Silyl enol ether in aldol reactions

The effects of the silacyclobutane moiety on the derived silyl enol ethers in aldol reactions were discovered earlier. It was also sugggested that these reactions proceed via pentacoordinate silicon species and boatlike transition states. 

Figure 4.85 Flow configuration for the aldol reaction of silyl enol ethers in a mixing-tee chip micro reactor [15],...

More recently, asymmetric Mannich-type reactions have been studied in aqueous conditions. Barbas and co-worker reported a direct amino acid catalyzed asymmetric aldol and Mannich-type reactions that can tolerate small amounts of water (<4 vol%).53 Kobayashi found that a diastereo- and enantioselective Mannich-type reaction of a hydrazono ester with silyl enol ethers in aqueous media has been successfully achieved with ZnF2, a chiral diamine ligand, and trifluoromethanesul-fonic acid (Eq. 11.31).54 The diastereoselective Mannich-type reaction... 

On the other hand, Ln(OTf)3 compounds, which were found to be effective catalysts for the hydroxy-methylation in aqueous media, also activate aldehydes other than formaldehyde in aldol reactions with silyl enol ethers in aqueous solvents.1121 One feature of the present reactions is that water-soluble... 

Although the saturated ketone can be obtained in nearly quantitative yields, the loss of synthetically valuable functionality is unfavorable and can be overcome by a modification of the tandem sequence. The use of the corresponding unsaturated silyl enol ethers in a tandem hydroformyla-tion/Mukaiyama aldol reaction gives the desired aldol adduct with complete... 

The aldol reaction of a silyl enol ether proceeds in a double and two-directional fashion, upon addition of an excess amount of an aldehyde, to give the silyl enol ether in 77 % isolated yield and more than 99 % ee and 99 % de (Sch. 33) [92]. This asymmetric catalytic aldol reaction is characterized by kinetic amplification of product chirality on going from the one-directional aldol intermediate to the two-directional product. Further transformation of the pseudo C2 symmetric product still protected as the silyl enol ether leads to a potent analog of an HIV protease inhibitor. Kinetic resolution of racemic silyl enol ethers by the BINOL-Ti catalyst (1) has been reported by French chemists [93]. 

Keck also investigated asymmetric catalysis with a BINOL-derived titanium complex [102,103] for the Mukaiyama aldol reaction. The reaction of a-benzyloxyalde-hyde with Danishefsky s dienes as functionalized silyl enol ethers gave aldol products instead of hetero Diels-Alder cycloadducts (Sch. 40) [103], The aldol product can be transformed into hetero Diels-Alder type adducts by acid-catalyzed cyclization. The catalyst was prepared from BINOL and Ti(OPr )4, in 1 1 or 2 1 stoichiometry, and oven-dried MS 4A, in ether under reflux. They reported the catalyst to be of BINOL-Ti(OPr% structure. 

The starting material is natural P-cyclocitral 76, converted to its methyl acetal 78. The extended enolate 77 is best realised as the silyl enol ether 79 and reaction with 78 followed by base gives the trienal 75. Repetition of the three steps gives all E retinal 74. The two extended aldol reactions go in excellent yield with total regioselectivity, only the base-catalysed eliminations with DBU are disappointing. 

There has been a quite limited number of reports of clay-catalysed aldol condensations. One of the more interesting of these is the aluminium-exchanged montmorillonite (Al3+-mont) catalysed cross-aldol reaction of silyl enol ethers with aldehydes (Reaction 6).34 The reaction proceeded smoothly under mild conditions to give the corresponding aldol adduct in good yield. 

Although lanthanide triflates are the first metal salts which were foimd to catalyze aldol reactions of aldehydes with silyl enol ethers efficiently in aqueous media, it has been difficult to realize asymmetric versions of lanthanide triflate-catalyzed reactions in such media. Recently, the first example of this type of reaction using chiral bis-pyridino-18-crown-6 (1) has been developed [38]. In the reaction of benzaldehyde with silyl enol ethers in water-ethanol (1 9), the cation size of lanthanide triflates strongly affected the diastereo- and enantioselectivities of the aldol adduct. For the larger cations such as La, Ce, Pr, and Nd, both diastereo- and enantioselectivities were high, while the smaller cations such as Sc and Yb showed no enantioselection. 

Further work from Nakajima resulted in the development of an aldol reaction of aldehydes with trimetho g silyl enol ethers in the presence of chiral... 

The aldol reaction to produce specific P-hydroxyketones was dramatically advanced by the recognition that silyl enol ethers in the presence of Lewis add catalysts could be used in the carbon-carbon bond-fomfing process (Mukaiyama aldol reaction) (Scheme 9.48). Thus, although it had been known for some time that silyl enol ethers could be prepared by the reaction between ketones and trialkylsilyl... 

CAB 3a is also an excellent catalyst (20 mol%) for the Mukaiyama condensation of simple enol silyl ethers of achiral ketones with various aldehydes. Furthermore, the reactivity of aldol-type reactions can be improved without reducing the enantioselec-tivity by using 10-20 mol% of 3c. Enantioselectivity can also be improved without reducing the chemical yield by using 20 mol% of 3b. The 3-catalyzed aldol process allows for the formation of adducts in a highly diastereo- and enantioselective manner (up to 99% ee) under mild reaction conditions [41a, cj. These reactions are catalytic, and the chiral source is recoverable and reusable (Equation 41). The observed high syn selectivities, together with their lack of dependence on the stereoselectivity of the silyl enol ethers, in 3-catalyzed reactions are fully consistent with Noyori s TMSOTf-catalyzed aldol reactions of acetals, and thus may reflect the acyclic extended transition state mechanism postulated in the latter 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). ... 

Loh, T. P., Chua, G. L., Vittal, J.J. and Wong, M.-W., Highly stereoselective indium trichloride-catalysed asymmetric aldol reaction of formaldehyde and a glucose-derived silyl enol ether in water, Chem. Commun., 1998, 861. 

Loh, T.-P. and Li, X.-R., Clay montmorillonite KIO catalyzed aldol type reaction of aldehydes with silyl enol ethers in water. Tetrahedron, 1999, 55,10789 10802. 

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