Nitroaldol reactions complex

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, 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. 

H. Sasai, T. Tokunaga, S. Watanabe, T. Suzuki, N. Itoh, M. Shibasaki, Efficient Diastereoselective and Enantiose-lective Nitroaldol Reactions from Prochiral Starting MaterialsStUtilization of La-Li-6,6 -Disubstituted BINOL Complexes as Asymmetric CatalystsUtJ. Org Chem 1995, 60, 7388-7389. 

Recently, a synthesis of tetrodotoxin from D-glucose was described (Scheme 36). After a Michael addition of the lithium salt of bis(phenylthio)-methane to the nitroolefin 116, the major component (117b) of the resulting epimeric mixture 117a + 117b was subjected to a reaction sequence that involved an intramolecular nitroaldol reaction, to give the complex nitro cyclohexane derivative 118. 

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 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. 

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 asymmetric catalytic nitroaldol reaction, also known as the asymmetric Henry reaction, is another example of an aldol-related synthesis of high general interest. In this reaction nitromethane (or a related nitroalkane) reacts in the presence of a chiral catalyst with an aldehyde, forming optically active / -nitro alcohols [122], The / -nitro alcohols are valuable intermediates in the synthesis of a broad variety of chiral building blocks, e.g. / -amino alcohols. A highly efficient asymmetric catalytic nitroaldol reaction has been developed by the Shibasaki group, who used multifunctional lanthanoid-based complexes as chiral catalysts [122-125],... 

Strongly chelating ligands provide a sterically rigid ligand frame, a prerequisite for induction of asymmetry at the lanthanide center. Complexes derived from (S)-( — )-BINOL were thoroughly studied in the nitroaldol reaction (Henry reaction, Scheme 27) [250]. 

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

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. 

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... 

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... 

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

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... 

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%... 

Finally, a fascinating development in the field of lanthanum-BINOL complexes remains to be mentioned [25]. These compounds so far have proved to catalyze enantioselectively hydrophos-phonylations of imines [26], nitroaldol reactions [27], Michael additions [28] and cpoxidations of... 

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 asymmetric nitroaldol reaction between naphthoxyacetoaldehyde and nitromethane (1 50 ratio) is effected by the ( )-BINOL-La complex 67 to give 66 with 92% ee in 80% yield, an intermediate for (S)-Propranolol (Scheme 19) [65,66] (cf. Section 3.2.5). 

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. 

ASYMMETRIC NITROALDOL REACTION USING LANTHANUM-LITHIUM-BINOL DERIVATIVE COMPLEX AS A CATALYST... 

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. 

The proposed mechanism for the asymmetric nitroaldol reaction catalyzed by heterobimetallic lanthanoid complexes is shown in Scheme 2 [9]. In the initial step, the nitroalkane component is deprotonated and the resulting lithium nitr-onate coordinates to the lanthanoid complex under formation of the intermediate I [ 10]. Subsequent addition of the aldehyde by coordination of the C=0 double bond to the lanthanoid(III) ionic center leads to intermediate II, in which the carbonyl function should be attacked by the nitronate via a six-membered transition state (in an asymmetric environment). A proton exchange reaction step will then generate the desired optically active nitroalkanol adduct with regeneration of the free rare earth complex LnLB. 

---