Subject Lactams

The mechanism of action of -lactam antibiotics has been the subject of several recent reviews <79MI51102, 79MI51103, 81MI51104, B-81MI51105, B-82MI51101). 

However, important as the /3-lactams are, they are but one of mai r families of anhbiotics (Chapter 5). Furthermore, most industrial microorganisms used to make j8-lactams are fungi this is atypical of anhbiotics as a whole where bacteria, particularly Streptomyces spp., predominate. Chapter 5 and some of the further reading at the end of this chapter provide the broad perspechve, including informahon on those anribiohcs made by total or partial chemical synthesis, against which this present account with its necessarily selechve subject matter should be read. 

The photocyclization of enamides has been the subject of detailed study and provides a valuable approach to the synthesis of alkaloids. A comprehensive review has been published.31 A variety of reaction types has been reported. The N-benzoylenamine 33, for example, is converted on irradiation to the trans-lactam 34 by a process involving conrotatory photocyclization followed by a thermally allowed [l,5]-suprafacial hydrogen migration.32 The influence of substituents on this transformation has been studied.33 The enacylamine 35 undergoes an analogous cyclization to give a mixture of cis- and trans-lactams 36, the ratio of which is solvent... 

The unsaturated amides (RCH=CHCONH2, where R = aryl or heteroaryl) in the presence of sodium acetate and NBS gave 3-bromoazetidin-2-ones 67 in moderate yield, probably by cyclization of 68 <99JCS(P1)2435>. The mesylate 69 cyclized in the presence of base to 70 and, after deprotection, the racemic P-lactam was subjected to lipase-mediated resolution to yield 71 (R = Et, ee 99%) and the amino acid 72 (R = Et, ee 98%) . 

A general synthetic route to p-lactam-fused enediynes (Scheme 2.321) has been successfully developed (848). When nitrone (771) was subjected to Kin-ugasa reaction conditions, two p-lactam containing products were obtained the elimination product (772) and the trans fused compound (773). 

The hydrolysis of racemic non-natural amides has led to useful products and intermediates for the fine chemical industry. Thus hydrolysis of the racemic amide (2) with an acylase in Rhodococcus erythrolpolis furnished the (S)-acid (the anti-inflammatory agent Naproxen) in 42 % yield and > 99 % enantiomeric excess1201. Obtaining the 7-lactam (—)-(3) has been the subject of much research and development effort, since the compound is a very versatile synthon for the production of carbocyclic nucleosides. An acylase from Comamonas acidovor-ans has been isolated, cloned and overexpressed. The acylase tolerates a 500 g/ litre input of racemic lactam, hydrolyses only the (+)-enantiomer leaving the desired intermediate essentially optically pure (E > 400)[211. 

The Ru-catalyzed cyclocarbonylation of a-allenic sulfonamides proceeds in the presence of Et3N under a CO atmosphere (20 atm) to yield ,/funsaturated lactams (Scheme 16.32) [36], In order to gain an insight into the reaction mechanism, a deuterium-substituted a-allenic sulfonamide was subjected to the carbonylation. The deuterium was found to be totally transferred to the methyl group. Based on this observation, a mechanism has been proposed which involves a ruthenacycle derived from addition of the Ru-H to the terminal double bond of allene (Scheme 16.33). 

Most of this chapter (Sect. 5.2) focuses on the chemical reactivity of the lactam bond and its hydrolysis by bacterial enzymes (lactamases), rather than to its metabolic degradation by mammalian enzymes. This is in contradistinction to other chapters of this book, where metabolism in mammals is the focus of discussion. The reason for the attention given here to the chemical reactivity and bacterial degradation of /3-lactams is that these issues have caused more pharmaceutical and clinical problems than metabolic hydrolysis. This also explains why the chemical stability of /3-lactams and their resistance to /3-lactamases have been the subject of countless studies, while the metabolism of these compounds has received less attention. 

To demonstrate the feasibility of organic synthesis using this support, the authors immobilized a N-Boc protected glycin (22) on the support (Scheme 7.5). After deprotection imine formation readily occurs with an excess of benzaldehyde. The product was then subjected to a Staudinger reaction with phenoxyacetylchlor-ide to yield the polymer supported / -lactam (26) which could be released to give the yS-lactam (27) with TEA in methanol. 

The stereochemical outcome for addition of r-l,3-dioxolan-4-yl and oxiranyl radicals to phenyl vinyl sulfone has been probed. The results indicated that the symanti selectivity could be altered by changing the group next to the radical in the diox-olanyl case but not in the oxiranyl case (bulky groups had a large xyn-directing effect) (Scheme 39). Several alkenyl-lactones and -lactams have been subjected to hydrosilylation conditions using carbohydrate-derived thiols as homochiral polarity reversal catalysts (yields 25-96% ee 5-95%) " ... 

N-Boc-N-(but-2-enoyl)amine is an excellent pronucleophile for the Ir-catalyzed allylic amination under salt-free conditions (cf. Table 9.3, entries 15-18). The products were subjected to RCM with good results, even upon application of the Grubbs I catalyst (Scheme 9.29) [27bj. The resultant N-Boc protected a,P-unsaturated y-lactams are valuable chiral intermediates with appUcations in natural products synthesis and medicinal chemistry. 

In subjects with normal renal function, the elimination half-life of meropenem is approximately 1 hour. Meropenem is excreted by the kidney with a half-life of 0.8 to 1.24 hours 65% to 83% of the dose is recovered in the urine as meropenem and 20% to 28% as the inactive open -lactam metabolite. 

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. 

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