Polyketide construction via hydrohydroxyalkylation and related alcohol C-H functionalizations: reinventing the chemistry of carbonyl addition

• Published in: Natural product reports 2014-01, Vol.31 (4), p.54-513
• Main Authors: Dechert-Schmitt, Anne-Marie R, Schmitt, Daniel C, Gao, Xin, Itoh, Takahiko, Krische, Michael J
• Format: Article
• Language: English
• Subjects: Biological Products - chemical synthesis; Biological Products - chemistry; Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bryostatins - chemical synthesis; Bryostatins - chemistry; Catalysis; Erythromycin - analogs & derivatives; Erythromycin - chemical synthesis; Erythromycin - chemistry; Humans; Hydrogenation; Macrolides - chemical synthesis; Macrolides - chemistry; Molecular Structure; Polyketides - chemical synthesis; Polyketides - chemistry; Rifamycins - chemical synthesis; Rifamycins - chemistry; Stereoisomerism
• ISSN: 0265-0568; 1460-4752
• DOI: 10.1039/c3np70076c

Covering: up to the end of 2013 Despite the longstanding importance of polyketide natural products in human medicine, nearly all commercial polyketide-based drugs are prepared through fermentation or semi-synthesis. The paucity of manufacturing routes involving de novo chemical synthesis reflects the inability of current methods to concisely address the preparation of these complex structures. Direct alcohol C-H bond functionalization via " C - C bond forming transfer hydrogenation " provides a powerful, new means of constructing type I polyketides that bypasses stoichiometric use of chiral auxiliaries, premetallated C -nucleophiles, and discrete alcohol-to-aldehyde redox reactions. Using this emergent technology, total syntheses of 6-deoxyerythronolide B, bryostatin 7, trienomycins A and F, cyanolide A, roxaticin, and formal syntheses of rifamycin S and scytophycin C, were accomplished. These syntheses represent the most concise routes reported to any member of the respective natural product families. Direct alcohol C-H bond functionalization bypasses the use of chiral auxiliaries, premetallated C -nucleophiles, and discrete alcohol-to-aldehyde redox reactions. This technology has enabled syntheses of 6-deoxyerythronolide B, bryostatin 7, trienomycins A and F, cyanolide A, roxaticin.