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Title:C—H oxidation reactions: development and application
Author(s):Reed, Sean
Director of Research:White, Maria C.
Doctoral Committee Chair(s):White, Maria C.
Doctoral Committee Member(s):Denmark, Scott E.; Katzenellenbogen, John A.; van der Donk, Wilfred A.
Department / Program:Chemistry
Discipline:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):C-H activation
allylic amination
C-H oxidation
Abstract:C—H activation (the cleavage of carbon-hydrogen bonds) reactions are emerging as a powerful new approach for complex molecule synthesis. The development of reactions that are selective, catalytic, mild, and efficient have the potential to significantly streamline the synthesis of organic molecules used in medicine, biological studies, materials chemistry, and other fields. This work describes both the development of the first general, linear allylic C—H amination reaction, as well as applications of a biomimetic non-heme iron catalyst towards generating diverse oxidation products and exploring biological pathways. Linear allylic amines are a common motif found in many organic molecules; however, their synthesis involves a lengthy, multi-step sequence that exposes the substrate to a variety of different reaction conditions (oxidative, reductive, nucleophilic). Methods that directly transform alpha olefins into linear allylic amines via C— H activation would therefore represent a potentially useful synthetic transformation. Through the use of two different palladium-catalyzed approaches, electrophile activation and nucleophile activation with catalytic Cr(salen)Cl and Brønsted base, respectively, good yields and high selectivities for the E linear aminated product could be obtained. The method was demonstrated for a large number of diverse substrates, and allylic amination is preferred in the presence of other potentially reactive functional groups (alcohols, epoxides, aryl triflates). This reaction was also applied to the synthesis of a deoxynegamycin analogue; comparison of the route enabled by direct C—H amination to the previously reported route revealed a significant decrease in step count and an overall increase in synthetic efficiency. C—H activation has other potential application beyond synthesis of known compounds; it can also be used to diversify natural products or pharmacophores. Nature utilizes this strategy routinely to generate libraries of different oxidized products. This work describes a small molecule enzyme mimic (“FePDP”) that demonstrates mixed hydroxylase/desaturase aliphatic C—H oxidation activity (in the presence of carboxylic acid directing groups) on a picrotoxinin derivative. Additionally, this biomimetic catalyst is used to explore oxidations of taxanes, the core structure found in the anti-cancer agent paclitaxel. Hydrogen-abstraction/ring contraction suggested a new late-stage, P450-mediated biosynthetic hypothesis for the formation of A-ring nortaxane natural products, and demonstrated evidence of radical intermediates for this class of stereoretentive non-heme iron catalysts. The FePDP catalyst was also used to access potentially useful taxane derivatives by stereoselectively installing oxidation at C2, which is critical for paclitaxel’s primary mode of action.
Issue Date:2013-02-03
URI:http://hdl.handle.net/2142/42383
Rights Information:Copyright 2012 Sean Reed
Date Available in IDEALS:2013-02-03
Date Deposited:2012-12


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