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

Abstract

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, the 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 these respective natural product families.

Towards the generalized iterative synthesis of small molecules

“…69 Application of this iterative strategy in a two-directional manner expedited construction of the key polyol portion of (+)-roxaticin (Figure 2d). 70 This methodology has proven to be highly versatile and readily scalable, enabling practical gram scale access to stereochemically complex building blocks for a wide range of highly complex polyketide natural products.…”

Saccharomyces cerevisiae as a tool for mining, studying and engineering fungal polyketide synthases

“…Currently, nearly all commercial polyketides are prepared through fermentation or semi-synthesis (Dechert-Schmitt et al, 2014; Wong and Khosla, 2012). Thus, elucidating the biosynthetic pathways of polyketides and characterizing the pathway enzymes is necessary for the production and diversification of natural products for pharmaceutical applications (Tibrewal and Tang, 2014).…”

Asymmetric Iridium-Catalyzed C–C Coupling of Chiral Diols via Site-Selective Redox-Triggered Carbonyl Addition

“…By exploiting the native reducing ability of alcohols, we have developed a broad, new family of redox-triggered carbonyl additions where hydrogen transfer from alcohols to π-unsaturated reactants results in the formation of electrophile-nucleophile pairs, which combine to give products of formal alcohol C-H functionalization [42, 43, 44, 45, 46, 47, 48]. These processes are redox-efficient as they merge alcohol oxidation and C-C bond construction events, bypassing discrete alcohol-to-aldehyde redox reactions, as well as manipulations required for the stoichiometric formation of premetalated reagents.…”