13- Lactam structural properties

The mechanism of acid hydrolysis is also different in acyclic amides and /1-lactams acid catalysis of acyclic amides proceeds via O-protonation (see Chapt. 4), whereas that of /1-lactams appears to be a unimolecular A1 type process, involving V-protonation (Fig. 5.6,b) [76], A-Protonation is not the result of reduced amide resonance but an intrinsic property of the /1-lactam structure, since bicyclic /1-lactams and monocyclic /1-lactams exhibit similar reactivity and behavior [76],... 

Several derivatives of the unsaturated and saturated lactams mentioned in this review have been submitted to pharmacological investigations, and various biological activities were found. In this section, an attempt is made to enumerate some derivatives together with their biological properties. Such compounds are shown in the lactam structure. 

These extensive SAR studies have shown that the rigid biaryl/nine-membered lactam structure of rhazinilam adopting a boat-chair conformation is an essential feature for its antimitotic properties. Moreover, the absolute aR configuration of the biaryl axis is, as in the allocolchicine and stegane series, absolutely required for biological... 

Although investigations to determine the structures and establish the beneficial properties of semisynthetic penicillins were aimed first and foremost at the production of more and more of such compounds, a number of examples can be found in the literature concerning their functional modifications (term suggested by Heusler) and nuclear analogues . Work on these unusual /3-lactam structures has been on the increase since the middle of the sixties, and the search for new cephalosporin syntheses has produced a vast number of compounds. 

B. J. Synthetic hydrogels 2. Copolymers of carboxyl-, lactam- and amide-containing monomers—Structure/ property relationships. Polymer 1988, 29, 691-700. 

With acid, the jS-lactam (30) undergoes cleavage and re-closure to give the rearranged salt (31 A similar rearrangement occurs with sodium methoxide or sodium cyanide in methanol. Some EHMO and CNDO calculations of the optical rotatory properties of j8-lactam structures have been reported. 

A keystone for understanding much of what will be covered in this chapter can be traced to the 1949 paper of Woodward et al. Amide resonance (Pauling, I960) is altered due to the strain in the p-lactam ring such that the contribution from the nonpolar resonance structure (1) is enhanced over that from the polar form (2). Although originally conceived to interpret the properties of penicillin, this concept applies also to cephalosporins and recent novel p-lactam structures. 

In October 1943 I suggested to Chain that penicillin had a p-lactam structure, because 1 could find no basic group in it by potentiometric titrations and because in some of its properties it seemed to resemble an N-acylthiazolidine more closely than a thiazolidine itself. Chain was immediately convinced and the structure was also accepted by Wilson Baker. However, Sir Robert Robinson had already proposed a thiazolidine oxazolone structure (which we thought would be less stable than penicillin) and would hear of no other. He was not alone in his view. One eminent organic chemist in Oxford threatened to give up chemistry if the p-lactam structure was correct. 

There is little information about the application of this type of polymerization reaction to a,a-disubstituted-3-lactams, but what is known indicates the crystalline structure-property relationships of these polymers are quite different from those... 

By virtue of their fused /3-lactam-thiazolidine ring structure, the penicillins behave as acylating agents of a reactivity comparable to carboxylic acid anhydrides (see Section 5.11.2.1). This reactivity is responsible for many of the properties of the penicillins, e.g. difficult isolation due to hydrolytic instability (B-49MI51102), antibacterial activity due to irreversible transpeptidase inhibition (Section 5.11.5.1), and antigen formation via reaction with protein molecules. 

The large number and diversity of available /3-lactams, mainly penicillins and cephalosporins, necessitate their classification. Penicillins can be classified primarily according to chemical structure. Table 5.2 shows that there is good correspondence between chemical structure and properties. The categorization of cephalosporins into chemically similar groups is not useful because their antimicrobial spectrum is not closely correlated with chemical structure, and classification into generations is based on their spectrum of microbial activity (Table 5.3). 

The discovery of thienamycin created great excitement it is a structurally novel P-lactam antibiotic of outstanding potency and has a remarkable spectrum of activity. It was the broadest spectrum antibiotic of its day. There was, however, a major problem thienamycin is not a stable molecule. Merck scientists were faced with the touchy problem of modifying thienamycin chemically to create a stable molecule while maintaining all its remarkable properties. Following considerable effort, they... 

Further studies of the isolated isoindolinone structure (lactam 57) showed that one of the diastereoisomers had interesting crystalline properties. This was used in order to demonstrate how a DCR process could further be directed and diastereomerically amplified through a selection pressure caused hy a phase change. Systems where DCLs are driven by crystallization have previously been reported [50-52], and have recently received new attention [53-56]. 

Since a knowledge of the correct tautomeric form of the pyrimidines is a requisite for understanding the mode of binding to active sites, as well as nucleic acid structure and modification, the formulae of the conventionally-named 2- and 4-hydroxypyrimidines are presented in the correct lactam, or pyrimidone, form in this chapter. Other physical properties of the pyrimidines, such as dissociation constants, protonation sites, and distribution coefficients, are presented in cases where there is a known relation to drug activity. Biogenesis and enzyme control mechanisms are discussed where they relate to an understanding of inhibitor action. 

A number of polymers have been made using ROP. Nylon-6, similar to structure and properties to nylon-6,6, is made from the ring opening of the lactam caprolactam. PEO is made from the ring opening of ethylene oxide and is made more stable by capping the ends preventing ready depolymerization. 

As a result of the intense interest in exploitation of the biological properties of the /3-lactam antibiotics a large number of nuclear analogs of the various naturally occurring structures have been synthesized. In addition to the carbapenems and oxapenams already described (Sections 5.12.3.4.2 and 5.12.3.4.3) a number of other novel bicyclic azetidinones have been reported. Examples of many of these are listed in Table 6. The methods used to synthesize these compounds are too varied to list in any systematic way. 

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