Nitroolefins asymmetric conjugate addition

Aluminum salen complexes have been identified as effective catalysts for asymmetric conjugate addition reactions of indoles [113-115]. The chiral Al(salen)Cl complex 128, which is commercially available, in the presence of additives such as aniline, pyridine and 2,6-lutidine, effectively catalyzed the enantioselective Michael-type addition of indoles to ( )-arylcrolyl ketones [115]. Interestingly, this catalyst system was used for the stereoselective Michael addition of indoles to aromatic nitroolefins in moderate enantiose-lectivity (Scheme 36). The Michael addition product 130 was easily reduced to the optically active tryptamine 131 with lithium aluminum hydride and without racemization during the process. This process provides a valuable protocol for the production of potential biologically active, enantiomerically enriched tryptamine precursors [116]. 

Chiral heterocychc amines as organocatalysts for asymmetric conjugate addition to nitroolefins and vinyl sulfones via enamine activation 07CC3123. 

High enantioselectivites in the aza-Michael reaction have been achieved using alternate organocatalysts, and the addition of benzotriazole to nitroolefins occurs with up to 94% ee using bifimctional catalysts such as (11.64). Guerin and Miller have developed an alternate approach to the enantioselective introduction of triazoles based on the asymmetric conjugate addition of azide followed by a 1,3-dipolar cycloaddition of the product with an alkyne. In this approach, the addition of hydrazoic acid to Michael acceptors such as (11.133) proceeds with good ee in the presence of the dipeptide (11.134). ... 

The asymmetric conjugate addition of activated methylenes is one of the most studied organocatalytic reactions. A wide variety of Michael acceptors such as enals, enones, a,P-unsaturated nitriles, nitroolefins, a,(i-unsaturated imides, and vinyl sulfones have been successfully employed as elechophiles with high degree of stereocontrol. 

Fig. 2.22 Asymmetric conjugate additions of p-ketoesters to nitroolefins catalyzed by bifunctional organocatalysts...

Scheme 2.93 PTC asymmetric conjugate additions of oxindoles to nitroolefins...

Scheme 2.136 Asymmetric conjugate addition of thioacetic acid to nitroolefins...

The utility of the alkylidene oxindole-derived vinylogous enolates was demonstrated in the y-selective asymmetric conjugate addition to nitroolefins (Scheme 38) [67, 68]. Dihydroquinine-derived thiourea 10 earned distinctirm as the most effective catalyst in terms of catalytic efficiency and stereocontroUing ability. The tertiary amine and the thiourea functionalities both appeared to be essential for ensuring catalytic activity. It should be noted that not only perfect y-selectivity but also very high /Z-selectivity were observed under the optimal conditions. A wide variety of nitroolefins and substituted alkylidene oxindoles were amenable to this protocol. 

The development of a highly enantioselective catalytic asymmetric conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes is described, as is its use in the synthesis of the selective endothelin A antagonist ABT-546. Employing 4 mol% of a bis(oxazoline)-Mg(OTf)2 complex with 5.5 mol% of an amine co-catalyst, the product nitroketone is obtained in 88% ee, with good yields. Particularly important to the reaction is the water content. While water is necessary during the generation of the catalyst, the water must then be removed in order to maximize selectivity and reactivity. The scope of the reaction has been extended to other ketoester and malonate nucleophiles, as well as other nitroolefins. 

Scheme 34.9 Asymmetric conjugate addition of oximes to nitroolefins.

Sulzer-Mosse S, AlexaMs A. Chiral amines as organocatalysts for asymmetric conjugate addition to nitroolefins and vinyl sulfones via enamine activation. Chem. Commun. 2007 (30) 3123-3135. 

Modified cinchona alkaloids 18 and 19, derived from quinine and quinidine, respectively, were utilized by Deng and co-workers for the catalytic asymmetric Michael additions of malonates to nitroolefins [49]. These catalysts effectively promoted the conjugate additions of methylmalonate to a variety of aromatic (90-99% yield 96-98% ee), heteroaromatic (97-99% yield 96-98% ee) and aliphatic (71-86% yield 94% ee) -substituted nitroolefins (Table 6.7). As the two alkaloids... 

The oxygen of the nitro moiety can also be involved in the formation of the C-O bond. In this context, Mamoka et al. [52] recently disclosed an asymmetric organo-catalytic synthesis of various isoxazoline-A -oxides by phase-transfer conjugate addition of bromomalonate to nitroolefins and subsequent ring-closing 0-alkylation (Scheme 16.26). 

In contrast to the extensive use of nitroolefins in asymmetric Michael additions [10], the vinylogous analogues, nitrodienes and nitroenynes, are less frequently utilized in the conjugate addition of enolate equivalents, despite the significant synthetic utility of the resulting products which possess carbonyl, nitro, and olefin functionalities. Likewise, studies on the hetero-Michael reaction with these acceptors have been very limited, possibly because of apprehension of the site-selectivity issue [11]. 

The asymmetric catalysis of the phosphonium aryloxide-arylhydroxide assembly 21 was also applicable to the y-selective conjugate addition of C2-unsubstituted azlactone to nitroolefins, where use of a polar solvent system was crucial for sufficient reaction efficiency and stereoselectivity (Scheme 19) [36]. Various... 

A practical and highly enantioselective Michael addition of malonates to enones catalysed by bifunctional primary amine-thiourea (5) derived from 1,2-diaminocyclohexane has been reported. The addition of weak acids and elevated temperature improved the efficiency of the Michael reaction. This approach enables the efficient synthesis of 1,5-ketoesters with good yields, excellent enantioselectivities (up to 99% ee), and low loading (0.5-5 mol%) of catalysts. A related bifunctional cinchona-thiourea catalyst has been involved in asymmetric organocatalysed conjugate addition reactions of monoth-iomalonates to nitroolefins. ... 

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