Thioacetals to ethers

Reduction of Acetals, Azaacetals and Thioacetals to Ethers. Brewster, J. H. In Comprehensive Organic Synthesis TVost, B. M., Fleming, I., Eds. Pergamon Press Oxford, 1991 Vol. 8, p 211. 

Deacetalization and dethioacetalization. Dimethyl acetals, 4-p-methoxy-phenyl-l,3-dioxolanes are cleaved withDDQ in the presence of water. For deprotection of thioacetals under mild conditions photochemical assistance seems advantageous. The same reaction principle of deacetalization can be extended to ether exchange. Thus alcohol protection is possible by mixing with 2,2-dimethoxypropane in the presence of DDQ, and proximal diols are converted to acetonides. Replacement of anomeric arylmethoxyl groups by this method complements other glycosylation procedures. 

Elimination of Thiophenol from Thioacetals. Conversion of thioacetals to vinyl sulfides is accomplished under exceptionally mild conditions by treatment with (CuOTOa-CeHe (eq 45). The reaction involves an a-phenylthio carbocation intermediate. Three factors contribute to the effectiveness of this synthetic method the Lewis acidity of a copperfT) cation that is unencumbered by a strongly coordinated counter anion, the solubility of the copper(I) triflate-benzene complex, and the insolubility of CuSPh in the reaction mixture. An analogous elimination reaction provides an effective route to phenylthio enol ethers from ketones (eq 46). ... 

Alkylidenation of esters on solid supports offers a special advantage in that the resulting enol ethers are resistant to hydrolysis (Scheme 4.43). The resin-bound ester is treated with the titanium reagent prepared from the thioacetal to produce the enol ether, which is further transformed into the benzofuran on treatment with trifluoroacetic add [102]. 

The hetero Diels-Alder [4+2] cycloaddition (HDA reaction) is a very efficient methodology to perform pyrimidine-to-pyridine transformations. Normal (NHDA) and Inverse (IHDA) cycloaddition reactions, intramolecular as well as intermolecular, are reported, although the IHDA cycloadditions are more frequently observed. The NHDA reactions require an electron-rich heterocycle, which reacts with an electron-poor dienophile, while in the IHDA cycloadditions a n-electron-deficient heterocycle reacts with electron-rich dienophiles, such as 0,0- and 0,S-ketene acetals, S,S-ketene thioacetals, N,N-ketene acetals, enamines, enol ethers, ynamines, etc. 

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 recent total synthesis of tubulysin U and V makes use of a one-pot, three-component reaction to form 2-acyloxymethylthiazoles <06AG(E)7235>. Treatment of isonitrile 25, Boc-protected Z-homovaline aldehyde 26, and thioacetic acid with boron trifluoride etherate gives a 3 1 mixture of two diastereomers 30. The reaction pathway involves transacylation of the initial adduct 27 to give thioamide 28. This amide is in equilibrium with its mercaptoimine tautomer 29, which undergoes intramolecular Michael addition followed by elimination of dimethylamine to afford thiazole 30. The major diastereomer serves as an intermediate in the synthesis of tubulysin U and V. 

This RCM has proven to be a useful synthetic method for the construction of a variety of heterocycles. Mono and bicyclic unsaturated ethers and sulfides are obtained from alkenyl thioacetals having an ether or sulfide linkage (Table 14.2) [30],... 

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. 

---