Aldol Reaction Using Silyl Enol Ethers

5 ALDOL REACTION USING SILYL ENOL ETHERS 

Because these asymmetric aldol reactions are ideal methods for constructing (3-hydroxy carbonyl compounds in optically active form, the development of an asymmetric aldol reaction without the use of an organostannane would be advantageous. Yamagishi and coworkers have reported the Mukaiyama aldol reaction using trimethylsilyl enol ethers in the presence of the BINAP-AgPF6 complex to afford the adducts with moderate enantioselectivities (Table 9.9).18 They have also assigned 

TABLE 9.9. Mukaiyama Aldol Reaction with Various Aldehydes 

Entry RCHO Silyl enol ether Yield (%) ee (%) 

2 1 AgPF6-BINAP complex 1 2 AgPFe-BINAP complex 

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Aldol Reaction Using Silyl enol Ethers... 

The BINAP silver(I) complex can be further applied as a chiral catalyst in the asymmetric aldol reaction. Although numerous successful methods have been developed for catalytic asymmetric aldol reaction, most are the chiral Lewis acid-catalyzed Mukaiyama aldol reactions using silyl enol ethers or ketene silyl acetals [32] and there has been no report which includes enol stannanes. Yanagisawa, Yamamoto, and their colleagues found the first example of catalytic enantioselective aldol addition of tributyltin enolates 74 to aldehydes employing BINAP silver(I) complex as a catalyst (Sch. 19) [33]. 

Because the aldol reaction is one of the most fundamental bond-construction processes in organic synthesis [86], much attention has been focused on the development of asymmetric catalysts for aldol reactions, using silyl enol ethers of ketones or esters as storable enolate components (the Mukaiyama aldol condensation) [87]. 

These findings brought about extensive studies of asymmetric aldol reactions using silyl enol ethers of thiol esters that employed other chiral diamines [24] or organometals such as Cu [25], Zr [26], Ti [27], B [28], Sc [29], and Pr... 

Although in the recent years the stereochemical control of aldol condensations has reached a level of efficiency which allows enantioselective syntheses of very complex compounds containing many asymmetric centres, the situation is still far from what one would consider "ideal". In the first place, the requirement of a substituent at the a-position of the enolate in order to achieve good stereoselection is a limitation which, however, can be overcome by using temporary bulky groups (such as alkylthio ethers, for instance). On the other hand, the ( )-enolates, which are necessary for the preparation of 2,3-anti aldols, are not so easily prepared as the (Z)-enolates and furthermore, they do not show selectivities as good as in the case of the (Z)-enolates. Finally, although elements other than boron -such as zirconium [30] and titanium [31]- have been also used succesfully much work remains to be done in the area of catalysis. In this context, the work of Mukaiyama and Kobayashi [32a,b,c] on asymmetric aldol reactions of silyl enol ethers with aldehydes promoted by tributyltin fluoride and a chiral diamine coordinated to tin(II) triflate... 

A similar enantiomer-selective activation has been observed for aldol " and hetero-Diels-Alder reactions.Asymmetric activation of (R)-9 by (/f)-BINOL is also effective in giving higher enantioselectivity (97% ee) than those by the parent (R)-9 (91% ee) in the aldol reaction of silyl enol ethers (Scheme 8.12a). Asymmetric activation of R)-9 by (/f)-BINOL is the key to provide higher enantioselectivity (84% ee) than those obtained by (R)-9 (5% ee) in the hetero-Diels-Alder reaction with Danishefsky s diene (Scheme 8.12b). Activation with (/ )-6-Br-BINOL gives lower yield (25%) and enantioselectivity (43% ee) than the one using (/f)-BINOL (50%, 84% ee). One can see that not only steric but also electronic factors are important in a chiral activator. 

Bismuth triflate has been reported by Dubac as an efficient catalyst for the Mukaiyama aldol reaction with silyl enol ethers [27] and was recently used with a chiral ligand, as reported by Kobayashi in an elegant hydroxymethylation reaction... 

Mukiayama aldol reactions between silyl enol ethers and various carbonyl containing compounds is yet another reaction whose stereochemical outcome can be influenced by the presence of bis(oxazoline)-metal complexes. Evans has carried out a great deal of the work in this area. In 1996, Evans and coworkers reported the copper(II)- and zinc(II)-py-box (la-c) catalyzed aldol condensation between benzyloxyacetaldehyde 146 and the trimethylsilyl enol ether [(l-ferf-butylthio)vinyl]oxy trimethylsilane I47. b82,85 Complete conversion to aldol adduct 148 was achieved with enantiomeric excesses up to 96% [using copper(II) triflate]. The use of zinc as the coordination metal led to consistently lower selectivities and longer reaction times, as shown in Table 9.25 (Eig. 9.46). 

