Lactam Chemistry

Lactams, and /S-lactams in particular, are interesting owing to their occurrence in biologically active compounds such as antibiotics related to penicillines. Insertion reactions of carbenes offer useful access to poly heterocyclic systems contain a -lactam nucleus, particularly when using rhodium and copper catalysis. Moreover, palladium catalyzed carbonyla-tion of azirines affords )S-lactam derivatives [93] in one step. 

Numerous examples of lactone synthesis have been reported [57, 94], particularly as applications of transition metal-catalyzed carbonylation [95, 96] reactions and as appUcations of CO2 [97]. 

Cyclic anhydrides are formed by carbonylation of lactone precursors (Example [98]). 

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The overall impression this year is of the amount of work being devoted to the development of stereoselective syntheses particularly, of course, in the area of i-lactam chemistry but also in other areas. 

Several reviews of P-lactam chemistry have appeared including a general survey with 407 references <99MI335>. Other reviews include discussions of thioester enolate-imine reactions , enantio- and diastereo-selective routes to azetidinones <99MI221>, the use of diazoketones in diastereoselective synthesis <99MI43>, and solid-phase and combinatorial syntheses of p-lactams <99MI955>. 

Much care has been taken in the selection of work to be included but, necessarily, the choice is subjective and the review is in no way comprehensive. P-Lactam chemistry dominates the field in terms of the number of publications. In contrast, studies of heterocycles containing two different heteroatoms appear to be neglected. In general, reviews are mentioned in the appropriate section but mention of a survey of heterocycles bearing fluorine or trifluoromethyl substituents <98MI3SS> is more appropriate here. 

Reviews including aspects of P-lactam chemistry are ketene-imine cycloaddition reactions <98CHE1222>, radical cyclization processes <98MI169>, combinatorial synthesis <98AJC875>, electrophilic cyclization of unsaturated amides <98T13681> and theoretical studies on the synthesis of P-lactams <98MI245>. 

Fluorinated Penicillins and Other -Lactams Chemistry and Biological Activity ... 

The development of antibacterial chemotherapy during the past 75 years has spearheaded the successful use of today s drugs to combat bacterial infections. Studies in (3-lactam chemistry were stimulated when (3-lactam ring, the four membered heterocycle, was recognized as a key structural feature as well as a key therapeutic feature of the bicyclic (3-lactam antibiotics such as penicillins, cephalosporins, and other classical antibiotics. The last two decades have registered the discovery of several nonclassical bicyclic (3-lactam antibiotics, e.g., thienamycin and carba-penems of natural origin like olivanic acids, carpetimycin, pluracidomycin, and aspareomycins. 

After the discovery of penicillins and cephalosporins as classical (3-lactam antibiotics and clinically useful active agents, the past few decades have witnessed a remarkable growth in the field of (3-lactam chemistry [1, 2]. The need for potentially effective (3-lactam antibiotics as well as more effective (3-lactamase inhibitors has motivated synthetic organic and medicinal chemists to design new functionalized 2-azetidinones. Besides their clinical use as antibacterial agents, these compounds have also been used as synthons in the preparation of various heterocyclic compounds of biological significance [3-7]. The potential use of some... 

On the basis of these experiments, we anticipated that conformationally constrained analogues of our open chain diamides (1 and 2) may increase activity against cancer cell lines. In (3-lactam chemistry, this kind of hypothesis had been tested, and it was established that certain (3-lactams are more effective at lowering cholesterol in human plasma when compared to open-chain substrates [12-15]. Therefore, preparation of (3-lactams of type 3 and related compounds was necessary to investigate a comparative study with diamides 1 and 2. 

Within the current synthetic effort in beta-lactam chemistry, 4-acetoxyazetidin-2-one and its derivatives play an important role in the total synthesis of many conventional beta-lactams and their analogues.There is therefore a requirement for a simple large-scale preparative method for this key intermediate. This synthesis is a modification of that reported by Clauss et al.7... 

Surprisingly, BSMAs that form aliphatic enolizable imines led to 4-alkyl-(3-lactams. The bissilylmethyl group reducing the acidity of the (3-proton was probably the cause of this highly interesting result, which has opened new synthetic potential in the (3-lactam chemistry. 

Finally, a section is devoted to developments in (5-lactam chemistry. Fused-ring systems are not included though often the purpose of the work on monocyclic systems is to develop synthons for fused-ring compounds. Recent reviews on the use of (5-lactams... 

Dr. David Johnson (1975-1982). Of all my senior managers, Dave Johnson was the one who knew most about organic chemistry and synthesis. He was a hard-driving chemist with a nose for practical solutions to process development problems. Being a student of Professor John Sheehan, his knowledge of (3-lactam chemistry was extensive. Indeed he was called on to represent Bristol-Myers in its many patent battles with Beecham in which Bristol-Myers staked out its own patent position covering ampicillin and amoxicillin trihydrates.8... 

The chemistry of O-alkyl derivatives of lactams (lactim ethers) is one of the least studied aspects of lactam chemistry. The lactams themselves have been much investigated in the preparation of polymers, in connection with penicillin (/3-lactams),1 and also because of the tendency of certain substituted derivatives to ring-close to cyclols, cylopeptides, or cyclodepsipeptides.2,3 A review on lactams has appeared.4... 

Organometallic reagents in /3-lactam chemistry 88T5615. Stereochemistry of electrophilic substitution in /3-lactams 90KGS1155. /3-Lactam antibiotics (see Section II,D,3,c). 

EG Mata. Solid-phase and combinatorial synthesis in beta-lactam chemistry. Curr Pharm Des 5 955—964, 1999. 

ADEPT with / -Lactamase Activation of (5-lactam-based prodrugs is based on the well-established (3-lactam chemistry. It was demonstrated that a molecule attached to the 3 position of cephalosphorins was eliminated through a 1,4-fragmentation reaction.11 Scheme 27 shows a general scheme of this reaction,... 

Figure 18-6. Enzymatic deprotection of amino- and carboxy groups in 3-lactam chemistry.

As an alternative to the well established phenylacetyl group in (3-lactam chemistry, recently a biocatalyzed procedure for the removal of phthalyl imide has been described (Fig. 18-2)[45, 71 Its general usefulness remains to be demonstrated, however. 

Protective Groups in -Lactam Chemistry. Wild, H. In The Organic Chemistry of fi-Lactams Georg, G. I., Ed. VCH Weinheim, 1993 pp 1-48. 

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