Reductions of ketals

The reagent of choice for the reduction of ketals to ethers is alone prepared in situ from lithium aluminum hydride and aluminum chloride in ether. At room temperature ethers are obtained in 61-92% yields [792, 934]. Cyclic ketals prepared from ketones and 1,2- or 1,3-diols afford on hydrogenolysis by alanes alkyl P- or y-hydroxyalkyl ethers in 83-92% yields [792]. 

Table21 Reduction of ketals,tliioketals,ketinifaics and ketoxiiiies...

This cleavage usually also provides, as a minor product, the ketone 3, formed by an intramolecular Meerwein-Ponndorf-Verley reduction and Oppenauer oxidation -Alkoxy ketones of this type (6) can be obtained as the major product by reduction of ketals (5) with diethylaluminum fluoride (1.2 equiv.) and pentafluorophenol (2.4 equiv.), (equation II). Note that the reduction is again effected with retention. 

The reduction of ketals to protected secondary alcohols is readily accomplished in high yield with borane-dimethyl sulphide upon activation with TMSOTf at —78 °C (eq 85). Other Lewis acids require higher temperatures, and 1 equiv of TMSOTf is essential for complete conversion of the ketal. The solvent has... 

Compounds having the 16,17 ketal, eg, budesonide, amcinonide, fluocinonide, halcinonide, triamcinolone acetonide, and flurandrenohde, also undergo metabohsm by routes that parahel that of cortisol metabohsm. Unsymmetrical acetals such as budesonide are also metabolized by routes not available to the more metabohcahy stable symmetrical 16a,17a-isopropyhdiene-dioxysubstituted compounds (desonide, flunisohde, and triamcinolone acetonide). Isozymes within the cytochrome P450 3A subfamily are thought to catalyze the metabohsm of budesonide, resulting in formation of 16a-hydroxyprednisolone and 6P-hydroxybudesonide (19,20) (Fig. 3) in addition to the more common metabohc steps (oxidation via reduction of A, etc). 

The cleavage proceeds by initial reduction of the nitro groups followed by acid-catalyzed cleavage. The DNB group can be cleaved in the presence of allyl, benzyl, tetrahydropyranyl, methoxy ethoxy methyl, methoxymethyl, silyl, trityl, and ketal protective groups. 

Reduction of the sodium salt of equilenin 17-ethylene ketal with lithium, sodium or potassium in ammonia at —70° occurs predominantly in the B-ring, affording, after acid hydrolysis, equilin (29) in up to 76% yield (55% isolated). The preferential reduction of the B-ring reflects the relative, but not absolute, resistance to reduction conferred on the A-ring by the naphthoxide ion. Some A-ring reduction does compete kinetically with B-ring reduction, since the epimeric 3-hydroxyestra-5,7,9-trien-17-ones are the major reaction by-products. Simple phenoxide ions usually reduce slowly... 

A carbonyl group cannot be protected as its ethylene ketal during the Birch reduction of an aromatic phenolic ether if one desires to regenerate the ketone and to retain the 1,4-dihydroaromatic system, since an enol ether is hydrolyzed by acid more rapidly than is an ethylene ketal. 1,4-Dihydro-estrone 3-methyl ether is usually prepared by the Birch reduction of estradiol 3-methyl ether followed by Oppenauer oxidation to reform the C-17 carbonyl function. However, the C-17 carbonyl group may be protected as its diethyl ketal and, following a Birch reduction of the A-ring, this ketal function may be hydrolyzed in preference to the 3-enol ether, provided carefully controlled conditions are employed. Conditions for such a selective hydrolysis are illustrated in Procedure 4. 

The solubility of many steroids in ammonia-tetrahydrofuran-/-butyl alcohol is about 0.06 A/, a higher concentration than has been reported in other solvent systems. Still higher concentrations may be possible in particular cases by suitable variation in the solvent ratios Procedure 3 (section V) describes such a reduction of estradiol 3-methyl ether at a 0.12 M concentration. A few steriods such as the dimethyl and diethyl ketals of estrone methyl ether are poorly soluble in ammonia-tetrahydrofuran-/-buty] alcohol and cannot be reduced successfully at a concentration of 0.06 even with a 6 hour reduction period. The diethyl ketal of estrone methyl ether is reduced successfully at 0.12 M concentration using a two-phase solvent system of ammonia-/-amyl alcohol-methylcyclohexane (Procedure 4, section V). This mixture probably would be useful for any nonpolar steroid that is poorly soluble in polar solvents but is readily soluble in hydrocarbons. 

