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Title:Harnessing cheminformatics for catalyst design I. Investigation into a general, asymmetric synthesis of cinchona alkaloid analogs towards asymmetric phase transfer II. Development of an enantioselective brønsted acid catalyzed four-component Ugi reaction
Author(s):Leising, Rebecca Marie
Advisor(s):Denmark, Scott E
Department / Program:Chemistry
Discipline:Chemistry
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:M.S.
Genre:Thesis
Subject(s):Cheminformatics
Phase transfer catalysis (PTC)
Bronsted acid catalysis
Ugi reaction
Abstract:A new paradigm for catalyst design through chemoinformatics utilizing quantitative structure activity relationship was investigated. Under this platform, two ‘core’ catalyst scaffolds were chosen. First, Cinchona alkaloids were studied against an asymmetric phase transfer catalyzed cyclopropanation reaction. Second, (R)-BINOL derived phosphoric acids were studied in regards to the brønsted acid catalyzed Ugi reaction. In regards to Cinchona alkaloids, the concentration was first on methodology develop to rapidly synthesize diverse Cinchona-like analogs in a highly enantioenriched fashion. Systematic examination of the C(9) aryl substitution on Cinchona-alkaloids would determine the overall steric and electronic roles of the C(9) position on catalyst activity. An asymmetric metalation of quinuclidine N–oxide and trapping of various aldehydes was explored. Quinuclidine was utilized as the bulk starting material. An improved synthesis of quinuclidine was developed through a Henbest modified Wolff-Kishner reduction of 3-quinuclidone. The poor solubility of quinuclidine N-oxide made an asymmetric lithiation was elusive. An alternative method was to resolve the resulting Cinchona-alkaloids from a racemic metalation and trapping. The foremost resolution method was a kinetic acylation of the resultant amino alcohol. However only a modest selectivity factor (6.4) was observed and not synthetically useful. The second ‘core’ investigated was (R)-BINOL derived phosphoric acids. The formation of the BPA catalysts was a synthetic collaboration, in order to rapidly access the fifty member training set. Several improvements were implemented in the synthesis of the (R)-BINOL backbone derivatives. The partial hydrogenation of (R)-BINOL occurred at a lower: temperature (24 °C), Adam’s catalyst loading (5 mol %), and pressure (150 psi) after only 24 hours. The bromination of dimethylated (R)-BINOL was optimized with Br2 as opposed to a soluble bromine source. A total of 20 catalysts were synthesized. A classical Ugi reaction was investigated using the isolated imine, to exclude the formation of Passerini byproducts. Since the Ugi reaction is traditionally catalyzed by the carboxylic acid component, the background reaction could serve as a significant problem. Optimization of the Ugi reaction occurred through a temperature and solvent survey. The background reaction was minimized in toluene at – 78 °C. The pKa dependence on brønsted acid catalysis of the Ugi reaction was demonstrated that both phosphoric acids and triflamides catalyzed the Ugi reaction. The low solubility of phosphoric acids in toluene lead to the exclusive use of phosphoramide catalysts. Ten BPA catalysts were screened and resulted in isolated enantioenriched amide, albeit in low selectivity (er 55:45). To combat a reversible stereodetermining isocyanide imine addition, a tethered Ugi reaction was investigated. By attaching the carboxylic acid to the imine, the capture of the nitrile with the carboxylic acid becomes an intramolecular reaction. An increased rate of nitrile capture would decrease the reversibility of the stereodetermining step. After a solvent survey, a solvent combination of toluene and benzotrifluoride (4:1) at room temperature was found to have a suppressed background reaction, due to minimal imine acid solubility. Twenty BPA catalysts were screened and an enantioenriched lactam was isolated, albeit low selectivity (er 55:54). Reversibility of the stereodetermining step remains a significant challenge.
Issue Date:2017-10-12
Type:Text
URI:http://hdl.handle.net/2142/99186
Rights Information:Copyright 2017 Rebecca M Leising
Date Available in IDEALS:2018-03-13
Date Deposited:2017-12


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