title: Rigid dipeptide surrogates: syntheses of enantiopure quinolizidinone and pyrroloazepinone amino acids from a common diaminodicarboxylate precursor.
abstract: A versatile and practical approach for synthesizing azabicyclo[X.Y.0]alkane amino acids of different ring sizes from a common diaminodicarboxylate precursor has been developed as a means for mimicking different peptide conformations. (2S,9S)-1-tert-Butyl 10-benzyl 5-oxo-2-[N-(PhF)amino] 9-[N-(BOC)amino]dec-4-enedioate (18) was first prepared in 83% yield by the Horner-Wadsworth-Emmons olefination of N-(PhF)aspartate beta-aldehyde 8 with pyroglutamate-derived beta-keto phosphonate 12 (PhF = 9-phenylfluoren-9-yl). The practicality of this approach for making azabicyclo[X.Y.0]alkane amino acids was then illustrated by the first synthesis of enantiopure quinolizidin-2-one amino acid 6 in seven steps and 40% overall yield from L-pyroglutamic acid. Hydrogenation of delta-keto alpha,omega-diaminosebacate 18, followed by lactam cyclization and protection, gave quinolizidin-2-one amino acid 6 as a single diastereomer. The versatility of this approach was next demonstrated by the synthesis of both ring-fusion isomers of pyrroloazepin-2-one amino acid 6 in 11 steps and 13% overall yield from pyroglutamic acid. Hydride reduction of 18, followed by methanesulfonate displacement, gave 5-alkylproline 22. Protective group manipulations, lactam cyclization, and removal of the ester group afforded readily separable pyrroloazepinone amino acids (7S)- and (7R)-7 in a 1:2 diastereomeric ratio. By introducing two new azabicycloalkane amino acids using our olefination approach, we have expanded the diversity of these important heterocycles for studying the conformational requirements for peptide biological activity.
authors.affiliation: Département de chimie, Université de Montréal, Québec, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Gosselin
authors.forename: W D
authors.initials: WD
authors.lastname: Lubell
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000600:Amino Acids, Dicarboxylic / Q000737:chemistry*; D001381:Azepines / Q000138:chemical synthesis*; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000138:chemical synthesis*; D008968:Molecular Conformation; D011758:Pyrroles / Q000138:chemical synthesis*; D015363:Quinolones / Q000138:chemical synthesis*; D013237:Stereoisomerism
chemical_list: D000596:Amino Acids; D000600:Amino Acids, Dicarboxylic; D001381:Azepines; D004151:Dipeptides; D011758:Pyrroles; D015363:Quinolones; C408126:pyrroloazepinone