Samarium(II) folding cascades involving hydrogen atom transfer for the synthesis of complex polycycles

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.

Cascades, Catalysis and Chiral Ligand Control with SmI2; The Rebirth of a Reagent

“…In 2018, we described a diversity-oriented synthesis of polycyclic systems bearing multiple stereocentres. [7] Simple, linear substrates can follow three different folding pathways triggered by reductive single electron transfer from SmI 2 . Two of the radical cascade pathways utilise 1,5-hydrogen atom transfer (1,5-HAT) to activate secondary alkyl and benzylic groups whereas the third route generates complex lactones via an extended SET pathway (Scheme 1).…”

“…Interestingly, 1,5-HAT rarely accompanies SmI 2 -mediated reactions as the rate of reduction of radicals typically outcompetes the rate of hydrogen atom abstraction. [7] By careful substrate design, in which the resultant radical is formed in proximity to the site of abstraction, 1,5-HAT can be incorporated in diversity-oriented, radical, carbon-carbon bond-forming cascade reactions.…”

“…Several substrates were found to undergo folding with moderate to good yield delivering [5,7] and [5,8] fused bicyclic products (Scheme 2). In most cases the product is formed with complete diastereocontrol, a result of the coordination of Lewis basic sites in the substrate to the oxophilic samarium ion during folding.…”

Diastereoselective Hydroxyethylation of β‐Hydroxyketones: A Reformatsky Cyclization‐Lactone Reduction Cascade Mediated by SmI2−H2O

“…[22] This work has culminated in the development of radical cascade reactions for the selective construction of complex architectures. [23][24][25][26][27][28][29] In the case of lactone reduction, we have described the ring size-selective reduction of six-membered lactones using SmI 2 À H 2 O that proceeds by electron-transfer to the lactone carbonyl and delivers the corresponding diol products (Scheme 1,b). [16,17] Inspired by Molander's seminal work on a highly diastereoselective SmI 2 -mediated intramolec-ular Reformatsky approach to 6-membered lactones, [30] here we describe a diastereoselective hydroxyethylation of β-hydroxyketones that delivers 1,3,5-triols and involves a SmI 2 À H 2 O-mediated Reformatsky cyclization-lactone reduction cascade (Scheme 1,c).…”

“…In particular, we have developed reductions of lactones, acyclic esters, carboxylic acids, nitriles, and amides, using SmI 2 activated by H 2 O . This work has culminated in the development of radical cascade reactions for the selective construction of complex architectures . In the case of lactone reduction, we have described the ring size‐selective reduction of six‐membered lactones using SmI 2 −H 2 O that proceeds by electron‐transfer to the lactone carbonyl and delivers the corresponding diol products ( Scheme ,b ) .…”