Scheme 1
illustrated in Scheme 1. In our previous synthesis of
the ketone of 14 proceeded with excellent diastereoselectivity
(98:2) to give the optically pure diol 15 in 87% yield (2
steps), after removal of the BOM group and recrystallization.
Oxidation of the secondary alcohol followed by Baeyer-
Villiger oxidation of the resulting ketone furnished cleanly
the bicyclic lactone 16 in 78% yield (2 steps). Lactone 17
was prepared from 16 in 86% overall yield by way of a four-
step sequence involving ethanolysis of the lactone, NaBH4
reduction of the resulting lactol, acid-catalyzed lactonization,
and protection of the diol as the TES ethers.
vinblastine, we performed a stereoselective coupling of
vindoline (2) with the 11-membered upper segment, which
was prepared by means of a radical cyclization of o-
alkenylthioanilides7 as well as a macrocyclization of ni-
trobenzenesulfonamide.8 According to this retrosynthesis,
analogue 3 could be obtained from the key intermediate 4,
which in turn would be derived from lactone 6 via thioamide
5. Lactone 6 could be synthesized from cis-fused bicyclic
lactone 7 in a simple operation. Crucial addition of an ethynyl
group to ketone 8 is likely to occur from the less hindered,
convex face. Finally, ketone 8 would be derived from the
readily available carboxylic acid 9.
With the requisite lactone 17 in hand, we next turned our
attention to the construction of the indole core using a radical
Our synthesis commenced with the preparation of the
known optically active malonate 10 (96% ee) according to
Trost’s procedure9 (Scheme 2). Malonate 10 was converted
into carboxylic acid 9 in 77% yield via Krapcho decar-
balkoxylation10 followed by base hydrolysis. Oxidative
lactonization of 9 catalyzed by H2WO4 afforded a lactone
(71%),11 which was protected as its BOM ether (93%).
DIBAL reduction of the lactone 11 followed by Wittig olefin-
ation afforded enol ether 12, which was cyclized under weak-
ly acidic conditions to give dihydropyran 13 in 80% for the
three steps. Hydroboration of 13 followed by oxidative
workup afforded an alcohol, which was subjected to TPAP
oxidation12 to give the requisite ketone 14 in 80% yield (2
steps). As expected, addition of lithium TIPS acetylide to
Scheme 2
(4) (a) Mangency, P.; Adriamialisoa, R. Z.; Langlois, N.; Langlois, Y.;
Potier, P. J. Am. Chem. Soc. 1979, 101, 2243. (b) Kutney, J. P.; Choi, L.
S. L.; Nakano, J.; Tsukamoto, H.; McHugh, M.; Boulet, C. A. Heterocycles
1988, 27, 1845. (c) Kuehne, M. E.; Matson, P. A.; Bornmann, W. G. J.
Org. Chem. 1991, 56, 513. (d) Magnus, P.; Mendoza, J. S.; Stamford, A.;
Ladlow, M.; Willis, P. J. Am. Chem. Soc. 1992, 114, 10232.
(5) For a review on medicinal chemistry of vinblastine, see: Antitumor
Bisindole Alkaloids from Catharanthus roseus (L.). In The Alkaloids; Brossi,
A., Suffness, M., Eds.; Academic Press Inc.; San Diego, CA, 1990; Vol.
37, Chapters 3 and 4, pp 133-204.
(6) Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.;
Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 2137.
(7) Tokuyama, H.; Yamashita, T.; Reding, M. T.; Kaburagi, Y.;
Fukuyama, T. J. Am. Chem. Soc. 1999, 121, 3791.
(8) (a) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353. (b) Kan, T.;
Fukuyama, T. J. Synth. Org. Chem., Jpn. 2001, 59, 779.
(9) Trost, B. M.; Bunt, R. C. Angew. Chem., Int. Ed. Engl. 1996, 35, 99.
(10) Krapcho, A. P. Synthesis 1982, 805.
(11) Ishii, Y.; Nakano, T.; Inoue, K. WO0206262.
(12) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
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