title: Diastereoselective hydroxylation of 6-substituted piperidin-2-ones. An efficient synthesis of (2S,5R)-5-hydroxylysine and related alpha-amino acids.
abstract: The synthesis of (2S,5R)-5-hydroxy-6-oxo-1,2-piperidinedicarboxylates (5) and related (3S,6R)-3-hydroxy-6-alkyl-2-oxo-1-piperidinecarboxylates has been developed. The approach is based on the asymmetric hydroxylation of enolates generated from the corresponding N-protected-6-substituted piperidin-2-ones. The utility of 5a as a precursor in the synthesis of (2S,5R)-5-hydroxylysine (1), an amino acid unique to collagen and collagen-like proteins, has also been demonstrated. (2S)-6-oxo-1,2-piperidinedicarboxylates (6) required for hydroxylation studies were prepared in 38-74% yield, starting from conveniently protected aspartic acid as inexpensive chiral adduct. Hydroxylation of 6 to 5 proceeds in high yield and excellent diastereoselectivity by treatment of their Li-enolate with (+)-camphorsulfonyloxaziridine at -78 degrees C. Ring opening of di-tert-butyl (2S,5R)-6-oxo-1,2-piperidinedicarboxylate ((5R)-5a) under reductive conditions afforded the corresponding 1,2-diol (17) in 91%, which was further transformed to (2S,5R)-5-hydroxylysine in four steps (84%). 17 is also a versatile intermediate in the preparation of tert-butyl (2S,5R)-2-[(tert-butoxycarbonyl)amino]-5-hydroxy-6-iodohexanoate (3) and tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-[(2R)-oxiranyl]butanoate (4), two amino acid derivatives used in the total synthesis of the bone collagen cross-link (+)-pyridinoline (2a).
authors.affiliation: UPR 9021 CNRS, Immunologie et Chimie Thérapeutiques, Institut de Biologie Moléculaire et Cellulaire, 15 rue René Descartes, F-67084 Strasbourg Cedex, France.
authors.forename: J
authors.initials: J
authors.lastname: Marin
authors.forename: C
authors.initials: C
authors.lastname: Didierjean
authors.forename: A
authors.initials: A
authors.lastname: Aubry
authors.forename: J-P
authors.initials: JP
authors.lastname: Briand
authors.forename: G
authors.initials: G
authors.lastname: Guichard
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry*; D001224:Aspartic Acid / Q000737:chemistry; D001842:Bone and Bones / Q000737:chemistry; D003094:Collagen / Q000138:chemical synthesis; D020650:Combinatorial Chemistry Techniques; D003500:Cyclization; D006900:Hydroxylation; D006901:Hydroxylysine / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D008968:Molecular Conformation; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010881:Piperidones / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D000596:Amino Acids; D010881:Piperidones; D006901:Hydroxylysine; D001224:Aspartic Acid; D003094:Collagen