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Title:Organoselenium redox-catalyzed, enantioselective syn-difunctionalization of alkenes
Author(s):Gilbert, Bradley Byron
Director of Research:Denmark, Scott E
Doctoral Committee Chair(s):Denmark, Scott E
Doctoral Committee Member(s):Fout, Alison R; Sarlah, David; Silverman, Scott K
Department / Program:Chemistry
Discipline:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):Catalysis, Organoselenium, Alkene Difunctionalization, Diamination, Dichlorination
Abstract:The first part of this dissertation serves as an introduction to the current state of electrophilic organoselenium-mediated and -catalyzed reactions of alkenes, as distinguished from other modes of organoselenium reactivity (e.g. Lewis base and peroxoselenenic acid reagents). Special attention is paid to the wealth of diastereoselective selenofunctionalization reactions with chiral, enantioenriched organoselenium electrophiles, as well as the growing field of selenofunctionalization-deselenenylation reactions catalyzed by achiral organoselenium reagents. Finally the intersection of these two approaches, enantioselective selenofunctionalization- deselenenylation reactions catalyzed by chiral, enantioenriched organoselenium electrophiles are discussed. The second part of this dissertation describes the development of a catalytic, enantioselective syn-dichlorination of alkenes using chiral, enantioenriched arylselenium catalysts. Enantioenriched, polyhalogenated terpenoids and lipids comprise a class of natural products of increasing academic and pharmaceutical interest; however, enantioselective methods to obtain the vicinal dihalides present in many of these molecules are lacking. The syn-dichlorination of alkenes catalyzed by diphenyl diselenide was first developed as a preamble to an enantioselective method, as it avoids many of the issues associated with enantioselective anti-dichlorination reactions involving electrophilic chlorine reagents by consequence of its mechanism. Accordingly, a wide variety of chiral diselenide precatalysts were synthesized and evaluated for enantioselectivity in the syn-dichlorination of alkenes. Catalysts were selected at first for evaluation based on their performance as reagents for diastereoselective methoxyselenenylations and related, non-catalytic reactions. Enantiomeric ratios were initially low, however high enough to serve as proof of concept for an asymmetric transformation. Further evaluation of a variety of catalyst scaffolds led to the development of rigid tetralin-derived diselenides. The best performing diselenide in this class afforded the syn-dichloride product in an enantiomeric ratio of 75:25. Further experiments were performed to determine whether a mechanistic leak could lead to the low enantioselectivities observed. The potential for competitive pathways wherein the electrophilic arylselenium species reacts with the alkene either at oxidation state Se(II) or Se(IV) was first examined. Slow addition of oxidant was performed in one reaction and slow addition of alkene substrate in the other to increase the probability of selenium being completely oxidized before encountering olefin or encountering olefin before it had the opportunity to be oxidized, respectively. The enantiomeric ratio of the dichloride product in both circumstances was identical to the product of the reaction where all components were combined in the usual manner. A similar result was observed when the dichloride e.r. was measured from an aliquot at one catalytic turnover and at complete conversion. It was concluded that either the organoselenium catalyst always reaches Se(IV) before reacting with the alkene or that the oxidation state of selenium at seleniranium ion formation is irrelevant to the enantiomeric ratio of the dichloride product. 1H NMR experiments demonstrated that the hypothetical resting state intermediate, the β- chloroalkyl arylselenium(IV) dichloride, can revert to the olefin, theoretically through re- formation of the seleniranium ion and subsequent de-complexation. It was hypothesized that the turnover-limiting step, intermolecular displacement of ArylSe(IV)+Cl by Cl–, is slow enough to allow for racemization of the resting state intermediate. The dichlorination method was adapted to chlorolactonzation in an effort to make seleniranium ion ring-opening irreversible through the formation of an ester C–O bond. Unfortunately, the turnover-limiting step was not accelerated to a significant degree and lactone formation / seleniranium ion ring-opening appeared to remain reversible. It was concluded that the enantiomeric ratios of the products obtained in both dichlorination and chlorolactonization might have been the consequence of Dynamic Kinetic Asymmetric Transformations (DyKAT), wherein the relative rates of displacement of selenium from diastereomeric resting state intermediates by chloride determined the final enantiomeric makeup of the products. The third part of this dissertation describes the adaptation of the enantioselective dichlorination method to diamination through the utilization of a bifunctional nucleophile. The tethering of the two nucleophilic atoms accelerates the second nucleophilic displacement step by virtue of intramolecularity such that it may no longer serve as the rate determining step. This change in mechanism allowed for significantly improved enantiomeric ratios for a large variety of oxazolidinone products obtained after a brief optimization of chiral catalyst to better suit the reaction conditions. Styrenyl olefins were diaminated in particularly good yields and enantioselectivities. Diaryl alkenes were difunctionalized in even higher yields and similarly good enantioselectivities; however, the products were obtained as mixtures resulting from N,N and N,O- difunctionalization in varying ratios, depending on the substrate. Dialkyl olefins were significantly less reactive and gave reduced yields with high enantiomeric ratios maintained. Attempts to extend the method to oxyamination with a carbamate reagent were met with moderate success.
Issue Date:2020-01-10
Type:Thesis
URI:http://hdl.handle.net/2142/108079
Rights Information:Copyright 2020 Bradley B. Gilbert
Date Available in IDEALS:2020-08-26
Date Deposited:2020-05


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