Type
Text
Type
Thesis
Advisor
Kathlyn A. Parker. . | Iwao Ojima. Frank W. Fowler.
Date
2011-05-01
Keywords
β-Amino Acid Synthesis, β-lactams, epimerization, Fluorine, Schiff base, trans β-lactams | Chemistry
Department
Department of Chemistry
Language
en_US
Source
This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.
Identifier
http://hdl.handle.net/11401/71577
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
β-Lactams are four-membered cyclic amides which can be found in many biologically active compounds. β-Lactams may possess two stereocenters. In enantiopure form, β-lactams can be used as chiral building blocks for the synthesis of various biologically relevant compounds, such as antibacterial drugs, antitumor agents, peptides, peptidomimetics and enzyme inhibitors. In addition, fluorine-containing β-lactams have drawn substantial interests among bioorganic and medicinal chemists. Studies have shown that the incorporation of fluorine efficiently blocks metabolism of the drug molecules, especially by cytochrome P-450 family of enzymes, providing improved pharmacokinetic properties. Different diastereomers of fluorine-containing β-lactams with high enantiopurity were synthesized utilizing a base-catalyzed C4-specific epimerization. Highly enantioenriched cis-β-lactams were obtained using the Staudinger [2+2] ketene-imine cycloaddition reaction, followed by kinetic enzymatic resolution. Ozonolysis of an exocyclic double bond of the enantioenriched cis-β-lactam afforded the key intermediate for selective epimerization, i.e. | a C4-formyl-β-lactam. The epimerization reaction was optimized for the isolation of trans-β-lactams. A difluorovinyl group was incorporated through a Wittig reaction, and subsequent modification of the substituents gave the desired 4-difluorovinyl-β-lactams. Using this protocol, a novel trans-difluorovinyl-β-lactam, (3S,4S)-1-(tert-butoxycarbonyl)-3-triisopropylsiloxy-4-(2,2-difluoroethenyl)azetidin-2-one with excellent enantiopurity, was obtained. These novel cis- and trans-fluorine-containing β-lactams can be used for the synthesis of fluorine-containing α-hydroxy-β-amino acids and their congeners or for the incorporation of fluorines into biologically active compounds via the β-lactam synthon method to investigate the effects of the fluorine moieties on their biological activities.
Recommended Citation
Chen, Wen, "Asymmetric Synthesis of Novel Fluorine-Containing β-Lactams for Application to Unnatural β-Amino Acid Synthesis" (2011). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 782.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/782