Nitroaldol heterobimetallic catalysts

Another highly useful heterobimetallic catalyst is the aluminum-lithium-BINOL complex (ALB) prepared from LiAlH4 and 2 equiv. of (/ )-BINOL. The ALB catalyst (10 mol %) is also effective in the Michael reaction of enones with various malonates, giving Michael products generally with excellent enantioselectivity (91-99% ee) and in excellent yields [23]. These results ate summarized in Table 8D.3. Although LLB and LSB complement each other in their ability to catalyze asymmetric nitroaldol and Michael reactions, respectively, the Al-M-(/ )-BINOL complexes (M = Li, Na, K, and Ba) are commonly useful for the catalytic asymmetric Michael reaction. 

Hydrophosphonylation, Nitroaldol Reaction (Kaneka Co., Hokko Chemical Industry). First industrial applications of the heterobimetallic catalysts developed by Shibasaki were realized for the synthesis of several chiral-building blocks. The catalysts are aluminum or lanthanoid cations coordinated to two and three binol ligands, respectively. In addition, one or several alkali metals are coordinated to the binol as well. The asymmetric hydrophosphonylation methodology (85) is now being applied to the preparation of several a-amino phosphonic acids... 

Fig. 11 Catalytic asymmetric nitroaldol reaction with Nd/Na heterobimetallic catalyst...

The utility of the anti-selective nitroaldol reaction was highlighted by the efficient large-scale synthesis of the key intermediate of a p3-adrenoreceptor agonist 4, which is under the clinical trial (Scheme 9). The anti-selective nitroaldol reaction of 4-benzyloxybenzaldehyde was conducted with 1 mol% of the heterogeneous heterobimetallic catalyst on 50 g scale, affording the desired product in 76% yield with antv.syn = >40 1 and 98% ee after recrystaUization. 

The Ln-BINOL derivative complexes are efficient asymmetric catalysts for Michael reactions and the epoxidations of enones. However, as was mentioned above, almost racemic products are obtained in the case of the asymmetric nitroaldol reaction of 2 with 12. For this transformation, a new class of catalysts, heterobimetallic species, have been developed. 

Another advantage was conferred by introducing 6,6 -substituents to BINOL. In general, catalytic asymmetric syntheses of fluorine-containing compounds are rather difficult.42 However, an effective asymmetric nitroaldol reaction of the rather unreactive a,ct-difluoro aldehydes proceeded satisfactorily when using the heterobimetallic asymmetric catalysts generated from 6,6 -bis[(triethylsilyl)-ethynyl]BINOL, as shown in Table 5 43 The -configuration of the nitroaldol adduct 71 showed that the nitronate reacted preferentially on the Si face of the... 

In 1992, Shibasaki et al. [8] reported for the first time on the use of recently developed chiral heterobimetallic lanthanoid complexes (LnLB) as chiral catalysts in the catalytic asymmetric Henry reaction (Scheme 1). In the following sections, this efficient concept of an asymmetric nitroaldol reaction, its scope and limitations, and its applications to complex stereoselective synthetic topics are described. 

A further example of a diastereoselective nitroaldol reaction using heterobimetallic lanthanoid complexes as catalysts was recently reported by Okamoto et... 

The LLB type catalysts were also successfully applied in the asymmetric ni-troaldol reaction of quite unreactive a,a-difluoro aldehydes. However, catalytic asymmetric nitroaldol reaction of a broad variety of a,a-difluoro aldehydes proceeded satisfactorily when using the heterobimetallic asymmetric catalysts with modified, 6,6 -disubstituted BINOL ligands [22]. The best results were obtained with the samarium (III) complex (5 mol%) generated from 6,6 -bis[(tri-ethylsilyl)ethynyl BINOL with enantioselectivities up to 95% ee. The ( -configuration of one representative nitroaldol adduct showed that the nitronate reacted preferentially on the Si face of aldehyde in the presence of (P)-LLB (20 mol% 74% yield 55% ee). It is noteworthy that the enantiotopic face selection for a,a-difluoro aldehydes is reverse to that for nonfluorinated aldehydes. The stereoselectivity for a,a -difluoro aldehydes is identical with that of P-oxa-aldehydes, suggesting that the fluorine atoms at the a-position have a great influence on enantioface selection. 

