Catalytic asymmetric Tsuji–Trost benzylation is a promising strategy for the preparation of chiral benzylic compounds. However, only a few such transformations with both good yields and enantioselectivities have been achieved since this reaction was first reported in 1992, and its use in current organic synthesis is restricted. In this work, we use N-unprotected amino acid esters as nucleophiles in reactions with benzyl alcohol derivatives. A ternary catalyst comprising a chiral aldehyde, a palladium species, and a Lewis acid is used to promote the reaction. Both mono- and polycyclic benzyl alcohols are excellent benzylation reagents. Various unnatural optically active α-benzyl amino acids are produced in good-to-excellent yields and with good-to-excellent enantioselectivities. This catalytic asymmetric method is used for the formal synthesis of two somatostatin mimetics and the proposed structure of natural product hypoestestatin 1. A mechanism that plausibly explains the stereoselective control is proposed.
Herein, we report a chiral-aldehyde/palladiumcatalyzed atom-economic asymmetric α-allylation of N-unprotected amino acid esters with unsaturated hydrocarbons. Chiralaldehyde catalysis provides active nucleophilic intermediates from amino acid esters, while palladium catalysis provides the active electrophilic π-allyl metal species via hydrometallation of the unsaturated hydrocarbons. Accordingly, asymmetric α-allylation of N-unprotected amino acid esters with both 1,3-dienes and allenes can be achieved with high efficiency, allowing various α,αdisubstituted unnatural α-amino acid esters to be generated in good-to-excellent yields and stereoselectivities. No N-allylation byproducts are formed in these two reactions. Based on the results of mechanistic control experiments, two reaction models are proposed. Overall, this work demonstrates a completely atomeconomical method for preparing structurally diverse chiral amino acids and provides guidance for developing further chiralaldehyde catalytic systems.
The direct catalytic hydrocarbylation of readily available amino acids with halohydrocarbons is one of the most straightforward methods leading to disubstituted non-proteinogenic amino acid compounds. However, all the re-ported methodologies depend on N-protected amino acids as starting materials. Herein, we report on three highly efficient aldehyde-catalyzed direct hydrocarbylations of N-unprotected amino acid esters with aryl-, allyl-, and benzyl halides. By promoting a simple chiral BINOL-aldehyde catalyst or combining catalysts of a chiral aldehyde and Lewis acid ZnCl2, the asymmetric arylation, allylation, and benzylation of amino acid esters with the corresponding halohydrocarbons proceed smoothly, producing disubstituted amino acids in moderate-to-high yields and good-to-excellent enantioselectivities. The asymmetric arylation reaction can be applied in the formal synthesis of the clinical candidate compound (+)-AG-041R. Based on the results given by control experiments, three reaction models are proposed to illustrate the stereoselective-control outcomes.
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