Such properties may be attributable to the compounds’
capacities to inhibit RNA polymerase.5 Accordingly, these
alkaloids have stimulated various synthetic studies over the
last 15 years or so and total syntheses have been reported
by the groups of Natsume, Albizati, Fukuyama, Kerr, and
Baran.6
cyclopropane 5 in the presence of silver tetrafluoroborate to
give adducts 6 (77%) and 7 (67%), respectively. These
products clearly arise through nucleophilic attack of C-3 of
the indoles on the allylic cation derived from electrocyclic
ring-opening of the compound 5. Reaction of cyclohexenyl
bromide 7 with 2 molar equiv of tert-butyllithium and
trapping of the ensuing cyclohexenyllithium with either
methyl chloroformate or the Weinreb amide of acetic acid7
then gave the corresponding R,â-unsaturated ester 88 (57%)
and methyl ketone 9 (59%), respectively.9 Subjection of the
former product to hydrogenation, at 1 atm, using 10% Pd
on C as catalyst gave a ca. 1:1 and chromatographically
separable mixture of the cis- and trans-1,2-disubstituted
cyclohexanes 10a (51%) and 10b (49%), respectively.
Analogous treatment of the acylated alkene 9 afforded a
chromatographically separable mixture of compounds 11a
(19%) and 11b (63%). Methylenation of compound 11a with
the Petasis reagent10 afforded the alkene 12a (82%) that upon
treatment with TMSOTf underwent cyclization to give the
tetracyclic compound 13a8 (84%) embodying the cis-ring
fused variant on the fischerindole framework. Conversion
of isomeric ketone 11b into the corresponding and targeted
alkene 12b, which incorporates key elements of natural
products such as hapalidoles C, D, E, F, and Q,4,6 was
accomplished in an efficient manner (80%) by using the
Petasis reagent. Furthermore, subjection of the latter com-
pound to what might be regarded as a biomimetic cyclization
reaction6d,g using TMSOTf afforded the tetracyclic indole
13b8 (81%) now embodying the framework associated with
the fischerindoles.11
Our approach to the title frameworks is shown in Scheme
1 and involved, in the opening stages, an investigation of
Scheme 1
The strategy detailed above can also be exploited in the
construction of enantiopure indole-substituted cyclohexenes
incorporating additional functionality likely to be useful in
developing total syntheses of the title alkaloids. The two gem-
dibromocyclopropanes used in examining this particular
aspect of the present studies were prepared by the pathway
shown in the early parts of Scheme 2. Thus, oxidation of
commercially available 1,6-heptadien-4-ol (diallyl alcohol)
to the previously reported12 diallyl ketone (14) was ac-
complished (90%) with pyridinium chlorochromate (PCC)13
(6) (a) Muratake, H.; Kumagami, H.; Natsume, M. Tetrahedron 1990,
46, 6351 and references therein. (b) Sakagami, M.; Muratake, H.; Natsume,
M. Chem. Pharm. Bull. 1994, 42, 1393. (c) Vaillancourt, V.; Albizati, K.
F. J. Am. Chem. Soc. 1993, 115, 3499. (d) Fukuyama, T.; Chen, X. J. Am.
Chem. Soc. 1994, 116, 3125. (e) Kinsman, A. C.; Kerr, M. A. Org. Lett.
2001, 3, 3189. (f) Kinsman, A. C.; Kerr, M. A. J. Am. Chem. Soc. 2003,
125, 14120. (g) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2004, 126,
7450.
(7) Oster, T. A.; Harris, T. M. Tetrahedron Lett. 1983, 24, 1851.
(8) The structure of this compound has been confirmed by single-crystal
X-ray analysis. (CCDC reference numbers: 8, 610988; 13a, 610989; 13b,
610990.)
(9) Attempts to effect analogous conversions of compound 6 through
its reaction with 3.0 molar equiv of t-BuLi then either acetyl chloride or
methyl chloroformate only resulted in the formation of the N-acyl or
N-carbomethoxy derivatives of the starting material. Similar treatment of
the readily derived N-Boc derivative of compound 6 gave the same products
while its N-Ts congener afforded low yields (ca. 30%) of the desired
cyclohexenes, viz. the N-Ts analogues of compounds 8 and 9.
(10) Petasis, N. A.; Bzowej, E. I. J. Am. Chem. Soc. 1990, 112, 6392.
(11) Methods are available for the demethylation of N-methylindoless
see, for example: Nakatsuka, S.; Asano, O.; Goto, T. Heterocycles 1986,
24, 2791.
the reaction of the parent indole (3) and its N-methylated
derivative (4) with gem-dibromocyclopropane 5, the last
compound being readily available through dibromocarbene
addition to cyclopentene. In the event, each of indoles 3 and
4 reacted smoothly at 18 °C with equimolar quantities of
(3) Dehmlow, E. V.; Scho¨nefeld, J. Justus Liebigs Ann. Chem. 1971,
744, 42.
(4) (a) Moore, R. E.; Cheuk, C.; Patterson, G. M. L. J. Am. Chem. Soc.
1984, 106, 6456. (b) Moore, R. E.; Cheuk, C.; Yang, X.-Q. G.; Patterson,
G. M. L.; Bonjouklian, R.; Smitka, T. A.; Mynderse, J. S.; Foster, R. S.;
Jones, N. D.; Swartzendruber, J. K.; Deeter, J. B. J. Org. Chem. 1987, 52,
1036. (c) Moore, R. E.; Yang, X.-Q. G.; Patterson, G. M. L. J. Org. Chem.
1987, 52, 3773. (d) Park, A.; Moore, R. E.; Patterson, G. M. L. Tetrahedron
Lett. 1992, 33, 3257. (e) Stratmann, K.; Moore, R. E.; Bonjouklian, R.;
Deeter, J. B.; Patterson, G. M. L.; Shaffer, S.; Smith, C. D.; Smitka, T. A.
J. Am. Chem. Soc. 1994, 116, 9935.
(5) (a) Doan, N. T.; Rickards, R. W.; Rothschild, J. M.; Smith, G. D. J.
Appl. Phycol. 2000, 12, 409. (b) Doan, N. T.; Stewart, P. R.; Smith, G. D.
FEMS Microbiol. Lett. 2001, 196, 135.
(12) Dreyfuss, M. P. J. Org. Chem. 1963, 28, 3269.
(13) Corey, E. J.; Suggs, J. W. Tetrahedron Lett. 1975, 2647.
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