Vinyl sulfoxides reduction

To gain understanding of the interdependence between the olefin reduction and the sulfoxide reduction, the saturated sulfoxide 52 was prepared and treated with BH3-THF. No reaction was observed under the similar conditions (Scheme 5.18). The unactivated vinyl sulfide 16 was also not reactive toward BH3-THF. These results indicated that sulfoxide and olefin were reduced simultaneously, not independently. Again this phenomenon was unexpected and pointed to the unique nature of this reaction. 

We have developed the efficient synthesis of the SERM drug candidate 1 and successfully demonstrated the process on a multiple kilogram scale to support the drug development program. A novel sulfoxide-directed borane reduction of vinyl sulfoxides was discovered. The mechanistic details of this novel reaction were explored and a plausible mechanism proposed. The sequence of asymmetric oxidation of vinyl sulfoxides followed by stereospecific borane reduction to make chiral dihydro-1,4-benzoxathiins was applied to the asymmetric synthesis of a number of other dihydro-1,4-benzoxathiins including the sweetening agent 67. 

Cycloaddition to vinyl sulfoxides, y-butyrolactones/ Dichloroketene (best generated by zinc reduction of trichloroacetyl chloride, 8,156) reacts with vinyl sulfoxides to form a-dichloro-y-butyrolactones in 50 80% yield. A polar mechanism involving a Pummercr-type rearrangement has been suggested. 

Deoxygenation of sulfoxides. Tris(phenylseleno)borane is an effective reagent for the reduction of sulfoxides under mild conditions. Although this reagent converts ketones to selenoketals, selective deoxygenation of keto sulfoxides is possible. Deoxygenation of vinyl sulfoxides also proceeds smoothly. 

Vinylic sulfoxide (30) is desulfurized to (31) with f-butyllithium (equation 80), and sulfone (32) affords triphenylethylene on reduction with aluminum amalgam or lithium aluminum hydride (equation 81). ... 

The synthesis of unnatural (+)-mesembrine (387) through the asymmetric synthesis of methyl (i )-l-[(3,4-dimethoxy)phenyl]-4-oxocyclohex-2-enyl acetate (390) by cycloaddition of enantiomerically pure vinyl sulfoxide with dichloroketene has been performed 189) (Scheme 43). Vinyl sulfoxide 388 [prepared by conjugate addition of enantiopure acetylenic sulfoxide with (3,4-dimethoxy)phenylcopper] reacted with trichloroacetyl chloride in the presence of freshly prepared zinc-copper couple in THF at 0°C to produce a mixture of mono- and dichloro lactones 389. Reduction of 389 with zinc in acetic acid followed by cyclization and methylation afforded methyl IR-[(3,4-dimethoxy)phenyl]-4-oxocyclohex-2-enyl acetate (390), treatment of which with methylamine brought about amidation and concomitant intramolecular Michael addition to provide 2-oxo-mesembrine (391). Successively, 391 was transformed to (+)-mesembrine (387) in 79% yield (three steps ketalization of an oxo group, reduction of lactam, and deketali-zation)(/S9). 

A simple and straightforward application was outlined in the synthesis of hydrohydrastinine as depicted in Scheme 10. Michael addition of 3,4-methyle-nedioxyphenylmethyl amine to vinyl sulfoxide 36 took place smoothly in refluxing methanol. Pummerer rearrangement in acetic anhydride afforded acetoxysulfide 37 in 90% yield and this was then cyclized to 38 with BF3 etherate in 93 % yield. Sulfide 38, which was rather unstable, was desulfurized with Raney nickel in 80 % yield. Hydrolysis of the acetyl group followed by reductive methy-lation afforded hydrohydrastinine (39) in good yield [24]. 

The [Co(trans-diammac)] -mediated DMSO reductase electrochemistry in Figure 5.20D was scaled up by using a large surface area reticulous vitreous carbon working electrode to enable the bulk catalytic reduction of racemic mixtures of chiral sulfoxides methyl p-io y sulfoxide, methyl phenyl sulfoxide and phenyl vinyl sulfoxide. Extraction of the electrochemical solution with chloroform followed by chiral HPLC revealed that R. capsulatus DMSO reductase is able to kinetically discriminate between the S- and i -sulfoxides the 5-enantiomer being reduced preferably (Figure 5.21). 

The first enantioselective synthesis of an aflatoxin building block was published in 1993 by Marino (57). He presented a synthesis of 32 in 80% enantiomeric excess and induced the stereospecificity via optically active vinyl sulfoxides (see Scheme 2.14). Catechol (40) was acylated, mono-iodinated and then coupled with chiral vinyl sulfoxide 85 under Stille conditions (- 86). Dichloroketene lactonization under reductive conditions followed by zinc-promoted dechlorination gave the major diastereomer 87. 

For references see Williams, R. V. Lin, X. New ketene equivalents for the Diels-Alder reaction. Vinyl sulfoxide cycloaddition. /. Chem. Soc., Chem. Commun. 1989, 1872-1873. Ruden, R. Bonjouklian, R. Cycloaddition of vinyl triphenyl-phosphonium bromide. New synthesis of cyclic phosphonium salts. Tetmhedron Lett. 1974, 15, 2095-2098. Ranganathan, S. Ranganathan, D. Mehrotra, A. K. Nitroethylene as a versatile ketene equivalent. Novel one-step preparation of prostaglandin intermediates by reduction and abnormal Nef reaction. J. Am. Chem. Soc. 1974, 96, 5261-5262. Kozikowski, A. P. Floyd, W. S. Kuniak, M. P. 1,3-Diethoxycarbonylallene an active dienophile and ethoxycar-bonylketene equivalent in the synthesis of antibiotic C-nucleosides. J. Chem. Soc., Chem. Commun. 1977, 582-583. 

A variety of methods for the reduction of sulfoxides to sulfides are available. PI3 rapidly reduces aryl alkyl and dialkyl sulfoxides and selenoxides, usually at —78 °C (eq 3). For example, treatment of ethyl phenyl sulfoxide with 1 equiv of PI3 (CH2CI2, -78 °C, 15 min) affords ethyl phenyl sulfide in 91% yield. Others have successfully employed this procedure. Dialkyl sulfoxides generally react in somewhat lower yield. A phenyl vinyl sulfoxide (eq 3, entry c) requires ambient temperatures to react. Selenoxides behave similarly, and P2I4 can usually be used in place of PI3. Treatment of decyl phenyl selenone with PI3 (CH2CI2, 0 °C, 30 min) affords a mixture of the reduced product, decyl phenyl se-lenide (69%), and the substitution product, n-decyl iodide. ... 

Besides simple alkyl-substituted sulfoxides, (a-chloroalkyl)sulfoxides have been used as reagents for diastereoselective addition reactions. Thus, a synthesis of enantiomerically pure 2-hydroxy carboxylates is based on the addition of (-)-l-[(l-chlorobutyl)sulfinyl]-4-methyl-benzene (10) to aldehydes433. The sulfoxide, optically pure with respect to the sulfoxide chirality but a mixture of diastereomers with respect to the a-sulfinyl carbon, can be readily deprotonated at — 55 °C. Subsequent addition to aldehydes afforded a mixture of the diastereomers 11A and 11B. Although the diastereoselectivity of the addition reaction is very low, the diastereomers are easily separated by flash chromatography. Thermal elimination of the sulfinyl group in refluxing xylene cleanly afforded the vinyl chlorides 12 A/12B in high chemical yield as a mixture of E- and Z-isomers. After ozonolysis in ethanol, followed by reductive workup, enantiomerically pure ethyl a-hydroxycarboxylates were obtained. 

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