Aldol reactions With silyl enol ethers

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... 

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... 

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... 

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... 

In addition to rare earth triflates, copper triflate was also found to be a stable Lewis acid in aqueous media. In a mixed aqueous solvent system (H20-EtOH-toIuene = 1 7 4), allylation of various aldehydes with tetraallyltin and aldol reactions with silyl enol ethers proceeded smoothly in the presence of Cu(OTf)2 (20 mol%) to give homoallylic alcohols and aldol adducts, respectively, in high yields (Schemes 3.9 and 3.10). 

Scheme 3.68 Dicobalt hexacarbonyl complex of propynals in organic synthesis erythro-selective aldol reaction with silyl enol ethers.

Reductive aldol reaction of a,(5-unsaturated esters and enones with aldehyde mediated by a transition metal hydride complex and a hydride source, such as hydrosilane, is a versatile process to produce p-hydroxy carbonyl compounds (Scheme 15a) [21]. This reaction is thought to be an alternative transformation of Lewis acid-catalyzed Mukaiyama-type aldol reaction with silyl enol ethers or silyl ketene acetals (Scheme 15b). 

Evans et al. applied the Mukaiyama aldol reaction to the total synthesis of the squalene synthase inhibitor zaragozic acid C (Scheme 8.23). ° Di-f-butyl tartrate 135 was protected as acetal 137, which was converted into silyl enol ether 138. The partner aldehyde 141 was synthesized by the Evans aldol reaction (139 —> 140). The Mukaiyama aldol reaction with silyl enol ether 138 and aldehyde 141 in the presence of (i-PrO)TiCl3 gave adduct 142 as a single isomer. These transformations gave the desired stereochemistry at the C3 to C7 positions. 

In 1991, Kobayashi el al. prepared novel chiral S/N ligands for the tin-mediated aldol reaction of silyl enol ethers with aldehydes. As an example, the reaction of benzaldehyde afforded the expected syn aldol product as the major product with a good yield and an enantioselectivity of up to 92% ee (Scheme 10.26). Moreover, other aldehydes such as substituted benzaldehydes or aliphatic unsaturated aldehydes were converted into their corresponding aldol products with enantioselectivities of more than 90% ee. It was checked that the corresponding diamine ligands provided less active complexes for the same reactions. 

Scheme 2.2 illustrates several examples of the Mukaiyama aldol reaction. Entries 1 to 3 are cases of addition reactions with silyl enol ethers as the nucleophile and TiCl4 as the Lewis acid. Entry 2 demonstrates steric approach control with respect to the silyl enol ether, but in this case the relative configuration of the hydroxyl group was not assigned. Entry 4 shows a fully substituted silyl enol ether. The favored product places the larger C(2) substituent syn to the hydroxy group. Entry 5 uses a silyl ketene thioacetal. This reaction proceeds through an open TS and favors the anti product. 

The crossed aldol reaction of silyl enol ethers with carbonyl compounds (Mukaiyama-aldol) was studied by Lubineau and co-workers... 

Sc(OTf)3 is an effective catalyst in aldol reactions of silyl enol ethers with aldehydes.49 Compared with other typical rare-earth-metal (Y, Yb) trifiates, Sc(OTf)3 has the strongest activity in the reaction of 1-trimethylsiloxycyclohexane with benzaldehyde in dichloromethane. Although the reaction scarcely proceeded at —78°C in the presence of Y(OTf)3 or Yb(OTf)3, the aldol adduct was obtained in 81% yield in the presence of Sc(OTf)3 (Scheme 9). 

S. Kobayashi, L Hachiya, The Aldol Reaction of Silyl Enol Ethers with Aldehydes in Aqueous Media Tetrahedron Lett. 1992,1625-1628. 

S. Kobayashi, T. Wakabayashi, S. Nagayama, H. Oya-mada, Lewis Add Catalysis in MiceUar Systems. Sc(OTf)3-Catalyzed Aqueous Aldol Reactions of Silyl Enol Ethers with Aldehydes in the Presence of a Surfactant Tetrahedron Lett. 1997,38, 4559-4562... 

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. 

In the following a few examples of the asymmetric aldol reaction are given. Silyl enol ethers (0-Si) resemble very much allylsilanes (C-Si) in terms of structure and mode of action. That is why Lewis base catalyzed aldol reactions of silyl enol ethers have been extensively studied. The first example of Lewis base catalyzed asymmetric aldol reaction of trichlorosilyl enol ether with chiral phosphoramide [80-91] was reported by Denmark et al. (Scheme 24). 

Recently it was found that the aldol reaction of silyl enol ethers with acetals or aldehydes is effectively promoted by a catalytic amount of trityl perchlorate to give the corresponding aldols in good yields (44,45). Polymer-bound trityl perchlorate also successfully catalyzed the aldol reaction (45). 

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). 

Cross aldol reactions of silyl enol ethers with acetals (25 - 26, and 27 - 28) are also mediated by EGA. The reaction runs smoothly at —78 °C in a CH2CI2— —LiClO —Et NClO —(Pt) system. At an elevated temperature protonation of both enol ether and acetal occurs competitively to give 28 in a poor yield. Table 5 summarizes yields and diastereoselectivities of 28 obtained by EGA, TiCl TMSOTf and TrtClO 5 . The EGA method is superior to TiCl with regard to the stereocontrol, and comparable with TMSOTf and TrtClO in both stereocontrol and yield. 

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. 

Carbonyl activation and deactivation.1 Aldehydes, but not ketones, undergo aldol condensation with silyl enol ethers at —78° in the presence of dibutyltin bistriflate. In contrast, the dimethyl acetals of ketones, but not of aldehydes, can undergo this condensation (Mukaiyama reaction) with silyl enol ethers at -78° with almost complete discrimination, which is not observed with the usual Lewis-acid catalysts. Thus dibutyltin bistriflate activates aldehydes, but deactivates acetals of... 

In 2002, Yamamoto and Momiyama reported an unusual aldol-like reaction with silyl enol ethers and nitrosobenzene in the presence of a catalytic amount of TESOTf (nitrosoaldol reaction).29 Usually, nucleophiles react with nitrosobenzene without Lewis acid to give the N adduct predominantly. In contrast, they reported that the reaction of silyl enol ethers and nitrosobenzene catalyzed by TESOTf afforded the... 

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. 

The blend SnC -ZnCli is an effective catalyst in the aldol reaction of silyl enol ethers with aldehydes (Eq. 87), acetals (Eq. 88), or ketones [122]. Product antilsyn ratios vary (32 69 to 89 11). The blend also catalyzes the Michael addition of silyl enol ethers with a,/3-unsaturated ketones (Eq. 89), yielding alkylation products (84-100 %) with anti selectivity antilsyn = 55 45 to 87 23). 

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. 

Akiyama, Y, Ishikawa, K, OzaM, S, Asymmetric synthesis of functionalized tertiary alcohols by diastereoselective aldol reaction of silyl enol ether and ketene silyl acetals with a-keto esters bearing an optically active cyclitol as a chiral auxihary, Synlett, 275-276, 1994. 

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. 

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