Preparation and isomerization of 5-epibenzylpenicillins

5-Epibenzylpenicillin methyl and benzyl ester were obtained by replacement of the phthalimido side chain of the corresponding 6-phthalimido-5-epipenicillanates, which were prepared from the natural isomer by the method of Kukolja. Base-catalyzed isomerization of silylated 5-epibenzylpenicillin methyl ester in the presence of triethylamine and DBN was investigated. With triethylamine, no epimerization was observed, whereas a mixture of 5 epimer and of the enantiomers of the 6 epimer and natural isomer was obtained when DBN was used as catalyst. These observations, which indicate an epimerization at position 3, are compared with the results of isomerizations of penicillanates with a different configuration and with other side chains. The general mechanism of epimerization of penicillanates is discussed. The antibiotic activity of the sodium salt of 5-epibenzylpenicillin, prepared by hydrogenolysis of the benzyl ester, is less than 0.1% of that observed for natural benzylpenicillin. © 1976, American Chemical Society. All rights reserved.status: publishe

Synthesis and circular-dichroism of 5(s)-1-azabicyclo[3.2.0]heptan-7-one

(5S)-1-Azabicyclo[3.2.0]heptan-7-one or epi-1-carbapenam was prepared by cyclization of (2S)-2-pyrrolidylacetic acid. The optical purity of this homoproline, which was obtained for the first time in an active form, was established by carrying out its synthesis by two independent reaction sequences. The circular dichroism curve of epi-1-carbapenam showed a negative Cotton effect at 231 nm with a shoulder at about 212 nm. This result was compared to our findings for the CD of penicillanates. © 1978, American Chemical Society. All rights reserved.status: publishe

Preparation and determination of configuration of 3-halogeno-3-methyl-5 alpha-cholestane epimers

3α- Chloro- 3β- methyl - and 3β- chloro- 3α- methyl - 5α- cholestane were prepared by reaction of hydrochloric acid with the two epimeric 3- hydroxy-3-methyl-5α-cholestanes. A better yield and cleaner conversion could be obtained with tetramethyl-1 -chlorovinylamine as chlorinating agent. Reaction of the two 3-methyl-5α-cholestanols with triphenylphosphine-carbon tetrachloride or phosphorus trichloride oxide-pyridine gave mixtures of 3- methyl - 5α- cholest-2-ene, 3- methyl - 5α- cholest-3-ene, and 3-methylene- 5α- cholestane. The two epimeric 3-fluoro-3- methyl - 5α- cholestanes were obtained by treatment of the two 3- methyl - 5α- cholestan-3-ols with (diethylamino)sulphur trif luoride. The configuration of the 3- halogeno-3-methyl-5α-cholestanes was determined from their 13C n.m.r. spectra. The availability of both 3-halogeno-3-methyl-5α- cholestane epimers allowed an unambiguous interpretation of the i.r. spectra in the 800-400 cm-1 region. © Royal Society of Chemistry.status: publishe

Synthesis of delta 3-1-methylene-1-carbacephems

The total synthesis of (+/-)-1-methylene-2,2- dimethyl-7-amino-1-carbacephem-4-carboxylic acid (1) is described. The reaction scheme was essentially that described by Christensen et al. for the synthesis of (+/-)-1-carbacephems. In vitro antibacterial activities of the 7-phenoxyacetyl and 7-D-alpha-phenylglycyl derivatives of 1 were compared with those of 7-(phenoxyacetamido)desacetoxycephalosporanic acid and cefalexin. Derivatives of 1 were 2-4 times less active against most of the sensitive organisms than the corresponding 7-aminodesacetoxycephalosporanic acid analogues. The activity of the 7-D-alpha-phenylglycyl derivative of 1 however was about 20 times lower than that of cefalexin when measured against Staphylococcus aureus ATCC 6538P.status: publishe

Attempted synthesis of methyl (+/-)-6(s), 5(r)-6-acylamino-1-carbapen-2-em-3-carboxylate

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Determination of configuration of 4 d-benzylpenicilloates

The configuration of the four dimethyl D-benzylpenicilloates was determined, and their stereochemical relationship to the dimethyl phthalimidopenicilloates, prepared according to Sheehan et al., was established, using a series of transformations and physicochemical techniques. The compounds designated as β and γ isomers in the Sheehan nomenclature were found to correspond to the γ and δ isomers of “Chemistry of Penicillin”, and to have the 5R,6S and the 5S,6S configuration, respectively. In the course of this study, 5-epi-6-epibenzylpenicillin methyl ester (γ-10) having the 5S,6S configuration was prepared for the first time. The isomer with the 5S,6R configuration, which was consequently denoted as δ isomer, was prepared from 5-epibenzylpenicillin methyl ester, and was identical with the β isomer of “Chemistry of Penicillin”. It was also established that sodium benzylpenicilloate a isomer, having the 5R,6R configuration of the natural penicillins, isomerized in aqueous solution to a mixture, containing mainly the isomer (5S,6R). © 1976, American Chemical Society. All rights reserved.status: publishe

Determination of the composition of gentamicin sulfates by 1H and 13C nuclear magnetic spectroscopy

The British Pharmacopoeia test controlling the composition of gentamicin sulfate is based on CW 60 MHz magnetic resonance spectroscopy. Application of this method to FT 90 MHz spectra was evaluated. Results clearly show the limitations of this technique and point out the need for more reliable assay methods. Thus a 13C nuclear magnetic resonance (NMR) procedure for quantitative analysis of gentamicin sulfate was developed. Ratios of 4 gentamicin components (C1, C2, C1a, and C2a) were obtained from peak height measurements of selected resonance signals in spectra recorded under steady-state conditions. Relative response factors were determined from spectra of a reference mixture or, alternatively, from spectra of the individual pure components. Results obtained by the 13C NMR method were in agreement with those obtained by liquid chromatography using pre-column derivatization.status: publishe

Penicilloates derived from penicillanic acid

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Circular-dichroism of monocyclic beta-lactams

The circular dichroism of a series of polysubstituted monocyclic β-lactams of known absolute configuration was measured. The compounds were prepared from the appropriate penicillanates by cleavage of the thiazolidine ring. All β-lactams showed a n → π* Cotton effect centered at about 225 nm. The sign of this Cotton effect is discussed in terms of the Ogura lactam rule. © 1978, American Chemical Society. All rights reserved.status: publishe

Preparation and stereochemical analysis of 5-epibenzylpenicillin (S)- and (R)-sulfoxide esters

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