P-Lactam cycle

In reality the situation is more subtle because very often the synthesis of me-too drugs is justified by a desire to improve the existing drug. Thus for penicilhns, the chemical structure that surrounds the P-lactamic cycle is still being modified. Current antibiotics that have been derived from this research (the cephalosporins for example) are more... 

Recall that the P-lactam cycle is not very stable and that it is opened in alkaline medium. The titration is achieved in alkaline medium with respect to a blank. From the practical standpoint, penicillin and 1M sodium hydroxide are brought together for 15 min. Then penicilloic acid is formed. 

After neutfalization with a normal solution of sulfuric acid in the presence of phe-nolphthalein, a decinormal iodine solution is added and the reaction is allowed to evolve over 15 min. The excess iodine is titrated with a 10 mol/L thiosulfate solution. According to some authors, opening the P-lactam cycle does not stop at the stage of penicilloic acid. It leads to penaldic acid and to penicillamine in equimolar quantities. 

The p-lactam cycle of penicillins (and of cephalosporins) is very labile. The formation of (temporary) complexes with metallic ions, in particular with transition metals, favors the destruction of these molecules by breaking the P-lactam cycle. The formation of temporary complexes favors the nucleophilic attack on the lactam cycle. Therefore, in a first step, penicilloic acid should form probably as a reactional intermediate, and, after, it should evolve into penicillamine. 

Formally related to seciuamines but containing a P-lactam cycle by transposition of the physostigmine system, charteUamides and chartellines were aU isolated from the species Chartella papyracea harvested in Rosc-off, France (Chevolot et al., 1985 Anthoni et al., 1987a, 1987b). AU of these derivatives have some antibacterial activity, and are probably used by the animal colony as defense substances. 

Tabtoxin J is a dipeptide exotoxin produced by Pseudomonas tabaci, the organism responsible for the wildfire disease of tobacco plants [141]. When hydrolyzed by peptidase, in vivo, this exotoxin releases tabtoxinine-p-lactam K, which inhibits Glutamine synthetase of the photorespiratory nitrogen cycle, causing chlorosis and death of tobacco plants [142]. 

We and others have demonstrated facile synthesis of a number of new anticancer active p-lactams. The p-lactam derivatives described herein are unique, and they demonstrate reasonable in vitro antitumor cytotoxicity. The stereochemical outcome of the Staudinger reaction as reported herein may offer our laboratory and others many additional opportunities to use p-lactams in the synthesis of biologically active compounds. Although the mechanism of action of the lead compounds has not been totally established, our research on cell cycle analysis offers intriguing... 

Moreover, intracellular accumulation and cytochrome P450 catalyzed bioactivation of p-lactams such as cephaloridine overwhelms of the GSH redox cycle by inhibiting glutathione reductase activity [35, 56], depletion of GSH and accumulation of GSSG [35, 42, 49,56]. Most of GSSG formed is subsequently reduced by glutathione reductase and GSH is regenerated with concomitant oxidation (consumption) of NADPH to NADP+ [104]. 

As a consequence, a poly(P-alanine) can only be formed by a ring-opening polymerization, in which the chain elongation proceeds directly by reaction of P-lactam with an acyl-enzyme intermediate. Because of the low nucleophilicity of the lactam nitrogen, this process requires activation of P-lactam by a water molecule. On this basis we have proposed the catalytic cycle for a CALB-catalyzed polymerization of P-lactam depicted in Figure 14.9. The mechanism described is in accordance with experimental data and is assisted by in-depth computational calculation of the reactions involved. It contains two starting steps (I and II), five steps for the chain elongation (III—VII), and is completed by the release of the polymer (VIII). 

Another more efficient catalytic version of the reaction consists of the interaction of ketones with chiral amines [6] to form enolate-like intermediates that are able to react with electrophilic imines. It has been postulated that this reaction takes place via the catalytic cycle depicted in Scheme 33. The chiral amine (130) attacks the sp-hybridized carbon atom of ketene (2) to yield intermediate (131). The Matmich-like reaction between (131) and the imine (2) yields the intermediate (132), whose intramolecular addition elimination reaction yields the p-lactam (1) and regenerates the catalyst (130). In spite of the practical interest in this reaction, little work on its mechanism has been reported [104, 105]. Thus, Lectka et al. have performed several MM and B3LYP/6-31G calculations on structures such as (131a-c) in order to ascertain the nature of the intermediates and the origins of the stereocontrol (Scheme 33). According to their results, conformations like those depicted in Scheme 33 for intermediates (131) account for the chiral induction observed in the final cycloadducts. 

Table 3.4 clearly shows that the condensation of five-membered rings, both pyrrolidine and pyrrolidinone, with enediyne system lowers the temperature of the Bergman cycloaromatization. These results are opposite to the data for enediyne systems condensed with small cycles (e.g., oxide ring or p-lactam). Thus, this assists the development of synthetic routes to the aromatic compounds with condensed pyrrolidinones and... 

The Bode group disclosed NHC-catalyzed highly enantioselective annulations of a,P,P -trisubstituted enals with cyclic sulfonylimines. Mechanistically, it is proposed that the combination of enal and free NHC leads to the formation of the Breslow intermediate, which is oxidized to form the key a,p-unsaturated acyl azolium. Tautomerization between the imine and the enamine occurs readily in the presence of base, and the enamine is intercepted by the key a,p-unsaturated acyl azolium to form a hemiaminal which further engages in a Stork-Hickmott-Stille-type annulation via a tight-ion-pair/aza-Claisen type transition state. Lactam formation follows the protonation of enolate and brings about catalyst turnover to complete the catalytic cycle (Scheme 7.113). 

Hayashi and Miyaura pioneered the enantioselective rhodium-catalyzed conjugate addition of arylboronic acids to a variety of Michael acceptors a,P-unsaturated ketones, esters, lactones, amides, and lactams [215]. Generally, water is used as a cosolvent and plays a key role in the catalytic cycle, illustrated in Scheme 5.111 (cycle A) for the conjugate addition of phenylboronic acid to cyclohexenone that, when catalyzed by the Rh(I)-(S)-BINAP complex, leads to 3-phenylcyclohexanone in 97% ee and 93% chemical yield [205a]. The key intermediates of the catalytic cycle, the hydroxorhodium complex 433, the phenylrhodium complex 434, and -bound rhodium enolate 435 were characterized by NMR spectroscopy. The reaction of the hydrorhodium complex 433 with phenylboronic acid leads to a transmetallation to give the phenylrhodium complex 434. Then, the insertion of the carbon-carbon double bond of cyclohexenone into the phenylrhodium bond leads to the formation of the... 

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