The application of trans-oxazolidine methyl ester synthons to the stereoselective synthesis of potential aminopeptidase inhibitors

Abstract

Aminopeptidases are enzymes that catalyze the hydrolytic cleavage of peptides from the N-terminus of amino acid or peptide substrates. It is widely distributed over the human, the animal and the plants, and are essential materials for protein maturation, activation and regulation of (non-)hormonal peptides. Aminopeptidase inhibitors suppress aminopeptidases activity so that prevent undesired replication of viruses or cells such as tumor. Ubenimex, commercial name of Bestatin, is one of aminopeptidase inhibitor which is marketed as treatment of acute myelocytic leukemia. Several stereoselective total syntheses of bestatin and its derivatives such as 2-thiolbestatin or bestatin thioamide have been reported. Most of bestatin analogs which have been reported contain aryl group at the N-terminus, but in this thesis, aryl group is substituted with isobutyl group or isopropyl group. Synthesis of new bestatin derivatives have been studied with two kinds of chiral synthons from D-leucine and D-valine. The precursors for corresponding β-amino-α-hydroxy acids were prepared via intramolecular conjugate addition between phenylsulfonylnitromethane and N-hydroxymethyl protected α-amino aldehydes. Bestatin derivatives which contain isobutyl group, (2S,3R)-3-amino-2-hydroxy-5-methylhexanoyl-L-leucine or isopropyl group, (2S,3R)-3-amino-2-hydroxy-4-methylpentanoyl-L-leucine are synthesized with peptide coupling between corresponding β-amino-α-hydroxy acids and L-Leu-OMe. Lapstatin, 3-amino-2-hydroxy-4-methylpentanoyl-valine, is one of aminopeptidase inhibitors which has similar vicinal amino alcohol structure to synthesized bestatin derivatives. But, lapstatin has not been fully identified its stereochemistry of the vicinal amino alcohol at the N-terminal amino acid residue, while the structure of bestatin derivatives were well established. Employing the developed synthetic method, lapstatin derivatives are also synthesized from corresponding β-amino-α-hydroxy acids in order to confirm its stereochemistry.