Epimerization sulfoxides

Penicillin sulfoxides can be epimerized by heat to afford thermal equilibrium mixtures of a- and /3-sulfoxides, the position of the equilibrium depending on the C(6) side chain (Scheme 5). Deuterium incorporation studies support a sulfenic acid, e.g. (18), as the intermediate in these transformations. This mechanism is also supported by the finding that when an a-sulfoxide epimerizes to a /3-sulfoxide there is a simultaneous epimerization at C(2) (71JCS(C)3540). With irradiation by UV light it is possible to convert a more thermodynamically stable /3-sulfoxide to the a-sulfoxide (69JA1530). 

In the case of steroidal propargylic alcohols the first rearrangement produced a mixture of allenyl sulfoxides, epimeric at the sulfur atom, which reacted with an added nucleophile to produce substituted allylic sulfoxides. Rearrangement of the sulfoxide resulted in the exclusive formation of a-hydroxy derivatives. This reaction sequence has been applied in a synthesis of hydrocortisone acetate74 (Nu = OCH3) from androstene-3,17-dione and in a transformation of mesantrol75 (Nu = malonate) to a spirolactone. 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

Section 5.10.3.2). Treatment of methyl 6-phthalimido penicillinate (jR)-sulfoxide (40) with JV-chlorosuccinimide in refluxing carbon tetrachloride gives an epimeric mixture of sulfinyl chlorides (41) which are ring closed to epimeric 3-methylenecepham sulfoxides (42a) using tin(IV) chloride. Reduction with phosphorus tribromide gives the desired methyl 7-phthalimido-3-methylenecepham 4-carboxylate (42b). 

The facile and selective oxidation of both primary and secondary hydroxy groups with certain nucleotides led Pfitzner and Moffatt (48) to explore the scope of the carbodiimide-methyl sulfoxide reagent with steroid and alkaloid alcohols. Relatively minor differences were apparent in the rate of oxidation of epimeric pairs of 3- and 17- hydroxy steroids whereas the equatorial lLx-hydroxyl group in several steroids was readily oxidized under conditions where the axial epimer was unreactive [cf. chromic oxide oxidation (51)]. 

The stereochemical course of the enantioface differentiation on the aldehyde is dictated by the configuration of the sulfoxide group sulfinyl-subsdtuted dihydroisoxazoles epimeric at C-5 (e.g., 18) provide aldol adducts 19 with the same configuration at the hydroxy-substituted carbon (C-2 ) independent of the absolute configuration at C-5, however, with different degrees of stereoselectivity23. 

Significantly, (a) a-sulfonyl carbanions of thiirane dioxides, generated from the latter in the presence of strong bases such as potassium t-butoxide19 and alkoxide ions99, do epimerize to relieve steric repulsion between substituents as in 42 above and (b) the a-hydrogen in aryl-substituted three-membered sulfoxides (e.g. 46c) are sufficiently acidic to... 

Another version of the double [2,3]-sigmatropic rearrangement, involving the sequence sulfenate - sulfoxide - sulfenate, has also been observed. For example, an effective one-pot epimerization procedure of 17a-vinyl-l 7/i-hydroxysteroids to the rather inaccessible 17-epimers has been achieved by the use of such a rearrangement (equation 35)137. Thus treatment of alcohol 76a with benzenesulfenyl chloride afforded the sulfoxide 77 as a single isomer and E-geometry of the olefinic double bond. Exposure of 77 to trimethyl phosphite in refluxing methanol produced a mixture of 76b and 76a in a 73 27 ratio. 

Photochemical oxygen transfer reactions involving sulfoxides have also been documented. For example, a photochemical rearrangement of 2-nitrophenyl phenyl sulfoxide to 2-nitrosophenyl phenyl sulfone224, and the inverse photoconversion of o-methylbenzoic acid225 have been reported. Finally, photochemical epimerizations of the sulfoxide centers... 

In a conceptually similar fashion, camphor-derived hydroxysulfide 9 is oxidized diastereospecifically into hydroxysulfoxide 10 whose absolute configuration has been determined by X-ray crystallography48. Heating this diastereomer to 145 °C causes complete epimerization at sulfur to form diastereomer 11 in quantitative yield (equation 12). This type of allylic sulfoxide can be deprotonated and then added in a Michael fashion to cycloalkenones (see p. 834). 

Related 2,3-anhydrogulofuranosyl sulfoxides have been employed in the stereo-controlled synthesis of P-arabinofuranosides [370]. The epimeric a-arabinofurano-sides have also been synthesized by the sulfoxide method, with the aid of the neighboring-group participation [371,372]. 

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