Facile preparation of the 1-Hydroxybenzotriazolyl ester of A/-Tritylpyroglutamic acid and its application to the synthesis of TRH, [D-His2]TRH and analogues incorporating c/s-And trans-4-hydroxy-L-proline

One-pot treatment of A-Trityl-L-glutamic acid with DCC followed by DCC-HOBt provided a high yielding synthesis of the 1-hydroxybenzotriazolyl ester of iV-Trityl- L-pyroglutamic acid (Trt-Glp). Coupling of this active ester with the methyl esters of Nim-Tritylated L-And D-histidine provided the corresponding dipeptides which upon saponification and coupling with the methyl esters of L-proline and trans- 4-hydroxy-L-proline (Hyp) gave the protected tripeptides Trt-Glp-L and D-His- (Nim-Trt)-Pro-OMe and Trt-Glp-L and D-His(Nim-Trt)-Hyp-OMe. Some 10% of the epimeric (at the His residue) products were formed during this procedure. Sequential saponification and one-pot Mitsunobu-Type intramolecular esterifica-Tion of the latter tripeptides, followed by transesterification with MeOH, provided the corresponding tripeptides Trt-Glp-L and D-His(iVini-Trt)-cHyp-OMe with inversion of configuration at C-4 of the Hyp ring. The observed conformer ratios about the His-Pro amide for all of these tripeptides are discussed in terms of structural features. Detritylation with trifluoroacetic acid followed by ammonoly- sis completed the synthesis of TRH and its analogues Glp-D-His-Pro-NH2, Glp-L-And D-His-Hyp-NH2and Glp-L-And -D-His-cHyp-NH2.