Chemistry and Biology of some tannin analogues and studies toward the synthesis of lihouidine

Open Access
Author:
Coca, Adiel
Graduate Program:
Chemistry
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
August 02, 2007
Committee Members:
  • Ken S Feldman, Committee Chair
  • Blake R Peterson, Committee Member
  • Raymond Lee Funk, Committee Member
  • Ming Tien, Committee Member
Keywords:
  • lps
  • lihouidine
  • tumor necrosis factor alpha
  • tnf
  • ellagitannin
  • tannin
  • lipopolysaccharide
  • coriariin a
  • pgg
  • beta penta galloyl glucose
Abstract:
The syntheses of three fluorescent tannin analogues (two monomers and one dimer) was accomplished. The synthesis of the dimeric ellagitannin/gallotannin proved especially challenging. The onset of the synthesis involved a hetero Diels-Alder dimerization of an orthoquinone unit catalyzed by Sc(OTf)3 to produce the core of the molecule, and a [3+2]-cycloaddition using a modification to the Sharpless Cu(I)-catalyzed protocol to attach the fluorescent tags. Several in vivo biological experiments were performed with these synthetic tannins and disappointedly the dimeric tannin was found inactive (unable to elicit TNF-? secretion from J744 cells). However, the two monomeric fluorescent gallotannins were found as active as the parent penta-O-galloyl-?-D-glucose that will allow further probing into the exact biological mechanism by which these tannins are able to achieve their documented tumoricidal action. Furthermore, studies towards the synthesis of lihouidine, a marine natural product with moderate anticancer properties, were pursued. A Buchwald-Hartwig arylamination was used to join two early fragments. Numerous acidic aerobic conditions failed to cyclize this adduct through a proposed biomimetic electrocyclization. Gratifyingly, subjection of this adduct to fuming nitric acid led to an unprecedented nitration/Michael-like cyclization cascade to form a key advanced intermediate in the synthesis.