Dissertation/Thesis Abstract

I. Total syntheses of bisanthraquinones through cascade reactions. II. Fluorine-18 radiochemistry to advance cancer imaging
by Yee Hwee, Lim, Ph.D., The Scripps Research Institute, 2010, 592; 3420142
Abstract (Summary)

(+)-Rugulosin, (+)-2,2'-epi-cytoskyrin A and the alleged rugulin, a family of naturally occurring modified bisanthraquinones have been synthesized via an expedient and extremely efficient route, herein named the “cytoskyrin cascade” which features alternate oxidation and Michael addition reactions. The alleged rugulin structure was proved to have been misassigned.

Bisanthraquinone BE-43472B, an octacyclic molecule, has been synthesized by a concise route involving a key cascade sequence featuring a Diels-Alder reaction, a hemiketal formation and a nucleophilic aromatic ipso substitution which led to the formation of the requisite octacyclic framework in near quantitative yield. Further elaborations of this advanced intermediate via a selective installation of C-3 hydroxy group, a chemoselective removal of the superfluous C-2 oxygen and the installation of the requisite C-1 oxygen through an epoxidation/oxirane rearrangement, then led to the first total synthesis of this natural product, BE-43472B, and the determination of its previously unknown absolute configuration.

A peptide selective for VCAM-1 has been successfully radiolabelled with 18F and evaluated in vitro and in vivo to determine its suitability as a PET tracer for the detection of cancer micrometastases. While it has binding selectivity and specificity for VCAM-1 as attested by the in vitro binding assay and serum stability, it lacks the binding affinity (Kd) necessary of a PET tracer.

A novel “detagging” method for 18F-radiolabelling featuring a trans-esterification followed by an intramolecular O → N acyl transfer rearrangement using amino alcohols has been developed. Both commercially available solid phase resins and fluorous phase tag were found to be amenable to this chemistry, at least on model systems.

An direct oxidative nucleophilic fluorination of electron-rich aromatic via a simple one-step protocol has been preliminarily developed. The synthesis of 4-[18F]fluorophenol was validated radiochemically.

Indexing (document details)
Advisor:
Commitee:
School: The Scripps Research Institute
School Location: United States -- California
Source: DAI-B 71/09, Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Organic chemistry, Nuclear physics
Keywords: Bisanthraquinones, Cancer imaging, Cascade reactions, Fluorine radiochemistry
Publication Number: 3420142
ISBN: 978-1-124-16887-6
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