Lactam-fused compounds, synthesis

Modeling studies based on a template structure constructed from the superposition of the energy-minimized benzo-fused ACE inhibitors shown in Figure 16.42 (compounds 27 and 29) suggested the synthesis of the 13-membered heterocyclic lactam analog (compound 28). ... 

The synthesis of spirocyclic and fused unusual (3-lactam derivatives has been discussed. The 2-azetidinone skeleton has been extensively used as a template on which to build the carbo(hetero)cyclic structure joined to the four-membered ring, using the chirality and functionalization of the (3-lactam ring as a stereocontrolling element. In many cases the compounds described in this chapter were included because of an interesting synthesis or structure, although limited biological data were found. 

As a consequence of the increased resistance of bacteria to classical /3-lactam antibiotics, several strategies devoted to the synthesis of new bi- and polycyclic /3-lactam derivatives have been developed, giving rise to a large number of compounds featuring enhanced antibacterial activity or better resistance toward /3-lactamases. It is the aim of this section to extend previous accounts on this subject in CHEC(1984) and CHEC-II(1996) and to summarize several recent methodologies concerning the preparation of these fused heterocycles. 

The biggest group of tricyclic compounds having a bridgehead nitrogen atom and extra one or more heteroatoms is the fused 4/6/6 system. Two main routes have been adopted for their synthesis either cyclization onto the nitrogen atom of a /3-lactam or by a cycloaddition process. Each of these routes can be achieved by either an intermolecular or an intramolecular reaction. 

The synthesis of aza[ ]adderanes and azahomo[ ]adderanes (n number of fused rings) containing /3-lactams at the terminus has been reported for the first time (see Section 2.04.6.3). Cycloaddition of DMAD to the norborene 7i-bond of 513 in the presence of a ruthenium catalyst yielded [5]homoladderane 514 in 89% yield (Equation 85) <1997SL38>. Other examples of these types of compounds are reported in Section 2.04.6.3. 

In a series of papers, Mathias and Moore described a new synthesis of isomunchnones 387 via the thermal cyclization of A -(chloroacetyl)lactams 386 (Fig. 4.125). Compound 386d, which would afford a 5-5 fused ring system, is stable up to 150°C. These isomunchnones can be captured by NPM to give fused 2-pyridones in moderate yields. The reaction with DMAD affords 389 in much lower yields (< 17%), and other olefinic dipolarophUes (fumarate, maleate, acrylate, and dicyanocyclobutene) are unreactive. Reaction of N-(chloroacetyl)benzamide in the presence of NPM gave 391 in low yield. 

The synthesis and biological evaluation of various p-lactams as anticancer agents have been demonstrated by Banik et al. [28]. The anticancer activities of these compounds have prompted them to study the synthesis of pyrroles bound to the P-lactams 4 and 5. They identified an expeditious synthetic method for the preparation of pyrroles fused with p-lactams by the reaction of 3-amino p-lactams with acetonylacetone in the presence of catalytic amounts (5 mol%) of molecular iodine at room temperature (Scheme 10.3). 

The recent discovery of different types of biological activity in spiro-fused heterocyclic compounds has generated considerable interest among synthetic and medicinal organic chemists [124], The synthesis and chemistry of spiro-fused P-lactams have also developed steadily. Most of the methods apphcable to the synthesis of monocychc fS-lactams are apphcable with certain hmitations to the synthesis of spiro-fused 2-azetidinones [125]. The literature survey reveals the synthesis of several natural products inspired spiro-2-azetidinones having antimicrobial activity, cholesterol absorption inhibition activity, antiviral activity, and fS-lactamase inhibition activity [126]. 

Moreover, in the past 10 years, a number of works involving a nucleophilic attack of a nitrogen nucleophile over an acylpalladium intermediate, generated in situ from simple and easily prepared starting compounds, has been reported to be dealing with the synthesis of heterocyclic compounds, that is, 2,3,4,5-tetrahydro-lH-2,4-benzodi-azepine-l,3-dione derivatives 30 [39], tetrahydro-P-carboline/tetrahydriisoquinoline fused 5-lactam derivatives 31 and 32, respectively [40], and substituted hydantoins 33 [41] (Scheme 13.14). 

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