Nucleophilic Aromatic Substitution—A Possible Key Step in Total Syntheses of Vancomycin

✍ Scribed by Prof. Kevin Burgess; Dongyeol Lim; Carlos I. Martinez

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: English
• Weight: 181 KB
• Volume: 35
• Category: Article
• ISSN: 0044-8249
• DOI: 10.1002/anie.199610771

✦ Synopsis

Vancomycin is a natural product with a complicated molecular architecture and clinical significance as an antibiotic for treatment of infections caused by gram positive bacteria. These two attributes have seduced several groups of organic chemists into attempting to prepare this molecule, but no successful synthesis has been reported to date.

O,sugar

F' vancomycin

In 1993 there were two reasons to suppose that a total synthesis of vancomycin might be achieved soon.['] First, the cyclic compound 1 had been prepared;[21 this closely resembles the "southwestern fragment" of vancomycin, which includes the biaryl linkage of rings A and B. Second, the bicyclic compound 2 had been made;[31 this is closely related to the central region of vancomycin, which incorporates the C , D, and E rings.

Despite this optimism, it apparently has not been convenient to exploit the syntheses of fragments 1 and 2 in a total synthesis, presumably for the following reasons. Vancomycin has only one chlorine atom on rings C and E, whereas both ortho positions on the corresponding aryl rings of 2 are chlorinated. These extra chlorine atoms were critical for the synthesis of 2, in which two thallium trinitrate-mediated couplings require both ortho phenolic positions to be blocked. Furthermore, the formation of 1, an oxidative coupling of the carbons marked a and b in structure [*I Prof.