Challenges and discoveries in the total synthesis of complex polyketide natural products

Abstract

Structurally complex polyketide natural products, isolated from a variety of marine and terrestrial sources, continue to provide a valuable source of rewarding targets for the synthetic chemist to tackle. In this account, we provide an overview of the total synthesis of several structurally fascinating polyketides with promising anticancer activity completed in our group based on our versatile asymmetric aldol methodology-spirastrellolide A methyl ester, leiodermatolide, rhizopodin and chivosazole F-and highlight the unanticipated challenges and discoveries encountered.

Unusual Rearrangement-Remercuration Reactions of Allylic Silanols

“…During our optimization process, in some reactions, we isolated small amounts of a side product which we eventually determined to be a 5-membered cyclic silanediol organomercurial compound. We immediately recognized that such intermediates could be extremely valuable in the construction of the functional-group stereochemical arrays found in carbohydrate and polyketide natural products, 26 and we wondered if we could bias the formation of this product through tuning of reaction conditions (Table 2). a Yield estimated from 1 H NMR integration with methyl phenyl sulfone as an internal standard.…”

Loss of Single‐Domain Function in a Modular Assembly Line Alters the Size and Shape of a Complex Polyketide

“…Modular type I polyketide synthases (PKSs) assemble a broad range of ecologically and pharmaceutically relevant molecules . In contrast to the chemical synthesis of complex polyketides, which often requires challenging, multistep transformations, type I PKSs connect and process simple acyl and malonyl thioester building blocks in a fully programmed fashion . Structural diversity results from variations in the biosynthetic program.…”

Diversification of polyketide structures via synthase engineering

“…While polyketides have a firmly established role in treating human diseases, polyketide drug discovery and development efforts have waned in recent years, which is on trend with natural product drug discovery as a whole. 1,2 The interplay of supply issues 3 and challenges faced by the synthetic chemist seeking to modify or fully synthesize a polyketide scaffold 4 have contributed to the deprioritization of natural product research by pharmaceutical companies who opted to redirect their resources to efforts in combinatorial chemistry. 5 An overall decline in the rate of drug discovery was observed concomitantly with the deprioritization of natural product research.…”