Stereoselective syntheses of 3-mercaptoproline derivatives protected for solid phase peptide synthesis

Stephen A. Kolodziej, Garland R. Marshall

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

The incorporation of cis- and trans-3-mercaptoproline (3-MPc and 3-MPt) into analogs of biologically active peptides has been shown to be an effective means for reducing the conformational mobility of the peptide backbone. We report herein a novel stereoselective synthetic route to L-1 and L-2, derivatives of 3-MPt and 3-MPc suitably protected for solid phase peptide synthesis. The optically active starting material was the previously reported cis-3-hydroxyprolinol derivative L-3. Oxidation of the C1 alcohol to the carboxylic acid, formation of the methyl ester and deprotection of the C3 alcohol yielded L-6 in an overall yield of 68%. Reaction of the secondary alcohol with thiolacetic acid under Mitsunobu conditions gave the thiolacetate L-7 in 77% yield with clean inversion of configuration. Conversion of L-7 to L-1 was accomplished in a one-pot sequence consisting of three steps: hydrolysis of the thiolacetate, formation of the thioether and hydrolysis of the methyl ester. The overall yield of L-1 from L-3 was 38%. Synthesis of L-2 required an epimerization of L-6, which was accomplished using a standard Mitsunobu inversion to give the trans-3-hydroxyproline derivative L-8. Transformation of L-8 to L-2 followed that described for L-1, except that removal of the methyl ester from L-10 required acidolysis in refluxing 4 N HCl. The overall yield of L-2 from L-3 was 18%. The availability of pure enantiomers of 3-MPt and 3-MPc protected for SPPS will greatly facilitate their use as conformational constraints for studying peptide-receptor interactions.

Original languageEnglish
Pages (from-to)274-280
Number of pages7
JournalInternational Journal of Peptide and Protein Research
Volume48
Issue number3
DOIs
StatePublished - 1996

Keywords

  • 3-substituted proline derivatives
  • Constrained aminoacids
  • Mercaptoproline

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