Lactams, conjugated

Wittmann, S. Schnabelrauch, M. Scherlitz-Hofmann, L Mollmann. U. Ankel-Fuchs. D. Heinisch. L. New synthetic siderophores and their P-lactam conjugates based on diamino acids and dipeptides. Bioorg. Med. Chem. 2002, 10. 1659-1670. 

Ghosh A, Miller MJ (1993) Synthesis of novel citrate-based siderophores and siderophore- J-lactam conjugates. Iron transport-mediated drug delivery. J Oig Chem 58 7652-7659... 

During the last two decades a lot of attention has beoi paid to develqmait of double mechanism antibiotics. One of plausible tQtproaches to such compounds is esterification of fluoroquinolone carboxylic adds with derivatives of cqthalospain andpatidllin. Such combination allows one to expand a spectrum of antibacterial activity of beta-lactams conjugated with quinolones due to complementary mechanisms of their actions [7,72]. 

Elecainide is weU absorbed and 90% of the po dose is bioavailable. Binding to plasma protein is only 40% and peak plasma concentrations are attained in about 1—6 h. Three to five days may be requited to attain steady-state plasma concentrations when multiple doses are used. Therapeutic plasma concentrations are 0.2—1.0 lg/mL. Elecainide has an elimination half-life of 12—27 h, allowing twice a day dosing. The plasma half-life is increased in patients with renal failure or low cardiac outputs. About 70% of the flecainide in plasma is metabolized by the Hver to two principal metaboUtes. The antiarrhythmic potency of the meta-O-dealkylated metaboUte and the meta-O-dealkylated lactam, relative to that of flecainide is 50 and 10%, respectively. The plasma concentrations of the two metaboUtes relative to that of flecainide are 3—25%. Elecainide is mainly excreted by the kidneys, 30% unchanged, the rest as metaboUtes or conjugates about 5% is excreted in the feces (1,2). 

A wide variety of /3-lactams are available by these routes because of the range of substituents possible in either the ketene or its equivalent substituted acetic acid derivative. Considerable diversity in imine structure is also possible. In addition to simple Schiff bases, imino esters and thioethers, amidines, cyclic imines and conjugated imines such as cinnamy-lidineaniline have found wide application in the synthesis of functionalized /3-lactams. A-Acylhydrazones can be used, but phenylhydrazones and O-alkyloximes do not give /3-lactams. These /3-lactam forming reactions give both cis and /raMS-azetidin-2-ones some control over stereochemistry can, however, be exercised by choice of reactants and conditions. 

Formal oxidation of pyrrolidine to the succinimide stage affords a series of compounds used as anticonvulsant agents for treatment of seizures in petit mal epilepsy. Knoevnagel condensation of benzaldehyde with ethyl cyanoacetate affords the unsaturated ester, 9. Conjugate addition of cyanide ion leads to the di-nitrile ester (10). Hydrolysis in mineral acid affords the succinic acid (11), presumably by decarboxylation of the intermediate tricarboxyllie acid. Lactamization with methylamine gives phensuximide (12). ... 

Indeno[l,2-rf]azepin-4-ol and its 10-bromo derivative appear to be in the lactam form 20. In base solution, however, there is UV and HNMR spectroscopic evidence for the 14k fully conjugated anions, e.g. 21.57... 

Many peptide antibiotics have novel structural motifs, such as cyclic structures and are often further modified, (such as in jS-lactamic antibiotics) and conjugated with sugars, lipids, and other molecules. 

Amides are very weak nucleophiles, far too weak to attack alkyl halides, so they must first be converted to their conjugate bases. By this method, unsubstituted amides can be converted to N-substituted, or N-substituted to N,N-disubstituted, amides. Esters of sulfuric or sulfonic acids can also be substrates. Tertiary substrates give elimination. O-Alkylation is at times a side reaction. Both amides and sulfonamides have been alkylated under phase-transfer conditions. Lactams can be alkylated using similar procedures. Ethyl pyroglutamate (5-carboethoxy 2-pyrrolidinone) and related lactams were converted to N-alkyl derivatives via treatment with NaH (short contact time) followed by addition of the halide. 2-Pyrrolidinone derivatives can be alkylated using a similar procedure. Lactams can be reductively alkylated using aldehydes under catalytic hydrogenation... 

The reactive compound chlorosulfonyl isocyanate (ClSOaNCO, forms P-lactams even with unactivated alkenes, as well as with imines, allenes, conjugated dienes, and cyclopropenes. With microwave irradiation, alkyl isocyanates also... 

Ketenes also add to imines in 2 + 2 cycloadditions giving the important g-lactams (20). The reglochemistry is predictable as the nitrogen is the nucleophilic atom in the imine. This is true even in conjugated imine (21) which gives (22) with azidoketene. The azido group can... 

The palladium-catalysed decarboxylative carbonylation of 5-vinyloxazolidin-2-ones 218 caused, unexpectedly, a ring enlargement process to 5-lactams 219 <00JA2944>. The conjugate addition of 4-phenyloxazolidin-2-one to a nitroalkene was used for the synthesis of diastereoisomers of dethiobiotin <00EJO3575>. Attempted deprotection of the O-TBDMS... 

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