Thiols acetal formation

The C23-C26 segment 173 was prepared from 180, which was derived from ribose (O Scheme 20). After 0-benzylation of 180, the resulting benzyl ether was treated with MeMgCl and CuBr Me2S to afford 181. Thiol acetal formation followed by selective silyla-tion provided 182. The dithioacetal was cleaved and the resulting aldehyde was reduced with NaBH4 to afford a diol, which was subjected to direct epoxidation to provide 173. 

Formation of the thioamidate of the pyrimidine-acetonitrile 233 followed by reaction with thiol-acetic acid 234 gave elegant and efficient formation of the five-membered ring 235 in 82% yield (Equation 64) <2001JOC4723>. 

An alternative to the synthesis of epoxides is the reaction of sulfur ylide with aldehydes and ketones.107 This is a carbon-carbon bond formation reaction and may offer a method complementary to the oxidative processes described thus far. The formation of sulfur ylide involves a chiral sulfide and a carbene or carbenoid, and the general reaction procedure for epoxidation of aldehydes may involve the application of a sulfide, an aldehyde, or a carbene precursor as well as a copper salt. This reaction may also be considered as a thiol acetal-mediated carbene addition to carbonyl groups in the aldehyde. 

The alcohol in hemiacetal/acetal formation can be replaced with a thiol (R-SH). In addition, a glycol can be replaced with a dithiol, and then you can follow a procedure similar to the one outlined in Figure 10-21. This procedure leads to an easy method for reducing a carbonyl (Figure 10-22). The reaction with a thiol is in the presence of the Lewis acid boron trifluoride, BFj. 

Addition of hydrogen sulfide and thiols is qualitatively similar to reaction with alcohols in that there are two stages, formation of hemithioacetal (or hemithio-ketal) followed by acid-catalyzed elimination of the hydroxy group and substitution of a second —SR (Equations 8.47 and 8.48). The transformation has been studied less extensively than hydration and acetal formation, and relatively little information on mechanism is available. The initial addition appears to be specific base-catalyzed, an observation that implies that RS is the species that adds. The situation is thus similar to cyanide addition. General acid catalysis has, however, been found at pH 1 to 2 for addition of weakly acidic alkyl thiols, and the reaction rate as a function of pH has a minimum and rises both on the... 

In the presence of catalytic amounts of a sufficiently strong acid, thiols and carbonyl compounds form, S, .S -acetals according to the mechanism of Figure 7.15. The thermodynamic driving force for this type of. S, .S -acetal formation is greater than that for the analogous <9,<9-acetal formation (there is no clear reason for this difference). For ex-... 

The synthesis of 38 began with 39. Acetal formation and chlorination adjacent to sulfur provided 40. Thiourea was used to introduce sulfur. Hydrolysis of 41 provided the free thiol and a ketal exchange (hydrolysis-protection) gave 42. This compound was configurationally stable at the anomeric center and thus, was resolved via the thioester derived from reaction with (-)-camphanyl chloride. The absolute configuration of the proper enantiomer was established by X-ray crystallography of this thioester. S-Alkylation of 43 with racemic mesylate 46 provided a mixture of diastereomers 47 (Erythronolide-6). 

Thiols are the sulfur analogs of alcohols (Section 15.11). The sulfur atom of a thiol is a better nucleophile than the oxygen atom of an alcohol. Thus, thiols react with aldehydes or ketones to form thioacetals or thioketals by a mechanism similar to that described for acetals and ketals. These sulfur derivatives form in high yield because the equdibrium constant for thioacetal formation is much greater than that for acetal formation. We use Lewis acids such as BFj or ZnCl2 rather than protic acids to catalyze the formation of the thioacetal. Both 1,2-ethanedithiol and 1,3-propanedithiol are used to form cyclic thioacetals and thioketals. 

A carbonyl group can be protected as a sulfur derivative—for example, a dithio acetal or ketal, 1,3-dithiane, or 1,3-dithiolane—by reaction of the carbonyl compound in the presence of an acid catalyst with a thiol or dithiol. The derivatives are in general cleaved by reaction with Hg(II) salts or oxidation acidic hydrolysis is unsatisfactory. The acyclic derivatives are formed and hydrolyzed much more readily than their cyclic counterparts. Representative examples of formation and cleavage are shown below. 

The aziridine aldehyde 56 undergoes a facile Baylis-Hillman reaction with methyl or ethyl acrylate, acrylonitrile, methyl vinyl ketone, and vinyl sulfone [60]. The adducts 57 were obtained as mixtures of syn- and anfz-diastereomers. The synthetic utility of the Baylis-Hillman adducts was also investigated. With acetic anhydride in pyridine an SN2 -type substitution of the initially formed allylic acetate by an acetoxy group takes place to give product 58. Nucleophilic reactions of this product with, e. g., morpholine, thiol/Et3N, or sodium azide in DMSO resulted in an apparent displacement of the acetoxy group. Tentatively, this result may be explained by invoking the initial formation of an ionic intermediate 59, which is then followed by the reaction with the nucleophile as shown in Scheme 43. 

The enolates of other carbonyl compounds can be used in mixed aldol reactions. Extensive use has been made of the enolates of esters, thiol esters, amides, and imides, including several that serve as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, titanium, and tin derivatives have all been widely used. The silyl ethers of ester enolates, which are called silyl ketene acetals, show reactivity that is analogous to silyl enol ethers and are covalent equivalents of ester enolates. The silyl thioketene acetal derivatives of thiol esters are also useful. The reactions of these enolate equivalents are discussed in Section 2.1.4. 

Ethonam (99), an imidazole derivative with a very different substitution pattern, is also reported to possess antifungal activity. To prepare it, alkylation of aminotetralin 94 with methylchloro-acetate gives the glycine derivative 95. Heating with formic acid then affords the amide 96 this compound is then reacted with ethyl formate to yield hydroxymethylene ester 97. Reaction with isothio-cyanic acid gives the imidazole-2-thiol 98. (The... 

Several palladium catalysts for formation of aryl sulfides from aryl halides have been investigated more recently. A combination of Pd2(dba)3 and DPEphos catalyzed the formation of a broad range of diaryl sulfides in the presence of 1 mol.% palladium and NaO-t-Bu base in toluene solvent.12,rThe highest yields of alkyl aryl sulfides were obtained from aryl triflates and n-butyl thiol catalyzed by a combination of palladium acetate and BINAP. However, these reactions contained 10 mol.% catalyst, were long, and required deactivated aryl triflates. A combination of Pd2(dba)3 and DPPF catalyzed the coupling of thiols with resin-bound aryl halides.121... 

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