Direct Access to α-Chiral Amino-Oxetanes via Boron-Assisted Aziridine Ring-Opening
Abstract
α-Chiral amino-oxetanes represent a high-value yet synthetically difficult to access scaffold class in medicinal chemistry, combining the favorable pharmacokinetic properties of the oxetane ring with an additional degree of molecular complexity and three-dimensionality. Here we report the first synthetic route to α-chiral amino-oxetanes bearing boron and silicon substituents via a boron-assisted aziridine ring-opening strategy. Treatment of multichiral borylated and silylated oxetanyl-aziridines with simple carboxylic acids proceeds under mild, base-free conditions with full regio- and diastereoselectivity, affording densely functionalized products in excellent yields. The methodology accommodates over 30 structurally diverse carboxylic acids, including complex building blocks and Nprotected amino acids, and extends to azetidine analogs in a scalable protocol. Mechanistic investigations combining density functional theory computations and kinetic studies reveal a novel boron-assisted activation mode: reversible proton transfer from the carboxylic acid to the aziridine nitrogen generates a reactive aziridinium/carboxylate ion pair, which undergoes rate-determining SN2 attack facilitated by boron-oxygen coordination, lowering the activation barrier by more than 10 kcal·mol-1. This work expands the boron- and silicon-enriched chemical space accessible for drug discovery while simultaneously establishing a versatile platform for the synthesis of densely functionalized, stereochemically complex amino-oxetane scaffolds.
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BibTeX
@misc{eisen2026direct,
title = {{Direct Access to α-Chiral Amino-Oxetanes via Boron-Assisted Aziridine Ring-Opening}},
author = {Lucie S. Eisen and Mireia Pujol and Volker Derdau and Elena Fernández and Enrique Gomez-Bengoa and Maria Mendez},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15009600/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009600/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Direct Access to α-Chiral Amino-Oxetanes via Boron-Assisted Aziridine Ring-Opening
AU - Lucie S. Eisen
AU - Mireia Pujol
AU - Volker Derdau
AU - Elena Fernández
AU - Enrique Gomez-Bengoa
AU - Maria Mendez
PY - 2026
DA - 2026/09/29
PB - ChemRxiv
DO - 10.26434/chemrxiv.15009600/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15009600/v1
AB - α-Chiral amino-oxetanes represent a high-value yet synthetically difficult to access scaffold class in medicinal chemistry, combining the favorable pharmacokinetic properties of the oxetane ring with an additional degree of molecular complexity and three-dimensionality. Here we report the first synthetic route to α-chiral amino-oxetanes bearing boron and silicon substituents via a boron-assisted aziridine ring-opening strategy. Treatment of multichiral borylated and silylated oxetanyl-aziridines with simple carboxylic acids proceeds under mild, base-free conditions with full regio- and diastereoselectivity, affording densely functionalized products in excellent yields. The methodology accommodates over 30 structurally diverse carboxylic acids, including complex building blocks and Nprotected amino acids, and extends to azetidine analogs in a scalable protocol. Mechanistic investigations combining density functional theory computations and kinetic studies reveal a novel boron-assisted activation mode: reversible proton transfer from the carboxylic acid to the aziridine nitrogen generates a reactive aziridinium/carboxylate ion pair, which undergoes rate-determining SN2 attack facilitated by boron-oxygen coordination, lowering the activation barrier by more than 10 kcal·mol-1. This work expands the boron- and silicon-enriched chemical space accessible for drug discovery while simultaneously establishing a versatile platform for the synthesis of densely functionalized, stereochemically complex amino-oxetane scaffolds.
ER -