Lactones sulfenylation

When /3-vinylbutenolide (158), prepared from /3-vinylbutyrolactone by a sulfenylation-sulfoxide elimination process, was reacted with the anion of a-methylcyclohexane-1,3-dione, two products (159) and (160) were produced in an 11 1 ratio (47% combined yield) (75CC337). Dehydration of these compounds with thionyl chloride in pyridine yielded (161) and (162), respectively (Scheme 35). The annelation products are useful intermediates for sesquiterpene lactone construction. 

Compound 35, along with some other structurally related sulfenylating agents, has also been found to be useful for the functionalization of 1,3-dicarbonyl compounds 38 (Eq. 9). Lactones and / -dicarbonyl compounds were a-sulfenylated in the presence of (DHQD)2PYR in high yields and moderate to good enantioselec-tivities (51-91% ee) [34]. 

The sulfmylation of esters, - lactones, carboxylic acids, > amides and lactams may be effected by reacticm of the corresptHiding lithium enolates in THF at -78 to 0 C with dimethyl or difdie-nyl disulfides, or, less conunmily, with methyl or fdienyl sulfmyl halides. The enolates of ketones, however, are insufficioitly nucleq diilic to react with dialkyl sulfides unless HMPA is added to the re-acticm mixture, although they do react smoothly with diaryl sulfides. This difference allows the selective sulfenylation of esters in the presence of ketones (entry 5, Table 3). ... 

Dehydrogenation reactions involving sulfur have proved important in the formation of a-iiKthylene-lactones such as (9 Scheme 10), but sulfenylation prior to alkylation is necessary for cfused systems in order to establish the correct geometry for exocyclic double bond formation. ... 

Owing to the urgent need of new drugs for the treatment of AIDS, many methods for converting the title lactones into antiviral dideoxynucleosides have been devised within the past few years. A viable synthesis of the potent anti-HIV agent 3 -deoxy-2, 3 -dehydrothymidine (d4T, 21) relies on trans selective sulfenylation of the lactone-derived silyl ketene acetal (20) with iV-(phenylthio)- -caprolactam (eq 11). In comparable fashion, (21) and related nucleosides have been prepared through seleneny-lation of (20). ... 

In 2005, the application of cinchona alkaloid derivatives as catalysts for enantiose-lective a-sulfenylation of activated C—H bonds in lactones, lactams, and P-dicarbonyl compounds 146 by electrophilic sulfur reagent 147 was reported by Jorgensen and coworkers (Scheme 6.44) [73]. Optically active a-sulfenylated products 148 were obtained in good to excellent yields and up to 86% ee in the presence of 10 mol% (DHQD)2PYR in toluene solvent at —30 or —40°C. Furthermore, the diastereose-lective reduction of a-sulfenylated (3-keto esters to give optically active a-sulfenylated (5-hydroxy esters was also demonstrated. 

We can use sulfenyl-lactonisation to illustrate the stereospecificity of the process when the alkene differs in geometry. Rokach28 has shown that the geometrical isomers of the unsaturated acid E-and Z-182 give the correct diastereoisomers of the lactones from anti addition of Cl and R S. 

Trost has used a,a-disulfenylated lactones as enolate precursors. As shown in equation (23), a,a-di-(phenylthio)- v-butyrolactone is treated sequentially with ethylmagnesium bromide and acetaldehyde to obtain -hydroxy lactone (8) in virtually quantitative yield. Oxidation of the phenylthio group and subsequent elimination of the resulting sulfoxide provides the unsaturated hydroxy lactone (9). The process was employed with more complex lactones in a total synthesis of iridoids. The method fails with a,a-di-sulfenylated ketones unless a catalytic amount of copper(I) bromide is included in the reaction mixture. 

This reaction has also been applied to a-sulfenyl esters (equation II) and a-sulfenyl lactones (equation HO-... 

Styrylindoles, 100 Sulfamic acid, 28 oi-Sulfenyl esters, 150 v-Sulfenyl lactones, 150 Sulfinamides, 100-101 SulTinates, 388-389 N-Sulfinyl-p-toluenesulfonamide, 50 Sulfonyl cMorides, 58 Sulfoxides, 3, 58 Sulfur dioxide, 346-346 Sulfuric acid, 347-348 Sulfuiyl chloride, 349-350 Super Hydride, 215-216, 307... 

Reaction with N-Bromosuccinimide (MBS). The behaviour of 2-sul-fenylated-tryptophan peptides towards NBS is of particular interest, since NBS can be used to modify this amino acid residue in proteins (see Section III.2.1.). In the following scheme, the reactions occurring upon treatment of a 2-sulfenylated tryptophan peptide with NBS are shown. Bromination at the 3-position of the indole moiety is followed by displacement of the halogen atom by the carbonyl function of the side chain amide, with concomitant cyclization to an imido-lactone (165). 

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