Twisted lactams

Kirby s configurationally rigid l-azaadamantan-2-one 1 is the extreme of this class.21 23,25 The nitrogen properties of this lactam are clearly amine-like while the carbonyl is ketonic in all respects. Twisted amides undergo rapid hydrolysis or reduction and exhibit enhanced reactivity. 

The properties of these compounds resemble those of the simple medium-ring lactams studied by Dunitz and Winkler (1975). A twisted conformation is observed for crystalline caprylolactam, where the preferred trans conformation cannot be properly accommodated in the nine-membered ring. 

The nitrogen atoms of the twisted amides discussed on pages 107-108 are to a greater or lesser extent pyramidal, and incipient lone pairs electron density is thus available for reactions with electrophiles. The classic example is the cage lactam [57] first prepared by Pracejus (1959), which has an amide nitrogen with near normal amine basicity. Brown and coworkers have measured rates of alkaline hydrolysis of a series of anilides [58] and [59] with related structures and find that the rate increases with increasing divergence... 

FIGURE 2. (a) A stericaUy twisted amide (b) an angularly constrained amide (c) a twisted lactam (d) an angularly constrained hydroxamic ester... 

However, initial experiments with this reagent gave poor results, with the secondary amide undergoing reduction along with the tertiary amide. Compound 101 [and 107, Fig. (29)] is sufficiently twisted such that the gem-dimethyl groups effectively block the (j-face of the tertiary amide, leaving the a-face relatively unencumbered. However, a modification of the alane procedure [60], proved satisfactory for this transformation. The piperazinedione 101 was pretreated with AlEt3, with the expectation that this Lewis acid would form a complex with the more exposed secondary lactam [106, Fig.(29).] and leave the tertiary lactam accessible for reduction. 

An ab initio study of the acid hydrolysis of the lactam l-azabicyclo[2.2.2]octan-2-one (described as a highly twisted amide ) and of the model compound 3-methyl-S-valerolactam showed that both proceed via a stepwise mechanism, but A-protonation is preferred to O-protonation by the twisted amide , whereas the reverse is the case for the model compound.92... 

May and coworkers proposed the plausible biosynthetic root to communesin A (70) shown in Fig. (12) (part 1) [50]. A quinone methide (75) derived from tryptamine and the related natural product, aurantioclavine (76), undergo a Diels-Alder reaction to form a polycyclic intermediate (77). This highly twisted lactam (77) should be easily cleaved by the residual primary amine to produce spiro lactam (78). Reduction of 78 and aminal closure afford a common intermediate (79) of communesins. Epoxidation and acylation of 79 afford 70. Expansion... 

The IR spectrum of the trans 3H,9a.H)- 49S) exhibits the lactam carbonyl band at 1638 cm , whereas the cw(3/I,9a )-(495) diastereomer at 1675 cm. As shown by Dreiding models the carbonyl group of the latter is twisted out of the plane, which explains the difference in the absorption <85H(23)889>. Characteristic cyclic ether, lactam, and lactone bands of the oxazino-oxazines (497) and (498) are given <64AP(297)632>. 

The intramolecular Schmidt reaction has provided a solution to the problem of bridgehead lactam synthesis. The bridged lactams incorporate a twisted amide unable to achieve standard planar geometry and can undergo rapid hydrolysis. Reaction of ketoazide with HBF4 in ether results in a mixture of two latams from which the desired quinoclidone 92 is isolated in 38% yield after recrystalization. ... 

Of the thermochromism dyes that indicate temperature, some of tfiem (including biantron (9)) change color by twisting the double bonds and (10) which shows piezochromism by lactam-lactim tautomerism. 

Out-of-plane deformations of the amide group from the stable planar form involve the pyramidalization of the amine group and/or twisting around the CO-N bond, which may be accompanied by pyramidalization of the carbonyl carbon atom. The stmcture and properties of nonplanar amides and lactams have been recently reviewed. ... 

---