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Published on: July 28, 2022
Modular diastereoselective synthesis of hindered cyclobutane amino nitriles through triplet nitrene-mediated ring
Jun-Jie Yin1, Su-Ge Xin1, Hengyi Cao2
1State Key Laboratory of Fluorine and Nitrogen Chemistry and Advanced Materials, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Abstract:
Cyclobutane amino nitriles (CBANs), as a class of sterically hindered α,α-disubstituted unnatural amino acid derivatives, have garnered notable interest in pharmaceutical research due to their capacity to enhance molecule potency, metabolic stability and selectivity. However, the advancement and exploration of the chemical space of CBANs are impeded by general synthetic strategies, particularly for sterically more hindered vicinal tetrasubstituted derivatives. Here we report the diastereoselective synthesis of congested CBANs using commercially available ketones or aldehydes through a modular and precise process. The key to this transformation involves harnessing the unique reactivity of triplet nitrene. This enables a diradical-mediated ring expansion of alkylidenecyclopropanes and is combined with a titanium(IV)-catalysed cyanylation step. The reaction, which is supported by experimental and computational mechanistic studies, readily delivers hindered vicinal mono- and di-substituted CBANs, along with spiro-fused architectures, showcasing substantial structural diversity. High functional-group compatibility, including with groups that are incompatible with traditional multi-step processes and are medicinally relevant, is also observed.
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