Sulfides, 3-hydroxy synthesis

Macrocyclic lactones. Ireland and Brown1 have adapted the Eschenmoser contraction of sulfides to a synthesis of five- and six-membered lactones. An example is formulated in equation (1). A hydroxy thioamide is esterified to give a chloro ester, which is then treated in sequence with Nal and phosphine I. The inelhod can also be used for preparation of macrocyclic lactones under high-dilution... 

Interestingly, when a fi-substituted alcohol is used in the Barton-McCombie reaction and if a [3-elimination process occurs faster than the hydrogen transfer step, then the formation of a double bond is observed. We have just seen such an example with a dixanthate (see Section 3.1.3). Many others are known as in [3-hydroxy sulfides [231] and [3-hydroxysulfones [232,233] in a modified Julia synthesis of olefins. 

Baeyer-Villiger oxidation has been used to selectively oxidize one of two methyl ketones (to esters) in the final step of a stereoselective synthesis of (—)-acetomycin, an antibiotic with potential anti-leukemia activity (equation 25)135. This reaction was accomplished using MCPBA as oxidant, with an excess of sodium bicarbonate and 5-/er/-bulyl-4-hydroxy-2-melhyl phenyl sulfide as a radical inhibitor. 

The by-product in this reaction apparently arises from reaction of the quinonemethide intermediate with the as yet unreacted parent phenol. Since initial evaluations showed bis (3-methyl-4-hydroxy-5-ferf-butyl-benzyl) sulfide, IX, to be a promising antioxidant, we sought an improved method for its synthesis. 

The ring opening of epoxides with thiols provides an efficient route for the formation of (3-hydroxy sulfides. A one-pot method for the direct synthesis of (3-hydroxy sulfoxides has been developed <07JOC4524>. Treatment of an epoxide with PhSH, Ga(O IT)3, and H202 directly provides the sulfoxide with little to no over oxidation. 

Alkene synthesis," Diphosphorus tetraiodide [or phosphorusflll) iodide] converts di- and trisubstituted /3-hydroxy sulfides into alkenes. The reaction is conducted for 2-6 hours in refluxing methylene chloride. The reaction is regiospecific, and involves anfi-elimination of the OH and RS groups. Yields are 80-90%. Thionyl chloride is the preferred reagent for a similar reaction with tetrasubstituted )S-hydroxy sulfides. 

Treatment of 2,3 Cpoxy-l-amines with Lewis acid induces a rearrangement to aziridinium ions that react efficiently with a nucleophiles to give functionalized hydroxy sulfides or hydroxy amines (Equation 23) <1997SL11>. Under the influence of ethylaluminium chloride, an epoxide tethered to an azide undergoes Lewis acid-assisted cyclization followed by an intramolecular Schmidt reaction and subsequent in situ reduction of the intermediate iminium species upon addition of sodium borohydride (Scheme 8). This protocol was used as a key step in a novel synthesis of indolizidine alkaloids of pharmaceutical interest <20030L583, 2004JOC3093>. 

It should be pointed out that enolates are oxidized by the (cam-phorylsulfonyl)oxaziridine at a much faster rate than sulfides. An example is the preparation of a-hydroxy ketone sulfide (9), an intermediate for the total synthesis of ( )-breynolide (eq 12). ... 

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