Myers AG.
*
et al.
Harvard University, Cambridge, USA
A Platform for the Discovery of New Macrolide Antibiotics.
Nature 2016;
533: 338-345
DOI:
10.1038/nature17967
Key words
erythromycin A - solithromycin - Boeckman cyclization - Mukaiyama aldol reaction
Significance
Since the discovery of erythromycin A in 1949 as a potent antibacterial natural product,
many synthetic and semisynthetic approaches have been investigated to improve its
activity or to reduce side effects. While some semisynthetic strategies were successful
(e.g., azithromycin), total synthetic approaches mostly failed to efficiently generate
larger quantities of analogues. 35 years after the celebrated synthesis of Woodward
and co-workers, Seiple, Zhang et al. reported a highly diverse total synthetic approach
towards new macrolide antibiotics that established more than 300 new variants of ketolides
and azaketolides.
Comment
Macrolide antibiotics disrupt bacterial growth by inhibiting protein synthesis. The
highly diverse synthetic approach of Myers and co-workers includes a vinylogous Mukaiyama
aldol reaction, a glycosylation according to Woodward’s protocol, and a Boeckman cyclization
to elaborate the key macrolactone motif. All reactions have proven to be robust towards
many functional groups, enabling this approach to establish new analogues that are
no longer restricted by the functional groups required for semisynthetic derivatizations.
Many of the synthesized macrolides showed high potencies.
