Kenichi Kanemoto

Novel Azalides Derived from Sixteen-Membered Macrolides

The design and synthesis of novel 15-membered 11-azalides and 16-membered 11,12-diazalide starting from 16-membered macrolides are reported. A mobile linear dialdehyde was isolated via a cyclic tetraol which was prepared by osmium oxidation of a conjugated diene. One-pot macrocyclization of this dialdehyde with an amine or a diamine afforded corresponding 15-membered azalides or 11,12-diazalide. Fundamental SAR studies of 15-membered 11-azalides disclosed their potentiality as a lead molecule for further chemical modifications. For environmental preservation, sustainable chemistry for synthesis of these azalides is also discussed.

Novel azalides derived from 16-membered macrolides. Part II: Isolation of the linear 9-formylcarboxylic acid and its sequential macrocyclization with an amino alcohol or an azidoamine

The design and synthesis of novel 14- to 16-membered 11-azalides starting from 16-membered macrolides are reported. A linear 9-formylcarboxylic acid was isolated via a mobile dialdehyde previously reported. Sequential macrocyclization of the formylcarboxylic acid with amino alcohol followed by deprotection afforded corresponding 14- to 16-membered azalides. On the other hand, reductive amination of the formylcarboxylic acid with an azidoamine followed by macrolactam formation with an amine generated from the azide gave 14- to 16-membered azalactams. Among these derivatives, 15-membered azalactams and 16-membered azalides exhibited characteristic in vitro antibacterial activities. Although optimization of 15-membered azalactams including demycarosyl analogues did not provide remarkably promising molecules, SAR studies of 16-membered azalides disclosed that substitution at the 15 position was very important for identification of a clinical candidate.

Computational study on formation of 15-membered azalactone by double reductive amination using molecular mechanics and density functional theory calculations

Formation of 15-membered azalactone by double reductive amination was analyzed using molecular mechanics and density functional theory calculations for simplified model compounds. As a result, the following aspects were clarified. When methylamine attacks a linear bis-aldehyde in the first step, there are possibilities that two regioisomers are formed. However, one of them exhibited remarkably stable energy level compared with the other. The stable isomer indicated a short distance between a methylamine moiety and an unreacted aldehyde. This short distance, about 2.3 Å, could be explained by hydrogen bonding, which implied relatively easy cyclization in the second step. Moreover, this cyclization process was supposed to be exothermic according to comparison of energy levels before and after cyclization.