Creation and manipulation of common functional groups en route to a skeletally diverse chemical library

Abstract

We have developed an efficient strategy to a skeletally diverse chemical library, which entailed a sequence of enyne cycloisomerization, [4 þ 2] cycloaddition, alkene dihydroxylation, and diol carbamylation. Using this approach, only 16 readily available building blocks were needed to produce a representative 191-member library, which displayed broad distribution of molecular shapes and excellent physicochemical properties. This library further enabled identification of a small molecule, which effectively suppressed glycolytic production of ATP and lactate in CHO-K1 cell line, representing a potential lead for the development of a new class of glycolytic inhibitors.diversity-oriented synthesis | glycolysis | skeletal diversity S tructurally diverse collections of small molecules provide a validated source of chemical probes for basic and translational biomedical research (1, 2). Variation of the scaffold architecture of such compound libraries is particularly desirable to enable identification of new bioactive chemical probes with higher probability and greater efficiency. High-throughput synthesis of skeletally diverse small-molecule libraries represents one of the most challenging aspects of diversity-oriented synthesis and requires identification of efficient reaction sequences that can rapidly convert a small subset of readily available compounds to a large number of skeletally diverse chemical entities for subsequent biomedical applications (3).Transition metal-catalyzed cycloisomerization of enynes represents a powerful method for structural diversification (4-6). Our group previously demonstrated that various reaction topologies could be controlled by a proper choice of the transition metal catalyst, as well as the functionalization of the starting enyne (7-10). Significant advances in this area can now enable incorporation of such transformations into synthetic strategies for the assembly of skeletally diverse chemical libraries (11)(12)(13)(14)(15)(16)(17)(18). However, several challenges remain to be addressed to facilitate access to high-diversity chemical libraries. Typically, multiple cycloisomerization precursors are manually assembled to yield different skeletal frameworks upon their cycloisomerizations. A smaller number of building blocks would minimize this laborious process and increase efficiency. Another limitation is the difficulty of subsequent diversification of cycloisomerization products, which is complicated by the lack of common functional groups and variable chemical reactivity of such compounds. Ideally, the cycloisomerization should provide access to products containing the same functional group to enable the next diversity-generating step, which should yield another common functional group. If such common and reactive functional groups are efficiently produced at every stage of the synthesis, this synthetic pathway can readily provide access to a structurally diverse library starting with only a small set of building blocks.We describe the development of a unique approach, which ha...

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A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products

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