Radicals as Chiral Catalysts for Asymmetric Radical Cyclization Reactions

Due to the innate highly reactive properties and short life-time, organic free radicals can often serve as promoters or intermediates to engage in various radical transformations, which are often otherwise difficult to access by ionic pathway-based mechanisms. With the evolvement of radical chemistry, chiral radical catalyzed-transformations have recently emerged as an attractive and robust platform for synthesis of chiral molecules of interest. Herein, we highlight several creative and strategic advances in chiral radical catalyst design, cyclization reaction achievements, and future challenges.Key ScientistsIn the 1980s, some pioneering studies by Feldman and Oshima revealed that the thiyl radical could catalyze cyclization of vinylcyclopropane with alkenes, providing access to racemic cyclopentanes. In 1996, Brian P. Roberts reported an interesting enantioselective hydrosilylation of prochiral alkenes by using thioglucose-derived chiral thiyl radical catalysts. Since then, chiral radical catalysis has become an emerging and promising catalytic strategy in organic synthesis. However, this field has not been extensively explored further until the Maruoka group in 2014 achieved the asymmetric C-C bond formation by employing a newly designed indanol core-based chiral thiyl radical catalyst. In this protocol, an enantioselective radical cyclization of vinylcyclopropanes with electron-rich alkenes was developed. In 2020, Chen and Xiao disclosed a nitrogen radical-catalyzed version of this reaction. Later, this strategy was further expanded to metalloradical catalyzed asymmetric radical cascade cyclization reactions by Zhang in 2021. Later on, Wang, Fu and Zhang et al. described a novel class of boryl radical-catalyzed asymmetric radical cycloisomerization reactions, further showcasing enormous synthetic potential of chiral radical catalysis. This Emerging Topic has focused on asymmetric radical cyclization reactions involving diverse chiral radical catalysts. Chiral radical covalent catalysis represents an emerging strategy for the stereocontrol of radical cyclization reactions. This distinct catalytic strategy mainly involves three key steps: (1) reversible intermolecular addition of chiral radical catalyst toward substrates to form new radical intermediates poised for subsequent new-bond-forming cyclization, (2) intramolecularly stereo-determining radical cyclization process, (3) final elimination process with regeneration of chiral radical catalyst. image