jo011184i_si_001.pdf (727.52 kB)
The Power of Visual Imagery in Synthesis Planning. Stereocontrolled Approaches to CGP-60536B, a Potent Renin Inhibitor
journal contribution
posted on 2002-05-14, 00:00 authored by Stephen Hanessian, Stephen Claridge, Shawn JohnstoneTwo strategies were developed toward the stereocontrolled synthesis of 8-aryl-3-hydroxy-4-amino-2,7-diisopropyloctanoic acids with predetermined stereogenic centers. This is a generic motif in a
new class of potent inhibitors of the enzyme renin, exemplified by CGP-60536B. The synthesis
relies on the utilization of l-pyroglutamic acid as chiron, and proceeds through the incorporation
of required functionality by exploiting internal induction. One of the strategies shows the power of
visual imagery in synthesis planning, akin to a Dali-like representation of objects that can be viewed
in more than one way. Thus, the entire carbon skeleton of the target molecule is encompassed in
a partially functionalized bicyclic indolizidinone precursor. In a second strategy, an intermediate
common to the first approach is elaborated into an appended γ-lactone which is alkylated through
enolate chemistry and ultimately transformed into the intended target compound. X-ray crystallography was used to corroborate the structures and stereochemistries of several intermediates.