A General Synthesis Strategy To Unnatural N-tert-Butanesulfinyl α-Amino Acids

Unnatural amino acids play a very important role mainly in enhancing resistance to enzymatic degradation of peptide, improving the peptide structural diversity as well as bioactivity. To obtain diverse unnatural amino acids, variety of methodologies have been developed.Among these protocols, direct asymmetric addition of Grignard reagent to glyoxylate imine.which can afford protected chiral amino acids, was undoubtedly one of the most practical and convenient approaches.However, serious background reaction always occured and caused poor stereoselectivity due to the bidentate chelation effect of the glyoxylate imine. Accordingly, the use of chiral sulfinyl as the chiral auxiliary is an ideal solution. Although sulfinyl imines have been widely exploited in various synthetic approaches, the asymmetric synthesis of chiral a-amino acids via the addition to N-sulfinyl imino acetates has rarely developed due to the complex nature of the N-sulfinyl imino acetates.Thereby, the key role in the direct asymmetric addition to N-sulfinyl imino acetate to chiral a-amino acids synthesis is developing one kind of general and practical nucleophilic reagent. Recently, Knochel and co-workers reported several protocols on the preparation and application of a series of multi-metallic organometallic reagent. The new Knochel reagents by lithium chloride, organic zinc halide and organic magnesium halide own properties of ester tolerant, high nucleophilicity,weak alkaline as well as simple preparation and mild reaction conditions. Herein, we report the highly diastereoselective addition of Type I Knochel reagents to N-tert-butyl sulfinyl imino acetate catalysis induced to the asymmetric synthesis of chiral a-amino acids and successfully used this method to obtain the 2,6-dimethyl-tyrosine(Dmt) for the transformation and development of the polypeptides. In a word, we achieved chiral a-amino acids with good to excellent diastereoselectivities and yields, and meanwhile extended the scope nucleophiles to chiral N-tert-butanesulfinyl imines.