Enones cyclic, tandem addition

Reaction at the C atom of nitronate salts is known with a variety of electrophiles, such as aldehydes (Henry reaction) and epoxides (191-193). Thus the incorporation of the nitro moiety and the cyclization event can be combined into a tandem sequence. Addition of the potassium salt of dinitromethane to an a-haloaldehyde affords a nitro aldol product that can then undergo intramolecular O-alkylation to provide the cyclic nitronate (208, Eq. 2.17) (59). This process also has been expanded to a-nitroacetates and unfunctionalized nitroalkanes. Other electrophiles include functionalized a-haloaldehydes (194,195), a-epoxyaldehydes (196), a-haloenones (60), and a-halosulfonium salts (197), (Chart 2.2). In the case of unsubstituted enones, it is reported that the intermediate nitronate salt can undergo formation of a hemiacetal, which can be acetylated in moderate yield (198). 

Yamamoto and coworkers reported a tandem highly enantioselective 0-nitroso aldol-conjugate addition reaction catalysed by 5a. Cyclic enones and aromatic nitroso compounds afforded the corresponding bicyclic products with excellent enantioselectivity (Scheme 9.49). The results considerably extended the control of regio- and stereochemistry for the synthesis of nitroso Diels-Alder adducts. 

This methodology has been applied successfully by the same group for the addition of phenyl moieties to a variety of unsaturated substrates. For instance, p-arylenals [74], a,p-unsaturated Af-acylamides, and cyclic maleimides [75] and the extension of the methodology to the tandem conjugate addition/aldol cyclization of p-(2-acylaryl)enones to afford optically active l-aryl-lW-indenes [76] represent examples of the work developed by Miyaura s group (Scheme 5.24). 

Furthermore, three-component coupling tandem Michael-aldol reactions were achieved by trapping the aluminium enolate intermediate with an aldehyde (Scheme 19.16a). Initiated by the asymmetric Michael addition of malonic esters to cyclic enones, several natural products were synthesised... 

In 2010, Jorgensen et al. developed an enantioselective tandem reaction of propargylated malononitriles with cyclic enones sequentially catalysed by a cinchona alkaloid-derived primary amine catalyst in the presence of (J )-mandelic acid as an additive for the first Michael step, and a gold catalyst for the second tandem exo-dig cyclisation-isomerisation reaction. " As shown in Scheme 7.62, the corresponding chiral bicyclic enones were achieved in good yields and high enantioselectivities of up to 96% ee, albeit low to moderate diastereoselectivities (34-66% de). 

Enantioselective Michael addition catalyzed by chiral aluminum Lewis acid is one of the most important methods to obtain enantiomerically pure compounds. As an early work in this fleld, in 1986, Shibasaki and coworkers reported catalytic enantioselective Michael addition of malonates to cyclic enones catalyzed by Li-Al bimetallic catalyst (72) (ALB) derived by premixing LiAlH4 and 2 equivalent of (R)-BINOL in THF (Scheme 6.86) [106, 107]. The structure of (R)-ALB was confirmed by X-ray crystallographic analysis of ALB-cyclohexenone complex. One notable advantage of ALB catalyst is that it works nicely in the tandem Michael-aldol sequence. 

Lee et al found that the reaction of cyclic 1,3-dicarbonyl compounds with a,P-unsaturated aldehydes did not give the Michael-type addition products observed for enones (see Section 8.4, Figure 8.26), but products from tandem Knoevenagel condensation and cyclization [210] (Figure 8.95). 

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