Beyond Polar Addition: A Radical Alternative for Enantioselective C–C Bond Formation Driven by Alkylzirconocenes Dual Reactivity
- 1School of Life Sciences
- 2Tsinghua University
- 3National Institute of Biological Sciences, 7 Science Park Road, Beijing, China, 102206
Abstract
The catalytic asymmetric addition of organometallic reagents to carbonyl compounds represents a fundamental strategy for the synthesis of enantioenriched alcohols. However, conventional carbanionic nucleophiles (e.g., organomagnesium and organolithium) often suffer from competing deprotonation pathways, uncatalyzed background reactions, limited functional-group tolerance, and sensitivity to moisture and air. Alkylzirconocenes, readily generated from abundant alkenes, offer an attractive alternative by virtue of their functional‑group compatibility, photochemical lability, and capacity for remote chain‑walking. Herein, we report a visible-light-enabled, nickel-catalyzed asymmetric radical addition of alkylzirconocenes to aliphatic aldehydes, providing efficient access to enantioenriched secondary alcohols in good yields with high levels of enantioselectivities. This transformation features broad functional-group tolerance, enabling the late-stage enantioselective modification of complex pharmaceutical molecules and natural products. Notably, alkylzirconocenes serve a dual role in this process, acting as both alkyl radical precursors and sources of Zr(III) species for carbonyl activation. Mechanistic investigations, including control experiments, radical‑clock experiments, kinetic analysis, nonlinear effect studies, support a nickel-catalyzed asymmetric radical addition pathway, wherein a Zr(III) species mediates the single-electron reduction of aliphatic aldehydes to generate ketyl radicals. This work establishes a new paradigm for asymmetric carbonyl addition that circumvents the intrinsic limitations of classical polar mechanisms.
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BibTeX
@misc{miao2026beyond,
title = {{Beyond Polar Addition: A Radical Alternative for Enantioselective C–C Bond Formation Driven by Alkylzirconocenes Dual Reactivity}},
author = {Wenqian Miao and Songlin Bai and Qingcui Wu and Xiangbing Qi},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15008464/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008464/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Beyond Polar Addition: A Radical Alternative for Enantioselective C–C Bond Formation Driven by Alkylzirconocenes Dual Reactivity
AU - Wenqian Miao
AU - Songlin Bai
AU - Qingcui Wu
AU - Xiangbing Qi
PY - 2026
DA - 2026/09/07
PB - ChemRxiv
DO - 10.26434/chemrxiv.15008464/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008464/v1
AB - The catalytic asymmetric addition of organometallic reagents to carbonyl compounds represents a fundamental strategy for the synthesis of enantioenriched alcohols. However, conventional carbanionic nucleophiles (e.g., organomagnesium and organolithium) often suffer from competing deprotonation pathways, uncatalyzed background reactions, limited functional-group tolerance, and sensitivity to moisture and air. Alkylzirconocenes, readily generated from abundant alkenes, offer an attractive alternative by virtue of their functional‑group compatibility, photochemical lability, and capacity for remote chain‑walking. Herein, we report a visible-light-enabled, nickel-catalyzed asymmetric radical addition of alkylzirconocenes to aliphatic aldehydes, providing efficient access to enantioenriched secondary alcohols in good yields with high levels of enantioselectivities. This transformation features broad functional-group tolerance, enabling the late-stage enantioselective modification of complex pharmaceutical molecules and natural products. Notably, alkylzirconocenes serve a dual role in this process, acting as both alkyl radical precursors and sources of Zr(III) species for carbonyl activation. Mechanistic investigations, including control experiments, radical‑clock experiments, kinetic analysis, nonlinear effect studies, support a nickel-catalyzed asymmetric radical addition pathway, wherein a Zr(III) species mediates the single-electron reduction of aliphatic aldehydes to generate ketyl radicals. This work establishes a new paradigm for asymmetric carbonyl addition that circumvents the intrinsic limitations of classical polar mechanisms.
ER -