Asymmetric Synthesis of Novel Fluorine-Containing Β-Lactams for Application to Unnatural Β-Amino Acid Synthesis

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Authors
Chen, Wen
Issue Date
1-May-11
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Thesis
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en_US
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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.
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The Graduate School, Stony Brook University: Stony Brook, NY.
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