Jack W. Fisher

Bicyclic pyrazolidinones, a new class of antibacterial agent based on the β-lactam model

Abstract Several bicyclic pyrazolidinones were synthesized as γ-lactam analogs of the β-lactam antibiotics. Two of these compounds exhibited in vitro antibacterial activity, and thus constitute a new class of antibacterial agents.

An enantioselective synthesis of loracarbef (LY163892/KT3777)

Abstract An enantioselective synthesis of the new, orally absorbable, totally synthetic β-lactam antibiotic, loracarbef (LY163892/KT3777) is described.

Iodide dealkylation of benzyl, PMB, PNB, and t-Butyl N-acyl amino acid esters via lithium ion coordination

Abstract Lithium iodide promotes ester dealkylation in compounds containing an amide carbonyl in the γ-position to the ester carbonyl, as is found in N-acyl amino acid esters. Activation of the ester carbonyl via lithium ion coordination is facilitated by aprotic non-polar solvents such as THF and EtOAc. This process is not limited to methyl esters but readily dealkylates benzyl, PMB, PNB, and t-butyl esters and is especially suitable for use with β-lactam esters because of the mild conditions.

Enantioselective Syntheses of 1-Carbacephalosporins from Chemoenzymically Derived β-Hydroxy-α-Amino Acids: Applications to the Total Synthesis of Carbacephem Antibiotic Loracarbef

Abstract Serine hydroxymethyltransferase (SHMT) derived from recombinant E. coli was found to be able to catalyze the condensation between glycine and 4-pentenaldehyde, affording enantiopure l -erythro-2-amino-3-hydroxy-6-heptenoic acid (AHHA) in high yield and throughput. Conversion of this chiral intermediate of biosynthetic origin to the oral carbacephalosporin antibiotic loracarbef (Lorabid®) via β-lactam forming reactions and subsequent Dieckmann cyclization was achieved.

Cleavage of chiral 4-phenyl-2-oxalidinones with TMSI: Application to the synthesis of carbacephems

Abstract A new technique for cleaving N-substituted 4-phenyl-2-oxazolidinones is described. Thus reaction of a 7-[4-phenyl-2-oxazolidinone]-carbacephem with TMSI and HMDS in acetonitrile, followed by DABCO, then aqueous hydrochloric acid gives the carbacephem nucleus, carbon dioxide, and acetophenone. This method allows a more versatile use of 4-phenyl-2-oxazolidinone as a chiral auxiliary and N-protective group in the synthesis of carbacephems.

Enantioselective synthesis of the carbacephem antibiotic loracarbef via Mitsunobu and Dieckmann cyclization from an unnatural amino acid

The nucleus of the carbacephem antibiotic loracarbef was synthesized in a highly efficient and enantioselective fashion from 2S,3S-2-amino-3-hydroxy-6-heptenoic acid (AHHA), which was derived from enzyme-catalyzed condensation of glycine and 4-pentenaldehyde. The bicyclic framework of this compound was established through sequential Mitsunobu reaction and aldol condensations.