ja6b03248_si_001.pdf (8.7 MB)
Rifamycin Biosynthetic Congeners: Isolation and Total Synthesis of Rifsaliniketal and Total Synthesis of Salinisporamycin and Saliniketals A and B
journal contribution
posted on 2016-05-27, 12:03 authored by Yu Feng, Jun Liu, Yazmin
P. Carrasco, John B. MacMillan, Jef K. De BrabanderWe describe the isolation,
structure elucidation, and total synthesis
of the novel marine natural product rifsaliniketal and the total synthesis
of the structurally related variants salinisporamycin and saliniketals
A and B. Rifsaliniketal was previously proposed, but not observed,
as a diverted metabolite from a biosynthetic precursor to rifamycin
S. Decarboxylation of rifamycin provides salinisporamycin, which upon
truncation with loss of the naphthoquinone ring leads to saliniketals.
Our synthetic strategy hinged upon a Pt(II)-catalyzed cycloisomerization
of an alkynediol to set the dioxabicyclo[3.2.1]octane ring system
and a fragmentation of an intermediate dihydropyranone to forge a
stereochemically defined (E,Z)-dienamide
unit. Multiple routes were explored to assemble fragments with high
stereocontrol, an exercise that provided additional insights into
acyclic stereocontrol during stereochemically complex fragment-assembly
processes. The resulting 11–14 step synthesis of saliniketals
then enabled us to explore strategies for the synthesis and coupling
of highly substituted naphthoquinones or the corresponding naphthalene
fragments. Whereas direct coupling with naphthoquinone fragments proved
unsuccessful, both amidation and C–N bond formation tactics
with the more electron-rich naphthalene congeners provided an efficient
means to complete the first total synthesis of rifsaliniketal and
salinisporamycin.