Nitroaldol asymmetric

The nitroaldol reaction or Henry reaction is a powerful and highly versatile carbon-carbon bond-forming reaction, allowing a plethora of key molecular frameworks, such as p-hydroxynitroalkanes, 1,2-amino alcohols or a-hydroxy carboxylic acids to be synthesised in a straightforward manner. Therefore, the development of practical catalytic asymmetric versions of this reaction is still largely desirable. The first catalytic asymmetric nitroaldol reaction was reported in 1992, " but despite its long history, relatively few chiral ligands have... 

Table 1. syn-Selective catalytic asymmetric nitroaldol reaction. 

In order to remove a proton from I, we added almost 1 equiv of base to the LLB catalyst. After many attempts, we were finally pleased to find that 1 mol% of second-generation LLB (LLB-II), prepared from LLB, 1 mol equiv of H20, and 0.9 mol equiv of butyllithium efficiently promoted the catalytic asymmetric nitroaldol reactions. Moreover, we also found that the use of LLB-II (3.3 mol%) accelerated these reactions. The use of other bases such as NaO-t-Bu, KO-t-Bu and Ca(0-i-Pr)2 gave less satisfactory results. The results are shown in Table 2 The structure of LLB-II has not yet been unequivocally determined. We propose here, however, that it is a complex of LLB and LiOH a proposed reaction course for its use in an improved catalytic asymmetric nitroaldol reaction is shown at the bottom of Scheme 4. Industrial application of a catalytic asymmetric nitroaldol reaction is being examined. 

H. Sasai, T. Suzuki, S. Arai, T. Arai, M Shibasaki, Basic Character of Rare Earth Metal Alkoxides. Utilization in Catalytic C-C Bond-Forming Reactions and Catalytic Asymmetric Nitroaldol Reactions, J. Am. Chem. Soc 1992,114, 4418-4420. 

H. Sasai, S. Watanabe, M. Shibasaki, A New Practical Preparation Method for Lanthanum-Lithium-Binaphtol Catalysts (LLBs) for Use in Asymmetric Nitroaldol Reactions, Enantiomer, 1997,2,267-271. 

H. Sasai, T. Suzuki, N. Itoh, K. Tanaka, T. Date, K. Oka-mura, M Shibasaki, Catalytic Asymmetric Nitroaldol Reaction Using Optically Active Rare Earth BINOL Complex Investigation of the Catalyst Structure, J. Am Chem Soc 1993,115,10372-10373. 

Palomo, C. Oiarbide, M. Mielgo, A. Unveiling reliable catalysts for the asymmetric nitroaldol (Henry) reaction. Angew. Chem. Int. Ed. 2004,43,5442-5444. 

Scheme 12.22 Asymmetric nitroaldol (Henry) reaction of various aldehydes (Pe-h) with nitromethane.

The catalytic asymmetric nitroaldol reaction was extended to a direct catalytic asymmetric nitro-Mannich-type reaction promoted by hetero-bimetallic catalysts (Scheme 2) [53-55] or by EtjNBOX-Cu complexes [56]. These topics are reviewed in Chap. 28.2. 

Shibasaki et al. have reported an asymmetric nitroaldol reaction catalyzed by chiral lanthanum alkoxide 18 to produce an optically active 2-hydroxy-1-nitroalkane with moderate-to-high enantiomeric excesses (Scheme 8B1.10) [27]. Apparently this novel catalyst acts as Lewis base. The proposed reaction mechanism is shown in Scheme 8B1.11, where the first step of the reaction is the ligand exchange between binaphthol and nitromethane. This reaction is probably the first successful example of the catalytic asymmetric reaction promoted by a Lew i s base metal catalyst. Future application of this methodology is quite promising. 

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. 