Carbonyl Addition Diethylzinc has been added to benzaldehyde at room temperature in the presence of an ephedra-derived chiral quat (8) to give optically active secondary alcohols, a case in which the chiral catalyst affords a much higher enantioselectivity in the solid state than in solution (47 to 48, Scheme 10.6) [30]. Asymmetric trifluoromethylation of aldehydes and ketones (49 to 50, Scheme 10.6 [31]) is accomplished with trifluoromethyl-trimethylsilane, catalyzed by a quaternary ammonium fluoride (3d). Catalyst 3d was first used by the Shioiri group for catalytic asymmetric aldol reactions from silyl enol ethers 51 or 54 (Scheme 10.6) [32]. Various other 1,2-carbonyl additions [33] and aldol reactions [34] have been reported. 

Independently, Yamamoto, Yanagisawa, and others reported the asymmetric aldol reaction using trimethoxysilyl enol ethers.19 The reaction was conducted with aldehydes and trimethoxysilyl enol ethers in the presence of Tol-BINAP-AgF to give the corresponding adducts with high enantioselectivities and diastereoselectiv-ities. They obtained vyra-aldol adducts as major products even when silyl enol ethers derived from cyclic ketones were used. Moreover, when a,(3-unsaturated aldehydes were employed as substrates, 1,2 adducts were obtained exclusively (Table 9.10). From an NMR study and correlation between the E Z ratio of the enol ethers and diastereoselectiviy, they proposed a cyclic transition state (Fig. 9.5). Thus, the reaction of E enol ethers proceeded via a boat form, whereas the reaction of Z enol ethers took place via a chair form. 

Hoveyda and coworkers reported that the silver complex generated from AgF2 and an amino acid-based ligand could be used for the asymmetric aldol reaction with silyl enol ethers and a-ketoesters (Table 9.11).23... 

This procedure illustrates a general method for the preparation of crossed aldols. The aldol reaction between various silyl enol ethers and carbonyl compounds proceeds smoothly according to the same procedure (see Table I). Silyl enol ethers react with aldehydes at -78°C, and with ketones near CTC. Note that the aldol reaction of silyl enol ethers with ketones affords good yields of crossed aldols which are generally difficult to prepare using lithium or boron enolates. Lewis acids such as tin tetrachloride and boron trifluoride etherate also promote the reaction however, titanium tetrachloride is generally the most effective catalyst. 

Sc(OTf)3-catalyzed aldol reactions of silyl enol ethers with aldehydes have recently been successfully performed in micellar systems [60]. Although the reaction proceeded sluggishly in water (without organic solvents), reactivity was remarkably enhanced by the presence of a small amount of a surfactant. In these systems, versatile carbon-carbon bond-forming reactions proceeded smoothly in water without the use of organic solvents. 

Suzuki, T., Hirama, M. Asymmetric aldol reaction of silyl enol ethers with aldehydes promoted by the combined use of chiral diamine coordinated tin(ll) triflate and tribulyltin fluoride. Chemtracts Org. Chem. 1989, 2, 268-270. 

The use of Ln(OTf)3 in the activation of aldehydes other than formaldehyde was also investigated [18], Several examples of the present aldol reaction of silyl enol ethers with aldehydes are listed in Table 14-1. In every case, the aldol adducts were obtained in high yields in the presence of a catalytic amount of Yb(OTf)3, Gd(OTf)3, or Lu(OTf)3 in aqueous media. Diastereoselectivities were generally good to moderate. One feature in the present reaction is that water-soluble aldehydes, for instance, acetaldehyde, acrolein, and chloroacetaldehyde, can be reacted with silyl enol ethers to afford the corresponding cross aldol adducts in high yields (entries 5-7). Some of these aldehydes are commercially supplied as water solutions and are appropriate for direct use. Phenylglyoxal monohydrate also worked well (entry 8). It is known that water often interferes with the aldol reactions of aldehydes with metal enolates and that, in the cases where such water... 

The demand for environmentally friendly chemistry and its widespread applicability have made water an increasingly popnlar solvent for organic transformations. Mixtures of water and other solvents snch as tetrahydrofnran are now commonly anployed for a number of organic transformations. For instance, the Lewis acid catalysed aldol reaction of silyl enol ethers, commonly known as the Mnkaiyama aldol reaction, which was firstly reported in the early seventies, can be carried ont in snch media. With titanium tetrachloride as the catalyst this reaction proceeds regioselectively in high yields, but the reaction has to be carried ont strictly nnder non-aqneons conditions in order to prevent decomposition of the catalyst and hydrolysis of the sUyl enol ethCTS. In the absence of the catalyst it was observed that water had a beneficial influence on this process (Table 4, entry D) . Nevertheless, the yields in the nncatalysed version WCTe still unsatisfactory. Improved results were obtained with water-tolerant Lewis acids. The first reported example for Lewis acid catalysis in aqueous media is the hydroxymethylation of silyl enol ethers with commercial formaldehyde solution using lanthanide trillates. In the meantime, the influence of several lanthanide triflates in cross-aldol reactions of various aldehydes was examined " " ". The reactions were most effectively carried out in 1 9 mixtures of water and tetrahydrofnran with 5-10% Yb(OTf)3, which can be reused after completion of the reaction (Table 19, entry A). Although the realization of this reaction is quite simple, the choice of the solvent is crucial (Table 20). 

