Bifunctional Iminophosphorane‐Catalyzed Enantioselective Nitroalkane Addition to Unactivated α,β‐Unsaturated Esters**

Abstract

Herein we describe the enantioselective intermolecular conjugate addition of nitroalkanes to unactivated α,β‐unsaturated esters, catalyzed by a bifunctional iminophosphorane (BIMP) superbase. The transformation provides the most direct access to pharmaceutically relevant enantioenriched γ‐nitroesters, utilizing feedstock chemicals, with unprecedented selectivity. The methodology exhibits a broad substrate scope, including β‐(fluoro)alkyl, aryl and heteroaryl substituted electrophiles, and was successfully applied on a gram scale with reduced catalyst loading, and, additionally, catalyst recovery was carried out. The formal synthesis of a range of drug molecules, and an enantioselective synthesis of (S)‐rolipram were achieved. Additionally, computational studies revealed key reaction intermediates and transition state structures, and provided rationale for high enantioselectivities, in good agreement with experimental results.

Catalytic, Asymmetric Michael-Aldol Annulations via a Stereodivergent/Stereoconvergent Path Operating under Curtin–Hammett Control

“…Most recently, Dixon and Yamazaki demonstrated the predominance of mode B in the additions of nitroalkanes to monoactivated α,βunsaturated esters. 30 Our current work carries the added complexity of the second Lewis basic electron-withdrawing group in the Michael acceptor; to the best of our knowledge, these systems have not been computationally modeled.…”

Second Generation Catalytic Enantioselective Nucleophilic Desymmetrization at P(V): Improved Generality, Efficiency and Modularity

“…In our own work (Scheme 1, D1), phenol nucleophiles were used in the desymmetrization step under ureidopeptide [148][149][150][151][152][153][154] bifunctional iminophosphorane (BIMP) catalysis, [155][156][157][158][159][160][161][162][163][164][165][166][167][168] however, to obtain high levels of enantioselectivity, phenol nucleophiles bearing an ortho-substituent were required, inherently limiting the scope of the reaction. Additionally, the optimal leaving group, 2-nitro-6-methyl-phenolate, 169 is a relatively weak Brønsted base, rendering the turnover of the optimal superbasic BIMP catalyst inefficient, which, in turn, forces an excessive 15 mol% catalyst loading to ensure high conversion of the starting material to product.…”

Regulating iminophosphorane PN bond reactivity through geometric constraints with cage-shaped triarylphosphines

“…Iminophosphoranes, the nitrogen analogues of phosphorus ylides in aza-Wittig reactions, 1 are increasingly used to design pincer type ligands for transition-metals 2 and main-group elements. 3 They have found recent applications in organocatalysis 4 and in the phosphine-mediated redox catalyzed Staudinger ligation of carboxylic acids and azides (Scheme 1a). 5 Iminophosphoranes are prepared by the Staudinger reaction, 1a whose reaction intermediates have been extensively investigated (Scheme 1b).…”