Seven-membered lactam

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]. 

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). 

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]. 

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. 

The dihomoallyl ether (93) is converted to the seven-membered ether 94 [25]. The hydroazulene 96 is obtained by the metathesis of the 1,8-diene 95 using MTO as a catalyst in solution [34]. Similarly, the seven-membered lactam 98 is prepared from 97 [35]. 

Subcutaneous application of 100 mg kg-1 to mice resulted in a 50% reduction of A/ brain levels after 3 h. The reduction was 40% 3 h after an oral dose of 100 mg kg-1. Further development of the compound by Eli Lilly included stereoselective placement of the hydroxyl group and locking of the spatial arrangement of two phenyl rings in a seven-membered lactam to yield 17 (LY 411575, HEK IC50 < 1 nM). 

DuPont s hybrid structure 19 [33] bears the signature of a dipeptide-based SAR on y-secretase and the reminiscent lead, which was synthesized in a matrix metalloproteinase (MMP) program. Removal of the central amide bond of the parent dipeptide, replacement of the hydroxamic acid by an amide, and introduction of a seven-membered lactam resulted in high activity and removed some of the problems associated with dipeptide lead structures. Hot labeling by photoactivation of I125-benzophenone specifically cross-linked the inhibitor to three cell-membrane proteins. 

As illustrated in Equation (182), a seven-membered lactam was formed by utilizing a ring closure reaction under Heck coupling conditions <20070BC655>. 

The method is useful for synthesis of five-, six- and seven-membered lactams, but not of P-lactams or macrolactams. The bridged lactam 2 was obtained from 1 in 77% yield by reaction with di-n-butyltin oxide. 

The reaction can be used to prepare five-, six-, and seven-membered lactams from y, S, and oj-aminocarboxylic acids. 

Furthermore, the sterically unfavorable, seven-membered lactams are readily obtainable from the 6-amino-6-deoxyaldonic acids. Thus, on treatment with alkali at room temperature, 6-amino-6-deoxy-L-gulono-l,4-lactone hydrochloride (157) gives L-gulono-l,6-lactam... 

Cycloadditions of electrophilic olefins or cumulenes to vinylcyclopropanes should also be mentioned in this context, since in most cases stepwise reactions starting with an electrophilic attack are very likely. One example operating with chlorosulphonyl isocyanate and providing a seven-membered lactam is depicted in equation 152 however, so far most reactions in this area have a limited synthetic potential. 

The accumulation of a great number of small particles into one polymer chain is an aggregation process resulting in a decrease in the translational entropy of the system. In the polymerization of cyclic monomers, the decrease of translational entropy is partially counterbalanced by the increase in rotational and vibrational entropy resulting from the conversion of a more or less rigid cyclic monomer into a flexible monomer unit inside a polymer chain. Thus the net entropy of polymerization of lactams is more positive (e.g. —3 eu for seven-membered lactams) than the entropy of polymerization of vinyl monomers (—25 to —30 eu). 

The planar cis-amide conformation in the seven-membered lactam already can impose some strain on the ring and thus increase its polymerizability. 

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