Thioketals reduction

AHylestrenol (37) is prepared from (32), an intermediate in the synthesis of norethindrone. Treatment of (32) with ethanedithiol and catalytic boron trifluoride provides a thioketal. Reduction with sodium in Hquid ammonia results in the desired reductive elimination of the thioketal along with reduction of the 17-keto group. Oxidation of this alcohol with chromic acid in acetone followed by addition of aHyl magnesium bromide, completes the synthesis... 

There are, however, two useful alkylating-redudng methods. One is the methylenation of the ester carbonyl group with Tebbe s reagent, the other is the conversion of thionolactones to cyclic thioketals and subsequent reduction. 

Another synthesis of the cortisol side chain from a C17-keto-steroid is shown in Figure 20. Treatment of a C3-protected steroid 3,3-ethanedyidimercapto-androst-4-ene-ll,17-dione [112743-82-5] (144) with a tnhaloacetate, 2inc, and a Lewis acid produces (145). Addition of a phenol and potassium carbonate to (145) in refluxing butanone yields the aryl vinyl ether (146). Concomitant reduction of the C20-ester and the Cll-ketone of (146) with lithium aluminum hydride forms (147). Deprotection of the C3-thioketal, followed by treatment of (148) with y /(7-chlotopetben2oic acid, produces epoxide (149). Hydrolysis of (149) under acidic conditions yields cortisol (29) (181). 

However, examples of the failure of thioketals to survive lithium aluminium hydride reduction have been reported (see ref. 134). 

Olefin formation by reduction of keto derivatives via tosylhydrazones, 354 Olefin formation by reduction of thioketals, 356... 

The selective organosilane reduction of ketone functions can be effected in the presence of a number of other functional groups including epoxides,320,366 ketals,86,367 thioketals,368 other ketones,369,370 /1-lactams,371 alkynes,372 esters,79,80,83,84,87,320,373,374 a-bromides,76,80,83 amides80,83,84,86,276,320,375... 

Treatment of a pentacyclic la, I I -(2-oxethano) thioketal steroid with excess Et3SiH/TFA causes reduction of the carbon-carbon double bonds as well as the 17-carbonyl group to give a single reaction product (Eq. 213).368 Other work utilizes trifluoroacetic acid, triethylsilane, and anisole in the presence of a catalytic amount of boron trifluoride etherate to reduce the acetyl carbonyl of a 3-acetyl-2-azetidinone derivative with a dr of 8 1 (Eq. 214).395... 

The enone (137) was allowed to react with MeMgBr—Cu2I2 complex at 0 °C to furnish the keto-ester (138), which was then reduced by NaBH4 to afford the lactone (139). On the other hand, consecutive thioketalization, desulfurization and reduction of the ester (138) gave the alcohol (140), which was allowed to react with pTsCl in pyridine to afford (141) after smooth and concomitant fragmentation. The compound (141) was converted to 5-epi-kessane (142) and dehydrokessane (143) 47). 

Addition to thionolactones cyclic ethers. A wide variety of alkyliithium reagents add to the C=S group of thionolactones. The adducts, after reaction with CH,I, can be isolated in high yield as mixed methyl thioketals. The methylthio group can be removed by reduction with triphenyltin hydride (AIBN) to give cyclic ethers. The reaction is not dependent on the ring size and can be stereoselective, as shown by the synthesis of the ether lauthisan (2) from a thionolactone (1). 

Reductions of keto esters to esters are not very frequent. Both Clemmensen and Wolff-Kizhner reductions can hardly be used. The best way is desulfurization of thioketals with Raney nickel (p. 130). Thus ethyl acetoacetate was reduced to ethyl butyrate in 70% yield, methyl benzoylformate (phenylglyoxy-late) to methyl phenylacetate in 79% yield, and other keto esters gave equally high yields (74-77%) [82J]. 

Fischwick has detailed a rapid synthetic approach to the imidazole based y-lactam alkaloid, (+/—) cynometiine (67), isolated from the stem bark of Cynometra hankei, and which has been shown to be a potential analgesic (16). Cesium fluoride induced formation of the ylide, from precursor 68, followed by cycloaddition to alkene 69 furnished the required adduct 70 in 71% yield as a 4 1 diastereomeric mixture in favor of the desired isomer. Deprotection of the thioketal followed by NaBH4 reduction delivered the desired racemic product (Scheme 3.17). 

Lithium naphthalenide has been used for reductive lithiation of thioketals (8, 306 9, 284), but has the disadvantage that naphthalene is sometimes difficult to separate from final products of alkylation. In such cases, lithium I -(dimethylamino)-naphthalenide can be used advantageously since dimethylaminonaphlhalene is removed from reaction mixtures by extraction with dilute acid.1... 

When the carbonyl compound is sensitive to both acids and bases, or for other reasons gives poor yields in both the Clemmensen and Wolff-Kishner reductions, a recourse may be reduction of the corresponding thioacetal or thioketal with hydrogen-saturated Raney nickel (Section 11-2B) ... 

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