General synthesis route to benanomicin-pradimicin antibiotics.
A general approach to the regio- and stereoselective total synthesis of the benanomicin-pradimicin antibiotics (BpAs) is described. Construction of the aglycon has been achieved by 1) the diastereoselective ring-opening of a biaryl lactone by using (R)-valinol as a chiral nucleophile and 2) the stereocontrolled semi-pinacol cyclization of the aldehyde acetal by using SmI(2) in the presence of BF(3)OEt(2) and a proton source to afford the ABCD tetracyclic monoprotected diol. This strategy enabled us to control the two stereogenic sites in the B ring (C-5 and C-6) and the regioselective introduction of the carbohydrate moiety. The ABCD tetracycle could serve as an ideal platform for the divergent access to various BpAs. The amino acid (D-alanine) was introduced onto the ABCD tetracycle. Glycosylation was promoted by the combination of Cp(2)HfCl(2) and AgOTf (1:2 ratio). Construction of the E ring followed by deprotection completed the first total synthesis of benanomicin A (2 a), benanomicin B (2 b), and pradimicin A (1 a). The route is flexible enough to allow the synthesis of other congeners differing in their amino acid and carbohydrate moieties.
Tamiya
Minoru
M
Department of Chemistry, Tokyo Institute of Technology, SORST-JST, 2-12-1 O-okayama, Meguro-ku, Tokyo, Japan.
Ohmori
Ken
K
Kitamura
Mitsuru
M
Kato
Hirohisa
H
Arai
Tadamasa
T
Oorui
Mami
M
Suzuki
Keisuke
K
D018943:Anthracyclines / Q000138:chemical synthesis* / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry; D016227:Benzoquinones / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D003500:Cyclization; D006031:Glycosylation; D007783:Lactones / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D013055:Spectrophotometry, Infrared; D013237:Stereoisomerism
D018943:Anthracyclines; D000900:Anti-Bacterial Agents; D016227:Benzoquinones; D007783:Lactones; C004532:quinone