Nitroalkenes, asymmetric conjugate addition

Recently, very effective asymmetric conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes has been reported, as shown in Scheme 4.10. The reaction of ethyl acetoacetate with nitrostyrene is carried out in the presence of 5 mol% of the preformed complex of magnesium triflate and chiral bis(oxazoline) ligands and a small amount ofW-methylmorpholine (NMM) to give the adduct with selectivity of 91%. The selectivity depends on ligands. The effect of ligands is presented in Scheme 4.10.63... 

In 1993, Alexakis et al. reported the first copper-catalyzed asymmetric conjugate addition of diethylzinc to 2-cyclohexenone using phosphorous ligand 28 (32% ee).36 An important breakthrough was achieved by Feringa et al. with chiral phosphoramidite (S,R,R)-29 (Figure 1), which showed excellent selectivity (over 98% ee) for the addition of 2-cyclohexenone.37 Since then, efficient protocols for the conversion of both cyclic and acyclic enones, as well as lactones and nitroalkenes, have been developed featuring excellent stereocontrol. 

Asymmetric Conjugate Addition with NitroaLkenes and Sulfones. 157... 

Asymmetric Conjugate Addition with Nitroalkenes and Sulfones... 

As shown in Eq. (4), parallel screening of ligand libraries has allowed us to establish that a closely related peptide-based phosphine ligand promotes the catalytic asymmetric conjugate addition of alkylzincs to nitroalkenes [14]. Not only are the corresponding alkyl nitrones obtained efficiently and in high diaster-eo- and enantioselectivity, appropriate acid workup can deliver the derived ketone directly. 

The first examples of catalytic asymmetric conjugate addition of alkylzinc reagents to trisubstituted nitroalkenes, such as PhC(Me)=CHN02, leading to the formation of nitroalkanes bearing a quaternary carbon stereogenic centre, have been reported. Reactions are promoted by the readily available amino acid-based phosphine (211)... 

The asymmetric conjugate addition of arylalkynes ArC=CH to nitroalkenes can be mediated by dimethylzinc (or diethylzinc) and (l/f,2/J)-2-(dimethylamino)-l,2-diphenylethanol as chiral ligand in toluene the resulting products were obtained in high ee (<99%) and good yields. The presence of 0.03 equiv. of galvinoxyl improved the reaction yield.259... 

S)-Pyrrolidine trifluoromethanesulfonamide 3a is a highly active catalyst for the asymmetric conjugate addition of aldehydes and ketones to nitroalkenes. The use of catalyst 3a (20 mol%) in i-PrOH at 0 °C, afforded a,a-dialkyl aldehydes with good to high yields and high to excellent levels of diastereo- and enantioselectivity (Scheme 9.20). In addition, the reactions of various cyclic and acyclic ketones with aromatic nitro-olefins indicated the usefulness of the catalyst. " Computational results corresponded with the observed stereoselectivities of 3a-catalysed Michael reactions. 

The asymmetric conjugate addition reaction has been applied to a,P-unsaturated amides,alkenylphosphonates, and ethenesulfonamides. Hayashi and co-workers have also applied the standard reaction conditions to nitroalkenes. The reaction was found to be applicable to a variety of arylboronic acids. The reaction was also extended to acyclic nitroalkenes without loss of selectivity, but not to nitrocycloheptene or nitrocyclopentene. Interestingly, the thermodynamically less stable cis isomers, e.g., 266, were formed in the reaction of nitrocyclohexene (265) with a wide range of arylboronic acids, e.g., 254. The initial products could be readily converted to the more stable trans isomers by treatment with base. 

Scheme 2.129 Asymmetric conjugate addition of diphenylphosphite to nitroalkenes...

The amine-catalysed asymmetric conjugate addition of aldehydes to nitroalkenes is a powerful tool for stereoselective carbon-carbon bond formation, and hence, a large number of chiral amine catalysts have been developed to date. ° In most amine-catalysed reactions, q n-conjugate adducts were obtained as major diastereomers. For instance, the reaction catalysed by a chiral pyrrolidine (5 )-6 gave a sy -conjugate adduct with excellent enantioselectivity (Scheme 17.13). In contrast, the reaction using a biphenyl-based amine catalyst (S)-7 is complementary to most amine-catalysed... 

Silyl nitronates, the preactivated nucleophiles of nitroalkanes, are also applicable in the asymmetric conjugated addition reaction with a,(S-unsaturated aldehydes, ketones, and nitroalkenes. Maruoka and co-workers [115] found that AT-spiro... 

Scheme 36 Asymmetric conjugate addition to nitroalkene 151 in the synthesis of (—)-botryodiplodin (155)...

In 2014, Hamashima and Kan reported the practical total syntheses of acro-melic acids A and B, having potent neuro-excitatory activity, which were based on enantioselective nickel-catalysed asymmetric conjugate additions of a-keto esters to nitroalkenes. Indeed, the key steps of the syntheses of these natural... 

Hayashi, T. Senda, T Ogasawara, M. Rhodium-Catalyzed Asymmetric Conjugate Addition of Organoboronic Acids to Nitroalkenes. J. Am. Chem. Soc. 2000,122,10716-10717. 

In a study of organocatalytic asymmetric conjugate addition (ACA) of nitroalkenes to aldehydes, ESI-MS has been used to identify intermediates and the stereoselective step. Starting with quasi-enantiomeric reaction products, MS is used for back-reaction 0 screening and supports the enamine mechanism (over the enol route). 0... 

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. 

This chapter covers the recent literature reports (ca. 2003 onward) on asymmetric conjugate addition of triorganoaluminum reagents to enones, a,(3-unsaturated systems, nitroalkenes and also mechanistically closely related allylic alkylation of allylic phosphonates. It also includes cascade processes where the intermediate enolates (conjugate addition) and alkenes (allylic alkylation) are used for the synthesis of more complex molecules. This chapter is organized as follows. In Sect. 2 we present the results in the asymmetric conjugate addition. In this part, the... 

Cinchona alkaloids or their derivatives. Mechanistically, Cinchona alkaloids deprotonate an acidic proton affording a contact ion pair hetween the anion and protonated amine, resulting in a chiral environment around the anion. A typical example which could potentially he applied to drug discovery is the asymmetric conjugate addition of enolate 325 to nitroalkene 326, catalysed hy Cinchona alkaloid 328, as descrihed hy Li et al. (Scheme 14.99). ... 

The conjugate addition of phosphorus nucleophiles of various oxidation states and in neutral or metallated form constitutes an efficient and well-known method for C—P bond formation [30]. In the case of phosphanes as nucleophiles especially, the corresponding phosphane-borane adducts have been used in 1,4-additions to Michael acceptors. Following the idea to use a chirally modified phosphorus nucleophile in asymmetric Michael additions to aromatic nitroalkenes, we synthesized the new enantiopure phospite 45 starting from TADDOL (44) with nearly quantitative yield. Due to the C2 symmetry, of the... 

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