attracted early attention as a consequence of its reputed
antibacterial and antitumor properties.11 Three syntheses of
12 have since been disclosed from laboratories headed by
Little,12 Curran,13 and Weinges.14 Application of the 1,3-
diyl trapping reaction and a tandem radical cyclization
featured prominently in the first two routes. The third
approach was enantioselective and consisted of a rather
lengthy sequence involving suitable structural modification
of commercially available catalpol.
Scheme 2
The first step in the present undertaking was the sequential
addition of the lithiated cyclopentenyl acetal 2 and vinyl-
lithium to 1. The organometallic nucleophile 2 was readily
available by conventional bromination-dehydrobromination
of 5,5-dimethyl-2-cyclopentenone15 followed by acetalization
and exposure to tert-butyllithium for the purpose of halogen-
metal exchange (Scheme 1). The choice of 2 was predicated
Scheme 1a
a (a) Br2, CH2Cl2, 0 °C, 40 min; Et3N, 20 °C, 3 h (77%). (b)
Ethylene glycol, Dowex 50X4-400, C6H6, reflux 3 days (80% brsm).
(c) tert-Butylithium, THF, -78 °C (brsm ) based on recovered
starting material).
on our expectation that arrival at intermediate D would
materialize from either of the originating diastereomeric
bisadducts A or B (Scheme 2). The proper incorporation of
an acetal as in D, previously shown to be capable of
controlling the directionality of subsequent ring closures,16
was expected to guarantee conversion to E as a prelude to
transannular aldolization as in F. This species is recognized
to be the dialkoxide of the cis, anti-fused tricycle 3. At the
experimental level, 3 can be isolated by flash chromatography
on silica gel. Most often, however, rapid assembly of the
linearly fused triquinane core in this fashion was directly
followed by acidic hydrolysis of the enol ether functionality
to give 4 in 24% overall yield (Scheme 3). Since seven
distinctively unique chemical steps operate sequentially while
progressing from 1 to 4, the average yield for each step is
80%.
by exposure to methanesulfonyl chloride and triethylamine
in CH2Cl2 containing a small amount of DMAP.17 Several
attempts to replace the chlorine atom in 5 by the necessary
angular methyl group failed. For example, the direct treat-
ment of 5 with trimethylaluminum led to no reaction.
Similarly, the prior dehydrochlorination of 5 did not provide
a feasible forum for the subsequent conjugate addition of
various methylcopper reagents.
A convenient and efficient alternative to these protocols
began in the form of an initial dissolving metal reduction
with lithium in liquid ammonia. Concurrent dechlorination
and reduction of the ketone carbonyl was seen without any
deleterious consequences in the highly oxygenated A-ring.
As in the case of 4, NOESY studies were implemented for
the purpose of establishing relative stereochemistry (see
formulas). For 6, the evidence was clear that the configu-
ration of the hydroxyl group was that required of the target.
Continued success was enjoyed with the lithium aluminum
hydride reduction of 6. Workup with dilute acid eventuated
in dehydrative 1,3-carbonyl transposition and the formation
of 7 (76%). Once protection of the hydroxyl substituent as
its MOM ether had been achieved, it proved an easy matter
to introduce the R-methyl group regiospecifically by con-
ventional condensation of the enolate anion of 8 with methyl
The hydroxyl group in 4 was next converted into the
chloride functionality in 5 with retention of configuration
(11) (a) Kupka, J.; Anke, T.; Giannetti, B. M.; Steglich, W. Arch.
Microbiol. 1981, 130, 223. (b) Giannetti, B. M.; Steffan, B.; Steglich, W.;
Kupka, J.; Anke, T. Tetrahedron 1986, 42, 3587. (c) Steglich, W. Pure
Appl. Chem. 1981, 53, 1233.
(12) Van Hijfte, L.; Little, R. D.; Petersen, J. L.; Moeller, K. D. J. Org.
Chem. 1987, 52, 4647.
(13) Fevig, T. L.; Elliott, R. L.; Curran, D. P. J. Am. Chem. Soc. 1988,
110, 5064.
(14) (a) Weinges, K.; Iatridou, H.; Dietz, U. Liebigs Ann. Chem. 1991,
893. (b) See also: Weinges, K.; Dietz, U. Oeser, T.; Irngartinger, H. Angew.
Chem., Int. Ed. Engl. 1990, 29, 680.
(15) Padwa, A.; Curtis, E. A.; Sandanayaka, V. P. J. Org. Chem. 1996,
61, 73.
(16) (a) Paquette, L. A.; Doyon, J. J. Am. Chem. Soc. 1995, 117, 6799.
(b) Paquette, L. A.; Doyon, J. J. Org. Chem. 1997, 62, 1723.
(17) Morwick, T. M.; Paquette, L. A. J. Org. Chem. 1996, 61, 146.
Org. Lett., Vol. 4, No. 1, 2002
72