| dc.description.abstract | This dissertation describes (i) advances in the stereoselective synthesis of β-fluoroamines, (ii) manipulation of ring closing metathesis conditions to access several carbocyclic rings displaying β-fluoroamines, (iii) the development of a new protocol for amide bond formation, and (iv) a formal synthesis of the peptide natural product (-)-feglymycin.
Straightforward access to β-fluoroamines is desirable considering β-fluorination of an alkyl amine functionality can alter a compound’s pKa, potency, lipophilicity, conformation, and pharmacokinetic properties. Therefore, we have developed a stereocontrolled route to acyclic and carbocyclic β-fluoroamines. Our approach leverages the discovery of an unprecedented syn-selective aza-Henry reaction. This reaction was used to access carbocyclic β-fluoroamines via an isomerization/ring closing metathesis (RCM) tactic that contains points of divergence to provide several ring sizes and to install additional functionalities.
New methods that redefine pathways to access complex natural products are also in demand. We have unveiled an approach applicable to synthetically challenging natural products that contain aryl glycine residues. This is highlighted by our progress toward (-)-feglymycin, a 13-mer peptide that contains nine electron-rich aryl-glycinamides, residues known to be susceptible to epimerization during their creation. Due to its potent anti-HIV properties as well as antibacterial activity, a facile and reproducible synthesis of feglymycin would greatly benefit the study of this powerful peptide. The incorporation of aryl glycine derivatives into peptides can be difficult due to their heightened acidity. Therefore, we developed a route that circumvents these difficulties by utilizing Umpolung Amide Synthesis (UmAS) to address the challenges of enantioselective aryl glycine synthesis and their subsequent incorporation into peptides. The methodology developed herein will provide an alternative route to access the amide backbone of other complex targets containing aryl-glycine residues without epimerization risk, and improved enantiopurity. | |
