Cascade reactions lactamization

Meijere et al. [117] group have investigated the direct synthesis of 3-spiro-cyclopropanated p-lactams 184 (Scheme 43) using novel three-component cascade reaction. Earlier, Alberto Brandi and coworkers [118-120] have applied nitrones 181 and bicyclopropylidene 182 to obtain cylcoadducts 183, which were further fragmented under acidic conditions to afford spiro-p-lactams 184. However, this reaction required longer reaction time for the formation of cycloadducts 183. 

Scheme 43 Three-component cascade reaction to afford 3-spirocyclopropanated [S-lactams...

Spirocyclopropanated (3-lactams have been prepared by a three-component cascade reaction [115]. A mixture of alkylhydroxylamine hydrochlorides, aldehydes, and bicyclopropylidene, under microwave heating in ethanol as solvent, furnished 3-spirocyclopropanated 2-azetidinones with good yields (Scheme 40). 

Vanderwal and coworkers [39] have recently reported an interesting method for the synthesis of polycyclic lactams from the pericyclic cascade reactions of Zincke aldehyde derivatives (5-amino-2,4-pentadienals). Under thermal conditions, Zincke aldehydes 89 are converted to Z-ot,p,y,5-unsaturated amides 90 via a cascade of pericyclic rearrangements [40] (Scheme 25). 

Steinhardt SE, Vanderwal CD (2009) Complex polycycUc lactams from pericyclic cascade reactions of Zincke aldehydes. J Am Chem Soc 131 7546-7547... 

Scheme 7.106 NHC-catalyzed as3mimetric Michael/Mannich/lactamization cascade reaction of 2-bromoenals with tosyl-protected o-amino aromatic aldimines reported by Hui.

Recently, Singh and co-workers reported an unprecedented Cu(I)/pybox-diPh-catalyzed highly enantioselective cascade alkynylation-lactamization reaction of readily available o-formyl methyl benzoates, aromatic amines, and terminal alkynes (Scheme 41) [66]. This protocol provides a straightforward and efficient approach to a wide range of enantiomerically enriched isoindolinones in good yield with an exceptionally high level of enantioselectivity. The methodology was further extended to the synthesis of synthetically important tetrahydroisoquinoline scaffolds in a two-step sequence with remarkable selectivity. 

Scheme 41 Asymmetric cascade aUcynylation-lactamization reaction...

Nocquet, P.-A., Hazelard, D., Compain, P. (2012). Synthesis of spirocyclopropyl y-lactams by tandem intramolecular azetidine ling-opening/closing cascade reaction synthetic and mechanistic aspects. Tetrahedron, 68, 4117-4128. 

The second one-pot cascade reaction was used to complete the synthesis of the natural product from acid 69. Reduction of the two azide groups of 69 produced the highly polar diamine 70, which was treated with EDC and HOBt to induce an intramolecular lactam cyclization and deliver the macro-palau amine 71. When the crude reaction mixture of 71 was heated in TEA, compound 72, proceeding through amidine tautomer 71, elicited the key transannular cyclization and delivered the palau amine in 17% overall yield from 69. The outcome stereochemistry was all in the control of the stereocenters within the substrate. 

SCHEME 6.90 Cascade reaction for the synthesis of spirocyclic lactams. 

By contrast, the use of allyltins /3-substituted by an electron-withdrawing group represents a particularly attractive option, due to their enhanced reactivity towards nucleophilic carbon radicals. For this purpose several allyltins were prepared with amide, ester, chloride, nitrile, trimethylsilyl and sulfones functionalities [292]. They have been used for the synthesis of 1,4-dienes [293] or 10-15 membered a-methylene lactones [294], in aminoacids [295] or carbohydrate chemistry [296]. The /3-functionalization by nonactivating alkyl groups is tolerated as well and was used in the synthesis of prostaglandins [297] or /3-lactams [298]. This was also applied to radical cascade reactions with up to four elementary steps with an excellent diastereoselectivity control (Scheme 6.34) [299]. 

Grigg has utilized the Heck reaction in several ways, from the simple cyclization of N-(2-iodobenzoyl)pyrrole (139) to afford tricyclic lactam (140) [100] to the complex cascade... 

A palladium(0)-catalysed cascade cyclization-Suzuki coupling reaction of various 1,6-enynes (72) with ArB(OH)2 has been developed as a new approach to the synthesis of stereodefined a-arylmethylene-y-butyrolactones, lactams, multifunctional tetrahy-drofurans, pyrrolidines, and cyclopentanes (73) (X = O, H2, Y = O, CH2, NR3). A 7r-allylpalladium intermediate and a chair-like transition state were suggested to account for the stereochemistry of this reaction.86... 

Alcaide et al. have used their methanesulfonate route to fused /3-lactams in a cascade sequence of reactions, including an intramolecular Diels-Alder reaction to obtain tetracyclic compounds (Scheme 17) <2003JOC3106>. 

The enantioselective synthesis of azabicyclic y-lactams starting from 2-azanorbornenones after treatment of a catalytic amount of RuCl2(PCy3)2 (= CHPh) in the presence of ethylene or allyl acetate proceeds also via ring rearrangement—alkene metathesis (ROM-CM-RCM) [41] (Scheme 19). If n = 0 or 3, no RCM occurs and a cyclic dialkenyl compound is formed by cascade ROM-CM reactions. 

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