Novel C₂-Symmetric Chiral Bifunctional Primary Amine Catalysts: Design, Synthesis and Application in Asymmetric Aldol Reaction

Abstract

The Aldol reaction of α-branched aldehydes with α-carbonyl aldehydes is a key organic synthetic transformation, which can directly construct high-value chiral 1,4-dicarbonyl compounds bearing quaternary carbon centers. However, few catalysts can efficiently mediate this asymmetric Aldol reaction. Thus, the development of highly efficient catalysts for such reactions represents a crucial strategy to address the aforementioned challenges. Herein, we report a series of novel C₂-symmetric chiral bifunctional primary amine catalysts that can efficiently promote this transformation. These catalysts employ 1,3-propanediamine as the linker and Tle-DPro as the catalytic moiety, and can be readily prepared via concise and efficient amide condensation steps. Under mild reaction conditions, this catalytic system efficiently catalyzes the asymmetric Aldol reaction of α-branched aldehydes with α-carbonyl aldehydes, affording a series of chiral 1,4-dicarbonyl products with excellent yields (up to 99%) and enantioselectivities (up to 99%). Notably, the C₂-symmetric bifunctional primary amine catalysts developed in this work can efficiently accommodate both α-branched and linear aldehydes. In contrast, classic organic secondary amine catalysts exhibit unsatisfactory performance, which unambiguously demonstrates the prominent superiority of this catalytic system for these transformations. Scale-up experiments demonstrate that this method exhibits promising industrial application potential. Furthermore, the obtained product ent-3a can be further converted into various high-value compounds, including α,β-unsaturated esters, chiral pyridazinones, (R)-pantolactone, and D-calcium pantothenate. In addition, HR-MS, ¹H NMR analyses, and kinetic studies (initial rate measurements) were conducted to preliminarily elucidate the reaction mechanism and reveal the catalyst structure–performance relationship, which provides a valuable reference for the further design and development of chiral primary amine catalysts.

Keywords

Aldol reaction / Chiral bifunctional primary amine catalysts / C₂-Symmetric / α-Branched aldehydes / α-Carbonyl aldehydes / 1,4-Dicarbonyls / Enamine catalysis / (R)-Pantolactone

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2026 SIOC, CAS, Shanghai, & WILEY-VCH GmbH