A New Class of Low‐Loading Catalysts for Highly Enantioselective, Metal‐Free Imine Reduction of Wide General Applicability

Abstract

An ew class of chiral Lewis bases for the enantioselective HSiCl 3 -mediated reduction of imines was developed. Through extensive catalyst structureo ptimization,a ne xtremelya ctive speciesw as identified that was able to promote the reduction of al arge variety of functionalized substrates in high yields with enantioselectivities typicallya bove 90 %w ith catalyst loadings as lowa s0 .1-1 mol %. The simple experimental procedure, the low cost of the reagents,t he mild reaction conditions, and the straightforward isolation of the product make the methodology attractive for large-scale applications.I ts synthetic potentiality was demonstrated by the preparation of advancedi ntermediates of important active pharmaceutical ingredients used in the treatmento fA lzheimer's and Parkinson's diseases,h yperparathyroidism,n europathic pains, and neurological disorders. The reactionw as also successfully performed in flow reactors, which thus demonstrated the possibility to realize in continuo processes to yield multigram quantities of product.The stereoselective reduction of C=Nb onds is probably the most popular approach to synthesize chiral amines. [1] Although in the last few years remarkable progress hasb een made in the development of efficient chiral organometallicc omplexes for the hydrogenationo fi mines, [2] the high costs of the precious metal species and their lack of general applicability make the discoveryo fn ew,h ighly performant catalysts greatly desirable. Moreover,i nt he case of C=N bond reduction, very often quite high catalyst loadings are required. [3] Metal-free catalytic methodologies represent av iable alternative option, and some efficient catalytic systemsh ave been reported, [4] but in these cases, high catalyst loadings are also necessary.Despitea ll the recent achievements in the field, the combination of inexpensive, nontoxic, easily available catalysts capable of performing at the very low loadings typical of organometallicc atalysis is an unmet challenge forp resent-day orga-nocatalysis. [5] Trichlorosilane-based reduction methods may offer an interesting opportunity in this sense. [6] Given that it is aw aste product of the silicon industry,H SiCl 3 is an extremely cheap reagent that is readily availableinlarge quantities andi s capable of reducing C=Nb onds with amazing chemoselectivity.I ts coordination with chiral Lewis bases hasa llowed the development of methods for the highly enantioselective catalytic reduction of imines. [7] Herein,w er eport the design and optimization of an ew class of enantiopure chiral picolinamides, easily preparedi nafew steps from amino acids, such as phenylalanine and tyrosine ( Figure 1). An extremely active species was identified that was able to promote the reduction of al arge variety of functionalizeds ubstrates in high yields with enantioselectivities typicallyh igher than 90 %a nd with catalyst loadings ranging from 0.1 to 1mol %, al evel that is exceptionally low for organocatalysis. Remarkably,t he new catalysts showed aw ide scope and were appli...

Solid Supported Chiral N‐Picolylimidazolidinones: Recyclable Catalysts for the Enantioselective, Metal‐ and Hydrogen‐Free Reduction of Imines in Batch and in Flow Mode

“…Notably, amine 11k , a direct precursor of rivastigmine (see below, Figure ), was obtained in 80% yield and 95% ee . In all cases, the supported catalyst showed to behave like the non‐immobilized catalyst under homogeneous conditions, and afforded the products with the ( R ) absolute configuration, thus suggesting that polymer‐supported P1 promotes the reduction according to the same mechanism as proposed for the homogeneous catalyst …”

“…We have recently reported a new class of highly active chiral Lewis bases, able to promote the reduction of a wide variety of imines with low catalyst loading (down to 0.1 mol%), occurring in quantitative yields and with enantioselectivities usually higher than 90% (Figure , catalyst type I) …”

“… [a] Reaction conditions : imine (0.1 mmol), HSiCl 3 (0.5 mmol), DCM(1 mL). [b] Isolated yield after chromatography. [c] The ee was determined by HPLC on chiral stationary phase; the absolute configuration was confirmed by comparison with literature data, see ref …”

“…[c] The ee was determined by HPLC on chiral stationary phase; the absolute configuration was confirmed by comparison with literature data, see ref …”

A Continuous-Flow, Two-Step, Metal-Free Process for the Synthesis of Differently Substituted Chiral 1,2-Diamino Derivatives

“…an easy-to-synthesize, very active catalyst A, recently reported by our group, 10 and performed some preliminary reductions in batch (Scheme 2).…”