Silyl thioacetate

Sc(() l f) ( is an effective catalyst of the Mukaiyama aldol reaction in both aqueous and non-aqueous media (vide supra). Kobayashi et al. have reported that aqueous aldehydes as well as conventional aliphatic and aromatic aldehydes are directly and efficiently converted into aldols by the scandium catalyst [69]. In the presence of a surfactant, for example sodium dodecylsulfate (SDS) or Triton X-100, the Sc(OTf)3-catalyzed aldol reactions of SEE, KSA, and ketene silyl thioacetals can be performed successfully in water wifhout using any organic solvent (Sclieme 10.23) [72]. They also designed and prepared a new type of Lewis acid catalyst, scandium trisdodecylsulfate (STDS), for use instead of bofh Sc(OTf) and SDS [73]. The Lewis acid-surfactant combined catalyst (LASC) forms stable dispersion systems wifh organic substrates in water and accelerates fhe aldol reactions much more effectively in water fhan in organic solvents. Addition of a Bronsted acid such as HCl to fhe STDS-catalyzed system dramatically increases the reaction rate [74]. 

Lanthanide triflates and Sc(OTf)3 effectively catalyze conjugate addition of SEE, KSA, and ketene silyl thioacetals under mild conditions (0°C to room temperature, 1-10 mol% catalyst) (Scheme 10.86) [69, 238]. After an aqueous work-up these Lewis acids can be recovered almost quantitatively from the aqueous layer and can be re-used without reduction of fheir catalytic activity. Eu(fod)3 also is effective in not only aldol reactions but also Michael addition of KSA [239]. The Eu(fod)3-catalyzed addition of KSA is highly chemoselective for enones in the presence of ketones. 

Three-component coupling reaction of a-enones, silyl enolates, and aldehydes by successive Mukaiyama-Michael and aldol reactions is a powerful method for stereoselective construction of highly functionahzed molecules valuable as synthetic intermediates of natural compounds [231c]. Kobayashi et al. recently reported the synthesis of y-acyl-d-lactams from ketene silyl thioacetals, a,/l-urisalu-rated thioesters, and imines via successive SbCl5-Sn(OTf)2-catalyzed Mukaiyama-Michael and Sc(OTf)3-catalyzed Mannich-type reactions (Scheme 10.87) [241]. 

In 1988, Mukaiyama et al. reported the Sn(OTf)2-50d-catalyzed asymmetric Michael reaction of a trimethylsilyl enethiolate, CH2=C(SMe)SSiMej (up to 70% ee) [243]. It was proposed that the catalytic reaction proceeded via an Sn(II) enethiolate. They also demonstrated that a BINOL-derived oxotitaniurn catalyzes the Michael addition of ketene silyl thioacetals to a-enone with high enantioselectivity (up to 90% ee) [244]. After this pioneering work other research groups developed new reaction systems for enantioselective Mukaiyama-Michael reactions. 

The polymer-supported Zr catalyst (12) is useful for asymmetric aza-Diels-Alder cycloaddition of benzaldehyde imine to Danishefsky diene [9]. The 6-substituted BINOL-Zr(IV) catalyst is useful for the enantioselective anft -preferred aldol reaction of benzaldehyde with ketene silyl thioacetal (15) (Scheme 5.5) [ 10]. The calculated charge densities on the oxygen atoms of the BINOL derivatives revealed that there is a good correlation between the charge density and the reactivity of 6-substituted BINOL [ 10]. 

FIGURE 2. Crystalline silyl thioacetate view of reference molecule and two neighbouring molecules showing labelling scheme and intermolecular Si S contacts. Reproduced by permission of the Royal Society of Chemistry. 

In the reaction of the tin(II) enolate derived from (1) with aldehydes, enantioselectivities are disappointingly low, while good diastereoselectivities are observed. Highly diastereo- and enan-tioselective aldol reactions of propionate derivatives with aldehydes have been achieved by using the ketene silyl thioacetal (7) instead of the tin(II) enolate. The complex (8) produced by mixing tin(n) triflate and the chiral diamine (6) works as an efficient chiral Lewis acid. The reaction of (7) with various aldehydes proceeds smoothly in the presence of (8) and dibutyltin diacetate in dichloromethane to afford the syn aldol adducts in high yields with almost perfect stereochemical control (eq 9). ... 

Keten thioacetals (428) are useful synthetic intermediates and a general method for their preparation is reaction of metalated silyl thioacetals with carbonyl derivatives. ... 

The carbanions derived from thioacetals, however, are typical -synthons. Most frequently used are 1,3-dithianes and C -silylated thioethers (see p. 33f. D. Seebach, 1969, 1973 B.-T. Grobel, 1974,1977). In these derivatives the proton is removed by butyllithium in THF. 

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. 

