Mukaiyama aldol reaction in aqueous media

Asymmetric Mukaiyama aldol reactions in aqueous media [EtOH-H20 (9 1)] were reported with FeCl2 and PYBOX ligands 27a [36] and 27b [37]. The latter provides product 28 with higher yield and diastereo- and enantioselectivity (Scheme 8.9). The ee values given are for the syn-diastereoisomer. Whereas ligand 27a is a derivative ofL-serine, compound 27b has four stereogenic centers, since it was prepared from... 

Lanthanide(ni) on ion exchange resins catalyse Mukaiyama aldol reactions in aqueous media, acetalisations, additions of silyl enol ethers to imines, saz-Diels-Alder reactions and the ringopening of epoxides with alcohols as depicted in Scheme 3.6.7. 

A chiral lanthanide complex catalyzes asymmetric Mukaiyama aldol reactions in aqueous media (Scheme 24). The changes in the water-coordination number is key to the mechanism of die catalytic reaction. The precatalysts yielded -hydroxy carbonyl compounds from aliphatic and aryl substrates widi high diastereomeric ratios and enantiomeric excesses of up to 49 1 and 97%, respectively. 

Kobayashi, S., Nagayama, S. and Busujima T, Catalytic asymmetric Mukaiyama aldol reactions in aqueous media, Tetrahedron, 1999, 55, 8739-8746. 

Munoz-Muniz, O., Quintanar-Audelo, M. and Juaristi, E., Reexamination of CeCla and InCla as activators in the diastereoselective Mukaiyama aldol reaction in aqueous media, J. Org. Chem., 2003, 68, 1622-1625. 

Enantioselective Mukaiyama aldol reactions in aqueous media constitute another important advance in the area. Two main difficulties need to be addressed. First, many cations hydrolyze very easily in water, and second, chiral... 

CUgiVlE 10 23. Mukaiyama aldol reaction in aqueous media. 

Kobayashi et al. studied the catalytic activity of many metal salts in Mukaiyama-aldol reactions in aqueous THE They came to the conclusion that the catalytic activity of a metal in aqueous media should be related both to the hydrolysis constant, /Ch, and water exchange rate constant (WERC) of the metal [8]. All metals with good catalytic activity had p/Ch values ranging between 4.3 and 10.08 and WERC > 3.2 X 10 s This was because when for a metal is < 4.3, the metal cation is readily hydrolyzed to generate oxonium ion, which then helps the decomposition of the silyl enol ethers. When pMh > 10.08 the Lewis acidity of the metal is too low to promote the reaction. When the WERC is < 3.2 x 10 m s, exchange of water molecules seldom occurred and aldehydes had a very little chance to coordinate to the metal to be activated. The metals which fulfill these criteria are Sc(III), Fe(II), Cu(II), Zn(ll), Y(IIl), Cd(Il), Ln(Ill) and Pb(ll). 

While aldol reactions stated above were smoothly catalyzed by the water-stable Lewis acids in aqueous media, a certain amount of organic solvent such as THF or EtOH had to be still combined with water to promote the reactions efficiently. To avoid the use of the organic solvents, we have developed a new reaction system in which Sc(OTf)3 catalyzes Mukaiyama aldol reactions in pure water without any organic solvents in the presence of a small amount of a surfactant such as sodium dodecyl sulfate (SDS). 

Sc(() l f) ( is an effective catalyst of the Mukaiyama aldol reaction in both aqueous and non-aqueous media (vide supra). Kobayashi et al. have reported that aqueous aldehydes as well as conventional aliphatic and aromatic aldehydes are directly and efficiently converted into aldols by the scandium catalyst [69]. In the presence of a surfactant, for example sodium dodecylsulfate (SDS) or Triton X-100, the Sc(OTf)3-catalyzed aldol reactions of SEE, KSA, and ketene silyl thioacetals can be performed successfully in water wifhout using any organic solvent (Sclieme 10.23) [72]. They also designed and prepared a new type of Lewis acid catalyst, scandium trisdodecylsulfate (STDS), for use instead of bofh Sc(OTf) and SDS [73]. The Lewis acid-surfactant combined catalyst (LASC) forms stable dispersion systems wifh organic substrates in water and accelerates fhe aldol reactions much more effectively in water fhan in organic solvents. Addition of a Bronsted acid such as HCl to fhe STDS-catalyzed system dramatically increases the reaction rate [74]. 

Aldol reactions of aldehydes with cycloakanones were performed in ionic liquids and catalyzed by FeCl3-6H20 [32]. Mukaiyama aldol reactions of silylenol ethers with aldehydes can be carried out in aqueous media however, among several Lewis acidic catalysts investigated, iron compounds were not the optimal ones [33], If silyl ketene acetals are applied as carbon nucleophiles in Mukaiyama aldol reactions, cationic Fe(II) complexes give good results. As catalysts, CpFe(CO)2Cl [34] and [CpFe(dppe) (acetone)] BF4 [35] [dppe = l,2-bis(diphenylphosphano)ethane] were applied (Scheme 8.8). No diastereomeric ratio was reported for product 26a. 

Mukaiyama aldol reactions of various silyl enol ethers or ketene silyl acetals with aldehydes or other electrophiles proceed smoothly in the presence of 2 mol % B(CgF5)3 [151a,c]. The following characteristic features should be noted (i) the products can be isolated as j8-trimethylsilyloxy ketones when crude adducts are worked-up without exposure to acid (ii) this reaction can be conducted in aqueous media, so that the reaction of the silyl enol ether derived from propiophenone with a commercial aqueous solution of formaldehyde does not present any problems (iii) the rate of an aldol reaction is markedly increased by use of an anhydrous solution of B(C6Fs)3 in toluene under an argon atmosphere and (iv) silyl enol ethers can be reacted with chloromethyl methyl ether or trimethylorthoformate hydroxymethyl, methoxy-methyl, or dimethoxymethyl Cl groups can be introduced at the position a to the carbonyl group. These aldol-type reactions do not proceed when triphenylborane is used (Eq. 92). 

Other chiral zinc based Lewis acid, such as zinc(II) complex with pybox, showed good stability in aqueous media and gave syn-adducts in moderate to excellent catalytic activity and enantioselectivity for asymmetric Mukaiyama aldol reactions (113,114). A simple combination of Lewis acidic zinc salt (Zn(OTf)2) and organocatalyst is also shown to be effective catalysts for the direct aldol reaction of acetone and aldehydes in the presence of water (115). 

Mukaiyama aldol reactions of various silyl enol ethers or ketene silyl acetals with aldehydes or other electrophiles like chloromethyl methyl ether and trimethylorthoformate proceed smoothly in the presence of 2 mol% of 1 (eq 1) (3, 5). These reactions can be carried out in aqueous media, so that the reaction of silyl enol ethers with an aqueous solution of formaldehyde does not present any problems. Triphenylboron catalyzes no aldol-type reactions. 

Pioneering work by Lubineau and coworkers showed that the aldol type reaction between a silyl enol ether and an aldehyde (the so-called Mukaiyama aldol reaction) occurred in water at room temperature with high syn stereoselectivity, albeit in low yields.However, the development of water-tolerant Lewis acids for this reaction has led to improved rates and chemical yields. Various lanthanides triflates, such as ytterbium triflate [Yb(OTf)3], scandium triflate [Sc(OTf)3], gadolinium triflate [Gd(OTf)3], or lutetium triflate [Lu(OTf)3], have been found to afford the aldol products between various aldehydes and silyl enol ethers in high yields in aqueous media, with good to moderate syn/anti diastereoselectivi-ties (Scheme 8.3, Table 8.1). ... 

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