G. Simig

Simple and condensed β-lactams. I: The application of diketene in β-lactam synthesis. The synthesis and functional group manipulations of diethyl 3-acetyl-4-oxoazetidine-2,2-dicarboxylates

Abstract Acylation of the N-substituted diethyl aminomalonates 3a – 3d with diketene furnished the ring tautomers 6a – 6d of the expected acetoacetyl derivatives 5 . By treatment with iodine and sodium ethoxide compounds 6a – 6d are smoothly converted into the β-lactam derivatives 2a – 2d . Deethoxycarbonylation of the ethylene ketals 7a – 7d of the latter furnishes mixtures of the corresponding diastereomeric monoesters 8 and 10 . The ethoxycarbonyl groups of the trans esters 8 are more reactive than those of the cis isomers 10 . This permits, under appropriate conditions, selective alkaline hydrolysis and NaBH 4 reduction of the trans esters 8 in the presence of the cis esters 10 . Reduction of the cis ester 10c under more forceful conditions furnishes the trans hydroxymethyl derivative 11c .

Simple and condensed β-lactams. Part 5. The synthesis of some (5RS,6SR)-2-(2-formylaminoethylthio)-6-(2-methyl-1,3-dioxolan-2-yl)carbapenem-3-carboxylic acid derivatives and related compounds

Starting with the 4-oxoazetidine-2-carboxylic acids (3a) and (3b), methods for the synthesis of derivatives of the racemic carbapenem-3-carboxylic acid (2), an analogue of the potent antibiotic thienamycin have heen developed. The synthetic steps included chain elongations by the methods of Arndt-Eistert and Masamune, diazo group transfers, oxidative removals of N-protecting 2,4- dimethoxybenzyl and p-methoxyphenyl groups, cyclization involving a carbene insertion reaction, and conversion of the ketone moiety of the bicyclic compound (13b) into an enethiol moiety via enolphosphate activation. The target compound, the sodium salt (14c) did not possess any useful biological activity.

Simple and condensed β-lactams. Part 7. Side chain extensions of some azetidin-2-one derivatives, and the formation of melillo's lactone, a strategic intermediate in the total synthesis of thienamycin, from 3-acetyl-1-benzyl-4-cyanomethylazetidin-2-one

The oxoazetidinecarboxylic acids (2a) and (2b) and the homologous acid (8b) were converted by treatment of their chlorides with ethyl diazoacetate into the diazo esters (4a, b), and (10b), respectively. Irradiation of the diazo ester (4b) afforded the diethyl and ethyl hydrogen malonates (17) and (18), respectively. Attempted thermal decarboxylation of the latter resulted in profound degradation to give a mixture of the isomeric compounds (19a, b). NaBH4 reduction at –78 °C of the diazo ester (4d) gave mixtures of the diastereoisomers of the diazo esters (4e) and (20). The (hydroxymethyl)-azetidinone (6b) was converted via the aldehyde (5b) and the nitroethyl derivative (22) into the acetals (23) and (25). Attempts to convert the nitrile (7a) into either the acid (8a) or the ester (9a) in acceptable yields, failed. The nitriles (7g) and (7e)[obtained in two steps from the nitrites (7c) and (7b), respectively] were converted by refluxing hydrochloric acid into Melillos lactone (28)(the key intermediate of a practical synthesis of the carbapenem antibiotic thienamycin) and its N-unsubstituted analogue (30), respectively.

The reaction of tris(4-methoxyphenyl)methyl chloride with sodium methoxide—non-operation of single electron transfer pathways

Tris(4-methoxyphenyl)methyl chloride (2) and sodium methoxide furnish, in methanol as well as in aprotic solvents, the normal substitution product methyl tris(4-methoxyphenyl)methyl ether (3) with partial replacement of the p-methoxy-groups of the substrate by the reagent. No reduction to tris(4-methoxyphenyl)methane takes place unlike the reaction in the absence of sodium methoxide (during which reaction exchange of methoxy-groups between substrate and methanol occurs to a much greater extent) and no single electron transfer products are formed unlike the reaction of triphenylmethyl halides (1a, b) and sodium methoxide. These differences are rationalized by invoking the irreversibility of formation of compound (3) by attack of methoxide at the central carbon atom of cation (12) as contrasted to the reversibility of formation of the conjugate acid of (3), (14), resulting from attack of methanol at the same site, and also the different stabilities and tendencies of formation of the tris(4-methoxyphenyl)carbenium (12) and triphenylcarbenium ions, respectively.