A Mukaiyama-type aldol reaction of silyl ketene thioacetal (48) with an aldehyde with large and small a-substituents (e.g. Ph and Me), catalysed by boron trifluoride etherate, gives mainly the iyn-isomer (49), i.e. Cram selectivity. For the example given, changing R from SiBu Me2 to Si(Pr )3 raises the syn preference considerably, which the authors refer to as the triisopropylsilyl effect. Even when the and R groups are as similar as ethyl and methyl, a syn. anti ratio of 5.4 was achieved using the triisopropylsilyl ketene thioacetal. 

The reactions proceeded efficiently under mild conditions in short time. The silyl enol ethers reacted with the activated acetals or aldehydes at -78 °C to give predominant erythro- or threo-products [136, 137] respectively. In the same manner, the aldol reaction of thioacetals, catalyzed by an equimolar amount of catalyst, resulted in <-ketosulfides [139] with high diastereoselectivity. In the course of this investigation, the interaction of silyl enol ethers with a,]3-unsaturated ketones, promoted by the trityl perchlorate, was shown to proceed regioselec-tively through 1,2- [141] or 1,4-addition [138]. The application of the trityl salt as a Lewis acid catalyst was spread to the synthesis of ]3-aminoesters [142] from the ketene silyl acetals and imines resulting in high stereoselective outcome. 

Because carbohydrates are so frequently used as substrates in kinetic studies of enzymes and metabolic pathways, we refer the reader to the following topics in Ro-byt s excellent account of chemical reactions used to modify carbohydrates formation of carbohydrate esters, pp. 77-81 sulfonic acid esters, pp. 81-83 ethers [methyl, p. 83 trityl, pp. 83-84 benzyl, pp. 84-85 trialkyl silyl, p. 85] acetals and ketals, pp. 85-92 modifications at C-1 [reduction of aldehydes and ketones, pp. 92-93 reduction of thioacetals, p. 93 oxidation, pp. 93-94 chain elongation, pp. 94-98 chain length reduction, pp. 98-99 substitution at the reducing carbon atom, pp. 99-103 formation of gycosides, pp. 103-105 formation of glycosidic linkages between monosaccharide residues, 105-108] modifications at C-2, pp. 108-113 modifications at C-3, pp. 113-120 modifications at C-4, pp. 121-124 modifications at C-5, pp. 125-128 modifications at C-6 in hexopy-ranoses, pp. 128-134. 

The reaction of Cjq with silylated nucleophiles [47] requires compounds such as silyl ketene acetals, silylketene thioacetals or silyl enol ethers. It proceeds smoothly and in good yields in the presence of fluoride ions (KF/18-crown-6) (Scheme 3.10). The advantage of the latter synthesis is the realization of the cyclopropanation under nearly neutral conditions, which complements the basic conditions that are mandatory for Bingel reactions. Reaction with similar silyl ketene acetals under photochemical conditions and without the use of F does not lead to methanofullerenes but to dihydrofullerene acetate [48]. 

Reductive desulfenylation of the thioacetal 2 should produce 4 a and 4 b in nearly equal amounts. Subsequent silylation of 4, generated in this manner, gave 5a and 5 b with the same diastereomeric ratio as before. Only when the desulfenylation of 2 was performed in the presence of chlorotrimethylsilane, were the diastereomers of 5 obtained in a different ratio (5 a, d.r. 60 40). This demonstrates that the silylation reaction of 4 is faster in this case than the epimerization. 

Preparation of a somewhat more complex leukotriene antagonist begins by aldol condensation of the methyl carbanion from quinoline (29-1) with meta-phthalalde-hyde (29-2) to give the stilbene-like derivative (29-3) dimer formation is presumably inhibited by the use of excess aldehyde. Reaction of that product with A,A-dimethyl-3-mercaptopropionamide in the presence of hexa-methylsilazane affords the silyl ether (29-4) of the hemimercaptal. Treatment of that intermediate with ethyl 3-mercaptopropionate leads to the replacement of the silyl ether by sulfur and the formation of the corresponding thioacetal (29-5). Saponification of the ester group leads to the carboxylic acid and thus to verlukast (29-6) [33]. 

Keto sulfides.1 In the presence of trityl tetrafluoroborate, silyl enol ethers react with thioacetals or -ketals to give 7-keto sulfides in 75-95% yield (equation I). The same products can be obtained directly from ketones and thioacetals by in... 

Boron aldol reactions have been used to stereoselectively construct the anti-3-hydroxy-2-methylcarbonyl system from carboxylate esters,58 and to combine a-hetero-substituted thioacetates with aldehydes or silyl imines enantio- and/or diastereo-selectively.59... 

Five steps were required to convert 75 into the iodide coupling partner 44 needed for union with dithiane 43 (Scheme 17.16). Thioacetal formation31 and concomitant deketalisation were instigated by reacting 75 with 1,3-propanedithiol under Lewis acid conditions. Triol 76 was isolated in 65% yield. The less-hindered primary hydroxyl of 76 was then selectively 0-tosylated, and the remaining hydroxyls masked as tert-butyldimethyl silyl (TBDMS) ethers. Iodide displacement on 77 with sodium iodide and copper bronze,32 and transketalisation with N-chlorosuccinimide (NCS)/silver nitrate33 finally secured 44. 

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