Unnatural α-amino acids are invaluable building blocks in synthetic organic chemistry and could upgrade the function of peptides. We developed a new mode for catalytic activation of amino acid Schiff bases, serving as a platform for highly congested unnatural α-amino acid synthesis. The redox active copper catalyst enabled efficient cross-coupling to construct contiguous tetrasubstituted carbon centers. The broad functional group compatibility highlights the mildness of the present catalysis. Notably, we achieved successive β-functionalization and oxidation of amino acid Schiff bases to afford dehydroalanine derivatives bearing tetrasubstituted carbon. A three-component cross-coupling reaction of an amino acid Schiff base, alkyl bromides, and styrene derivatives demonstrated the high utility of the present method. The diastereoselective reaction was also achieved using menthol derivatives as a chiral auxiliary, delivering enantiomerically enriched α-amino acid bearing α,β-continuous tetrasubstituted carbon. The synthesized highly congested unnatural α-amino acid could be derivatized and incorporated into peptide synthesis.

Direct catalytic asymmetric addition of allylic cyanides to N-diphenylphosphinoyl ketoimines with a bimetallic catalytic system comprising Ph-BPE/[Cu(CH3CN)4]ClO4/LiOAr is described. Intermediary alpha-adducts readily isomerized to afford synthetically useful alpha,beta-unsaturated nitriles bearing an optically active tetrasubstituted carbon. Applicability to aromatic, heteroaromatic, and aliphatic ketoimines exemplifies wide substrate generality. Transformation of the product into densely functionalized material showcases the utility of the present protocol.

A direct copper-catalyzed highly chemoselective α-amination is described. Acylpyrazole proved to be a highly efficient enolate precursor of a carboxylic acid oxidation state substrate, while preactivation by a stoichiometric amount of strong base has been used in catalytic α-aminations. The simultaneous activation of both coupling partners, enolization and metal nitrenoid formation, was crucial for obtaining the product, and wide functional group compatibility highlighted the mildness of the present catalysis. The bidentate coordination mode was amenable to highly chemoselective activation over ketone and much more acidic nitroalkyl functionality. Deuterium exchange experiments clearly demonstrated that exclusive enolization of acylpyrazole was achieved without the formation of a nitronate. The present catalysis was applied to late-stage α-amination, allowing for concise access to highly versatile α-amino acid derivatives. The product could be transformed into variety of useful building blocks.

We report that a hard Lewis base substantially affects the reaction efficiency of direct catalytic asymmetric gamma-addition of allyl cyanide (1a) to ketones promoted by a soft Lewis acid/hard Brønsted base catalyst. Mechanistic studies have revealed that Cu/(R,R)-Ph-BPE and Li(OC(6)H(4)-p-OMe) serve as a soft Lewis acid and a hard Brønsted base, respectively, allowing for deprotonative activation of 1a as the rate-determining step. A ternary catalytic system comprising a soft Lewis acid/hard Brønsted base and an additional hard Lewis base, in which the basicity of the hard Brønsted base Li(OC(6)H(4)-p-OMe) was enhanced by phosphine oxide (the hard Lewis base) through a hard-hard interaction, outperformed the previously developed binary soft Lewis acid/hard Brønsted base catalytic system, leading to higher yields and enantioselectivities while using one-tenth the catalyst loading and one-fifth the amount of 1a. This second-generation catalyst allows efficient access to highly enantioenriched tertiary alcohols under nearly ideal atom-economical conditions (0.5-1 mol % catalyst loading and a substrate molar ratio of 1:2).

We designed highly active and practical bis(imidazole)/zinc complexes for transesterification reactions. X-ray crystallographic analysis was used to confirm the structures of the zinc complexes and an equivalent of bis(imidazole) ligand was crucial for high catalytic activity. The octahedral zinc complex 8c was prepared in up to multigram scale by mixing Zn(OCOCF3)2·xH2O and meta-bis(imidazolylmethyl)benzene ligand 7j (two equivalents to zinc ion) and storable under air at room temperature for at least 9 months. The stable nature of the catalyst was amenable to recovery/reuse at least five times without a significant loss of reactivity. The transesterification reaction proceeded without strict reaction conditions, and expanded substrate generalities, including sterically demanding secondary and tertiary alcohols, were applicable. Remarkably, the present zinc catalyst proved highly effective for valuable monomer synthesis from readily available methyl acrylate derivatives. Chemoselective transesterification reactions of unprotected-amino alcohols were also achieved, using not only simple methyl ester but also unprecedented dimethyl carbonate. 5

Direct catalytic asymmetric conjugate addition of terminal alkynes to alpha,beta-unsaturated thioamides under proton transfer conditions is described. Soft Lewis acid/hard Brønsted base cooperative catalysis is crucial for simultaneous activation of terminal alkynes and thioamides, affording the beta-alkynylthioamides in a highly enantioselective manner. Control experiments suggested that the intermediate copper thioamide enolate can work as Brønsted base to drive the catalytic cycle via proton transfer. The divergent transformation of the thioamide functionality highlights the synthetic utility of the alkynylation products.

We developed a chemoselective catalytic activation of carboxylic acid for a 1e − radical process. α-Oxidation of a variety of carboxylic acids, which preferentially undergo undesired decarboxylation under radical conditions, proceeded efficiently under the optimized conditions. Chemoselective enolization of carboxylic acid was also achieved even in the presence of more acidic carbonyls. Extensive mechanistic studies revealed that the cooperative actions of iron species and alkali metal ions derived from 4 Å molecular sieves substantially facilitated the enolization. For the first time, catalytic enolization of unprotected carboxylic acid was achieved without external addition of stoichiometric amounts of Brønsted base. The formed redox-active heterobimetallic enediolate efficiently coupled with free radical TEMPO, providing synthetically useful α-hydroxy and keto acid derivatives.

A direct catalytic asymmetric addition of allyl cyanide to ketones with a bimetallic catalytic system comprising (R,R)-Ph-BPE/[Cu(CH(3)CN)(4)]ClO(4)/LiOAr is described. Exclusive gamma-addition of allyl cyanide was observed, affording optically enriched tertiary alcohols bearing Z-configured alpha,beta-unsaturated nitriles. The reaction proceeded under proton-transfer conditions, utilizing soft Lewis acid/hard Brønsted base bifunctional catalysis. The applicability of the reaction to aromatic, heteroaromatic, and aliphatic ketones demonstrates its wide substrate generality.