Enantioselection nitroaldol reaction

In addition, highly enantioselective nitroaldol reactions were performed by Bandini et al. by using a new class of C2-symmetric oligothiophene ligands, in 2007. Thus, associated to copper, these C2-symmetric bis(amino) ligands allowed the synthesis of a wide range of enantiomerically enriched nitroalcohols... 

The enantioselective nitroaldol reaction of phe-nylalaninals 45 with nitromethane was also promoted with the N-anthracenylmethyl ammonium fluorides in the presence of potassium fluoride.1411 Interestingly, as shown in Scheme 16, the major product was the (2R,3S)-isomer 46a when N,N-dibenzyl-(S)-phenylalaninal and 12 (R=benzyl, X=F) were used while the (2S,3S)-isomer 46b was major when N-tert-butoxycarbonyl derivative 45b and 12 (R=allyl, X=Br) together with potassium fluoride were used. The nitroalcohols 46a and 46b were respectively converted to amprenavir 47a, a HIV protease inhibitor, and its diastereomer 47b. The... 

The catalytic activity of a lanthanum (R)-BINOL complex tethered either on silica (62a) or MCM-41 (62b) was evaluated for the enantioselective nitroaldol reaction of cyclohexanecarboxaldehyde (Se), hexanal (Sf), iso-butyraldehyde (Sg) and hydro-cinnamaldehyde (Sh) with nitromethane inTHF (Scheme 12.22) [166]. The silica-anchored lanthanum catalyst 62a gave 55-76% e.e. and yields up to 87%, while the PMS-immobilized catalyst 62b revealed slightly higher e.e.s (57-84%) for the same aldehydes. The homogeneous counterparts showed similar catalytic performance, albeit within a shorter reaction time. The increased enantioselectivity observed for the MCM-41 hybrid catalyst 62b was explained by transformations inside the channels, which is also reflected by lower yields due to hindered diffusion. The recyclability of the immobilized catalysts 62b was checked with hydrocin-namaldehyde (Ph). It was found that the reused catalyst gave nearly the same enantioselectivities after the fourth catalytic run, although the time period for achieving similar conversion increased from initially 30 to 42 h. 

The nitroaldol reaction, particularly involving ketones has been relatively unexplored in the field of asymmetric organocatalysis. Employing cupreines and cupreidines as catalysts, Deng [63] presented an enantioselective nitroaldol reaction of a-ketoesters... 

The catalytic asymmetric Henry reaction has been reviewed.42 Mild and efficient enantioselective nitroaldol reactions of nitromethane with various aldehydes have been catalysed by chiral copper Schiff-base complexes yielding the corresponding adducts with high yields and good enantiometric excess.43,44... 

The enantioselective nitroaldol reaction in the presence of alkaloid-based organo-catalysts has been investigated by the Matsumoto group [127]. A further focus of this study was investigation of the effect of high pressure on the course of the reaction. Addition of nitromethane to benzaldehyde at atmospheric pressure resulted in a low (4%) yield and 18% ee when a catalytic amount (3 mol%) quinidine was... 

LLB-type catalysts were also able to promote diastereoselective and enantioselective nitroaldol reactions starting from substituted nitroalkanes. In preliminary work, however, LLB itself gave unsatisfactory results in terms of both diastereoselectivity (syn/anti ratio 63 37 to 77 23) and enantioselectivity (<78% ee).32 To address the problem of modest enantio- and diastereoselectivities with... 

Figure 21. Proposed transition states of diastereoselective and enantioselective nitroaldol reactions.

The LLB catalysts described above served an important role in demonstrating the proof of principle for catalysis with lanthanide-BINOL complexes. In addition, they were the first catalysts for the enantioselective nitroaldol reaction and gave respectable selectivities in synthetically useful yields. However, the reactions required at least 3.3 mol % of the catalysts for efficient conversion, and at that loading the reactions are rather slow. Clearly, the need for more effective catalysts is indicated. Consideration of the mechanism for the catalytic asymmetric... 

Enantioselective nitroaldol reaction (Henry reaction) of simple trifluoromethyl ketone was reported by Tur and Saa [27] (Table 8.7). Reaction of trifluoromethyl ketones with nitromethane in the presence of lanthanum (III) triflate salt complex and Proton Sponge (1) (0.25 equiv. each) gave tertiary nitroaldols in 50-93% yields with... 

Table 13.36 Diastereo- and enantioselective nitroaldol reactions RCHO...

Catalytic asymmetric nitroaldol (Henry) reactions of ketones lead to synthetically versatile chiral tertiary nitroaldols. Enantioselective nitroaldol reactions of a-keto esters have been achieved using chiral Cu and Mg complexes, and cinchona alkaloids [140]. However, there are no reports on the asymmetric synthesis of tertiary nitroaldols derived from simple ketones. Even for a racemic version, only a few methodologies with limited substrate scope are available. The difficulty arises from the attenuated reactivity of ketones and their strong tendency toward a retro-nitroaldol reaction under basic conditions. (S)-LLB catalyst was found suitable to promote retro-nitroaldol reaction and a kinetic resolution of racemic tert-nitroaldols was realized. (S)-LLB preferentially converted the matched (R)-enantiomer into ketone and nitromethane, whereas the mismatched (S)-enantiomer remained unchanged and was recovered in an enantiomerically... 

Very recently a number of additional copper complexes with chirality derived from sources other than bisoxazoline ligands have been reported for application in enantioselective nitroaldol reactions [46]. Of particular interest was an application of iminopyridine ligand (161) in a Cu(II)-catalyzed nitroaldol reaction, Pedro and CO workers reported efficient addition of (154) to o-anisaldehyde (160) with good enantioselectivity (Scheme 17.33) [47]. 

Henry Reactions. An enantioselective nitroaldol reaction was catalyzed by a Cu(OAc)2-oxazoline complex. Various aldehydes were treated with nitromethane in the presence of the copper catalyst giving the desired /3-nitroalcohols in good to excellent yields and enantiomeric excesses (eq 32). 

Interfacially active guanidinium-thiourea bifunctional catalyst 190 catalyzes highly enantioselective nitroaldol reactions in the presence of an external base such as KOH in toluene/water biphasic conditions. Although the retro-nitroaldol reactions generally proceed under basic conditions, addition of KI inhibits the retro-process. A cooperative reaction mode between guanidinium and thiourea moieties is supported by experiments using structural variants of 190. A positive nonlinear effect is observed between the enantiomeric excess of 190 and the product 191. These results support the hypothesis that self-a egation of 190 is necessary for catalysis (Scheme 28.22) (96, 97). Catalyst 190 has been used in the synthesis of chiral tertiary alcohol products obtained in nitroaldol reactions of nitroalkanes and a-ketoesters [98],... 

A new class of chiral bifunctional cinchona-alkaloid catalyst with urea moiety at C5 has recently been reported by Connon and coworkers, and successfully applied in enantioselective nitroaldol reaction of nitromethane with aromatic... 

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