| Title | Synthesis of cis-4-hydroxy-L-proline and its incorporation into biologically important peptides | |
| Authors | George Stavropoulos, Vassiliki Magafa, Kostas Karagiannis and Dionissios Papaioannou
Department of Chemistry, University of Patras, Patra 260 10, Greece |
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| Citation | Stavropoulos, G., Magafa, V., Karagiannis, K. and Papaioannou, D.: Synthesis of cis-4-Hydroxy-L-proline and its incorporation into biologically important peptides, Epitheorese Klin. Farmakol. Farmakokinet. 9(2-3): 103-106 (1995) | |
| Publication Date | 1995 | |
| Full Text Language | English | |
| Order – Buy | pharmakonpress[at]pharmakonpress[.]gr | |
| Keywords | Peptide synthesis, cis-4-hydroxy-L-proline. | |
| Other Terms | review article | |
| Summary | An efficient intramolecular Mitsunobu reaction resulted in the conversion of trans-4-hydroxy-N-trityl-L-proline (Trt-Hyp) to 5-trityl-2-oxa-5-aza-bicyclo[2.2.1]heptane-3-one. This lactone is a key intermediate in the synthesis of cis-4- hydroxy-L-proline (CHyp) and derivatives suitable for use in peptide synthesis. Methanolysis catalysed by triphenyiphosphine (TPP)-diethyl azodicarboxylate (DEAD) transformed the lactone into the methyl ester of cis-4-hydroxy-N-trityl-L-proline, while ammoniolysis in isopropyl alcohol gave the corresponding amide. Detritylation of lactone, ester and amide was affected by treatment with p-toluenesulfonic acid. On the other hand saponification of the lactone provided cis-4-hydroxy-N-trityl-L-proline which after O-benzyiation and carboxy activation allowed the incorporation of cHyp into model peptides such as Trt-Cys(Trt)-cHyp(Bzl)-Lys(Trt)-Gly-NH2 and Trt-cHyp(Bzl)-Leu-Gly-NH2. Similar methodology was applied to the TRH analogue Glp-His(Nm-Trt)- Hyp-OH, prepared by SPPS on the bulky and mild acid sensitive solid support 2-chlorotrltyl resin, to convert it to Glp-His(Nm– Trt)-cHyp lactone with inversion of configuration at C-4 of the Hyp residue. Trans-esterification of this lactone with MeOH/TPP-DEAD, followed by detritylation, provided the tripeptide ester GIp-His-cHyp-OMe which gave the corresponding amide and acid on ammoniolysis and saponification, white x-ray crystallography, FT-IR and ¹H NMR techniques were used for structure identification of the thus prepared compounds. | |
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