Lactams, bicyclic

Under a CO atmosphere and in the presence of Ru2(CO),2, 1-aza-1,3-dienes are converted to unsaturated y-lactams. Bicyclic lactams are formed in the reaction of... 

The peptidic nature of penicillin was not recognized immediately after its isolation. In its jS-lactam bicyclic ring structure the tripeptide -(L-a-aminoadipoyl)-L-cysteinyl-D-valine is hidden but in 1960 it was discovered in extracts of Penicillium by Arnstein et al. [11]. Experiments on biosynthesis of penicillins in the intact mycelium of the producing fungi did not lead to unequivocal results, due to the poor permeability of the cell wall. Protoplasts, naked cells obtained after enzymatic removal of the outer wall, however, were able to serve in studies with radioactively labeled potential precursors, and in cell-free systems from Cephalosporium acremonium, the route to isopenicillin N was finally revealed [12]. The tripeptide L-a-aminoadipoyl-L-cysteinyl-D-valine first forms the j -lactam moiety and a second, oxidative step closes the thiazolidine ring between the -carbon of valine and the thiol of cysteine (Fig. 9). 

In his cephalosporin synthesis methyl levulinate was condensed with cysteine in acidic medium to give a bicyclic thiazolidine. One may rationalize the regioselective formation of this bicycle with the assumption that in the acidic reaction mixture the tMoI group is the only nucleophile present, which can add to the ketone. Intramolecular amide formation from the methyl ester and acid-catalyzed dehydration would then lead to the thiazolidine and y-lactam rings. The stereochemistry at the carboxylic acid a-... 

Other interactions of /3-lactams with electrophiles include the oxidative decarboxylation of the azetidin-2-one-4-carboxylic acid (85) on treatment with LTA and pyridine (81M867), and the reaction of the azetidin-2-one-4-sulfinic acid (86) with positive halogen reagents. This affords a mixture of cis- and trans-4-halogeno-/3-lactams (87), the latter undergoing cyclization to give the bicyclic /3-lactam (88) (8UOC3568). 

The bicyclic lactam A hydrolyzes 10 times faster than the related monocyclic compoAnd B. 

The bicyclic compound (76) gave carbon dioxide, the saturated amine (122), and the unsaturated lactam (123). 

Chiral bicyclic lactams as useful precursors and templates for asymmetric syntheses 97CC1. 

Monocyclic 2-methoxyazocines 1 (see Section 1.1.1.1.1.) can be hydrolyzed to the corresponding lactams with anhydrous hydrogen bromide, but only in low yield. NMR spectroscopy reveals that, in contrast to the benzannulated systems (vide supra), the products mainly exist as their bicyclic tautomers 3.28... 

Figure 2.3 An example of a stereospecific biotransformation resolution of bicyclic lactams. A and Ai are an enantiomer pair as are B and Bi.

Some other examples of tram allylations with allylsilanes are the bicyclic lactam 21123 and the imidazolidinone derivative 23124. 

Lactam antibiotics are bicyclic or monocyclic azetidinone ring-containing compounds (Fig. 1). They kill bacteria by preventing the assembly of (4-3) peptidoglycans. These covalently closed net-like polymers form the matrix of the cell wall by which the bacteria can divide and multiply, despite their high internal osmotic pressure. 

Syntheses of a number of bicyclic lactams and their qualitative polymerizabilities related to the steric strains were described and comprehensively summarized by Hall23>s4), as simply shown in Table 7. 

Melting points of the polymers from bicyclic lactams are expected to be appreciably high because of some conformational restriction of the main chain due to the ring structural unit, as seen from the examples54 presented on page 25. 

It has also been known that the polymerization of some bicyclic lactam ethers, for example, 3-aza-10-oxabicyclo[4.3.1]decan-4-one 60 was accompanied by the cleavage of the ether bond55,56. ... 

A new class of bicyclic oxalactam, 8-oxa-6-azabicyclo[3.2.1]octan-7-one 61 was synthesized by intramolecular cyclization of 3,4-dihydro-2H-pyran- 2-carboxamide 62 using p-toluenesulfonic acid as a catalyst in an equivalent mixture of DMF and benzene at 100 °C for 4 hours57, S8. Corresponding conversion of 3-cyclohexane carboxamide 63 to bicyclic lactam 64 has never been accomplished54. ... 

Similarly a marked increase of regioselectivity has been shown in the catalyzed Diels-Alder reactions of the chiral bicyclic lactame 24 (Scheme 3.9) with a variety of dienes [27] (isoprene, mircene, (E,E)-L4-dimethylbutadiene, 2,3-di-methylbutadiene, 2-siloxybutadiene). The catalyzed reactions were more regio-selective and totally enJo-antz-diastereoselective anti with respect to the bridgehead methyl group). The results of the cycloadditions with isoprene and mircene are reported in Scheme 3.9. The cycloadducts have then been used to provide interesting fused carbocycles [28] with high enantiomeric purity as shown in Scheme 3.10. 

Shao reported the microwave-assisted hetero-Diels-Alder cycloaddition reaction of a series of acetylenic pyrimidines to introduce a fused lactone/lactam ring, with no degradation of either reactants or products typical for the harsh thermal conditions (150-190°C, 15-144h) [131]. In contrast to the results reported when conventional heating was applied, the Diels-Alder cycloaddition under microwave irradiation gave a high yield of the desired fused lactones or lactams [132]. This reaction provided a practical and general method for the preparation of fused bicyclic pyridines 205 (Scheme 74). 

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