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Benoît Y. Michel and Peter Strazewski
Chemistry - A European Journal 2009, 15, 6244-6257
Total syntheses of a conformationally locked North-type methanocarba puromycin analogue and its dinucleotide derivative
An original synthetic approach is described for the first synthesis of an enantiopure methanocarba puromycin (= 3'-aminoacylamino-3'-deoxy adenosine) analogue, which is conformationally locked in a North-type pucker and exhibits both a pseudo-axial hydroxyl and a pseudo-equatorial aminoacyl group, and its dinucleotidic cytidine derivative. The syntheses were accomplished in 18 and 19 steps, respectively, using as key steps from D-ribose: 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 and compared to the peptidyl transfer kinetics of natural puromycin and other natural and synthetic ribosomal A site substrates.
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