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Title:Slow-release cross-coupling and an advanced method for β-glycosylation: methods stimulated by amphotericin B
Author(s):Knapp, David
Director of Research:Burke, Martin D
Doctoral Committee Chair(s):Burke, Martin D
Doctoral Committee Member(s):van der Donk, Wilfred A; Katzenellenbogen, John A; Moore, Jeffrey S
Department / Program:Chemistry
Discipline:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):Direct-Release
Slow-Release
Amphotericin B
Glycosylation
Cross-Coupling
Abstract:Amphotericin B (AmB) represents a clinically vital but toxic antibiotic that additionally has the ability to form ion channels in biological membranes, a capacity normally associated with proteins. Better understanding the dynamics of channel formation and how it relates to AmB’s antifungal activity would stand to enable both the rational development of derivatives that have a better therapeutic index, and the design of the small molecule prosthetics with the capacity to treat currently incurable human diseases. Efficient access to derivatives of AmB would greatly facilitate these goals. In this context, several methodological advances have been made that were stimulated by studies toward an efficient and flexible total synthesis of AmB. In response to challenges encountered in the construction of the AmB polyene, a new cross-coupling protocol was developed whereby N-methyliminodiacetic acid (MIDA) boronates can be used directly in Suzuki-Miyaura cross-coupling (SMC) reactions, enabling air-stable MIDA boronates to act as surrogates for boronic acids. Additionally, conditions were identified under which MIDA boronates could be slowly hydrolyzed in the SMC reaction, enabling an in situ “slow-release” of the boronic acid. This slow release effect enables the efficient cross-coupling of a variety of otherwise unstable boronic acids. The synthesis and isolation of 2-pyridyl MIDA boronate and its derivatives demonstrates that even the most unstable boronic acids may be rendered stable and competent cross coupling partners by conversion to the corresponding MIDA boronates. Further, the use of “fast-release” conditions enabled the construction of the AmB heptaene as well as a variety of polyenyl natural products both within and outside our research group. To overcome the challenging 1,2-cis glycosidic bond found in AmB a mycosamine sugar donor synthesis was developed incorporating a new directing group for neighboring group participation. The use of this new directing group enabled efficient glycosylation of, and ultimately the completion of, a critical building block in the context of the iterative cross-coupling (ICC)-based synthesis of AmB. The potential of this glycosylation strategy for rapidly accessing AmB derivatives was also demonstrated in the synthesis of a C3’-deaminomycosamine sugar donor and its efficient attachment to a protected amphotericin aglycone.
Issue Date:2012-07-30
Type:Thesis
URI:http://hdl.handle.net/2142/95661
Rights Information:Copyright 2012 David Knapp
Date Available in IDEALS:2017-03-03
Date Deposited:2012-12


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