The 17-ethylene ketal of androsta-l,4-diene-3,17-dione is reduced to the 17-ethylene ketal of androst-4-en-3,17-dione in about 75% yield (66% if the product is recrystallized) under the conditions of Procedure 8a (section V). However, metal-ammonia reduction probably is no longer the method of choice for converting 1,4-dien-3-ones to 4-en-3-ones or for preparing 5-en-3-ones (from 4,6-dien-3-ones). The reduction of 1,4-dien-3-ones to 4-en-3-ones appears to be effected most conveniently by hydrogenation in the presence of triphenylphosphine rhodium halide catalysts. Steroidal 5-en-3-ones are best prepared by base catalyzed deconjugation of 4-en-3-ones. ... 

A. Birch Reduction of the Diethyl Ketal of Estrone 3-Methyl Ether in Annmonia-Methylcyclohexane-f-Amyl AlcohoP ... 

The crude ketal from the Birch reduction is dissolved in a mixture of 700 ml ethyl acetate, 1260 ml absolute ethanol and 31.5 ml water. To this solution is added 198 ml of 0.01 Mp-toluenesulfonic acid in absolute ethanol. (Methanol cannot be substituted for the ethanol nor can denatured ethanol containing methanol be used. In the presence of methanol, the diethyl ketal forms the mixed methyl ethyl ketal at C-17 and this mixed ketal hydrolyzes at a much slower rate than does the diethyl ketal.) The mixture is stirred at room temperature under nitrogen for 10 min and 56 ml of 10% potassium bicarbonate solution is added to neutralize the toluenesulfonic acid. The organic solvents are removed in a rotary vacuum evaporator and water is added as the organic solvents distill. When all of the organic solvents have been distilled, the granular precipitate of 1,4-dihydroestrone 3- methyl ether is collected on a filter and washed well with cold water. The solid is sucked dry and is dissolved in 800 ml of methyl ethyl ketone. To this solution is added 1600 ml of 1 1 methanol-water mixture and the resulting mixture is cooled in an ice bath for 1 hr. The solid is collected, rinsed with cold methanol-water (1 1), air-dried, and finally dried in a vacuum oven at 60° yield, 71.5 g (81 % based on estrone methyl ether actually carried into the Birch reduction as the ketal) mp 139-141°, reported mp 141-141.5°. The material has an enol ether assay of 99%, a residual aromatics content of 0.6% and a 19-norandrost-5(10)-ene-3,17-dione content of 0.5% (from hydrolysis of the 3-enol ether). It contains less than 0.1 % of 17-ol and only a trace of ketal formed by addition of ethanol to the 3-enol ether. 

The hydrogenation of 5a-cholestanone (58) in methanolic hydrobromic acid over platinum gives 3j5-methoxycholestane ° (61). This compound is also obtained from the palladium oxide reduction of (58) in methanol in the absence of acid. Hydrogenation of 5 -cholestanone also gives the 3j5-methoxy product under these conditions. Reduced palladium oxides are quite effective for the conversion of ketones to ethers. The use of aqueous ethanol as the solvent reduces the yield of ether. Ketals are formed on attempted homogeneous hydrogenation of a 3-keto group in methanol. ... 

The double bond migration which normally occurs on forming ethylene ketals from A -3-ketones has frequently been utilized to form derivatives of the A -system. The related transformation of A -3-ketones into A -3-alcohols is usually accomplished by treatment of the enol acetate (171) (X = OAc) with borohydride. This sequence apparently depends on reduction of the intermediate (172) taking place faster than conjugation ... 

Birch reduction of the diethyl ketal of estrone 3-methyl ether in ammonia-methylcyclohexane-t-amyl alcohol,... 

Deuteration at C-3 by lithium aluminum deuteride reduction of 5a-pregnane-3, 20-dione 3-tosylhydrazone 20-ethylene ketal, 177... 

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