Total Synthesis of the Chlorine-Containing Hapalindoles K, A, and G

摘要

Indole alkaloids of the terrestrial blue-green algae are structurally diverse natural products and have elicited a broad response in the form of new chemical methods and preparations. This enterprise is driven, in part, by the diverse biological activity that is often associated with metabolites of cyanobacteria resident in these algae. Beginning with the syntheses of (non-chlorine-containing). hapalindoles J and M by Muratake and Natsume, fischerindole, hapalindole, welwitindolinone, and ambiguine natural products have been accessed by total synthesis. The chlorine-containing congeners further increase the functional and stereochemical diversity of this natural product class, but solutions for their synthesis are few in number. Fukuyama and Chen reported the first synthesis of a hapalindole that contains a chiral secondary alkyl chloride (hapalindole G, 3). The syn relationship between the chlorine and the methyl groups was established by a cyclopropane-ring-opening reaction with lithium chloride. In 2005, Baran and co-workers reported the syntheses of fischerindoles I and G. The configuration at C13 of these linear tetracycles is diastereomeric to that in 3, and was also constructed through a series of stereospecific transformations, including an epoxide-ring-opening reaction. The same neopentyl chloride is contained within welwitindolinone A, and the solution reported by Wood and co-workers involved a chloronium-induced [l,2]-methyl shift to establish the and relationship between methyl and chlorine. Equally elegant was the preparation of (+)-welwitindolinone A from (—)-fischerindole I by Baran and co-workers.