A sequential esterification-ring closing metathesis-Nozaki–Hiyama–Kishi strategy for constructing a natural product-like library of tetrahydrofuran-containing macrolides

Abstract

Polyketide-like macrolides (pMLs) represent a privileged class of compounds with a high incidence of bioactivity, however their structural complexity challenges their synthesis and more general study. Here we report the synthesis of a library of tetrahydrofuran-containing pMLs underpinned by a robust and convergent build/couple/pair/couple synthetic approach. The library comprises 170 pMLs originating from 17 building blocks, 10 of which were synthesized using a proline-catalyzed α-chlorination aldol reaction. Northern and southern hemisphere building blocks were coupled using either an oxidation/Horner-Wadsworth-Emmons sequence or a saponification/Steglich esterification strategy. Coupled fragments were cyclized via ring closing metathesis to yield macrocycles 14–16 atoms in size, which we diversified using 3 eastern side chain vinyl iodides through a Nozaki–Hiyama–Kishi reaction.