Reaction of 2-mercapto-1-methylimidazole (methimazole) with tris(dimethylamino)borane, B(NMe2)3, provides the tetrahedral dimethylamine adduct of tris(methimazolyl)borane, [(Me2HN)B(methimazolyl)3]. By contrast, imidazole, 2-methylimidazole, 2-chloroimidazole and benzimidazole provide the homoleptic tetra-azolyl systems H[B(azolyl)4], and the same product is obtained even when a substoichiometric quantity of the heterocyle is employed. The change in reaction outcome is correlated with the variation of basic pKa for the heterocycles. A simple acid-base reaction with elimination of HNMe2 is proposed for the reaction with the weakly basic, but more strongly acidic, methimazole. However, for the more strongly basic imidazoles, initial coordination of the heterocycle imine nitrogen to the weakly Lewis acidic boron centre in B(NMe2)3 to form the tetrahedral adduct [(azole)B(NMe2)3] is proposed. The greater availability of the NMe2 lone pairs in this species results in increased basicity and a rapid reaction with further heterocycle to provide the observed H[B(azolyl)4] products. For 2-nitroimidazole, the low basicity (and increased N-H acidity) results in the formation of [(HNMe2)B(2-nitroimidazolyl)3] on reaction with B(NMe2)3, analogous to the product formed with methimazole. Both [(HNMe2)B(methimazolyl)3] and H[B(benzimidazolyl)4] have been structurally characterised by single crystal X-ray crystallography. This chemistry has been exploited to provide a new synthesis of borate-centred tripod ligands, whereby N-methylimidazole is used to activate B(NMe2)3 to reaction with methimazole to form the new ligand [(N-methylimidazole)B(methimazolyl)3] in good yield and a complex of this ligand with Ru(II) has been structurally characterised.
The mechanism of the enantioselective addition of diethylzinc to N-(diphenylphosphinoyl)benzalimine with catalysis by bicyclic 2-azanorbornyl-3-methanols was studied by quantum chemical calculations. The mechanism proved to differ from that of the addition of diethylzinc to aldehydes and also from an earlier proposed mechanism. The results of the calculations were used to identify several factors responsible for the selectivity. The theoretical evaluation was performed in connection with an experimental study of the effects of introducing an additional stereocenter in the ligand. An efficient route to both diastereomers of new bicyclic 2-azanorbornyl-3-methanols with an additional chiral center (the secondary alcohol group) is also presented. In the best case, an enantiomeric excess of up to 97 % was obtained with these new ligands.
The potent neurotoxin (K)-pumiliotoxin C has been prepared in 8 steps starting from 2-cyclohexenone. Key steps are a tandem asymmetric conjugate addition-allylic substitution reaction and a tandem Heck-allylic substitution reaction. q
4'-Azidocytidine 3 (R1479) has been previously discovered as a potent and selective inhibitor of HCV replication targeting the RNA-dependent RNA polymerase of hepatitis C virus, NS5B. Here we describe the synthesis and biological evaluation of several derivatives of 4'-azidocytidine by varying the substituents at the ribose 2' and 3'-positions. The most potent compound in this series is 4'-azidoarabinocytidine with an IC(50) of 0.17 microM in the genotype 1b subgenomic replicon system. The structure-activity relationships within this series of nucleoside analogues are discussed.
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