Chromium-Catalyzed Radical-Involved Asymmetric Carbonyl Additions

Abstract

Asymmetric carbonyl addition reactions have long been recognized as a powerful platform for synthesizing chiral alcohols, garnering significant attention in synthetic chemistry. Over the past few decades, notable progress has been made in this field through the use of organometallic reagents and two-electron polar addition processes. However, these approaches often face challenges related to functional group compatibility, particularly when employing strongly basic alkyl nucleophiles, and the construction of vicinal stereocenters remains difficult due to the limited availability of chiral alkylmetal nucleophiles, whether presynthesized or formed in situ. As a result, there is a continued demand for the development of alternative strategies for asymmetric carbonyl additions.

Radical reactions, known for their high functional group tolerance, mild reaction conditions, and distinct reactivity, offer a promising alternative to traditional polar processes. Specifically, radical-based asymmetric carbonyl additions present a compelling solution to the aforementioned challenges. Despite their potential, several hurdles remain, including (1) challenging reactivity control due to the thermodynamically unfavorable direct radical carbonyl addition, (2) undesired background reactions and difficulties in controlling stereoselectivity due to the transient nature of radical intermediates, and (3) the complexities in elucidating the mechanisms involving radical species. Drawing inspiration from the Nozaki–Hiyama–Kishi reactions, our group has focused on establishing a robust platform for radical-based asymmetric carbonyl additions using chromium catalysis. This approach has enabled previously challenging asymmetric transformations and provided new insights into the underlying mechanisms.

In this Account, we summarize our key achievements in the field, categorized by various radical generation strategies, and highlight the significant potential of chromium-catalyzed asymmetric carbonyl additions for synthesizing useful chiral molecules with vicinal stereocenters and their synthetic applications. We first established Cr-catalyzed asymmetric additions to aldehydes and ketones using racemic alkyl halides as radical precursors. Additionally, we explored the use of protected imines, activated alkenes, conjugate dienes, 1,3-enynes, and racemic allenes as effective radical precursors in asymmetric additions to aldehydes, enabled by Cr catalysis or metallaphotoredox catalysis. Furthermore, we developed a triple-catalysis system to achieve the asymmetric α-C–H addition of N-sulfonyl benzylamines to aldehydes, producing β-amino alcohols with vicinal stereocenters.

Extensive studies, including radical trapping, UV–vis spectroscopy, kinetic isotope effects, and DFT calculations, have revealed two principal transition state (TS) models. For alkyl radicals bearing α π functionalities (e.g., double/triple bonds, carbonyl groups), the reaction often proceeds via a cyclic six-membered TS, whereas radicals lacking such conjugation may follow an acyclic direct radical addition TS facilitated by Cr-to-carbonyl single electron transfer. These mechanistic scenarios differ notably from those in Ni- or Cu-catalyzed radical cross-couplings, thus broadening the landscape of enantioselective radical chemistry. This Account aims to stimulate further research into radical-based asymmetric addition reactions, offering efficient pathways to complex enantioenriched molecules.