Outpacing H-Phosphonate Oxidation: Enantioconvergent Deborylative Synthesis of α-Stereogenic Alkyl Phosphonates
- 1Department of Chemistry
- 2Colorado State University
- 3Lilly Institute of Genetic Medicine, Lilly Seaport Innovation Center
Abstract
The growing biomedical relevance of α-stereogenic alkyl phosphonates, such as their use in enhancing the metabolic stability of oligonucleotide therapeutics, motivates versatile approaches to their asymmetric synthesis. The enantioconvergent coupling of C(sp3) building blocks and H-phosphonates offers a straightforward synthetic disconnection. Herein we report the first asymmetric deborylative C(sp3)–P coupling, harnessing the synthetic modularity of alkylboron reagents to streamline access to structurally diverse, enantioenriched α-stereogenic alkyl phosphonates. Developing an oxidative C(sp3)–P coupling must contend with the susceptibility of H-phosphonates to oxidation, a property underlying their established use as sacrificial reductants in copper catalysis. We propose a twofold strategy to overcome the facile P–H oxidation: (1) kinetically favoring N–H over P–H activation to promote aminyl-radical-mediated C(sp3)–BPin bond scission and (2) incorporating a strong X-type donor into the chiral ligand to suppress Cu(II)–P homolysis. The resulting transformation combines high enantioselectivity with broad tolerance for functional groups and pharmaceutically relevant heterocycles. Cyclic voltammetry supports our proposal that an anionic pincer ligand renders Cu(II) less oxidizing than its neutral counterparts. The stoichiometric reaction of the transient Cu(II)–phosphonate intermediate with a persistent trityl radical establishes its competence for C(sp3)–P bond formation. Hammett analysis revealed accelerated coupling of electron-deficient alkylboron substrates, corroborating the design principle that increasing electron density at Cu, as achieved with the anionic ligand scaffold, promotes the oxidative coupling. Density functional theory calculations identified C(sp3)–P reductive elimination as the enantiodetermining step and attributed stereocontrol to differences in alkyl-fragment distortion energy within the chiral ligand pocket. Together, these findings establish ligand-controlled modulation of Cu redox properties and radical-trapping reactivity as a strategy for reconciling asymmetric oxidative coupling with oxidation-sensitive nucleophiles.
Related
- Convergent Approach for the Asymmetric Synthesis of Vinyl Sulfoximines via Ruthenium-Catalyzed Enantioselective Alkylation of Sulfenamides with (Diazomethyl)phosphonates
- Copper-Catalyzed Enantioconvergent Synthesis of Sulfoxides from Racemic Sulfinate Esters and Organoboronic Acids
- Asymmetric Reductive Three‐Component Annulation Reaction for Constructing Fused N‐Heterocycles With Contiguous Stereogenic Centers
- Chirality Relay via Non-stereogenic Carbocations: from Stereogenic Alcohol to Twisted Tricyclic Skeleton
- Phosphorus(V) Umpolung Converts Electrophilic Phosphates into Nucleophilic H-Phosphonates
BibTeX
@misc{talimonyuk2026outpacing,
title = {{Outpacing H-Phosphonate Oxidation: Enantioconvergent Deborylative Synthesis of α-Stereogenic Alkyl Phosphonates}},
author = {Ofeliya Talimonyuk and Tanner J. Schubert and Grace M. Bergan and Ambre Carpentier and Yongxian Li and Mahesh M. Parsutkar and Joseph R. Martinelli and Robert S. Paton and Yuyang Dong},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010820/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010820/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Outpacing H-Phosphonate Oxidation: Enantioconvergent Deborylative Synthesis of α-Stereogenic Alkyl Phosphonates
AU - Ofeliya Talimonyuk
AU - Tanner J. Schubert
AU - Grace M. Bergan
AU - Ambre Carpentier
AU - Yongxian Li
AU - Mahesh M. Parsutkar
AU - Joseph R. Martinelli
AU - Robert S. Paton
AU - Yuyang Dong
PY - 2026
DA - 2026/10/22
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010820/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010820/v1
AB - The growing biomedical relevance of α-stereogenic alkyl phosphonates, such as their use in enhancing the metabolic stability of oligonucleotide therapeutics, motivates versatile approaches to their asymmetric synthesis. The enantioconvergent coupling of C(sp3) building blocks and H-phosphonates offers a straightforward synthetic disconnection. Herein we report the first asymmetric deborylative C(sp3)–P coupling, harnessing the synthetic modularity of alkylboron reagents to streamline access to structurally diverse, enantioenriched α-stereogenic alkyl phosphonates. Developing an oxidative C(sp3)–P coupling must contend with the susceptibility of H-phosphonates to oxidation, a property underlying their established use as sacrificial reductants in copper catalysis. We propose a twofold strategy to overcome the facile P–H oxidation: (1) kinetically favoring N–H over P–H activation to promote aminyl-radical-mediated C(sp3)–BPin bond scission and (2) incorporating a strong X-type donor into the chiral ligand to suppress Cu(II)–P homolysis. The resulting transformation combines high enantioselectivity with broad tolerance for functional groups and pharmaceutically relevant heterocycles. Cyclic voltammetry supports our proposal that an anionic pincer ligand renders Cu(II) less oxidizing than its neutral counterparts. The stoichiometric reaction of the transient Cu(II)–phosphonate intermediate with a persistent trityl radical establishes its competence for C(sp3)–P bond formation. Hammett analysis revealed accelerated coupling of electron-deficient alkylboron substrates, corroborating the design principle that increasing electron density at Cu, as achieved with the anionic ligand scaffold, promotes the oxidative coupling. Density functional theory calculations identified C(sp3)–P reductive elimination as the enantiodetermining step and attributed stereocontrol to differences in alkyl-fragment distortion energy within the chiral ligand pocket. Together, these findings establish ligand-controlled modulation of Cu redox properties and radical-trapping reactivity as a strategy for reconciling asymmetric oxidative coupling with oxidation-sensitive nucleophiles.
ER -