Terry T. Conway

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. 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.

Nuclear analogs of β-lactam antibiotics. XI. Synthesis of 3-methyl-7-β-(phenoxyacetamido)-Δ3-desthiocephem-4-carboxylic acid

Treatment of the acid 3 with triethylamine in refluxing tert-butyl alcohol gave the decarboxylated product 4 which was isomerized to the desired Δ3 isomer 5 using DBN. Reduction of the azido functions in 4 and 5 followed by coupling to phenoxyacetic acid and debenzylation gave the acids 11 and 8, respectively. Attempts to prepare dienic cephalosporins failed. The halogenation of 4 and 5 was studied and is discussed.

Nuclear analogs of β-lactam antibiotics. X. Synthesis of 2-substituted desthiocephalosporins

The syntheses of the desthiocephem system from the enol 2 is described. Thus conversion of 2 to its triflate 3 followed by treatment with the sodium salts of malonate esters gave the cyclized products 4a–c. Azide reduction followed by coupling of phenoxyacetic acid and hydrogenolysis gave the acids 7 and 8. Compound 15 was also prepared.

The Synthesis of 4a-Aminoalkyl-1,2,3,4,4a,9-Hexahydrophenanthrenes. Versatile Intermediates for Potential CNS Drugs. I

The synthesis of 1-aminoalkyl-1-hydroxy-2,2-tetramethylene-1,2,3,4-tetrahydronaphthalenes and their Wagner–Meerwein rearrangements into 4a-aminoalkyl-1,2,3,4,4a,9-hexahydrophen-anthrenes are described.

NUCLEAR ANALOGS OF β‐LACTAM ANTIBIOTICS. XI. SYNTHESIS OF 3‐METHYL‐7‐β‐(PHENOXYACETAMIDO)‐Δ3‐DETHIOCEPHEM‐4‐CARBOXYLIC ACID

Treatment of the acid 3 with triethylamine in refluxing tert-butyl alcohol gave the decarboxylated product 4 which was isomerized to the desired Δ3 isomer 5 using DBN. Reduction of the azido functions in 4 and 5 followed by coupling to phenoxyacetic acid and debenzylation gave the acids 11 and 8, respectively. Attempts to prepare dienic cephalosporins failed. The halogenation of 4 and 5 was studied and is discussed.