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Title:Semisynthesis of amphotericin B and its derivatives via iterative cross-coupling
Author(s):Gray, Kaitlyn
Director of Research:Burke, Martin D.
Doctoral Committee Member(s):Denmark, Scott E.; van der Donk, Wilfred A.; Orlean, Peter A.
Department / Program:Chemistry
Discipline:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):amphotericin B
iterative cross-coupling
semisynthesis
polyene
MIDA boronate
Abstract:Despite almost 40 years of investigation, the mechanism of action of amphotericin B (AmB), a potent but toxic antimycotic, has eluded the scientific community. The leading hypothesis involves insertion into the lipid bilayer of fungal cells followed by self-assembly into ion permeable channels that disrupt the transmembrane electrochemical gradient and induce cell death. This self-assembly into a protein-like ion channel complex puts AmB outside the paradigm of most chemotherapeutic agents which operate via the inhibition of protein targets. In this way, AmB also represents an outstanding prototype for small molecules that replicate the function of protein ion channels whose deficiency underlies currently incurable human diseases. Understanding the mechanism of this unique natural product at an atomistic level would also further enable the synthesis of antifungal derivatives with a better therapeutic index. However, due to the challenges present in the synthesis of this complex natural product and its derivatives, structure/function data are limited. The study of AmB would be greatly aided by the development of a modular and flexible total synthesis of this complex small molecule and its derivatives. Toward this end, we developed a strategy for the synthesis of polyene natural products via the iterative Suzuki-Miyaura cross-coupling of bifunctional polyenyl MIDA boronate building blocks. This methodology was taken on to complete efficient total syntheses of all-trans-retinal, β-parinaric acid, and one half of AmB. In order to validate this iterative cross-coupling methodology as an effective endgame strategy, we proceeded with a semisynthesis of AmB. Degradation of the natural product allowed access to an excellent model for an advanced intermediate in the proposed total synthesis. The iterative cross-coupling strategy then proved effective in converting this intermediate into the final product, validating the endgame strategy of the total synthesis. This same methodology was then applied to the semisynthesis of an AmB derivative lacking the C35 hydroxyl group. The completion of this synthesis required the development of a protecting group strategy that was robust to various chemical transformations, but also able to be cleaved under mild conditions such that the sensitive structure of the derivative could survive. The lessons learned from the synthesis of C35 deoxy AmB have informed the synthetic strategies currently under investigation towards a total synthesis of the natural product and will hopefully lead to the rapid synthesis of other mechanistically informative derivatives. With a solid understanding of the molecular underpinnings of the mechanism of action of AmB, we stand to enable the synthesis of derivatives with a better therapeutic index. Additionally, amphotericin B may serve as a prototype for the development of a new class of pharmaceuticals that can serve as substitutes for defective protein-based ion channels, thus operating as molecular scale prosthetics.
Issue Date:2012-02-01
Genre:thesis
URI:http://hdl.handle.net/2142/29536
Rights Information:Copyright 2011 Kaitlyn Gray
Date Available in IDEALS:2014-02-01
Date Deposited:2011-12


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