Aldol and Nitroaldol Reactions

Mayoralas et al. [70] reported the aldol reaction of hydroxyacetone with different aldehydes catalyzed by immobilized L-proline on a mesoporous support. Heterogenized L-proline on MCM-41 showed higher enantioselectivity (80% ee) than its homogeneous counterpart (75% ee) in the aldol reaction of benzaldehyde with hydroxyacetone in dimethylsulfoxide (DMSO) solvent with the assistance of microwave heating. 

The immobilized catalyst (SiO2-[bmim]BF4-L-prohne, 70) displayed higher enantioselectivity (64% ee) with acceptable activity (51% yield) than the homogeneous conditions (60% ee, 62% yield) in the aldol reaction of acetone and benzaldehyde [71b]. Additionally, this system was even more efficient than the PEG-prohne- 

With homogeneous Proline/ DMSO 60% ee, 62% yield With heterogeneous SILC 70 64% ee, 51% yield 

Entry R Solvent (Hex CH2CI2) Temperature rq Time [h] Yield [%] dr (syn/anti) ee [%] (symanti) 

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Aldol and Nitroaldol Reactions (Preparation of Chiral Quaternary Ammonium Fluorides)... 

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. 

Aldol and Related Condensations As an elegant extension of the PTC-alkylation reaction, quaternary ammonium catalysts have been efficiently utilized in asymmetric aldol (Scheme 11.17a)" and nitroaldol reactions (Scheme ll.lTb) for the constmction of optically active p-hydroxy-a-amino acids. In most cases, Mukaiyama-aldol-type reactions were performed, in which the coupling of sUyl enol ethers with aldehydes was catalyzed by chiral ammonium fluoride salts, thus avoiding the need of additional bases, and allowing the reaction to be performed under homogeneous conditions. " It is important to note that salts derived from cinchona alkaloids provided preferentially iyw-diastereomers, while Maruoka s catalysts afforded awh-diastereomers. 

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]. 

The use of lanthanide complexes in asymmetric catalysis was pioneered by Danishefsky s group with the hetero-Diels-Alder reaction,and their utility as chiral Lewis acid catalysts was shown by Kobayashi. The Brpnsted base character of lanthanide-alkoxides has been used by Shibasaki for aldol reactions, cyanosilylation of aldehydes and nitroaldol reactions.The combination of Lewis acid and Brpnsted base properties of lanthanide complexes has been exploited in particular by Shibasaki for bifunctional asymmetric catalysis. These bimetallic lanthanide-main-group BINOL complexes are synthesized according to the following routes ... 

This review describes the first catalytic asymmetric Mukaiyama-aldol reaction of fluorine-substituted ketene silyl acetals with aldehydes and the catalytic asymmetric He (nitroaldol) reaction of 2,2-difluoroaldehydes with nitromethane to provide the optically active aldols and nitroaldols, respectively, which must be versatile synthetic intermediates for the fluorinated protease inhibitors. 

The Henry (nitroaldol) reaction was reported under very mild reaction conditions, in aqueous media using a stoichiometric amount of a nitroalkane and an aldehyde, in NaOH 0.025 M and in the presence of cetyltrimethylammonium chloride (CTAC1) as cationic surfactant (Eq. 8.94) 240 Good to excellent yields of (i-nitroalkanol are obtained. Under these conditions several functionalities are preserved, and side-reactions such as retro-aldol reaction or dehydration of 2-nitroalcohols are avoided. 

Stereoselective formation of carbon carbon and carbon heteroatom bonds remains an important goal in synthetic chemistry. Very recently lanthanide alkoxides were successfully utilized in enantioselective C-C bond forming reactions. Catalysis of aldol, cyanosilylation, nitroaldol and Michael reactions has been ascribed to the basic character of lanthanide alkoxides [158, 250, 251]. Ln3(OfBu)9 was successfully employed in test runs and subsequently optically active bidentate ligands were used (Fig. 35) [250a]. 

Nitroalkanes having an a-hydrogen atom undergo aldol-type condensation with aldehydes and ketones in the presence of a base to give p-hydroxy nitro compounds or nitroethylene compounds. The reaction is known as the Henry reaction " or nitroaldol reaction. 

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 use of these materials in a range of reactions [isomerization of alkenes and alkynes, C—C bond formation, aldol condensation, Knoevenagel condensation, nitroaldol reactions, Michael addition, conjugate addition of alcohols, nucleophilic addition of phenylacetylene, nucleophilic ring opening of epoxides, oxidation reactions, Si—C bond formation, Pudovik reaction (P—C bond formation) and synthesis ofheterocycles] have been discussed in detail by Ono [248], as well as in the other cited reviews. We will thus discuss here only selected examples. 

The Henry reaction is an aldol-type reaction between a nitroalkane and an aldehyde in the presence of a base. Since basic reagents are also catalysts for the aldol condensation, the nitroaldol reactions must be strictly controlled. An interesting alternative lies in the use of surfactants to perform the reaction in an aqueous medium [63], The Reformatsky reaction, which involves a-haloketones and aldehydes, can be mediated by zinc, tin or indium in water in the latter case the proportion of undesirable reduction products could be strongly reduced [64]. 

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. 

Some of the catalyst systems used in the asymmetric aldol reaction are also effective in related reactions. Thus, bifunctional catalysts and L-prohne-based organocatalysts have been used to good effect in the nitroaldol reaction and Mannich reaction. The latter process is also effectively catalysed by enantiomeri-cally pure Bronsted acids. Furthermore, much recent progress has been made in the development of a catalytic asymmetric Morita-Baylis-Hillman reaction using Lewis/Bronsted acid catalysts and bifunctional catalysts. 

Catalytic asymmetric nitroaldol reaction. In the presence of this alkoxide, a-chloro ketones or nitro alkanes undergo aldol reactions (equation 1 and 11). 

Nitroaldol Reaction (The Henry Reaction). The nitroaldol reactions (or Henry reaction) is an aldol type reaction between a nitro compound and a carbonyl compound. The primary aldol products may be dehydrated to the corresponding alkenes. 

To start with the first option of such a chemoenzymatic process sequence, namely initial biotransformation and subsequent chemocatalytic or classical chemical reaction(s), an early example from the Gijsen and Wong [40] already in 1995 demonstrated a one-pot process for the synthesis of a cyclitol, which is based on an initial enzymatic aldol reaction of aldehyde 37 with 0-monophosphorylated dihy-droxyacetone, followed by a subsequent spontaneous cyclization via intramolecular Horner-Wadsworth-Emmons olefination reaction (Scheme 19.14). Furthermore, the resulting functionalized cyclopentene derivative 39 was deprotected in situ in the presence of an added phosphatase. By means of this one-pot three-step process, the desired trihydroxylated cyclopentene derivative 40 was formed, which was then further transformed via acetylation into the desired product 41 with an overall yield of 71%. A closely related process represents the combination of an enzymatic aldol reaction with a subsequent nitroaldol reaction (Henry reaction). Examples for such a type of process were developed independently by the Wong [41] and Lemaire [42] groups. 

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