Initial investigations showed that the treatment of trimethylsilyl nitronate 23a (R1 = Me) with benzaldehyde (R2 = Ph) in the presence of (S,S)-6b (X = HF2, 2 mol %) in TH F at —98 °C for 1 h and at —78 °C for 1 h and subsequent hydrolysis with 1M HC1 at 0 °C, resulted in clean formation of the corresponding nitroalkanol 24 (R1 = Me, R2 = Ph) in 83% yield (anti/syn = 74 26) with 33% ee (anti isomer) (entry 1 in Table 9.5). Notably, the poor diastereo- and enantioselectivities were dramatically improved by switching the catalyst to (S,S)-6c (X = HF2) possessing a radially extended 3,3-aromatic substituent (Ar), and 24 (R1 = Me, R2 = Ph) was obtained in 92% yield (anti/syn = 92 8 with 95% ee (anti isomer) (Table 9.5, entry 2). This asymmetric nitroaldol protocol tolerates various aromatic aldehydes to afford anti-nitroaldols selectively, being complementary to Shibasaki s method... 

Table 9.5 Asymmetric nitroaldol reactions catalyzed by chiral quaternary ammonium bifluorides 6.

During the course of studies on these asymmetric nitroaldol reactions catalyzed by chiral ammonium bifluorides 6 (X= HF2), the reaction of 23a was attempted with trans-cinnamaldehyde, a representative a,P-unsaturated aldehyde, under the influence of (R,R)-6c (X = HF2, 2mol%) in THF at — 78 °C. The starting aldehyde was consumed within 30 min at this temperature and, surprisingly, the 1,4-addition product 25 was obtained predominantly as a diastereomeric mixture with concomitant formation of the initially expected nitroaldol (1,2-addition product) 26 [72% combined yield, 25/26 = 17 1, syn/antiof25 = 85 (4% ee) l 5 (25% ee)] (Scheme 9.13). 

In addition to this highly enantioselective metal-catalyzed approach, several orga-nocatalytic versions of the asymmetric nitroaldol reaction have recently been reported. The Najera group used enantiomerically pure guanidines with and without C2 symmetry as chiral catalysts for the addition of nitromethane to aldehydes [126], When the reaction was conducted at room temperature yS-nitro alcohols of type 120 were obtained in yields of up to 85% but enantioselectivity, 26% ee or below, was low. A selected example is given in Scheme 6.52. Higher enantioselectivity, 54% ee, can be obtained at a low reaction temperature of —65 °C, but the yield (33%) is much lower. 

For a review about the asymmetric nitroaldol reaction, see M. Shibasaki, H. Grocer in Comprehensive Asymmetric Catcdysis, Volume 3, Eds. ... 

Sasai, H. Suzuki, T. Arai, S. Arai, T. Shiba- 446 saki, M. Basic character of rare earth metal alkoxides. Utilization in catalytic C-C bondforming reactions and catalytic asymmetric nitroaldol reactions./. Am. Chem. Soc. 1992,... 

A. Catalytic, asymmetric nitroaldol reaction promoted by the lanthanoid-lithium-BINOL complex (LnLB)... 

C. Application of catalytic, asymmetric nitroaldol reactions using nitromethane... 

F. Tandem inter-intramolecular catalytic, asymmetric nitroaldol reaction... 

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. 

Figure 9. Catalytic asymmetric nitroaldol reactions promoted by catalyst 49.

The lanthanoid and group 3 metals, the so-called rare earth elements, are generally regarded as a group of 17 elements with similar properties, especially with respect to their chemical reactivity. However, in the above-mentioned catalytic asymmetric nitroaldol reactions, pronounced differences were observed both in the reactivity and in the enantioselectivity of the various rare earth metals used.29 For example, when benzaldehyde (54) and nitromethane (12) were used as starting materials, the EuLB complex gave 55 in 72% ee (91% yield) compared to 37% ee (81% yield) in the case of LLB (-40 °C, 40 h). The unique relationship... 

C. Application of Catalytic, Asymmetric Nitroaldol Reactions Using... 

The nitroaldol (Henry) reaction6 is a powerful synthetic transformation and has been utilized in the construction of numerous natural products and other useful compounds.30 31 As shown in Figure 9, as little as 3.3 mol % of the LLB complex is a general and effective catalyst for the asymmetric nitroaldol reaction. The... 

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... 

Catalytic, Asymmetric Nitroaldol Reactions Promoted by Various LLB-type Complexes... 

Catalytic, Asymmetric Nitroaldol Reactions of ot,a-difluoro Aldehydes... 

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