Synthesis of Specific Deuterium Labeled Tyrosine and Phenylalanine Derivatives and Their Use in the Total Synthesis of [8-Arginine]vasopressin Derivatives: The Separation of Diastereomeric [8-Arginine]vasopressin Derivatives by Partition Chromatography^1,2

Derivatives of tyrosine specifically deuterated at the α carbon ([α-²H₁] tyrosine) and at both the a and Β carbons ([α,Β,Β-²H₃]tyrosine) and a derivative of phenylalanine specifically deuterated at the α carbon ([α-²H₁]phenylalanine) have been synthesized in high yield. These labeled compounds have been resolved enzymatically, and the enantiomers and racemates have been converted to N-tert-butyloxycarbonyl derivatives. The deuterium labels were not exchanged under the conditions of the syntheses. The protected derivatives as well as specifically deuterated derivatives of S-benzylcysteine and of glycine were used to prepare specifically deuterated analogues of [8-arginine]vasopressin using solid phase peptide procedures. The use of improved synthetic procedures resulted in considerable improvements in the yields of [8-arginine]vasopressin compared with previous reports. In addition, new solvent systems for partition chromatography purification of [8-arginine]vasopressin on Sephadex were developed which allowed a facile one-step separation of diastereomers of [8-arginine]vasopressin containing a racemic amino acid at either the l-hemicystine or the 2-tyrosine positions of the hormone. The following specifically deuterated hormone derivatives were synthesized: [9-[α,α-²H₂]glycinamide,8-arginine]vasopressin (15), [l-hemi-[α-²H₁]cystine,8-arginine]vasopressin (21), [l-hemi[Β,(Β-²H₂]cystine,8-arginine]vasopressin (17), [2-[α-2H1]tyrosine,8-arginine]vasopressin (19a), [2-[α,Β,Β-²H₃]tyrosine,8-arginine]vasopressin (20), [3-[α-²H₁]phenylalanine,8-arginine]vasopressin (18a), [1-hemi-D-[α-²H₁]cystine,8-arginine]vasopressin (16), [2-D-[α,-²H₁]tyrosine,8-arginine]vasopressin (19b), [l-hemi-D-cystine,3-[α-²H₁]phenylalanine,8-arginine]vasopressin (18b).