Total syntheses of a conformationally locked North-type methanocarba puromycin analogue and a dinucleotide derivative.
An original synthetic approach for the first synthesis of an enantiopure methanocarba puromycin (3'-alpha-aminoacylamino-3'-deoxyadenosine) analogue and its cytidine dinucleotide derivative is described. Each compound is conformationally locked in a North-type pucker and exhibits both a pseudoaxial hydroxy group and a pseudoequatorial aminoacyl group. The syntheses were accomplished from D-ribose in 18 and 19 steps, respectively, with key steps being a ring-closing metathesis, a Luche reduction, a Simmons-Smith cyclopropanation, a Mitsunobu coupling, a Mattocks bromoacetylation, a regioselective and a stereoselective nucleophilic substitution, a chemoselective phosphoramidite coupling and a Staudinger-Vilarrasa coupling. Both molecules are being tested for peptidyl transfer efficiency in ribosomes for comparison with the peptidyl transfer kinetics of natural puromycin and other natural and synthetic ribosomal A site substrates.
Michel
Benoît Y
BY
UMR 5246, CNRS, Laboratoire de Synthèse de Biomolécules, Université Claude Bernard Lyon 1, Villeurbanne, Université de Lyon, 69622 Lyon, France.
Strazewski
Peter
P
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D008968:Molecular Conformation; D009711:Nucleotides / Q000737:chemistry*; D011691:Puromycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D012270:Ribosomes / Q000737:chemistry*; D013237:Stereoisomerism
D000900:Anti-Bacterial Agents; D009711:Nucleotides; D011691:Puromycin