Conformationally constrained dipeptide surrogates with aromatic side-chains: synthesis of 4-aryl indolizidin-9-one amino acids by conjugate addition to a common alpha,omega-diaminoazelate enone intermediate.
Four methyl 9-oxo-8-(N-(Boc)-amino)-4-phenyl-1-azabicyclo[4.3.0]nonane carboxylates (11, 4-Ph-I(9)aa-OMe) were synthesized from (2S,8S,5E)-di-tert-butyl-4-oxo-5-ene-2,8-bis[N-(PhF)amino]azelate [(5E)-7, PhF = 9-(9-phenylfluorenyl)] via a seven-step process featuring a conjugate addition/reductive amination/lactam cyclization sequence. Various nucleophiles were used in the conjugate addition reactions on enone (5E)-7 as a general route for making alpha,omega-diaminoazelates possessing different substituents in good yield albeit low diastereoselectivity except in the case of aryl Grignard reagents (9/1 to 15/1 drs). 6-Phenylazelates (6S)-8d and (6R)-8d were separated by chromatography and diastereoselective precipitation and independently transformed into 4-Ph-I(9)aa-OMe. From (6S)-8d, (2S,4R,6R,8S)-4-Ph-I(9)aa-OMe 11 was prepared selectively in 51% yield. Reductive amination of (6R)-8d provided the desired pipecolates 9 along with desamino compound 10, which was minimized by performing the hydrogenation in the presence of ammonium acetate. Subsequent ester exchange, lactam cyclization, and amine protection provided three products (2R,4S,6S,8R)-, (2R,4S,6S,8S)-, and (2S,4S,6R,8S)-4-Ph-I(9)aa-OMe 11 in 10, 6, and 6% yields, respectively, from (6R)-8d. Ester hydrolysis of (2S,4R,6R,8S)-11 furnished 4-phenyl indolizidin-9-one N-(Boc)amino acid 3 as a novel constrained Ala-Phe dipeptide surrogate for studying conformation-activity relationships of biologically active peptides.
Cluzeau
Jérôme
J
Département de Chimie, Université de Montréal, C. P. 6128, Succursale Centre Ville, Montréal, Québec, Canada H3C 3J7.
Lubell
William D
WD
D000586:Amination; D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry; D003998:Dicarboxylic Acids / Q000737:chemistry*; D004151:Dipeptides / Q000737:chemistry*; D006841:Hydrocarbons, Aromatic / Q000737:chemistry*; D006865:Hydrogenation; D007212:Indolizines / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D018716:Molecular Mimicry; D015394:Molecular Structure; D013237:Stereoisomerism
D000596:Amino Acids; D003998:Dicarboxylic Acids; D004151:Dipeptides; D006841:Hydrocarbons, Aromatic; D007212:Indolizines; C010038:azelaic acid