Novel enantioselective organocatalytic reactions to access promising scaffolds for medicinal chemistry and natural product synthesis via fluorinated intermediates
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Rodriguez-Alvarado, Melanie.
Novel enantioselective organocatalytic reactions to access promising scaffolds for medicinal chemistry and natural product synthesis via fluorinated intermediates. Retrieved from
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TitleNovel enantioselective organocatalytic reactions to access promising scaffolds for medicinal chemistry and natural product synthesis via fluorinated intermediates
Date Created2021
Other Date2021-05 (degree)
Extent1 online resource (xxii, 248 pages)
DescriptionThe demand for chiral synthetic compounds has led the field of asymmetric catalysis to discover, explore and develop new catalytic strategies to achieve pure optically active compounds. The Organocatalysis field, a division of asymmetric catalysis, is defined as the use of organic molecules to catalyze chemical transformations. This field has grown exponentially over the past decades. Discussed herein is use of chiral organic catalysts in the synthesis of both enantiopure Medicinal Drugs and complex Natural Product motifs. In Medicinal Drug synthesis, a selective introduction of a fluorine atom to the alpha position of an aldehyde via a double enamine organocascade using (L)-proline resulted in a gem-chlorofluoro stereogenic center. This fluorination was achieved using a mild, operationally simple, organocatalytic protocol allowing direct access to carbon-fluorine stereocenter formation. The synthesized gem-chlorofluoro stereocenters were further utilized as fluorinated intermediates in the synthesis of fluorinated LpxC inhibitors against Gram-Negative bacteria. The synthesized fluorinated enantiopure LpxC inhibitors were tested for antibacterial activity and showed micromolar activity of ≤12.5 μg/mL against Pseudomonas Aeruginosa, one of the pathogens with growing multidrug resistance. Furthermore, new strategies for the asymmetric synthesis of optically active synthons for alkaloid synthesis were studied. It is known that ylides derived from quaternary ammonium salts can undergo competing [2,3]- and [1,2]- (i.e., Stevens) rearrangements, and diastereoselective versions of Stevens [1,2]-rearrangements have been exploited in synthesis to establish complex polycyclic backbones of alkaloid scaffolds. However, these methods require pre-installed stereogenic centers and enantiopure ammonium ylide starting materials, which are not trivial to access. Moreover, while the first examples of catalytic asymmetric [2,3]- and formal [2,3]-rearrangements of ammonium ylides have been recently reported by the Tambar and Smith groups, the corresponding catalytic asymmetric [1,2]-rearrangement remains elusive. Inspired by the works of Tambar and Smith and using insight from a very recent report by Singleton et. al. regarding how to bias these two competing reactions, in combination with our own rational design, efforts to develop the first catalytic asymmetric [1,2]-Stevens rearrangement of an ylide formed from a quaternary ammonium salt are reported.
NotePh.D.
NoteIncludes bibliographical references
Genretheses, ETD doctoral
LanguageEnglish
CollectionGraduate School - Newark Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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