Catalytic asymmetric nitroaldol reaction

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, 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. 

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. 

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... 

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... 

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

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

Figure 24. A possible mechanism for catalytic asymmetric nitroaldol reactions.

The structure of LLB-II is still not secure. However, a reasonable proposal is that it is composed of a complex of LLB and LiOH. A proposed reaction course for an improved catalytic, asymmetric nitroaldol reaction is shown in Figure 25. The key feature of this proposal is the formulation of a discrete complex (II) between LLB and the lithio nitronate. This species is proposed to be a faster-acting reagent than the protio-form. In support of this hypothesis is the observation that treatment of the lithium nitronate (0.9 mol %) generated from nitropropane and butyllithium, with 69g (1 mol %), 2, and nitropropane (83) under similar conditions as those described above, gave comparable results (59% yield, syn/anti, 94/6,94%... 

Figure 25. Proposed mechanism for the catalytic asymmetric nitroaldol reaction promoted by LLB, LLB-II, or LLB-Li-nitionate.

In both catalytic, asymmetric Michael reactions and nitroaldol reactions, enones and/or aldehydes appear to coordinate to the lanthanoid metal. Why, then, is LSB more effective for catalytic, asymmetric Michael reactions, whereas LLB is more effective for catalytic, asymmetric nitroaldol reactions This disparity might arise from slight differences in bond lengths in the chelated intermediate, as well as slight differences in bite angle for the BINOL moiety caused by varying the alkali metal. 

For example, an effective procedure for the synthesis of LLB (where LL = lanthanum and lithium) is treatment of LaCls 7H2O with 2.7 mol equiv. BINOL dilithium salt, and NaO-t-Bu (0.3 mol equiv.) in THF at 50 °C for 50 h. Another efficient procedure for the preparation of LLB starts from La(0-/-Pr)3 [54], the exposure of which to 3 mol equiv. BINOL in THF is followed by addition of butyllithium (3 mol equiv.) at 0 C. It is worthy of note that heterobimetallic asymmetric complexes which include LLB are stable in organic solvents such as THF, CH2CI2 and toluene which contain small amounts of water, and are also insensitive to oxygen. These heterobimetallic complexes can, by choice of suitable rare earth and alkali metals, be used to promote a variety of efficient asymmetric reactions, for example nitroaldol, aldol, Michael, nitro-Mannich-type, hydrophosphonylation, hydrophosphination, protonation and Diels-Alder reactions. A catalytic asymmetric nitroaldol reaction, a direct catalytic asymmetric aldol reaction, and a catalytic asymmetric nitro-Mannich-type reaction are discussed in detail below. 

The nitroaldol (Henry) reaction has been recognized as a powerful synthetic tool and has been used in the construction of numerous natural products and other useful compounds. We succeeded in realizing the first example of a catalytic asymmetric nitroaldol reaction by the use of a catalytic amount of LLB. 

Having succeeded in obtaining the first results from a catalytic asymmetric nitroaldol reaction, we attempted to apply the method to the catalytic asymmetric synthesis of biologically important compounds. The nitroaldol products were readily converted into /3-amino alcohols and/or ct-hydroxy carbonyl compounds and convenient syntheses of three kinds of optically active /1-blocker are presented in Sch. 8 [55-57]. 

Catalytic asymmetric nitroaldol reactions promoted by LLB or its derivatives require at least 3.3 mol % asymmetric catalyst for efficient conversion, and even then the reactions are rather slow. To enhance the activity of the catalyst, consideration of the possible mechanism of catalytic asymmetric nitroaldol reactions is clearly a necessary prerequisite to formulation of an effective strategy. One possible mechanism of catalytic asymmetric nitroaldol reactions is shown at the top of Sch. 10. We strove to detect the postulated intermediate I by use of a variety of methods, but were unsuccessful, probably owing to the low concentrations of the intermediate, which we thought might be ascribed to the presence of an acidic OH group in close proximity. 

Having developed an efficient catalytic asymmetric nitroaldol reaction, we next applied our attention to a direct catalytic asymmetric aldol reaction. The aldol reaction is generally regarded as one of the most powerful carbon-carbon bond-forming reactions. The development of a range of catalytic asymmetric aldol-type reactions has proven to be a valuable contribution to asymmetric synthesis. In all these catalytic asymmetric aldol-type reactions, however, preconversion of the ketone moiety to a more reactive speeies such as an enol silyl ether, enol methyl ether or ketene silyl... 

The basic character of lanthanide alkoxides such as Lu3(Of-Bu)9 seem to effect aldol, cyanosilylation, aldol, and Michael reactions [111]. Complexes 2 and 22, abbreviated as LnMB (Ln = lanthanide, M = alkali metal, B = BR IOL) [112] were thoroughly studied in the catalytic, asymmetric nitroaldol reaction (Henry reaction eq. (10)) [113]. 

Sasai, H., Itoh, N., Suzuki, T., Shibasaki, M. Catalytic asymmetric nitroaldol reaction an efficient synthesis of (S)-propranolol using the lanthanum binaphthol complex. Tetrahedron Lett. 1993, 34, 855-858. 

By using the catalyst prepared as described above, the first example of a catalytic asymmetric nitroaldol reaction was realized. The results are summarized in Scheme 3. Starting from prochiral aldehydes 1 to3, the desired products 4 to 6 were obtained in good chemical yields and with enantioselectivities up to 90% ee [8]. The amount of the catalyst is not shown in Scheme 3 due to the unknown structure of the catalyst (at this time). 

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