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Title page for ETD etd-06202012-130554


Type of Document Dissertation
Author Aldrich, Leslie Nichole
URN etd-06202012-130554
Title Progress toward the total synthesis of marineosins A and B; total synthesis of tambjamine K and unnatural analogs with improved anticancer activity, and discovery of selective M1 antagonists
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Craig W. Lindsley Committee Chair
Brian O. Bachmann Committee Member
Gary A. Sulikowski Committee Member
P. Jeffrey Conn Committee Member
Keywords
  • pyrrole
  • alkaloids
  • tambjamine
  • muscarinic acetylcholine receptors
  • prodigiosin
  • marineosin
Date of Defense 2012-05-10
Availability unrestricted
Abstract
Progress toward the total synthesis of marineosins A and B, prodigiosin-like alkaloids with novel spiroiminal centers, is described. The synthesis of the proposed biosynthetic precursor was completed and the viability of an inverse electron demand hetero Diels-Alder reaction to produce the spiroiminal core was investigated. Synthesis of the fully elaborated spiroiminal core of marineosin A has been achieved with a model substrate and efforts to compete the total synthesis of marineosin A utilizing these optimized methods are ongoing. The route involves a key, stereoselective conjugate addition/ aldol reaction sequence, a substrate-controlled, stereoselective epoxidation followed by regioselective epoxide opening, and a late-stage acid-mediated cyclization of a hydroxyketoamide to form the spiroaminal.

The total synthesis of tambjamine K, another prodigiosin relative, was completed, and a focused library of unnatural analogs was prepared. Derivatives with improved anticancer activity and no general cytotoxicity were discovered and the mechanisms of action investigated.

Microwave assisted organic synthesis was utilized to developed conditions for the synthesis of 3,6-disubstituted-[1,2,4]-triazolo-[4,3,b] pyridazines, a scaffold indicated by a high throughput screen to possess antagonist activity at the M1 muscarinic acetylcholine receptor. Elucidation of structure-activity relationships around this scaffold led to the discovery of M1 antagonists with unprecedented selectivity for M1 over the other muscarinic receptor subtypes.

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