Simple and condensed β-lactams. Part 9. Elaboration of the 3-(1-hydroxyethyl) side chains of potential intermediates of carbapenem antibiotics via the 2-methyl-1,3-dioxolan-2-yl group

Deketalization of the trans compounds methyl and ethyl (2RS,3RS)-1-(2,4-dimethoxybenzyl)-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxoazetidine-2-carboxylates (5b) and (5c), and of the cis[or (2RS,3SR)] isomer (6b) of the latter leads to 85 : 15 mixtures of the trans- and cis-compounds methyl (2RS,3RS)- and (2RS,3SR)-3-acetyl-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate (7a) and (8a), respectively of the corresponding ethyl esters (7b) and (8b). Sodium borohydride reduction of the mixture of the trans- and cis-esters (7b) and (8b) gives a mixture of the 1′-epimeric trans-compounds ethyl (2RS,3RS)-1-(2,4-dimethoxybenzyl)-3-[(1RS)- and (1SR)-1-hydroxyethyl]-4-oxazetidine-2-carboxylate (9b) and (10b). Similar mixtures of 1′-epimeric compounds of the types (9) and (10), carrying a variety of substituents attached to position 2 of their azetidine rings were obtained by successive deketalization and reduction of the corresponding trans-(5) and cis-(6) compounds or their mixtures, as well as by other methods. Ring closure of a mixture of the pair of the 1′-epimeric trans-compounds p-nitrobenzyl 2-diazo-4-{(2RS,3SR)-3-[(1RS)- and (1SR)-1-hydroxyethyl]-4-oxo-azetidin-2-yl}-3-oxobutanoates (9n) and (10n) gave a mixture of the 1′-epimeric compounds p-nitrobenzyl 6-[(1RS)- and (1SR)-1-hydroxyethyl]-2,7-dioxo-(3RS,5RS,6SR)-carbapenam-3-carboxylates (11) and (12) which was converted into a mixture (13) of the 1′-epimeric bis-protected thienamycin analogues p-nitrobenzyl 2-(2-formylaminoethylthio)-6-[(1RS)- and (1SR)-1-hydroxyethyl]-7-oxo-(5RS,6SR)-carbapen-2-em-3-carboxylates.

Reactions of some p-substituted triphenylmethyl chlorides with alcohols, alkali-metal alcoholates, and tributylamine

The p-methoxylated triphenylmethyl chlorides (4a–c), when heated with alcohols, give mixtures of the corresponding triarylmethanes (5a–c)(via the hydride transfer to the corresponding triarylmethylium cations) and the alkyl (substituted triphenylmethyl) ethers (7a–c)(via polar substitution reactions). Part or all of the ether (7c) may be further converted into the substituted triphenylmethanol (6c). In the reaction of the mono-p-methoxylated halides (4a) and (4c) with methanol, the substitution products (7a) and (7c)[and/or (6c)] are formed as the main products, while the main product of the reaction of the di-p-methoxylated halide (4b) with methanol is the substituted triphenylmethane (5b). When the methanol is replaced by [2H4] methanol, no reduction product is formed from the halide (4c). Reaction of halide (4c) with ethanol furnishes exclusively the substituted triphenylmethane (5c). The p-chlorophenyl(diphenyl)methyl chloride (4d) gives, with methanol, mainly or exclusively the ether (7d), and with ethanol, under mild conditions, gives the ether (9d). However, under vigorous conditions, the substituted triphenylmethane (5d) is formed. The reduction of the p-methoxylated triphenylmethyl chloride (4c) by alcohols as well as its conversion into alkyl (p-methoxylated triphenylmethyl) ethers are accompanied, to a certain degree, by exchange of the p-methoxy group of the substrate and the alkoxy group of the alcohol; no similar exchange of the p-chlorine atom of halide (4d) was observed. Explanations for all observed differences are offered.The reactions of the substituted triphenylmethyl chlorides (4b–d) with alkoxides in the corresponding alcohols give the corresponding alkyl (substituted triphenylmethyl) ethers (7b), (7c), (9c), and (9d), respectively, in excellent yields.The reaction of the triarylmethyl chloride (4d) with potassium t-butoxide in THF in the presence of acetone led, among other products, to the formation of oligomeric material which indicates the operation of single-electron-transfer induced processes. Reaction of the same chloride (4d) with tributylamine in refluxing cumene or t-butylbenzene led to the exclusive formation of a series of products [(5d) and (14)–(17)] all of which may be derived from the intermediacy of the substituted triphenylmethyl radical (18); the latter, in turn, is thought to arise as a result of dissociative electron transfer from tributylamine to chloride (4d).

Simple and Condensed β-Lactams. Part 6. A Synthesis of the p-Nitrobenzyl Esters of the Racemic Forms of the Carbapenem Antibiotics PS-5 and PS-6 and Their 6-Epimers.

Die aus den Komponenten (Ic) und (II) erhaltlichen Azetidinone (IIIa) bzw. (IIIb) (jeweils cis/trans-Gemisch) werden zu den Monoestern (IV) (cis/trans- Gemische jeweils getrennt) umgesetzt, aus denen uber die angegebenen Stufen die Verbindungen (VIII) zuganglich sind.