posted on 2020-09-04, 15:35authored byMaxwell
J. Moore, Shiwei Qu, Ceheng Tan, Yu Cai, Yuzo Mogi, D. Jamin Keith, Dale L. Boger
A next-generation
total synthesis of vancomycin aglycon is detailed
that was achieved in 17 steps (longest linear sequence, LLS) from
the constituent amino acid subunits with kinetically controlled diastereoselective
introduction of all three elements of atropisomerism. In addition
to new syntheses of three of the seven amino acid subunits, highlights
of the approach include a ligand-controlled atroposelective one-pot
Miyaura borylation–Suzuki coupling sequence for introduction
of the AB biaryl axis of chirality (>20:1 dr), an essentially instantaneous
and scalable macrolactamization of the AB ring system nearly free
of competitive epimerization (>30:1 dr), and two room-temperature
atroposelective intramolecular SNAr cyclizations for sequential
CD (8:1 dr) and DE ring closures (14:1 dr) that benefit from both
preorganization by the preformed AB ring system and subtle substituent
effects. Combined with a protecting group free two-step enzymatic
glycosylation of vancomycin aglycon, this provides a 19-step total
synthesis of vancomycin. The approach paves the way for large-scale
synthetic preparation of pocket-modified vancomycin analogues that
directly address the underlying mechanism of resistance to vancomycin.