Spiro-Fused 3-Lactams

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]. 

---

The synthesis of (5-lactams having a small fused ring is of interest since the large strain of the ring should substantially alter the reactivity of (5-lactams. Several approaches for the synthesis of spiro-[5-lactams have been described in literature. 

Unusual sources for nitrogen-substituted carbenes are 1,3,4-oxadiazolines such as 6. Thermal reaction of 6 with 4-bromo-l-butene furnishes only one diastereomer of spiro-fused /1-lactam cyclopropane 76. However, precursors similar to 6 react less selectively with other olefins. 

The copper-catalysed 3 + 2-cycloaddition reactions of nitrones with alkynes leading to / -lactams have been extensively reviewed. The 3+2-cycloaddition reactions of dialkyl-substituted 2-benzylidenecyclopropane-l,l-dicarboxylates (54) and C-carbamoyl nitrones (53) produced simple isomeric spiro[cyclopropane-l,4-isoxazolidine] cycloadducts (55), which are readily transformed into isoxazolidine-fused / -lactams (56) in high yields (Scheme 15). BINOL-derived chiral phosphorami-date Au(l) catalysts have been used to catalyse the 3+2-cycloaddition of A(-allenyl amides with nitrones to produce chiral 4-alkylidenyl isoxazolidines in high yields and excellent enantioselectivity (up to 99% cc). The 3+2-cycloaddition of a-phenylnitroethene and (Z)-CA -diphenylnitrone in polar media (nitromethane and water) yielded 3,4-fra 5 -2,3,5-triphenyl-4-nitroisoxazolidine via a zwitterionic, two-step mechanism. ... 

In recent years, spiro-fused fS-lactams have drawn considerable interest because of their diverse biological properties. As a detailed coverage is not possible within the scope of this chapter, selected examples of synthetic and semisynthetic spiro-fused P-lactams with the type of bioactivity associated with them are listed in Table 3.1. 

Other reviews and chapters of books which only discuss a specific heterocycle are mentioned in the appropriate section of this chapter. The organization of the chapter is similar to that adopted previously except that the (3-lactams have been divided into monocyclic 3-lactams (including bicyclic spiro compounds) and fused (3-lactams . The latter heading embraces a large volume of work and the reporting is necessarily more than usually. selective. 

In the past decade, the chemistry of j0-lactam carbenes has proved successful for the construction of complex spiro- or fused heterocyclic scaffolds of medicinal relevance. To that purpose, their synthetic potential has been further explored with a study on their reactivity towards 3,6-di(2-pyrimidinyl)tetrazine (28). Diversely substituted / -lactam carbenes have been found to smoothly react with (28) to furnish the two novel heterocyclic scaffolds (29) or (30) depending solely on the reaction temperature (i.e., 100 and 140 °C, respectively) (Scheme 4). 

The regioselectivity and reactivity of the 1,3-dipolar cycloaddition reactions of nitril-imines with acrylonitrile and methyl acrylate have been investigated. The 1,3-dipolar cycloaddition reactions of nitrilimines with isatin imines yielded spiro[indolin-3,3 -1,2,4-triazol] derivatives under classical and microwave conditions/ An extensive study of the 1,3-dipolar cycloaddition reactions of nitrilimines with a,/ -unsaturated lactones, thiolactones, and lactams has been presented. In all cases, regioisomeric mixtures were obtained with the 5-substituted pyrazole as the major cycloadduct. me5 o-Tetrakis(pentafluorophenyl)porphyrin (51) reacts with iminonitriles (52) yielding pyrazolin-fused chlorines (53) via a 1,3-dipolar cycloaddition reaction (Scheme 17). ... 

---