Dicarboxylic Acid Monoesters in β- and δ-Lactam Synthesis

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Synthetic Chemistry

Background:

• The Castagnoli-Cushman reaction is a known method for synthesizing δ-lactams.
• Exploring novel synthetic pathways for medicinally relevant heterocyclic compounds is crucial.

Purpose of the Study:

• To investigate the reaction of a specific N-sulfonylglycine ester with imines under acetic anhydride catalysis.
• To understand how substrate modifications influence the outcome of the Castagnoli-Cushman reaction and related cyclizations.

Main Methods:

• Reaction of N-(2-methoxy-2-oxoethyl)-N-(phenylsulfonyl)glycine monomethyl ester with imines.
• Utilizing acetic anhydride as a promoter at elevated temperatures.
• Synthesizing a modified substrate with a hexafluoroisopropyl alcohol residue.

Main Results:

• Unexpected formation of 3-amino-2-azetidinones via cyclization involving a methylene group adjacent to an acid moiety.
• Successful synthesis of the desired δ-lactams when the alcohol residue was replaced with hexafluoroisopropyl.
• Demonstration of altered reactivity based on the ester moiety's alcohol residue.

Conclusions:

• Substrate modification significantly impacts the cyclization pathway in reactions involving N-sulfonylglycine esters and imines.
• The study provides a novel route to 3-amino-2-azetidinones and highlights a strategy for directing Castagnoli-Cushman reactions.
• This research contributes to the synthetic toolkit for accessing medicinally important heterocyclic scaffolds.