1 research outputs found
Chemoenzymatic Total Synthesis and Structural Diversification of Tylactone-Based Macrolide Antibiotics through Late-Stage Polyketide Assembly, Tailoring, and Cî—¸H Functionalization
Polyketide synthases
(PKSs) represent a powerful catalytic platform
capable of effecting multiple carbon–carbon bond forming reactions
and oxidation state adjustments. We explored the functionality of
two terminal PKS modules that produce the 16-membered tylosin macrocycle,
using them as biocatalysts in the chemoenzymatic synthesis of tylactone
and its subsequent elaboration to complete the first total synthesis
of the juvenimicin, M-4365, and rosamicin classes of macrolide antibiotics
via late-stage diversification. Synthetic chemistry was employed to
generate the tylactone hexaketide chain elongation intermediate that
was accepted by the juvenimicin (Juv) ketosynthase of the penultimate
JuvEIV PKS module. The hexaketide is processed through two complete
modules (JuvEIV and JuvEV) in vitro, which catalyze elongation and
functionalization of two ketide units followed by cyclization of the
resulting octaketide into tylactone. After macrolactonization, a combination
of in vivo glycosylation, selective in vitro cytochrome P450-mediated
oxidation, and chemical oxidation was used to complete the scalable
construction of a series of macrolide natural products in as few as
15 linear steps (21 total) with an overall yield of 4.6%