Kenneth S. Feldman
- Professor of Chemistry
Research Interests
Total synthesis of natural and unnatural products; new synthetic methods.
Organic Synthesis
Professor Feldman's research interests span several areas of organic synthesis. One part of his program emphasizes the total synthesis of natural product target molecules, both as a testing ground for the development of new methodology for stereoselective construction of complex functional arrays and as a source of probe molecules to explore interactions with biological receptors. Another focus of the Feldman group is exploratory methodology development based on the interactions of reactive carbenes with proximate functionality. The goal of these studies is to devise efficient transformations for rapid assembly of polyheterocyclic target molecules. These projects rely on all of the intellectual and experimental advances of contemporary organic synthesis and offer a wide range of opportunities for inquiry.
One of the natural products projects explores the
synthesis chemistry and immunomodulatory activity of a class of
secondary plant metabolites called ellagitannins, exemplified by the
dimer coriariin A (1). Several structural features of these compounds
pose difficult challenges for organic synthesis, including the
diastereoselective (atrop-selective) coupling of aromatic rings and the
regioselective construction of diaryl ethers in polyphenolic
substrates. We are developing novel solutions to these problems, and
their application in ellagitannin synthesis has recently resulted in
the preparation of coriariin A as well as several structural analogues.
Recent in-house assays with human immune system cells demonstrated that
coriariin A and related analogues can either upregulate secretion of
tumor necrosis factor alpha (TNFa) or, alternatively, suppress its
lipopolysaccharide (LPS, a bacterial toxin)-stimulated release,
depending on the structural details of the tannin construct tested (Figs. 1 and 2).
Enhanced release of TNFa presumably underlies the remarkable in vivo
antitumor activity of coriariin A, while systemic overproduction of
this cytokine stimulated by the bacterial toxin LPS can result in the
often fatal condition septic shock. We are actively probing the
mechanism by which these tannin species either agonize or antagonize
LPS activity in an effort to develop a molecular-level understanding of
the functional, structural and stereochemical requirements for
biological activity. Companion studies designed to identify tannin
analogs that can either 1) be targeted specifically to tumors, or 2)
antagonize LPS activity with greater potency, are ongoing as well.
A second synthesis project is based on the facile
generation of reactive alkylidene carbene intermediates 3 from
combination of select nucleophiles with alkynyliodonium salts 2 (Fig. 3).
These carbene intermediates participate in a range of subsequent
intramolecular transformations, including C-H insertion, alkene
cycloaddition, heteroatom (lone pair) addition, and arene
addition/expansion, to furnish carbocyclic and heterocyclic products
related to various families of alkaloids. The antileukemic alkaloids
deoxyharringtonine (4) and pareitropone (5), the cytotoxic marine
principle agelastatin A (6), and the selective VCAM-1 induction
inhibitor halichlorine (7) are current synthesis targets of this
chemistry.
