Marcel Menard

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.

Structure-activity relationships of carbapenems that determine their dependence on porin protein D2 for activity against Pseudomonas aeruginosa.

A number of carbapenem derivatives were examined to determine the structure-activity relationships required for dependence on porin protein D2 for activity against Pseudomonas aeruginosa. As suggested by J. Trias and H. Nikaido (Antimicrob. Agents Chemother. 34:52-57, 1990), carbapenem derivatives, such as imipenem and meropenem, containing a sole basic group at position 2 of the molecule utilize the D2 channel for permeation through the outer membrane of pseudomonads; they are more active against D2-sufficient strains of P. aeruginosa. Our results indicated that carbapenems with a basic group at position 1 or 6 of the molecule did not depend on the D2 channel for activity; i.e. they were equally active against D2-sufficient and D2-deficient pseudomonal strains. However, addition of a basic group at position 1 or 6 of a carbapenem derivative already containing a basic group at position 2 resulted in its lack of dependency on the D2 pathway. Comparison between meropenem and its 1-guanidinoethyl derivative, BMY 45047, indicated that they differed in their dependence on D2; while meropenem required the D2 channel for uptake, BMY 45047 activity was independent of D2. Meropenem and BMY 45047 had similar affinities for the penicillin-binding proteins of P. aeruginosa. However, BMY 45047 and meropenem differed in the morphological changes that they induced in pseudomonal cells. While meropenem induced filamentation, BMY 45047 induced filaments only in BMS-181139-resistant mutants and not in imipenem-resistant mutants or in carbapenem-susceptible P. aeruginosa strains. These results suggested that in Mueller-Hinton medium the uptake of BMY 45047 through the non-D2 pathway is more rapid than that of meropenem through the D2 porin. In summary, the presence of a basic group at position 2 of a carbapenem is important for its preferential uptake by the D2 channel. However the addition of a basic group at position 1 or 6 of a carbapenem already containing a basic group at position 2 dissociates its necessity for porin protein D2 for activity.

Novel mimics of sialyl Lewis X: design, synthesis and biological activity of a series of 2- and 3-malonate substituted galactoconjugates.

A series of potent inhibitors of P-selectin as potential anti-inflammatory agents is reported. These compounds are derivatives of galactocerebrosides bearing a malonate side chain in positions 2 and 3 of the galactose moiety. Based on the binding mode of sialyl Lewis X, the two acidic groups of the malonate are designed to form ionic interactions with two important lysines in the active site of P-selectin, Lys113 and Lys111. On the other hand, the 4- and 6-hydroxy groups on the galactose ring are arranged to chelate the calcium ion in the P-selectin active site. The synthesis and the biological activity of this series of compounds are described. Lead compounds having a greater potency than sialyl Lewis X are identified.

Studies Toward the Stereocontrolled Synthesis of a Key Azetidinone-Acid Intermediate in the Preparation of a New Carbapenem

Abstract An efficient and stereocontrolled preparation of the key a/etidinone-acid 5a is described.

Synthesis of a 4β-carboxyethyl derivative of thienamycin

Abstract A stereoselective synthesis of the 4β-carboxyethyl derivative of thienamycin ( 1 ) is described. The stereochemistry of the substituent at C-4 of the carbapenem was obtained by equilibration of the ester group in the 1-azabicyclo[4.2.0]octane intermediates, 8 and 9 , with base. This favored the 5α-ester ( 8 ) which was then transformed into the imide ( 14 ). Regioselective opening of the imide with lithium allyloxide gave the azetidinone ( 15 ) which was converted into the title compound.

The synthesis of an asparenomycin analog

Abstract The synthesis of an analog of the carbapenem antibiotics, the asparenomycins, is described. This analog lacks the methyl group in the 6-alkylidene side chain while a methyl group has been placed at the 1β-position. The key step involved the Lewis acid-catalyzed rearrangement of an epoxide to an allylic alcohol.