An Approach for Simultaneous Synthesis of cis- and trans-3-Substituted Proline-Glutamic Acid Chimeras

Abstract

Synthesis of cis-and trans-3-substituted proline-glutamic acid chimeras with suitable protection for peptide synthesis through Fmoc-strategy was accomplished in six steps from benzyl (2S)-4-oxo-1-(9-phenyl-9H-fluoren-9-yl)pyrrolidine-2-carboxylate, which had been synthesized from trans-4-hydroxyproline in three steps. This methodology involved generation of cis-and trans-3-alkylated proline moieties, and manipulation of functionality and protecting groups to obtain proline-chimera monomers in appropriate form for peptide synthesis.Key words: benzyl 4-oxo-N-(9-phenylfluoren-9-yl)proline ester, alkylation, cis-and trans-3-substituted proline-glutamic acid chimeras, Fmoc-amino acid, peptides Proline plays a significant role in protein folding and refolding due to its distinctive feature of introducing a reversal in backbone conformation, which results in the nucleation of turns and breaking of helix structures in proteins. 1 When placed as a second residue (i+1) of a short and linear peptide, L-proline has been found to induce type I/II β-turns involving an intramolecular hydrogen bond between C=O of the first (i) and NH of the fourth (i+3) residue. 2 Proline chimeras, which merge side chain functionality of an amino acid with the conformational rigidity of proline, have been developed into important tools for studying the biological activity of natural amino acids and peptides. 3 3-Substituted proline moieties 4 with an appropriate side chain were found to mimic and stabilize natural β-turn types I, II, and II′. These moieties have shown high potential for the investigation of biologically active conformations of peptides and for their pharmaceutical use. 3a,e,4a,5 In past decades, several analogues of proline chimeras with different stereochemistry and functionality at C-3 position have been designed and synthesized. 3a,c,d,5b,6 Most of these methodologies were designed with the aim to synthesize a diastereomer with preferred stereochemistry, although some of them were found suitable for the synthesis of both diastereomers at the C-3 stereocenter of the proline moiety. We developed a strategy for the synthesis of both cis-and trans-3-substituted proline-glutamic acid chimeras (Figure 1) in one reaction step and in a 4:3 ratio by alkylation at the C-3 position of amino ketone 2. As both of these diastereomers were obtained in nearly equal amounts, this synthetic strategy enabled us to avoid the controlled epimerization step, which has been used widely to get a preferred enantiomer or diastereomer from a mixture of enantiomers or diastereomers, respectively. Next, necessary reaction steps were followed to obtain these diastereomers in the protected form for their incorporation into peptides. Figure 1 Stereochemical orientation of cis-and trans-3-alkylated proline moietiestrans-4-Hydroxy-L-proline (1) has emerged as a useful and versatile chiral tool for the incorporation of different functionalities into the proline moiety. A number of derivatives of this compound have been synthesized in their fully protected for...