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Vancomycin latest

16 September 2020 - antimicrobial

A new vancomycin total synthesis has been reported by Moore et al. in a recent article in JACS (DOI). Vancomycin is a critical antibiotic in the war on bugs. In his book on the human body, author Bill Bryson explains how this war is progressing: the humans are loosing. The use of antibiotics is widespread but most often for no good reason, microbial resistance is rampant and the pharmaceutical industry is not interested in developing new ones. Good thing then that the Boger group at Scripps (Dale Boger is a Corey child) is still marching on and has been marching since 1999 (DOI). In October 1999 when Bogers published his first vancomycin synthesis he was already defeated in the quest for the compound by total synthesis guys David A. Evans (DOI) and K. C. Nicolaou (DOI) who had their publications on the same day of 17 December 1998, cozily back to back in The Angewandte. In production by the way, the bacterium amycolatopsis orientalis takes care of everything.

The authors explain that their ultimate goal is to make new vancomycin analogues and hence new antibiotics, in case the parent becomes obsolete. But the vancomycin molecule is complex. It is a heptapeptide chain forming the axis of a strained tricycle. In one of the cycles is incorporated a biphenyl unit that has one of two possible atropisomeric configurations. Another part of the molecule has two diastereomeric centers. The ultimate yields of the efforts published 20 years ago did not exceed 1% and suffered poor diastereoselectivity. The new Bogers effort boasts an ultimate yield of 5% in just 19 steps. Importantly diastereoselectivity has improved considerably.

I am going to mention just one reaction, the first step that adds two methoxy groups to (S)-4-phenyl-oxazolidin-2-one. Simple reaction? A combined Borylation NHOOOBOBOOOBOBOONHOOONNClClIrIr+ (producing hazardous hydrogen gas) and Chan-Lam coupling takes a whopping 36 + 30 hours at elevated temperatures to complete. The final product is also contaminated with the mono-methylated compound. OBOBOONHOOOONHOOOHNOO-Cu+2OO-O And that was just step 1.