Deuteride

Sodium borodeuteride (NaBD4) and lithium aluminum deuteride... 

The isotopic purity of the products from a lithium aluminum deuteride reduction is usually equivalent to that of the reagent. The presence of moisture has little effect on the isotope composition of the products, causing only the decomposition of some of the reagent. For the best results, however, it is advisable to distill the solvent— usually ether, tetrahydrofuran or dioxane depending on the desired reaction temperature—from lithium aluminum hydride directly into the reaction flask. In this manner the reduction of 3-keto-5a-steroids (60), for example, gives the corresponding 3a-di alcohols (61) in 98% isotopic purity. ... 

Reduction of Steroidal Ketones with Lithium Aluminum Deuteride... 

This reaction does not need any special handling and the reduction conditions commonly used witli lithium aluminum hydride (see chapter 2) are equally applicable with lithium aluminum deuteride. 

As a general procedure, a mixture of the steroidal ketone (50 mg) and lithium aluminum deuteride (20 mg) in dry ether (5 ml, freshly distilled from lithium aluminum hydride) is heated under reflux until the reduction is complete according to thin layer chromatography test. The excess deuteride is then decomposed by the careful addition of a few drops of water and the reaction mixture is worked up by the usual procedure. For hindered ketones or esters the use of other solvents, such as tetrahydrofuran or dioxane, may be preferable to allow higher reaction temperatures. 

Reduction of Cholest-5-en-3-one with Lithium Aluminum Tri-t-butoxy Deuteride. 

A suspension of lithium aluminum deuteride (80 mg) in dry tetrahydrofuran (6 ml) is stirred and cooled in an ice bath while f-butanol (0.4 ml) is added dropwise, followed by a tetrahydrofuran solution of crude cholest-5-en-3-one (200 mg, mixed with cholest-4-en-3-one). The stirring and cooling is continued for 0.5 hr at 0° and then at room temperature for 2 hr. The... 

Reduction with metal deuteride complexes (section Ill-A) is undoubtedly the most convenient way to convert carbonyl compounds into the corresponding deuterated alcohols. For stereochemical reasons, however, it is sometimes necessary to resort to reductions with alkali metals in O-deuterated alcohols, or in liquid deuterioammonia-O-deuterioalcohol mixtures. 

A good example is the reduction of 11-keto steroids (69) which gives only the llJ -hydroxy derivatives (70) with metal deuterides. Generally, the 1 la-alcohols are obtained in good yield by reduction with lithium in liquid ammonia-methanol mixtures. By analogy, llj -dj-lla-alcohols (71) are expected when a deuterioammonia-methanol-OD system is used. (For an alternate preparation of an 11/5-dj-l la-hydroxy steroid, see section III-C). 

Two techniques, electrochemical reduction (section IIl-C) and Clem-mensen reduction (section ITI-D), have previously been recommended for the direct reduction of isolated ketones to hydrocarbons. Since the applicability of these methods is limited to compounds which can withstand strongly acidic reaction conditions or to cases where isotope scrambling is not a problem, it is desirable to provide milder alternative procedures. Two of the methods discussed in this section, desulfurization of mercaptal derivatives with deuterated Raney nickel (section IV-A) and metal deuteride reduction of tosylhydrazone derivatives (section IV-B), permit the replacement of a carbonyl oxygen by deuterium under neutral or alkaline conditions. 

During the course of these mechanistic studies a wide range of possible applications of this reaction have been revealed. When the reduction is carried out with lithium aluminum deuteride and the anion complex decomposed with water, a monodeuterio compound (95) is obtained in which 70% of the deuterium is in the 3a-position. Reduction with lithium aluminum hydride followed by hydrolysis with deuterium oxide yields mainly (70 %) the 3j5-di-epimer (96), while for the preparation of dideuterio compounds (94) both steps have to be carried out with deuterated reagents. ... 

The extent of olefin formation depends on the position of the functional group, " on the degree of a-substitution and on the concentration of the hydride (or deuteride). Usually olefin formation can be largely suppressed by increasing the concentration of lithium aluminum deuteride. With certain tosylhydrazones, however, such as the C-17 derivative (103), olefin (104) is a major product irrespective of the quantity of the reagent used. ... 

