Stereoselective total synthesis of topographically constrained designer amino acids: 2′, 6′-dimethyl-β-methyltyrosines

Xinhua Qian, K. C. Russell, Lakmal W. Boteju, Victor J. Hruby

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66 Scopus citations

Abstract

The constrained aromatic α-amino acid 2′, 6′-dimethyl-β-methyl tyrosine (Figure 1) 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 α,β-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 α- and the β-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 α-position of the N-acyloxazolidinones using di(n-butyl)boron triflate/DIEA/NBS as reagents at low temperature. In both 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 SN2 mechanism. (Electrophilic azidation using 2,4,6-triisopropylsulfonyl azide also was achieved). The 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.

Original languageEnglish (US)
Pages (from-to)1033-1054
Number of pages22
JournalTetrahedron
Volume51
Issue number4
DOIs
StatePublished - Jan 23 1995

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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