title: Enzymatic preparation of 5-hydroxy-L-proline, N-Cbz-5-hydroxy-L-proline, and N-Boc-5-hydroxy-L-proline from (α-N-protected)-L-ornithine using a transaminase or an amine oxidase.
abstract: N-Cbz-4,5-dehydro-L-prolineamide or N-Boc-4,5-dehydro-L-prolineamide are alternative key intermediates for the synthesis of saxagliptin, a dipeptidyl peptidase IV (DPP4) inhibitor recently approved for treatment of type 2 diabetes mellitus. An efficient biocatalytic method was developed for conversion of L-ornithine, N-α-benzyloxycarbonyl (Cbz)-L-ornthine, and N-α-tert-butoxycarbonyl (Boc)-L-ornithine to 5-hydroxy-L-proline, N-Cbz-5-hydroxy-L-proline, and N-Boc-5-hydroxy-L-proline, respectively. Rec. Escherichia coli expressing lysine-ε-aminotransferase and rec Pichia pastoris expressing L-ornithine oxidase were used for these conversions. N-Cbz-5-hydroxy-L-proline, and N-Boc-5-hydroxy-L-proline were chemically converted to key intermediates N-Cbz-4,5-dehydro-L-prolineamide and N-Boc-4,5-dehydro-L-prolineamide, respectively.
authors: Process Research & Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, NJ 08903, USA.
authors: R L
authors: RL
authors: Hanson
authors: R M
authors: RM
authors: Johnston
authors: S L
authors: SL
authors: Goldberg
authors: W L
authors: WL
authors: Parker
authors: R N
authors: RN
authors: Patel
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives*; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000378:metabolism*; D001483:Base Sequence; D055162:Biocatalysis; D002851:Chromatography, High Pressure Liquid; D004151:Dipeptides / Q000096:biosynthesis*; D004926:Escherichia coli / Q000201:enzymology; D005656:Fungal Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D005800:Genes, Fungal; D007004:Hypoglycemic Agents; D050830:L-Amino Acid Oxidase / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D051306:L-Lysine 6-Transaminase / Q000378:metabolism*; D008969:Molecular Sequence Data; D009952:Ornithine / Q000031:analogs & derivatives / Q000378:metabolism*; D010843:Pichia / Q000201:enzymology / Q000302:isolation & purification; D011392:Proline / Q000031:analogs & derivatives* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012988:Soil Microbiology; D020578:Sphingomonas / Q000201:enzymology / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D004151:Dipeptides; D005656:Fungal Proteins; D007004:Hypoglycemic Agents; D011993:Recombinant Fusion Proteins; D011392:Proline; C502994:saxagliptin; D009952:Ornithine; D050830:L-Amino Acid Oxidase; D051306:L-Lysine 6-Transaminase; D000218:Adamantane