Catalytic Asymmetric Staudinger–aza-Wittig Reaction for the Synthesis of Heterocyclic Amines

Abstract

Many natural products and medicinal drugs are heterocyclic amines possessing a chiral quaternary carbon atom in their heterocyclic ring. Herein, we report the first catalytic and asymmetric Staudinger-aza-Wittig reaction for the desymmetrization of ketones. This highly enantioselective transformation proceeds at room temperature to provide high yields-even on multigram scalesof nitrogen heterocycles featuring a chiral quaternary center. The products of this reaction are potential precursors for the synthesis of pharmaceuticals. A commercially available small P-chiral phosphine catalyst, HypPhos, induces the asymmetry and is recycled through in situ reduction of its oxide, mediated by phenylsilane in the presence of a carboxylic acid. The efficiency, selectivity, scalability, mild reaction conditions, and broad substrate scope portend that this process will expedite the syntheses of chiral heterocyclic amines of significance to chemistry, biology, and medicine. Chiral heterocyclic amines are very common structural elements within the plethora of biologically active natural products and medicinally relevant compounds. Indeed, more than 50% of the unique small-molecule drugs approved by the U.S. Food and Drug Administration through 2012 contained a nitrogen heterocycle. 1,2 Six-membered heterocyclic amines, especially piperidines and piperazines, account for more than a quarter of the heterocyclic amine drugs; they appear, for example, in the structures of cocaine, morphine, codeine, and paroxetine (Scheme 1a). Among chiral heterocyclic amines, those possessing chiral quaternary carbon centers are particularly difficult to synthesize; more generally, the construction of quaternary centers in organic molecules remains one of the greatest problems in synthetic chemistry. 3,4 This challenge increases in difficulty when all *

Preparation of 2-phospholene oxides by the isomerization of 3-phospholene oxides

“…Among the P-heterocycles with various ring size, the five-membered derivatives received special attention due to their optimal bond angles and shapes [13,14]. Besides their application as ligands [13,15], the five-membered heterocycles may also be valuable organocatalysts in reactions involving a P(III)-P(V) redox cycle, such as in catalytic Wittig-, aza-Wittig-, Staudinger-, Appel-and other reactions [16][17][18][19][20][21]. The ring strain of the four-and five-membered derivatives makes them highly susceptible to deoxygenation, thus they are ideal organocatalysts in P(III)-P(V) redox-coupled transformations [18,22,23].…”

Convergent Synthesis of Polysubstituted Furans via Catalytic Phosphine Mediated Multicomponent Reactions

“…nBu 3 P=O (20 mol%) instead of nBu 3 P; 51% yield nBu 3 P=O (100 mol%) instead of nBu 3 P; 58% yield without nBu Control experiments.Based on the results of this work and previous reports[59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75]97], a multiple domino process is proposed to rationalize the formation of tetra-substituted furans 3 (Scheme 5, left). The catalytic cycle starts with the nucleophilic addition of nBu3P to an activate alkene 1 like acrylates, the resulting intermediate undergoes a C-acylation reaction with acyl chloride 2 to give a phosphonium enolate A.…”

“…Under the reported conditions, various reducible functional groups such as ketones, aldehydes, olefins, nitriles, and esters were well tolerated. Based on these encouraging findings, a number of important stoichiometric phosphine-involved reactions, including (aza-)Wittig [59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75], Mitsunobu [76][77][78], Staudinger [79][80][81][82][83][84], Appel [85,86], Cadogan [87], and others [88][89][90][91][92][93] have been successfully developed into the catalytic phosphine mediated ones.…”

Recent investigations into synthesis and pharmacological activities of phenoxy acetamide and its derivatives (chalcone, indole and quinoline) as possible therapeutic candidates

“…Moreover, they have been widely found as a key structural material and dominate the field of dyestuff synthesis [ 131 ], agro-based chemicals [ 132 ] and supramolecular chemistry [ 133 ]. They have attracted attention because of their synthetic utility in catalysis [ 134 ], photosensitizers [ 135 ], polymer chemistry [ 136 ] and nanotechnology applications [ 137 ]. Therefore, considerable attention needs to be given in order to develop effective new techniques to synthesize various novel aza heterocyclic candidates.…”