Stereoselective hydrogen atom transfer to acyclic radicals: a switch enabling diastereodivergent borylative radical cascades

Tian Ye,Yi-Feng Wang,Hui-Min Xia,Xi Zhou,Feng-Lian Zhang,Zhi-Xiang Yu

doi:10.1038/s41467-022-28071-8

Abstract

Radical cascade reactions are powerful tools to construct structurally complex molecules. However, the stereochemical control of acyclic radical intermediates remains a persistent challenge, due to the low differentiation between the two faces of these species. This hurdle further makes stereodivergent synthesis rather more difficult to be accomplished, in particular for intermediates resulted from complex cascades. Here we report an efficient strategy for stereoselective hydrogen atom transfer (HAT) to acyclic carbon radicals, which are generated via N-heterocyclic carbene (NHC)-boryl radicals triggered addition-translocation-cyclization cascades. A synergistic control by the NHC subunit and a thiol catalyst has proved effective for one facial HAT, while a ZnI2-chelation protocol allows for the preferential reaction to the opposite face. Such a stereoselectivity switch enables diastereodivergent construction of heterocycles tethering a boron-substituted stereocenter. Mechanistic studies suggest two complementary ways to tune HAT diastereoselectivity. The stereospecific conversions of the resulting boron-handled products to diverse functionalized molecules are demonstrated.

Highlights

Radical cascade reactions are powerful tools to construct structurally complex molecules
Chelation by the use of Lewis acids has been applied so that the corresponding acyclic systems become rigid and high diastereoselectivity is possible to be realized[16,17]. These approaches have proven effective in certain cases, some limitations and drawbacks still remain: (i) most methods are restricted to specific substrates with the preinstallation of different functional groups onto specific positions for steric, electronic, or complexation purposes, but such tactics are hardly applied in the reduction of radicals derived from complex radical cascades; (ii) stereocontrol is highly temperature-dependent and relatively lower temperature is often necessary to ensure high diastereoselectivity, but this becomes disfavored for radical cascades that need high temperature[18,19]; (iii) diastereodivergent hydrogen atom transfer (HAT) reactions have only been reported in limited cases[20], and a general strategy for diastereodivergency is still lacking
N-heterocyclic carbene (NHC)-BH3/thiol catalyst-controlled stereoselective HAT to acyclic radicals generated via borylative radical addition-translocation-cyclization (RATC)

Summary

Introduction

Radical cascade reactions are powerful tools to construct structurally complex molecules. The stereochemical control in these reactions remains an inherently difficult issue when acyclic carbon stereocenters are created through complex cascade processes, due to the persistent challenge associated with the low differentiation between the two faces of acyclic alkyl radicals[6,7] This hurdle makes the stereodivergent synthesis, which is highly demanded in medicinal studies[8], rather difficult to be achieved. The following HAT to the resulting acyclic radical III with high stereocontrol is perceived to be a major challenge for achieving the goal of stereoselective and stereodivergent synthesis of boron-tethered indolines

Methods

Results

Conclusion