Abstract
In 2002, mannopeptimycins 1-5 are isolated from Streptomyces hygroscopicus LL-AC98 as potent antibiotics by He and his co-workers. Mannnopeptimycins exhibited antimicrobial activity against Gram-positive bacteria, including methicillin-resistant streptococci and vancomycin-resistant enterococci. Mannopeptimycins consist of 6 amino acids including 3 unnatural residues. Aiha-A (α-amino-β[4'-(2' -imino-imida -zolidiny1)]-(β-hydroxypropionic acid-A) and Aiha-B are unnatural cyclic guanidine containing amino acids which are only found in mannopeptimycins. For further elucidation of mechanism of action and structure-activity relationships of mannnopeptimycins, the development of efficient synthetic methodology is important. However, there has been no synthetic report for mannopeptimycin aglycon. Only recently, syntheses of Aiha-A and Aiha-B were disclosed by two groups. Herein, we wish to report the total synthesis of proposed structure of mannopeptimycin aglycon 6. Aiha-A and Aiha-B were synthesized from the common synthetic intermediate 19 via asymmetric aldol reaction with aldehyde 17. Threo product 21 smoothly cyclized to afford the corresponding N,0-cyclic acetal 22 in the presence of silica-gel. On the other hand, erythro product 20 did not form the N,0-cyclic acetal due to steric repulsion. 20 and 22 were readily separated by using silica gel column chromatography. A cyclic guanidine moiety was introduced using Goodman reagent to afford Aiha A 26 and Aiha B 28, respectively. L-Ser 8 was coupled with Aiha-B 28 using HATU. The following condensation with Aiha-A 26 using HATU afforded the undesired product 31. We could overcome the problem by employing PyBOP as a condensation agent. The coupling between 25 and 30, and the crucial macrolactamization proceeded well using HATU. Global deprotection under hydrogenation condition afforded the aimed product 6 in good yield. The structure was confirmed by ^1H NMR, ^<13>C NMR, ^1H-^1H COSY, HMBC, HSQC, MS analyses.