The aldol reactions of silyl enol ethers with aldehydes also proceed smoothly in water/ethanol/toluene [17]. The reactions proceed much faster in this solvent than in water/THF (Eq. 2). Furthermore, the new solvent system involves continuous use of the catalyst by a very simple procedure. Although the water/ethanol/toluene (1 7 4) system is one phase, it easily becomes two phases by adding toluene after the reaction is completed. The product is isolated from the organic layer by a usual work-up. On the other hand, the catalyst remains in the aqueous layer, which is used directly in the next reaction without removing water. It is noteworthy that the yields of the second, third, and fourth runs are comparable with that of the first run. 

The aldol reactions of silyl enol ethers with aldehydes were also found to proceed smoothly in water-ethanol-toluene [20]. Some reactions proceeded much faster in this solvent system than in THF-water. Furthermore, the new solvent system realized continuous use of the catalyst by a very simple procedure. 

Asymmetric aldol reaction of silyl enol ethers. (16,221-222). The use of TiCI4 as promoter of aldol condensation of silyl enol ethers with aldehydes, first reported in 1973 (6,590-591), has seen wide use, but has the drawbacks that 1 cquiv. of the Lewis acid is required and that an asymmetric version requires use of chiral aldehydes or chiral silyl enol ethers. More recently, the combination of a salt and a weak Lewis acid, neither effective catalysts themselves, was found to be effective in catalytic (5-10 mol %) amounts. Further research showed that tin(ll) triflatc when coordinated with a chiral diamine can effect catalytic asymmetric allylation of aldehydes (13,302) and Michael reactions (15,313-314), even though this complex cannot promote aldol condensation. Eventually the combination of tin(Il) triflatc, a chiral diamine,... 

Several examples of the present aldol reactions of silyl enol ethers with aldehydes in water-ethanol-toluene are summarized in table 6. 3-Pyridinecarboxaldehyde as well as 2-pyiidinecarboxaldehyde, salicylaldehyde, and formaldehyde-water solution worked well. As for silyl enol ethers, not only ketone enol ethers but also silyl enolates derived from thioesters were used. In every case, the adducts were obtained in high yields in the presence of 10mol% Yb(OTf)3. 

The chiral acyloxyborane 7 (CAB) has also been found to be an excellent catalyst for asymmetric Mukaiyama-Michael type aldol reaction between silyl enol ethers and aldehydes (Scheme 8). Yamamoto et al. [27] have used 20 mol % of CAB in propionitrile at -78 °C as a highly efficient catalyst for the condensation of several E and Z silyl enol ethers and ketene acetals with a variety of aldehydes (yields 49-97 %, 80-97 % ee). 

The properties of the /7-benzyloxybenzylamine (BOBA) resin 7e have been reported. Support 7e forms imines that undergo aldol reactions with silyl enol ethers and the resulting y-ketoamines can be cleaved oxidatively using 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ). In contrast, treatment of the support with triflic acid (TfOH) or trimethylsilyltriflate (TMSOTf) resulted in cleavage at the benzylic ether group of 7e affording... 

Chiral 3,5,6-trihydroxyheptanoic acids are potentially useful intermediates for the synthesis of natural products. The backbone can be constructed by a titanium-mediated aldol reaction of silyl enol ether 536 with 929. The syn adduct 949 is formed exclusively, as predicted by the chelation-controlled Cram cyclic model. 

Scandium triflate-catalyzed aldol reactions of silyl enol ethers with aldehyde were successfully carried out in micellar systems and encapsulating systems. While the reactions proceeded sluggishly in water alone, strong enhancement of the reactivity was observed in the presence of a small amount of a surfactant. The effect of surfactant was attributed to the stabiMzation of enol silyl ether by it. Versatile carbon-carbon bondforming reactions proceeded in water without using any organic solvents. Cross-linked Sc-containing dendrimers were also found to be effective and the catalyst can be readily recycled without any appreciable loss of catalytic activity.Aldol reaction of 1-phenyl-l-(trimethylsilyloxy) ethylene and benzaldehyde was also conducted in a gel medium of fluoroalkyl end-capped 2-acrylamido-2-methylpropanesulfonic acid polymer. A nanostmctured, polymer-supported Sc(III) catalyst (NP-Sc) functions in water at ambient temperature and can be efficiently recycled. It also affords stereoselectivities different from isotropic solution and solid-state scandium catalysts in Mukaiyama aldol and Mannich-type reactions. 

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