Trimethylsilyl aldol reaction

By using the directed aldol reaction, unsymmetrical ketones can be made to react regioselectively. After conversion into an appropriate enol derivative (e.g. trimethylsilyl enol ether 8) the ketone reacts at the desired a-carbon. 

For example in the so-called Mukaiyama aldol reaction of an aldehyde R -CHO and a trimethylsilyl enol ether 8, which is catalyzed by Lewis acids, the required asymmetric environment in the carbon-carbon bond forming step can be created by employing an asymmetric Lewis acid L in catalytic amounts. 

Aldol reaction of the a-trimethylsilylated enolate 9 with aldehydes provides nearly equal amounts of chromatographically separable ( )- and (Z)-isomers of iron-acyl complexes 11 via silyloxide elimination from the intermedate aldolate 10 (Table 3). This methodology has been the most commonly employed entry to the (Z)-isomer series. 

TiIV compounds also work well at promoting cross-aldol reactions between two different aldehydes and/or ketones without prior activation or protection (Scheme 19).74 Claisen condensation and Knoevenagel condensation are promoted by TiX4, an amine, and trimethylsilyl triflate.75-77... 

Mukaiyama aldol reactions of aldehydes with silyl enol ethers are amongst the most widely used Lewis-acid-mediated or -catalyzed reactions. However, trimethylsilyl triflate is not active enough to promote these reactions,66 and more active silicon-based Lewis acids have been developed. One example is the species generated by mixing trimethylsilyl triflate (or chloride) and B(OTf)3,319,320 for which the formulation R3Si + [B(OTf)4] is suggested by NMR experiments. Only a catalytic amount of this was needed to complete Mukaiyama aldol reactions of... 

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). 

TABLE 9.25. MUKAIYAMA ALDOL REACTION OF BENZYLOXYACETALDEHYDE AND A TRIMETHYLSILYL ENOL ETHER"... 

A special case is the ring-forming reaction in the lactone acetal 568,69. When 5 is treated with trimethylsilyl trifluoromethanesulfonate (trimethylsilyl triflate TMSOTf) in the presence of triethylamine at 0°C the cisjtrans mixture 6a and 6b is formed in ca. 50% yield. In this intramolecular aldol reaction the probable intermediate is the oxonium ion 7. 

A stereoselective Mukaiyama-type aldol reaction of bis(trimethylsilyl)ketene acetals produces silyl aldols with syn stereoselectivity, predominantly due to steric effects.23... 

Asymmetric induction in the aldol reaction of enolsilane and metal enolate nucleophiles with yS-substituted aldehydes gives rise to both excellent yields and good diastereoselectivities (equation 128)507. The best diastereoselectivity was obtained using a trimethylsilyl enolate in the presence of boron trifluoride-etherate (92 8 anti. syn). The key step in the synthesis of the N-terminal amino acid analogue of nikkomycin B and Bx (nucleoside peptide antibiotics) has been performed using this type of methodology508. 

Mukaiyama aldol reaction (6, 590-591). This reaction is generally effected with TiCl4 in stoichiometric amounts as the promotor. This lanthanide complex is also effective and can be used as a catalyst if trimethylsilyl chloride is also present.2 Yields are >80% in the case of aromatic aldehydes, and are >50% in the case of... 

High yields of bis(arylmethylidene)tetrahydrothiopyran-4-ones are achieved through a double aldol reaction of tetrahydrothiopyran-4-one with benzaldehydes in the presence of iV-(trimethylsilyl)diethylamine and LiC104 (Equation 26) <2005SL2317>. 

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... 

Scheme 9.13. Aldol reaction of an a-diazo trimethylsilyl enol ether.

The authors used (5)-carvotanacetone (dihydrocarvone) as starting material (Scheme 34). To prepare the linearly conjugated sUylenol ether, they used the Kharash protocol and attained y-alkylation by Mukaiyama aldol reaction with trimethylorthoformate (195). The ketoacetal 295 was a-hydroxylated according to Rubottom by silylenol ether formation followed by epoxidation and silyl migration. Acid treatment transformed 296 to the epimeric cyclic acetals 297 and 298. endo-Aceta 297 was equilibrated thereby increasing the amount of exo-acetal 298. The necessary unsaturated side chain for the prospected radical cyclization was introduced by 1,4-addition of a (trimethylsilyl)butynylcopper compound. 

The hydrophobicity-driven association of reactant molecules in aqueous solution has even been found in aldol reactions. The trimethylsilyl ether of cyclohexanone adds to benzaldehyde in aqueous solution at 20 °C in the absence of a catalyst to give aldol addition products with a synlanti stereoselectivity opposite to that of the acid-catalyzed reaction carried out in dichloromethane [746]. 

In the lithium and cesium enolates of o-methoxyacetophenone, the methoxy oxygen coordinates with the smaller lithium cation but not with the cesium cation . Other examples of lithium enolate chemistry include a thermochemical analysis of the aldol reaction of lithiopinacolonate with pivalaldehyde and a comparison of the proton affinities and aggregation states of lithium alkoxides, phenolates, enolates, -dicarbonyl enolates, carboxylates and amidates. Although the lithium enolate of cyclopropanone itself remains unknown, derivatives (accompanied by their aUenoxide isomer) have been implicated in the reaction of a-(trimethylsilyl) vinyl lithium with CO. That both species are seemingly formed is surprising because cyclopropanone enolate is expected to be much less stable than its acyclic isomer cyclopropene is less stable than allene by almost 90 kJmol-. ... 

To determine the aetivated faee of a carbonyl group in an acetylenic aldehyde-CAB 2 complex, an aldol reaction of acetylenic aldehydes with the trimethylsilyl enol ether derived from acetophenone was performed in the presence of 20 mol % 2 under conditions similar to those in the Diels-Alder reaction (Eq. 32). Good enantioselec-tivity was, with the predominant enantiomer corresponding to attack on the re face, as expected. Although it is essential to stress that the results of an aldol reaction cannot be directly used to explain the transition state in cycloaddition, the effective steric shielding of the si face of the coordinated aldehyde is consistent with cycloaddition via the proposed transition-state model 16. 

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. 

There is a dichotomy in the sense of syn-anti diastereofacial preference, dictated by the bulkiness of the migrating group [94]. The sterically demanding silyl group results in syn diastereofacial preference but the less demanding proton leads to anti preference (Sch. 35). The anti diastereoselectivity in carbonyl-ene reactions can be explained by the Felkin-Anh-like cyclic transition-state model (Ti) (Sch. 36). In the aldol reaction, by contrast, the now inside-crowded transition state (Ti ) is less favorable than Tg, because of steric repulsion between the trimethylsilyl group and the inside methyl group of aldehyde (Ti ). The syn-diastereofacial selectivity is, therefore, visualized in terms of the anti-Felkin-like cyclic transition-state model (T2 )-... 

---