Asymmetric Alkylation of Anthrones, Enantioselective Total Synthesis of (−)- and (+)-Viridicatumtoxins B and Analogues Thereof: Absolute Configuration and Potent Antibacterial Agents

A phase
transfer catalyzed asymmetric alkylation of anthrones with
cyclic allylic bromides using quinidine- or quinine-derived catalysts
is described. Utilizing mild basic conditions and as low as 0.5 mol
% catalyst loading, and achieving up to >99:1 dr selectivity, this
asymmetric reaction was successfully applied to produce enantioselectively
(−)- and (+)-viridicatumtoxins B, and thus allowed assignment
of the absolute configuration of this naturally occurring antibiotic.
While the developed asymmetric synthesis of C10 substituted anthrones
is anticipated to find wider applications in organic synthesis, its
immediate application to the construction of a variety of designed
enantiopure analogues of viridicatumtoxin B led to the discovery of
highly potent, yet simpler analogues of the molecule. These studies
are expected to facilitate drug discovery and development efforts
toward new antibacterial agents.