Challenges and opportunities in the discovery, development, and commercialization of pathogen-targeted antibiotics.

The use of antibiotics directly correlates with the increase in antimicrobial resistance (AMR). Targeting novel antibiotics to patients with multidrug-resistant (MDR) pathogens should enhance their durability and slow development of resistance. The discovery, development, and clinical adoption of pathogen-targeted antibiotics have been hampered by technical and regulatory challenges.

A novel highly stereoselective synthesis of 2,3-disubstituted 3H-quinazoline-4-one derivatives.

[structure: see text]. An efficient three-step synthesis of chiral 3H-quinazoline-4-one derivatives from commercial materials is disclosed. The Mumm reaction of imidoyl chloride with alpha-amino acids followed by reductive cyclization affords enantiomerically pure (ee >93%) quinazoline-4-ones in good overall yield.

Zinc carbenoid-mediated chain extension: preparation of alpha,beta-unsaturated-gamma-keto esters and amides.

An efficient one-pot preparation of alpha,beta-unsaturated-gamma-keto esters and amides has been developed. A zinc carbenoid-mediated chain extension of a beta-dicarbonyl substrate provides access to an intermediate zinc enolate, which is treated sequentially with a halogen and amine base. This method has been applied to a variety of ester and amide starting materials, as well as to amino acid-derived substrates and to a formal synthesis of (R,R)-(-)-pyrenophorin.

Ring expansions of beta-keto lactones with zinc carbenoids: syntheses of (+)-patulolide A and (+/-)-patulolide B.

A one-pot ring expansion/oxidation/elimination method has been developed in which beta-keto lactones are converted efficiently to alpha,beta-unsaturated-gamma-keto lactones. The reaction can be successfully applied to a variety of ring sizes. Alkene stereochemistry is dependent upon ring size and reaction conditions.