of 11 and 8).
(4) Ramesh, P.; Reddy, N. S.; Venkateswarlu, Y.; Reddy, M. V. R.;
Faulkner, D. J. Tetrahedron Lett. 1998, 39, 8217.
Scheme 2a
(5) Faulkner, D. J.; Venkateswarlu, Y. PCT Int. Appl., WO0027839,
2000. CAN 132:352768.
(6) (a) Lin, S.; Dudley, G. B.; Tan, D. S.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2002, 41, 2188. (b) Tan, D. S.; Dudley, G. B.; Danishefsky,
S. J. Angew. Chem., Int. Ed. 2002, 41, 2185.
(7) Shi, B.; Hawryluk, N. A.; Snider, B. B. J. Org. Chem. 2003, 68,
1030.
(8) (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) Dudley, G. B.; Danishefsky, S. J.;
Sukenick, G. Tetrahedron Lett. 2002, 43, 5605. (d) Snider, B. B.; Hawryluk,
N. A. Org. Lett. 2001, 3, 569. (e) Snider, B. B.; Shi, B. Tetrahedron Lett.
2001, 42, 9123. (f) Magnus, P.; Waring, M. J.; Ollivier, C.; Lynch, V.
Tetrahedron Lett. 2001, 42, 4947. (g) Magnus, P.; Ollivier, C. Tetrahedron
Lett. 2002, 43, 9605. (h) Mehta, G.; Umarye, J. D. Org. Lett. 2002, 4, 1063.
(i) Mehta, G.; Umarye, J. D.; Gagliardini, V. Tetrahedron Lett. 2002, 43,
6975. (j) Mehta, G.; Umarye, J. D.; Srinivas, K. Tetrahedron Lett. 2003,
44, 4233. (k) Shipe, W. D.; Sorensen, E. J. Org. Lett. 2002, 4, 2063. (l)
Nakazaki, A.; Sharma, U.; Tius, M. A. Org. Lett. 2002, 4, 3363. (m) Boyer,
F.-D.; Hanna, I. Tetrahedron Lett. 2002, 43, 7469. (n) Du, X.; Chu, H. V.;
Kwon, O. Org. Lett. 2003, 5, 1923. (o) Brummond, K. M.; Gao, D. Org.
Lett. 2003, 5, 3491.
a Reagents, conditions, and yields: (a) LDA, THF, -70 °C f
rt, CH2dCHCH2Br, 12 h, 85%; (b) LDA, THF, -70 °C f rt, CH3I,
12 h, 84%; (c) Li, CH2dCH(CH2)2Br, THF, ))), rt, 1 h; (d) PCC,
silica gel, CH2Cl2, rt, 4 h; 70% (for two steps).
2. Thus, kinetic alkylation14 of (R)-carvone 3 using LDA
and allyl bromide generated a 6:1 epimeric mixture of
6-allylcarvones 4, which on a second alkylation with LDA
and methyl iodide generated, exclusively, the cis-6-allyl-6-
(9) (a) Nguyen, T. M.; Lee, D. Tetrahedron Lett. 2002, 43, 4033. (b)
Nguyen, T. M.; Seifert, R. J.; Mowrey, D. R.; Lee, D. Org. Lett. 2002, 4,
3959.
(10) Hughes, C. C.; Kennedy-Smith, J. J.; Trauner, D. Org. Lett. 2003,
5, 0000.
(11) Srikrishna, A.; Anebouselvy, K. Tetrahedron Lett. 2002, 43, 2769.
(12) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (b)
Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3013. (c) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
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Org. Lett., Vol. 6, No. 2, 2004