Asymmetric Synthesis of the Aminocyclitol Pactamycin, a Universal Translocation Inhibitor

An asymmetric total
synthesis of the aminocyclopentitol pactamycin
is described. The title compound is delivered in 15 steps from 2,4-pentanedione.
Critical to this approach was the exploitation of a complex symmetry-breaking
reduction strategy to assemble the C1, C2, and C7 relative stereochemistry
within the first four steps of the synthesis. Multiple iterations
of this reduction strategy are described, and a thorough analysis
of stereochemical outcomes is detailed. In the final case, an asymmetric
Mannich reaction was developed to install a protected amine directly
at the C2 position. Symmetry-breaking reduction of this material gave
way to a remarkable series of stereochemical outcomes leading to the
title compound without recourse to nonstrategic downstream manipulations.
This synthesis is immediately accommodating to the preparation of
structural analogs.