Lactam/lactone rings

Schemes 15 and 16 summarize the syntheses of intermediates that represent rings A and D of vitamin Bi2 by the Eschenmoser group. Treatment of lactam/lactone 51, the precursor to B-ring intermediate 8 (whose synthesis has already been described, see Scheme 8), with potassium cyanide in methanol induces cleavage of the y-lac-tone ring and furnishes intermediate 76 after esterification of the newly formed acetic acid chain with diazomethane. Intermediate 76 is produced as a mixture of diastereomers, epimeric at the newly formed stereocenter, in a yield exceeding 95%. Selective conversion of the lactam carbonyl in 76 into the corresponding thiolactam...

A particular mechanism of barbiturate ring opening has been observed for some barbiturates hydroxylated on the side-chain. The mechanism and relevance of this tautomeric lactam-lactone equilibrium are discussed in Chapt. 11. 

Using the phthalimide/methylthioether-pair, a variety of photochemical transformations resulting in medium- and macrocyclic sulfur containing amines, lactams, lactones, and crownether analogues, respectively, with a maximum ring-size of 38 atoms have been described [26,27]. Scheme 10 summarizes some selected examples. 

Griesbeck et al. have developed the decarboxylative photocyclization (PDC) of phthalimido oo-alkylcarboxylates (15) as a versatile route to macrocyclic ring systems (16). The carboxylate serves as electron donor and C02 is eliminated during the course of the reaction. Applying this concept, the syntheses of medium- and macrocyclic amines, polyethers, lactams, lactones, as well as cycloalkynes were accessible but the limitations... 

These methods parallel the syntheses just described for the five-membered rings. As indicated in structures 5158, standard reactions of aliphatic chemistry can be extended to the preparation of piperidines, tetrahydropyrans, and tetrahydrothiopyrans (53 Z = N, O, S) glutarimides, glutaric anhydrides, and glutaric thioanhydrides (55 Z = N, O, S) and -lactams, -lactones, and -thiolactones (58 Z = N, O, S) (Scheme 37). 

The structure of NPI-0052 offered unique substitutions about the y-lactam-(3-lactone ring system with functional groups that significantly enhanced its potency and potential for drug development, as highlighted in this account. 

In 1973, Khuong-Huu et al. isolated three alkaloids anantine (94), cyno-metrine (95), and cynodine (96), from the leaves of Cynometra ananta, a plant of the Leguminoseae family native to Zaire. The structures were deduced on the basis of spectral and chemical evidence (752). The structures bear some similarity to that of pilocarpine (7), which contains a lactone ring instead of a lactam ring. Treatment of cynometrine with polyphosphoric acid yielded the N-methylated anantine (97). The latter compound could not be prepared by a simple N-methylation of anantine. Hydrolysis of cynodine afforded cynometrine and benzoic acid. 

The chemoselective hydrolysis of an acetoxy group in the presence of a 7-lactone ring has been reported in the presence of PLE (eq 9). In a benzylpenicillin, PLE catalyzes the chemoselective hydrolytic opening of the P-lactam ring, the methoxycarbonyl moiety remaining uneffected (eq 10). ... 

The y-lactone ring in cardenolides has also been modified.Digitoxigenin (520) or isodigitoxigenin (521) were directly transformed into a mixture of isomeric lactams (523) by treatment with ammonia or methylamine. The lactol-amide intermediate (522) could be isolated when the reaction was performed at room temperature, and this was transformed to the lactam (523) by dilute acid. Gitoxigenin (524) reacted in an analogous way to afford the related lactams (525). From these experiments, it appears that the reaction with cardenolides gives... 

Similarly, the lactone ring of the muscarinic agonist pilocarpine was changed into various, still active isosteres such as the corresponding thiolactone, lactam, lactol, and thiolactol. A series of aspirin isosteres has been prepared... 

The transition-metal-catalyzed carbonylation reaction has been extensively investigated, and especially the carbonylative ring expansion reaction of strained heterocycles has been shown to be a useful and efficient procedure to synthesize lactams, lactones, and thiolactones.203 The carbonylation of epoxides and aziridines 450 is a powerful tool to construct the /Mactone and /Mactam skeletons 451 (Scheme 142).204 This type of reactions can be regarded as a hetero-[3 + 1]-cycloaddition. 

A series of alkenes 20, derived from amino acids, react with the dienol 21a to give adducts 22. Formation of the additional lactone and lactam rings occurs prior to isolation of the product. A complete facial selectivity, but only moderate (22a) to low (22b and 22c) yields are obtained9. To prevent lactone ring formation several protected derivatives of dienol 21 were reacted with alkylidene malonic ester 20a. Only diene 21g reacts in an acceptable yield and selectivity10. 

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