Simple Synthesis of cis-4-Hydroxy-L-Proline and Derivatives Suitable for Use as Intermediates in Peptide Synthesis.

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Abstract
An intramolecular Mitsunobu reaction in the presence of triphenylphosphine-diethyl azodicarboxylate (TPP-DEAD) resulted in the conversion of trans-4-hydroxy-N-trityl-L-proline to 5-triphenylmethyl-2-oxa-5-aza-bicyclo[2.2.1]heptan-3-one. This bicyclic lactone proved to be a key intermediate in the synthesis of cis-4-hydroxy-L-proline and derivatives thereof. TPP-DEAD-catalysed methanolysis of the key lactone gave the methyl ester of cis-4-hydroxy-N-trityl-L-proline, while ammonolysis in isopropyl alcohol provided the corresponding amide. p-Toluene-sulfonic acid treatment of the lactone, ester and amide led to detritylation and formation of the corresponding p-toluenesulfonates. Saponification of the key intermediate provided cis-4-hydroxy-N-trityl-L-proline which was first benzylated and then elaborated to the 1-hydroxybenzotriazolyl ester. This last ester and the three p-toluenesulfonates prepared above were utilised for the incorporation of cis-4-hydroxy-L-proline in the synthesis of model peptides.