A further example of a diastereoselective nitroaldol reaction using heterobimetallic lanthanoid complexes as catalysts was recently reported by Okamoto et al. [18] in connection with a novel approach to lc/.,24( R)-dihydroxyvitamin D3... 

The catalytic asymmetric nitroaldol reactions promoted by LLB or its derivatives require at least 3.3 mol% of asymmetric catalysts for efficient conversion. However, even in the case of 3.3 mol% of catalyst, reactions are rather slow. Attempts were made to reduce the required catalytic amount and accelerate the reactions, which led to a second-generation heterobimetallic lanthanoid catalyst (LLB-II), prepared from LLB, 1 mol equiv of H20, and 0.9 mol equiv of butyllith-ium. The use of only 1 mol% of LLB-II efficiently promoted catalytic asymmetric nitroaldol reactions and additionally LLB-II (3.3 mol%) accelerated these reactions [32]. A comparison of the efficiency of LLB (or LL(B-a)) and the second-generation catalysts LLB-II (or LL(B-a)-II) is given in Scheme 9. The structure of LLB-II has not yet been unequivocally determined. However, it appears that it is a complex of LLB and LiOH. 

In conclusion, chiral heterobimetallic lanthanoid compexes LnMB, which were recently developed by Shibasaki et al., are highly efficient catalysts in stereoselective synthesis. This new and innovative type of chiral catalyst contains a Lewis acid as well as a Bronsted base moiety and shows a similar mechanistic effect as observed in enzyme chemistry. A broad variety of asymmetric transformations were carried out using this catalysts, including asymmetric C-C bond formations like the nitroaldol reaction, direct aldol reaction, Michael addition and Diels-Alder reaction, as well as C-0 bond formations (epoxidation of enones). Thereupon, asymmetric C-P bond formation can also be realized as has been successfully shown in case of the asymmetric hydrophosphonylation of aldehydes and imines. It is noteworthy that all above-mentioned reactions proceed with high stereoselectivity, resulting in the formation of the desired optically active products in high to excellent optical purity. 

Scheme 2.43 Enantioselective anti-selective nitroaldol reaction with the use of chiral heterobimetallic neodymium(iii) sodium(i) amidephenol catalyst.

This kind of heterobimetallic complexes are excellent catalysts for a wide range of reactions, including epoxidation of enones, hydrophosphonylation of imines and aldehydes, and a range of asymmetric C-C bond formation reactions, involving Michael addition reaction, Diels-Alder reaction, aldol and nitroaldol reaction, etc. The alkaU metal has a profoimd effect on the catalytic property of these compounds. 

Although heterobimetallic complexes afforded nitroaldol adducts in good stereoselectivity, most reactions required a long reaction time even with relatively high catalyst loadings (3-10 mol%). To achieve a more efficient catalysis, a strategy to accelerate the reaction was investigated. A plausible mechanism of catalytic asymmetric nitroaldol reaction is shown in Scheme 13.42. The concentration of intermediate (A) was considered to be rather low in the reaction mixture because of an... 

Shibasaki and coworkers have developed lanthanoid-lithium-BINOL complexes (LLB catalysts) as efficient catalysts for the asymmetric nitroaldol (Henry) reaction (59-46). The heterobimetallic asymmetric catalysts effectively mediate the reaction of a variety of aldehydes with nitroalkanes to afford the corresponding desired nitroaldols with high enantioselectivity (Scheme 4). We examined the capability of the LLB complexes as asymmetric catalysts for the nitroaldol reaction of 2,2-difluoroaldehydes with nitromethane (47). 

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