Abstract
The expedient assembly of complex, natural product-like small molecules can deliver new chemical entities with the potential to interact with biological systems and inspire the development of new drugs and probes for biology. Diversity-oriented synthesis is a particularly attractive strategy for the delivery of complex molecules in which the 3-dimensional architecture varies across the collection. Here we describe a folding cascade approach to complex polycyclic systems bearing multiple stereocentres mediated by reductive single electron transfer (SET) from SmI2. Simple, linear substrates undergo three different folding pathways triggered by reductive SET. Two of the radical cascade pathways involve the activation and functionalization of otherwise inert secondary alkyl and benzylic groups by 1,5-hydrogen atom transfer (HAT). Combination of SmI2, a privileged reagent for cascade reactions, and 1,5-HAT can lead to complexity-generating radical sequences that unlock access to diverse structures not readily accessible by other means.
Highlights
The expedient assembly of complex, natural product-like small molecules can deliver new chemical entities with the potential to interact with biological systems and inspire the development of new drugs and probes for biology
The synthesis of complex small molecules that can interact with biological systems is of paramount importance in science
Building on the successful use of 1,5-hydrogen atom transfer (HAT) to activate secondary alkyl groups in the folding cascades, we proposed that remote activation of a benzylic position could lead to alternative product architectures
Summary
The expedient assembly of complex, natural product-like small molecules can deliver new chemical entities with the potential to interact with biological systems and inspire the development of new drugs and probes for biology. While the first two approaches target defined structure space of known biological relevance, diversity-oriented synthesis attempts to deliver a diverse range of molecular architectures than can give access to unexplored activity and the promise of greater potency[4,5,6,7,8,9]. While recent reports in the field of diversity-oriented synthesis have utilised radical reactions to access diverse molecular space[31,32,33,34], the exploitation of HAT in such processes remains largely unexplored
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