Aldol additions of silyl enol ethers

Aldol additions of silyl enol ethers and silyl ketene acetals can be catalyzed by (Cp)2Zr2+ species including [(Cp)2ZrO-/-liu 1 and (Cp)2Zr(03SCF3)2.58... 

As shown in Scheme 8, the synthesis of aldehyde 45 was achieved in eight steps utilizing the common precursor 31 [46-48], Remarkably, the Mukaiyama aldol addition of silyl enol ether 46 to aldehyde 47 proceeded with anti-Felkin selectivity, which was attributed to involvement of the Weinreb amide and aldehyde carbonyl... 

Cationic Pd complexes can be applied to the asymmetric aldol reaction. Shibasaki and coworkers reported that (/ )-BINAP PdCP, generated from a 1 1 mixture of (i )-BINAP PdCl2 and AgOTf in wet DMF, is an effective chiral catalyst for asymmetric aldol addition of silyl enol ethers to aldehydes [63]. For instance, treatment of trimethylsi-lyl enol ether of acetophenone 49 with benzaldehyde under the influence of 5 mol % of this catalyst affords the trimethylsilyl ether of aldol adduct 113 (87 % yield, 71 % ee) and desilylated product 114 (9 % yield, 73 % ee) as shown in Sch. 31. They later prepared chiral palladium diaquo complexes 115 and 116 from (7 )-BINAP PdCl2 and (i )-p-Tol-BINAP PdCl2, respectively, by reaction with 2 equiv. AgBF4 in wet acetone [64]. These complexes are tolerant of air and moisture, and afford similar reactivity and enantioselec-tivity in the aldol condensation of 49 and benzaldehyde. Sodeoka and coworkers have recently developed enantioselective Mannich-type reactions of silyl enol ethers with imi-nes catalyzed by binuclear -hydroxo palladium(II) complexes 117 and 118 derived from the diaquo complexes 115 and 116 [65]. These reactions are believed to proceed via a chiral palladium(fl) enolate. 

The Lewis acid mediated addition of silyl enol ethers or silylketcne acetals to oc-alkoxyaldehydcs is the most versatile and reliable method of providing chelation control in aldol-type additions3. The stereochemical outcome is as predicted by Cram s cyclic model11 ... 

A combination of diethylzinc with sulfonamides 18 or 19 offers another possibility for the enantioselective acetate aldol reaction39,41. The addition of silyl enol ethers to glyoxylates can be directed in a highly enantioselective manner when mediated by the binaphthol derived titanium complex 2040. 

Aldol reaction between a, -acetylenic ketones and silyl enol ethers. TrC104 is an efficient catalyst for 1,2-addition of silyl enol ethers to a,(3-acetylenic ketones.2... 

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). 

C/C-connections pericyclic reactions, ene reactions, allylation of carbonyls, Grignard-type additions to carbonyl, aldol-type additions of silyl enol ethers to carbonyl, epoxide opening with cyanide, etc. 

Lewis acid catalyzed aldol coupling of silyl enol ethers with substituted cyclohexanone acetals showed an excellent preference for equatorial attack (95-l(X)%). In accord with this general rule, additions of a silyl enol ether to equatorially or axially substituted chiral spiroketals derived from -menthone gave 00% equatorial attack and formation of a single one of the four possible diastereoisomers (Scheme 9) 3, 4 -pjjjg methodology, followed by protection of the hydroxy group (X = OTHP, (XIPh.i) and alkaline removal of the chiral auxiliary was used for the synthesis of several natural products. ... 

The pinwheel shape of a f-butyl propionate derived silylketene acetal (see Section 2.4.2.1) was revealed by a single-crystal X-ray diffraction analysis. Several different catalysts were reported to promote the aldol-type condensation of alkyl enol ethersand silyl enol ethers with aldehydes, acetals and various other electrophiles. In some cases the reaction proceeded with high simple stereoselection. The mechanism of the Lewis acid mediated additions to acetals (see Section 2.4.2.3) was investigated in detail, as well as the uncatalyzed aldol reaction of silyl enol ethers with aldehydes promoted by the hydrophobic effect (see Section 2.4.2.1). 

