STEREOSELECTIVE TOTAL SYNTHESIS OF TOPOGRAPHICALLY CONSTRAINED DESIGNER AMINO ACIDS - 2',6'-DIMETHYL-BETA-METHYLTYROSINES

摘要

The constrained aromatic alpha-amino acid 2', 6-dimethyl-beta-methyl tyrosine (Figure I) was designed to provide specific local constraints to peptides or peptide mimetics. We report here methods for the total asymmetric synthesis of all four stereoisomers. The precursors used were alpha,beta-unsaturated acid derivatives, (2E) 3-(4')-methoxy-2',6'-dimethyl-2- propenoic acid (5) and crotonyl chloride (6). In order to introduce chirality at both the alpha- and the beta-positions of the amino acids, optically pure 4-phenyl-2-oxazolidinones (Xc) were coupled to 5 and 6. The key steps for the synthesis were: (1) a Michael type addition using either methylmagnesium bromide/copper (I) bromide-dimethyl sulfide complex or 4-methoxy-2,6-dimethylphenylmagnesium bromide/copper (I) bromide-dimethyl sulfide complex as nucleophiles; (2) an asymmetric bromination of the alpha-position of the N-acyloxazolidinones using di(n-butyl)boron triflate/DIEA/NBS as reagents at low temperature, In bath cases, the stereoselectivies and yields were excellent; (3) amination was achieved in nearly quantative yield by treating the bromides with azide exchange resin via an S(N)2 mechanism. (Electrophilic azidation using 2,4,6-triisopropylsulfonyl azide also was achieved). Tile excellent stereoselectivity (80-98% ee/de) and overall yield(30-60%) made these optically pure amino acids available in amounts practical for peptide synthesis and further conformational and structure-activity relationship studies of various peptide analogues. [References: 40]