Thioketal

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

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. 

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... 

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). 

Cat. I2, MeOH, rt, 24 h, >80% yield.Benzylidene ketals and thioketals are also cleaved under these conditions. 

AII3, CH3CN, benzene, 10 min, 70-92% yield.Ethyl ketals are cleaved under these conditions, but thioketals are not affected. 

RSH, cond. HCl, 20°, 30 min. These conditions were used to protect an aldose as the methyl or ethyl thioketal. 

PhSH, BF3-Et20, CHCI3, 0°, 10 min, 86% yield. ZnCl2 and MgBr2 have also been used as catalysts. With MgBr2 acetals can be converted to thioketals in the presence of ketones. ... 

Ph3CC104, Ph3COMe, CH2CI2, -45°, 2.5 h aq. NaHC03, 84-96% yield.A diethyl thioketal could be cleaved in the presence of a diphenyl thioketal. 

For (n = 2, 3) T1(N03)3, CH3OH, 25°, 5 min, 73-99% yield.These conditions have been used to effect selective cleavage of a, 3-unsaturated thioketals. ... 

The successful preparation of Il,ll-d2-5l5-androstan-3o -oh and 11,11-d2-(25R)-5a-spirostane in 83% and 91% isotopic purity by Raney nickel treatment of the 11,1 l-d2-12-ethylene thioketal derivatives further confirms the low degree of isotope scrambling with C-12 keto steroids. 

An older method,which also retains the double bond in its original location, utilizes the fact that thioketal formation from A" -3-ketones does not induce bond migration. Subsequent desulfurization with Raney nickel gives the A" -olefin (see section XI-D). 

The thioketal (155) is formed from 3jS-hydroxypregn-5-en-20-one acetate (154) and is desulfurized by treatment with Raney nickel. ... 

This procedure was provided by Dr. J. Fishman. If the intermediate thioketal (155) is not purified, the over-all yield of olefin (156) is 75%. ... 

The hydrolysis of dehydrocholic acid trishemithioketal (29) can be performed selectively to yield the 7,12-bishemithioketal (30), the 12-monohemi-thioketal (31) or the free triketone (32). ... 

Dimethyl ketals and enol ethers are stable to the conditions of oxime formation (hydroxylamine acetate or hydroxylamine hydrochloride-pyridine). Thioketals and hemithioketals are cleaved to the parent ketones by cadmium carbonate and mercuric chloride. Desulfurization of thioketals with Raney nickel leads to the corresponding methylene compounds, while thioenol ethers give the corresponding olefin. In contrast, desulfurization of hemithioketals regenerates the parent ketone. ... 

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

Thioketals are readily prepared by reaction of saturated 3-ketones with thiols or dithiols in the presence of boron trifluoride or hydrogen chloride catalysts. Selective protection of the 3-ketone in the presence of a 6-ketone is possible by carrying out the reaction in diluted medium. Similarly, 3-ketones react selectively with monothiols " " or with bulky dithiols in the presence of 6-, 7-, 11- and 12-ketones. 

Thioketals are readily formed by acid-catalyzed reaction with ethane-dithiol. Selective thioketal formation is achieved at C-3 in the presence of a 6-ketone by carrying out the boron trifluoride catalyzed reaction in diluted medium. Selective protection of the 3-carbonyl group as a thioketal has been effected in high yield with A" -3,17-diketones, A" -3,20-diketones and A" -3,l 1,17-triones in acetic acid at room temperature in the presence of p-toluenesulfonic acid. In the case of thioketals the double bond remains in the 4,5-position. This result is attributed to the greater nucleophilicity of sulfur as compared to oxygen, which promotes closure of intermediate (66) to the protonated cyclic mercaptal (67) rather than elimination to the 3,5-diene [cf. ketal (70) via intermediates (68) and (69)]." " ... 

Cross-conjugated dienones are quite inert to nucleophilic reactions at C-3, and the susceptibility of these systems to dienone-phenol rearrangement precludes the use of strong acid conditions. In spite of previous statements, A " -3-ketones do not form ketals, thioketals or enamines, and therefore no convenient protecting groups are available for this chromophore. Enol ethers are not formed by the orthoformate procedure, but preparation of A -trienol ethers from A -3-ketones has been claimed. Another route to A -trien-3-ol ethers involves conjugate addition of alcohol, enol etherification and then alcohol removal from la-alkoxy compounds. 

Thioketals are prepared efficiently from dithiols, but not from monothiols. However, 6-ketones do not react with ethanedithiol/boron trifluoride in the presence of a diluent such as acetic acid. 

Thioketals are readily prepared by treating the corresponding ketone with ethanedithiol and propane-1,3-dithiol. The 12-ketone fails to react with monothiols such as ethanethiol or thiophenol or with the bulkier 1-phenylethane-1,2-dithiol or tetralin-2,3-di thiol. The A Ei2-ketone... 

Ketals other than ethylene ketals are prepared by the orthoformate procedure with heating. Thioketals are obtained from dithiols, monothiols and hemithioketals by the boron trifluoride-catalysis method. Hemi-thioketals have also been prepared in high yield by the exchange proce-dure.""""... 

Unsubstituted 20-ketones undergo exchange dioxolanation nearly with the same ease as saturated 3-ketones although preferential ketalization at C-3 can be achieved under these conditions. " 20,20-Cycloethylenedioxy derivatives are readily prepared by acid-catalyzed reaction with ethylene glycol. The presence of a 12-ketone inhibits formation of 20-ketals. Selective removal of 20-ketals in the presence of a 3-ketal is effected with boron trifluoride at room temperature. Hemithioketals and thioketals " are obtained by conventional procedures. However, the 20-thioketal does not form under mild conditions (dilution technique). ... 

Androst-4-ene-3,l7-dione 3-Ethylene Thioketal A solution of androst-4-ene-3,17-dione (1.42 g, 5 mmoles) in acetic acid (20 ml) is treated with ethanedithiol (0.47 g, 5 mmoles) and a solution of 0.45 of p-toluenesulfonic acid monohydrate in acetic acid (5 ml). After 1 hr at room temperature, the pale yellow solution is poured into water and the resulting suspension is extracted with chloroform. The chloroform solution is washed with water, 5 % sodium hydroxide solution and water, dried (Na2S04) and evaporated. Chromatography of the resulting oil (1.93 g) over silica gel yields androst-4-ene-3,17-dione bisethylene thioketal, mp 173-175° [0.16 g, eluted with petroleum ether-benzene (1 2)] and androst-4-ene-3,17-dione 3-ethylene thioketal, mp 173-176° [1.38 g (76%), eluted with benzene-ethyl acetate (19 1)]. 

Deuteration at C-12 by desulfurization of 12-thioketals with Raney Nickel preparation of the ethylene thioketal, 172 desulfurization of the mercaptal, 173... 

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

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