Lactams seven-membered

The synthesis of five-, six-, and seven-membered cyclic esters or timides uses intramolecular condensations under the same reaction condifions as described for intermolecular reactions. Yields are generally excellent. An example from the colchicine synthesis of E.E. van Ta-melen (1961) is given below. The synthesis of macrocyclic lactones (macrolides) and lactams (n > 8), however, which are of considerable biochemical and pharmacological interest, poses additional problems because of competing intermolecular polymerization reactions (see p. 246ff.). Inconveniently high dilution, which would be necessary to circumvent this side-... 

Carbonylation of halides in the presence of primary and secondary amines at I atm affords amides[351j. The intramolecular carbonylation of an aryl bromide which has amino group affords a lactam and has been used for the synthesis of the isoquinoline alkaloid 498(352], The naturally occurring seven-membered lactam 499 (tomaymycin, neothramycin) is prepared by this method(353]. The a-methylene-d-lactam 500 is formed by the intramolecular carbonylation of 2-bromo-3-alkylamino-l-propene(354]. 

In 1997, Lindstrom and Somfai reported aza-[3,3]-Claisen enolate rearrangements of vinylaziridines (Scheme 2.45) [70]. Treatment of l-acyl-2-vinylaziridines 179 with LHMDS resulted in the stereoselective formation of seven-membered lactams 181, presumably through a boat-like transition state 180. 

The in situ activation of 2-aminopimelic acid 1-amide with triethyl phosphite led to the corresponding seven-membered lactam under forced conditions in 52% yield [11b]. 

An auxiliary controlled enantioselective route to generate seven-membered ring lactams 75 used the a-alkylation of cyclic hydrazide derivatives 74. Initially, 6-chloro hydrazides 73,bearing the chiral information in the M-amino-pyrrolidine function underwent amidocyclization in the presence of a base. A subse-... 

The use of cycloadditions for synthesizing medium-sized ring lactams is more or less restricted to the generation of seven-membered rings. The simplest method to generate azepinones seems to be the [6-1-1] reaction of a 1,6-dicar-boxylic acid chloride 148/152 and a phosphinimine 149, the in situ formed chloro enamine 150 underwent a Chapman rearrangement to give a cyclic imide 151/153 (Scheme 28)] [36]. 

The principles set forth above account reasonably well for the course of bifunctional condensations under ordinary conditions and for the relative difficulty of ring formation with units of less than five or more than seven members. They do not explain the formation of cyclic monomers from five-atom units to the total exclusion of linear polymers. Thus 7-hydroxy acids condense exclusively to lactones such as I, 7-amino acids give the lactams II, succinic acid yields the cyclic anhydride III, and ethylene carbonate and ethylene formal occur only in the cyclic forms IV and V. 

The use of heterogeneous catalysts in this reaction has also been achieved palladium-montmorillonite clays [93] or palladium/activated carbon [94] in the presence of dppb transformed 2-allylphenols into lactones, the regiose-lectivity of the reaction being largely dependant on the nature of the support. Very recently, palladium complexes immobilized onto silica-supported (polyaminoamido)dendrimers were used as catalysts in the presence of dppb for the cyclocarbonylation of 2-allylphenols, 2-allylanilines, 2-vinylphenols, and 2-vinylanilines affording five-, six-, or seven-membered lactones and lactams. Good conversions are realized and the catalyst can be recycled 3-5 times [95]. 

Caprolactam (5.68, Fig. 5.21) has a seven-membered lactam ring and is a major industrial compound in the production of Nylon , its polymer. This compound shows only moderate levels of toxicity in mice and rats when administered orally. The hydrolysis product 6-aminohexanoic acid (5.69) was a minor metabolite in rats [176]. Hydroxylation in the y-position to yield 5.70 without preliminary hydrolysis of the lactam linkage has been shown to be the major metabolic pathway. This metabolite hydrolyzes in urine to produce 6-amino-4-hydroxyhexanoic acid (5.71), which is in equilibrium with the corresponding lactone (5.72). 

Hydrolytic cleavage of a seven-membered ring occurs in the metabolism of chlordiazepoxide (5.82, Fig. 5.22,a) and other benzodiazepines (see also Sect. 11.9). The lactam ring opened metabolite 5.83 was detected in humans and dogs and is believed to be generated by hydrolysis of the intermediate lactam [181][182], However, the diazepine ring can be split by other mech-... 

An especially attractive strategy is simultaneous cyclization/cleavage by RCM [42, 43]. This concept was first introduced by van Maarseveen in the synthesis of seven-membered lactams [44] and subsequently employed by many groups. Recently, this strategy was employed in the solid phase synthesis of epothilone A [45, 46] and dysidiohde analogues [47,48]. 

By annulation onto the seven-membered ring 2.3.2.1 Lactamization and N-alkylation... 

Another chiral synthesis of the azepine nucleus of Balanol (397) was developed by Wu and Jacobsen, once again converting a cyclohexanone oxime tosylates 399 to a seven-membered lactam (equation 162). The use of a mixture of oxime isomers did not cause... 

Contrary to the phosphine-catalyzed reaction of the allene buta-2,3-dienoate, which adds to CgQ in a ]3-i-2] cycloaddihon ]354], the allene amide 317 forms the cyclobutane annulated fuUerene derivahve in good yields (Scheme 4.63) [355]. The reaction was also performed with similar allene amides bearing a six- or seven-membered lactam. 

Similar results were encountered in the reaction of 69 (generated thermally from the corresponding 2,5-dihydro-1,3,4-thiadiazole) with benzylidene malonodinitrile or a-cyano-substituted cinnamates (97). In these cases, seven-membered lactams or... 

Conformational analysis of hexahydro-lH-azepin-2-one (caprolactam) confirms that it, like other five- to eight-membered lactams, has the cis conformation. The 1SN NMR shift for the seven-membered lactam in CHCI3 appears at 259.7 p.p.m. (upfield from HNO3) (76JA5082). Solvent shifts for the 1SN resonance of caprolactam have been determined (78MI51601). In TFA/(15N-H) is 92.5 0.5 Hz. 

Caprolactam or (hexahydroazepin-2-one) is, without doubt, the most important azepine derivative. This seven-membered lactam is produced in vast quantities as an intermediate for the manufacture of nylon 6 (B-75MI51601, B-70MI51601). Polymerization, which is carried out at high temperatures with water as the initiator or at low temperatures with a strong base (e.g. NaH), proceeds by attack at the caprolactam carbonyl by the amino function of the open-chain monomer, e -aminohexanoic acid. 

Tethering an iodobenzene and a furane moiety through a y0-lactam led to the formation of a unique tetracyclic y0-lactam derivative (5.17.). Oxidative addition followed by the carbopalladation of the furane ring resulted in the closure of the seven membered core in a so called heteroaryl Heck reaction "... 

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