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Metal-free, Stereoselective in batch and in flow synthesis of pharmaceutically relevant chiral amines

corresponding

ELISABETTA MASSOLO, LAURA RAIMONDI, MAURIZO BENAGLIA*
*Corresponding author
Dipartimento di Chimica, Universita’ degli Studi di Milano, Italy

Abstract

The stereoselective reduction of imines represents one of the most popular strategy to synthesize chiral amines, a class of compounds of outmost importance for pharmaceuticals. Organocatalytic methods offer an attractive alternative to the traditional metal-based hydrogenation, and afford enantiopure molecules without the problem of possible traces of toxic metals in the final API (active pharmaceutical ingredient). Trichlorosilane was successfully employed, in the presence of catalytic amounts of chiral Lewis bases, as reducing agent to synthesize several biologically active chiral amines, either in batch and in flow mode: the use of supported chiral catalysts in catalytic reactors, the development of enantioselective metal-free catalytic methodologies in micro(meso) reactors and the design, fabrication and use of 3D-printed reactors to afford chiral amino alcohols are discussed


Chiral amines are very important pharmacophore that can be found in several pharmaceuticals and agrochemical compounds (1). Among the several available methodologies, the stereoselective reduction of imines represents one of the most popular entry to this fundamental class of compounds; in this framework, the so-called organocatalytic methodologies are gaining an increasing attention. The possibility to synthesize enantiopure amines with a metal-free catalytic approach, that avoids the issue due to the presence of traces of toxic metals, is especially attractive in the pharmaceutical field.

In this context, the use of trichlorosilane to perform the C=N reduction has many positive features and has been successfully investigated by numerous academic research groups including ours (2). Trichlorosilane is a non-toxic, colorless volatile liquid, a waste product of the silicon industry, available at the cost of most organic solvents, that, in the presence of catalytic amounts  of (chiral) Lewis bases, is able to efficiently reduce ketoimines, with high chemioselectivity and under mild reaction conditions.

Our research group developed different chiral Lewis bases,(3) f ...




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