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Total Syntheses of a Conformationally Locked North ‐Type Methanocarba Puromycin Analogue and a Dinucleotide Derivative
Author(s) -
Michel Benoît Y.,
Strazewski Peter
Publication year - 2009
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200802629
Subject(s) - chemistry , stereochemistry , phosphoramidite , enantiopure drug , cytidine , puromycin , derivative (finance) , organic chemistry , enantioselective synthesis , oligonucleotide , enzyme , dna , biochemistry , catalysis , financial economics , economics , protein biosynthesis
Locked in translation : Crucial insight into the ribosomal catalysis of peptide‐bond formation is expected to be gained from the target compounds, which feature conformational locking in a North‐ type pucker, designed to interfere with the translation of the genetic code. The compounds were prepared from D ‐ribose in 18 and 19 steps by a multi‐step synthetic route described here (see scheme).An original synthetic approach for the first synthesis of an enantiopure methanocarba puromycin (3′‐α‐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.