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Modular Synthesis of α‐Quaternary Pyrrolines by Pyridoxal‐Catalyzed Sequential Reactions With Precise Chirality Relay

Year: 2026

Type: article

Abstract: ABSTRACT The construction of molecular architectures bearing two contiguous stereocenters, particularly those featuring a quaternary carbon, remains a significant synthetic challenge. Herein, we report a modular one‐pot, two‐step strategy that combines carbonyl catalysis with sequential electrophilic functionalization, enabling the direct, efficient, and highly stereoselective conversion of readily available aminoacetonitrile into α‐quaternary cyanopyrrolines. The process begins with a chiral pyridoxal‐catalyzed asymmetric α‐conjugate addition of unprotected aminoacetonitrile to α,β‐unsaturated ketones, bypassing the need for NH 2 group preprotection. The resulting enantioenriched adduct undergoes subsequent reaction with a diverse range of electrophiles, delivering the desired products in high yields with excellent diastereoselectivities and enantioselectivities (up to 99% yield, > 20:1 dr, and 98% ee). The stereocenter installed in the first step acts as a chirality relay, dictating the facial selectivity during the second C–C bond‐forming event and ensuring precise construction of two contiguous stereogenic centers. This operationally simple and modular approach provides direct access to structurally diverse, enantiomerically enriched 1‐pyrrolines from simple starting materials, offering a versatile route to an important class of bioactive scaffolds.

Source: Transformative Chemistry

DOI: 10.1002/tch2.70021