James L. Douglas

Nuclear analogs of β-lactam antibiotics. II. Synthesis of O-2-isocephems

The preparation by total synthesis of a new class of β-lactam antibiotics is reported. Conversion of alcohol 1b to its mesylate 9b followed by hydrolysis of the acetal to the enol 1b and base-catalyzed ring closure gave benzyl 7- β-azido-Δ3-O-2-isocephem-4-carboxylate 8b. Similarly prepared were the 3 -methyl, 3 -benzyl, and 3 -phenethyl analogs (32b–d). Reduction of the azides followed by coupling of the resultant amines with phenoxyacetic acid and removal of the benzyl groups by hydrogenolysis gave the acids 35a–e which exhibited high antibacterial activity. The structural assignments to the O-2-isocephems which were made on the basis of their spectral characteristics (ir, uv, and nmr) are discussed.

Nuclear analogs of β-lactam antibiotics. VII. Synthesis of 2-isocephems

The synthesis of 7-β-phenoxyacetamido-3-methyl-Δ3-2-isocephem-4-carboxylic acid 14b and its corresponding α-sulfoxide 15 and sulfone 17 is described. Treatment of the bismesylates 4a, 4b, and 10 with hydrogen sulfide triethylamine gave the corresponding 7-β-amino-Δ3-2-isocephems 12a–c which were coupled with phenoxyacetic acid to yield the amides 13a–c. Hydrogenolysis of 13b and c gave the acids 14a–b which were active as antibiotics. Compound 14b was oxidized to its sulfoxide 15 with sodium metaperiodate and to its sulfone 17 with m-chloroperbenzoic acid. Conversion of 13c to its sulfoxide 16b followed by halogenation gave the 1α-chloro sulfoxide 18 which was converted to the acid 19. The stereochemical assignments in the 2-isocephem series are discussed.

A mild and efficient method for aromatic chlorination of electron-rich arylalkyl amines

Abstract Sulfuryl chloride was used to chlorinate electron-rich arylalkyl amines in a mild and efficient one-pot transformation with simple product isolation via precipitation. Protection of the amine was not needed.

Nuclear analogs of β -lactam antibiotics. IX. Synthesis of 7-methoxy 2-isocephems and O-2 isocephems

The syntheses of 7-methoxy-7-phenoxyacetamido-3-methyl-Δ3-isocephem-4-carboxylic acid 11a, 7-methoxy-7-phenoxyacetamido-3-rnethyl- Δ3-O-2-isocephem-4-carboxylic acid 11b and 7-methoxy-7-(2-thienyl)acetamido-3-acetoxymethyl- Δ3-O-2-isocephem-4-carboxylic acid 11c are described. A sequence analogous to that used to prepare 7-methoxy cephalosporins was used: Schiff base anions were thiomethylated and the Schiff bases hydrolyzed to free amines. The amines were acylated and thiomethyl to methoxyl conversion effected with mercuric ion catalysis. Removal of protective esters gave the acids 11a, 11b, and 11c. Compound 11c showed a modest level but broad spectrum of antibacterial activity.