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STEREOSELECTIVE NUCLEOPHILIC FLUOROMETHYLATIONS:
FROM METHODOLOGY TO MECHANISTIC STUDIES
By
Fang Wang
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(Chemistry)
December 2012
Copyright 2012 Fang Wang
Object Description
| Title | Stereoselective nucleophilic fluoromethylations: from methodology to mechanistic studies |
| Author | Wang, Fang |
| Author email | chemwangfang@yahoo.com;wangf@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Chemistry |
| School | College of Letters, Arts And Sciences |
| Date defended/completed | 2012-10-10 |
| Date submitted | 2012-11-19 |
| Date approved | 2012-11-20 |
| Restricted until | 2012-11-20 |
| Date published | 2012-11-20 |
| Advisor (committee chair) | Prakash, G. K. Surya |
| Advisor (committee member) |
Olah, George A. Hogen-Esch, Thieo E. Shing, Katherine |
| Abstract | This dissertation is primarily focused on two topics, namely asymmetric nucleophilic fluoromethylation reactions and the relevant mechanistic studies. The asymmetric nucleophilic fluoromethylation reactions were achieved using robust nucleophilic fluoromethylating reagents and a series of cinchona alkaloid-derived catalysts. The employment of the trifluoromethyl group as a conformational stabilizer and a probe advanced the knowledge of conformational behavior of cinchona alkaloids and their derivatives. ❧ Chapter One briefly reviews the history and state of the art of organofluorine chemistry. The major achievements in synthetic organofluorine chemistry are discussed in a chronological order, which illustrates a clear overview of the developments in this field in recent years. ❧ Chapter Two describes the 1,4-addition of α-fluoro(phenylsulfonyl)methane derivatives to a variety of α,β-unsaturated carbonyl compounds using phosphine-based catalysts. ❧ Chapter Three conveys a novel synthetic strategy for the preparation of α-fluoro(disulfonyl)methane and its chloro and methoxy analogues. On the basis of this method, fluoro(bisphenylsulfonyl)methane (FBSM), a versatile monofluoromethylating reagent, is easily synthesized on large scale with high yield and selectivity. ❧ Chapter Four demonstrates the catalytic asymmetric 1,4-addition of α-fluoro-α-nitro(phenylsulfonyl)methane (FNSM) to α,β-unsaturated ketones using cinchona alkaloid-based thiourea catalysts. As implied by theoretical calculations and X-ray crystal structures, α-fluoro-α-nitro(phenylsulfonyl)methide anion adopts pyramidal geometry at the anionic carbon center, while its non-fluorinated counterpart assumes a planar structure. Such structural difference leads to fundamentally different origins in stereoselectivities. ❧ Chapter Five involves the enantioselective synthesis of α-stereogenic γ-keto esters. By employing nitro(phenylsulfonyl)methane (NSM) as a surrogate for an acyl anion, the integrated Michael addition reaction-oxidative methanolysis protocol allows the preparation of various γ-keto esters with high optical purities. ❧ Chapter Six demonstrates the introduction of a trifluoromethyl group into cinchona alkaloid scaffold as conformational stabilizer and probe, revealing a wealth of conformational information, which otherwise difficult to achieve. ❧ Chapter Seven discusses hindered CF3 rotations observed in cinchona alkaloid-based scaffolds, which allows the exploration of the nature of noncovalent C-H•••F-C interactions. ❧ Chapter Eight is focused on quantitative investigation of conformational behavior of cinchona alkaloids. By utilizing the CF3 conformational tool described in Chapter Six, the conformational behavior of a trifluoromethylated quinidine derivative in various solvents was analyzed via Linear Free Energy Relationship. These results enables the quantitatively assessment of the accuracy of theoretical calculations in cinchona alkaloid conformational analysis. |
| Keyword | asymmetric catalysis; cinchona alkaloids; conformational analysis; DFT calculation; fluoromethylation |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Rights | Wang, Fang |
| Access conditions | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@usc.edu |
| Archival file | uscthesesreloadpub_Volume6/etd-WangFang-1315.pdf |
Description
| Title | Page 1 |
| Full text | STEREOSELECTIVE NUCLEOPHILIC FLUOROMETHYLATIONS: FROM METHODOLOGY TO MECHANISTIC STUDIES By Fang Wang A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (Chemistry) December 2012 Copyright 2012 Fang Wang |
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