Synthesis of the Azabicyclo[3.1.0]hexane Ring Core of Ficellomycin

Michael Alan McMechen


Ficellomycin, produced by Streptomyces ficellus, is a naturally occurring secondary metabolite that exhibits antibacterial activity against multidrug resistant Gram-positive bacteria in vitro, but shows poor efficacy in vivo due to the instability of its azabicyclo[3.1.0]hexane ring core. The effectiveness of ficellomycin against Gram-positive bacteria regardless of resistant strain indicates the possibility of a unique mechanism of action due to the azabicyclo[3.1.0]hexane ring core, compared to currently available antibiotics. To improve ficellomycin’s stability and antibacterial activity, a simplified derivative of the azabicylco[3.1.0] ring core was synthesized in a scheme modeled after Shipman et al. by a convergent synthetic pathway characterized by a Lewis Acid promoted double cyclization. Beginning with glyoxylic acid monohydrate undergoing a dehydration and subsequent esterification reaction with benzyl carbamate, methyl 2-(((benzyloxy)carbonyl)amino)-2-methoxyacetate was produced in an 80% overall yield. The methoxyacetate was chlorinated and phosphorylated in a one-pot reaction to produce methyl 2-(((benzyloxy)carbonyl)amino)-2-(dimethoxyphosphoryl)acetate in an average overall yield of 56%. The phosphorylacetate was reacted with pent-4-enal in a basic environment to produce methyl (E)-2-(((benzyloxy)carbonyl)amino)hepta-2,6-dienoate in an average yield of 46%. Epoxidation of the dienoate averaged a 53% yield and subsequent azide addition completed at a 30% yield to afford methyl (E)-7-azido-2-(((benzyloxy)carbonyl)amino)-6-hydroxyhept-2-enoate. The final azide alcohol was reacted with triphenylphosphine in toluene to produce the aziridine and further promote the aziridine to cyclize the alkene chain creating the azabicycle in a single reaction. NMR analysis shows characteristic peaks of the azabicycle product in an impure solution of stereoisomers and reactant contaminants. Purification techniques are being developed. Cyclization trials and synthesis of ficellomycin amino acid derivatives are on going.

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