The Power of Organic Synthesis and
Structure-Activity Relationships
Organic synthesis has evolved at a
remarkably rapid pace over the past century. While the 1970’s were a
decade that initiated the development of selective reactions
particularly in a stereochemical sense, it has been clear since the
1980’s that synthetic chemists can prepare even the most complex
targets. The continuing discovery and development of new synthetic
methods have now made practical syntheses of large quantities of
complex molecules a reality. This has been particularly true in the
polyketide field where asymmetric methods targeting the stereochemical
structure common to these targets are plentiful. Recently, these
methods have been highlighted in the gram-scale synthesis of complex
natural products such as discodermolide and other polyketides.
Classic analogue design seeks to optimize biological activity through
systematic structural modification. While polyketides such as
erythromycin, pikromycin, amphotericin, rifamycin, bafilomycin and
several others have been studied from a medicinal chemistry perspective
including numerous analogues, systematic modification to their
structures have not been accomplished. Of course erythromycin’s
biological activity comes from pendant sugars and therefore
modifications to the polyketide skeleton have been justifiably
limited. There are, however, examples of drastically simplified
analogues of polyketides retaining biological activity. Wender’s
simplified bryostatin and Romo’s pateamine A analogue are two such
examples. With its relatively simple structure, the epothilones, a set
of compounds with which we are quite familiar, were arguably the first
polyketide to be exhaustively studied with SAR.
By focusing our interest on polyketides we have harnessed powerful
synthetic techniques capable of reliably delivering sources of the
natural material as well as analogues. When deemed necessary we have
also contributed new synthetic methods for the construction of
particular structural units common to these targets but not well
serviced by current technology. We have already completed the total
synthesis of several complex
polyketides such as epothilone A-D, myriaporones 1, 3 and 4 as well as
peloruside A. In addition, late stage efforts are focused on
apoptolidin, ambruticin, cornexistin, and acutiiphycin.
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