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. 

Enantioselective additions of lithium enolates to aldehydes forming aldols ( 3-hydroxyaldehydes) are synthetically well established and have been reviewed elsewhere [20]. A catalytic variant, the Mukaiyma aldol reaction, i.e., the addition of silyl enol ethers to aldehydes, is usually mediated by chiral Lewis acids [21,22]. 

Significant advances in the development of a catalytic asymmetric variant of the aldol reaction have been developed recently. Both enantiomericaUy pure Lewis acids and Lewis bases have been applied to the addition of silyl enol ethers to aldehydes and ketones and highly diastereoselective and enantioselec-tive additions have been achieved. Often, the mode of diastereoselectivity can be rationalised from a consideration of the relevant open or closed transition states. 

Mikami reported that BINOL derived titanium complex efficiently catalyzed the aldol reaction of silyl enol ether with excellent control of both absolute and relative stereochemistry [106] (Scheme 14.37). The reaction was proposed to proceed via a prototropic ene reaction pathway that is different from that of Mukaiyama aldol condensation. A cyclic antiperiplanar transition-state model was proposed to explain the pref erential formation of the syn diastereomer from either (E)- or (Z)-silyl enol ethers [106]. Further modifications of the catalyst system include the use of perfluorophenols and other activating additives [107], or performing the reaction in supercritical fluids [108]. Furthermore, the nucleophile could be extended to enoxysilacyclobutane derivatives [109]. 

The results of the aldol additions with silyl enol ethers further refined our new model of a Lewis base-catalyzed-Lewis acid-mediated pathway. Use of the N value was clearly predictive of substrate scope, validating our mechanistic scheme and the role of the ionized chloride in the complex. Gratifyingly, the sense of asymmetric induction in all these reactions is the same using the chiral bisphosphoramide (RJi)-S. 

Diones are important intermediates in a number of syntheses of cyclopent-2-enones by aldol cyclization, and several routes to them have been published (see Review section). An attractive new approach involves the Michael addition of silyl enol ethers to nitro-olefins catalysed by Lewis acids, which leads directly to the 1,4-dione without isolation of nitroketone or related intermediates (Scheme 15). A feature of the method is that it is highly regiospecific in the selective formation of 1,4-diones with no double-bond migration in the silyl enol ether. 

At the time the chemistry of main group enolates flourished already for a while, that of late transition metals had a shadowy existence in synthetic organic chemistry. Their stoichiometric preparation and the sluggish reactivity - tungsten enolates, for example, required irradiation to undergo an aldol addition [24a] - did not seem to predestine them to become versatile tools in asymmetric syntheses [27]. The breakthrough however came when palladium and rhodium enolates were discovered as key intermediates in enantioselective catalyses. After aldol reactions of silyl enol ethers or silyl ketene acetals under rhodium catalysis were shown to occur via enolates of the transition metal [8] and after the first steps toward enantioselective variants were attempted [28], palladium catalysis enabled indeed aldol additions with substantial enantioselectivity... 

Silver(I) complexes with Tol-BINAP (270) were used by Yamamoto and coworkers for mediating diastereoselective and enantioselective Mukaiyama aldol additions. According to the authors conclusion, the mechanism does not involve transmetallation to silver enolates but follows the usual carbonyl group activation [135]. Hoveyda and coworkers used silver(II) fluoride in the presence of a dipeptide-type ligand for enantioselective additions of silyl enol ethers to a-keto esters [136]. The reaction of 2-trimethylsilyloxyfuran with aromatic and aliphatic aldehydes was catalyzed with chromium salen complex in the presence of protic additives like isopropanol [137]. Various protocols of enantioselective Mukaiyama aldol reactions that use water as cosolvent have been elaborated ... 

The conditions used for the Mukaiyama-aldol type reactions employing InCh (see Section 8.2) were found by Loh et al. to be useful in Michael-type additions of silyl enol ethers to a,P-unsaturated carbonyl compounds [49] (Figure 8.25). 

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