Tcmheitron Letters. Vo1.32. No.41, pp 5769-5772, 1991 Priitcd in Great Britain 0040-4039/91 $3.00 + .oo Pergamon Press plc ASYMMETRIC SYNTHESIS OF TOPOGRAPHICALLY CONSTRAINED AMINO ACIDS: SYNTHESIS OF THE OPTICALLY PURE ISOMERS OF a$-DIMETHYL-PHENYLALANINE AND a$-DIMETHYL- 1,2,3,4-TETRAHYDROISOQUINOLINE-3-CARBOXYLIC ACID Wieslaw M. Kazmierski and Victor J. Hruby* Department of Chemistry, University of Arizona, Tucson, AZ 85721 U.S.A. Abstract: All four isomers of a$-dimethylphenylalanine and a$-dimethyl-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid have been synthesized in high optical purity for use in the design of topographically constrained peptides. Recently we have proposed a new approach for the design of bioactive peptides using the concept of topographical constraints.’ As an example of this approach, we have utilized 1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid (Tic, Figure 1) as a replacement of phenylalanine and tyrosine into somatostatin derived mu opioid antagonists. This led to one of the most mu opioid receptor potent and selective peptides known to date, D-Tic-C~s-Tyr-D-Trp-Arg-Thr-Pdn-Thr-NH~.2 Utilizing both NMR lalc and theoretical calculations,3 we found that an N-terminal D-Tic residue has a gauche(-) side chain conformation (x1 = +60”), while an acylated Tic residue has a guache(+) side chain conformation (xt = -60’) (Figure 1) owing to pseudoallylic strains.1a4 In order to obtain access to amino acids with complementary conformational behavior of their side chain moieties (e.g. g(-) when acylated and g(+) when on an N-terminal position), there is a need for a general method for the asymmetric synthesis of the four individual isomers of a$-dimethylphenylalanine (4a’, 4a”, 4b’, 4b” on Scheme l), with the idea of stabilizing the pipecolic acid ring conformation by two bulky (e.g. methyl) substituents. We have tested this idea by molecular mechanics calculations (SYBYL, version 5.3) and, indeed, found a strong stabilization of the gauche(-) conformation for N-acylated a$dimethylated Tic derivatives. The method of Seebach and co-workers5 seemed to be particularly suitable for controlling the stereochemistry at both a- and B-carbon atoms on the same step in the reaction scheme, though other approaches could conceivably be u~ed.~ Both L- and D-alanine were converted to their N-methyl amides, condensed with pivaloyl aIdehyde and the resulting imines were cyclized to the substituted imidazolidin-4-ones 2a and 2b (Scheme 1) respectively, 5769