Stereoselective Amine Synthesis Mediated by a Zirconocene Hydride to Accelerate a Drug Discovery Program

Abstract

Chiral amine synthesis remains a significant challenge in accelerating the design cycle of drug discovery programs. A zirconium hydride, due to its high oxophilicity and lower reactivity, gave highly chemo-and stereoselective reductions of sulfinyl ketimines. The development of this zirconocene-mediated reduction helped to accelerate our drug discovery efforts and is applicable to several motifs commonly used in medicinal chemistry. Computational investigation supported a cyclic half-chair transition state to rationalize the high selectivity in benzyl systems.

Zirconium Hydride Catalysis Initiated by Tetrabutylammonium Fluoride

“…The challenge of product decomplexation from group IV metallocenes has been commented on previously . Currently, we propose a preliminary mechanism (Figure A) based on these results and literature support whereby after hydride delivery proceeding through an intramolecular half-chair transition state, ( 39 , based on our previous studies) a 4-membered zirconocene complex ( 40 ) is formedin accordance with this metal’s penchant for 3–5 membered rings . This product-catalyst complex could become turnover limiting.…”

“…We next evaluated a representative group of sulfinyl ketimines as the substrate scope for this transformation (Figure ). In comparison to the stoichiometric use of Schwartz’s reagent, this catalytic reduction exhibited similar characteristics of high functional group tolerance, high chemoselectivity, and high diastereoselectivity . Protic functionalities such as the free aniline ( 11 ) and phenol ( 12 ) were well-toleratedproviding higher isolated yields than the stoichiometric use of Schwartz’s reagent.…”

“…Recently, we shared the development of a convenient method utilizing Schwartz’s reagent (zirconocene chloride hydride, initially reported by Wales and Weingold and developed by Schwartz and co-workers) , that was conducted at room temperature and under an ambient atmosphere (Figure C) . Schwartz’s reagent proved to be highly diastereoselective in the reduction of chiral sulfinyl ketimines derived from Ellman’s auxiliary resulting from its high oxophilicity and bulky cyclopentadienyl ligands.…”