Deuteration at C-3 by Lithium Aluminum Deuteride Reduction of 5a.-Pregnane-3,20-dione 3-Tosylhydrazone 20-Ethylene keta ... 

The following general procedure has been used for the reduction of the tosylhydrazone derivatives of various steroidal ketones. A mixture of the tosylhydrazone (50 mg) and sodium borodeuteride (50 mg) in dry dioxane (3 ml) is heated under reflux for 2 hr, and then the excess deuteride is decomposed by the addition of a few drops of acetic acid. Ether is added and the resulting solution is washed with 2 N sodium bicarbonate solution and... 

The treatment of ketoximes with lithium aluminum hydride is usually a facile method for the conversion of ketones into primary amines, although in certain cases secondary amine side products are also obtained. Application of this reaction to steroidal ketoximes, by using lithium aluminum deuteride and anhydrous ether as solvent, leads to epimeric mixtures of monodeuterated primary amines the ratio of the epimers depends on the position of the oxime function. An illustrative example is the preparation of the 3(x-dj- and 3j5-di-aminoandrostane epimers (113 and 114, R = H) in isotopic purities equal to that of the reagent. 

Deuteration at C-3 by Reduction of 5a.-Androstan-3-one Oxime with Lithium Aluminum Deuteride... 

A solution of 5a-androstan-3-one oxime (112 0.6 g) in dry ether (40 ml) is added dropwise to a boiling suspension of lithium aluminum deuteride (1.6 g) in dry ether (80 ml). The reaction mixture is heated under reflux for... 

Deuterioboration is one of the most important recent additions to the array of methods for saturating double bonds with deuterium. The easy accessibility of metal deuterides (lithium aluminum deuteride or sodium borodeuteride) facilitates the in situ preparation of deuteriodiborane which reacts with steroidal double bonds with a high degree of site and/or stereospecificity, depending on the location of the double bond. " ... 

The successful labeling of the elusive 14a-position in cholestane represents a very important application of this reaction.It is known that hydroboration of the double bond in 5of-cholest-14-ene (174) occurs on the a-side. Consequently, by using deuteriodiborane (generated by the reaction of boron trifluoride etherate with lithium aluminum deuteride) and then propionic acid for hydrolysis of the alkylborane intermediate, 14a-d,-5a-cholestane (175) is obtained in 90% isotopic purity. This method also provides a facile route to the C-15 labeled analog (176) when the alkylborane derived from 5a-cholest-14-ene is hydrolyzed with propionic acid-OD. ... 

A suspension of lithium aluminum deuteride (1.6 g) in dry tetrahydrofuran (60 ml) is added dropwise to a stirred and cooled (with ice-salt bath) solution of 5a-androst-l4-ene-3j3,17j3-diol (179, 1.6 g) and boron trifluoride-etherate (13.3 g) in dry tetrahydrofuran (60 ml). The addition is carried out in a dry nitrogen atmosphere, over a period of 30 min. After an additional 30 min of cooling the stirring is continued at room temperature for 2 hr. The cooling is resumed in a dry ice-acetone bath and the excess deuteriodiborane is destroyed by the cautious addition of propionic acid. The tetrahydrofuran is then evaporated and the residue is dissolved in propionic acid and heated under reflux in a nitrogen atmosphere for 8 hr. After cooling, water is added and the product extracted with ether. The ether... 

In the past few years metal deuterides have become commercially available at reasonable prices. This has encouraged the use of these reagents for reactions involving deuteride displacements of suitable leaving groups. The attractive feature of these reactions is the stereospecificity of the deuterium insertion. 

The most common leaving groups are sulfonate esters and halides. For the sake of convenience, the discussion of certain dehalogenation reactions is also included in this section even though they may not involve 8 2 type displacement. Benzylic alcohols are also known to be displaced by hydrides or deuterides, but there is no evidence for the application of these reactions to the steroid field. 

Replacement of a primary or secondary hydroxyl function with deuterium is usually carried out by first converting the alcohol into a mesylate or tosylate ester, which can then be displaced by treatment with lithium aluminum deuteride. The... 

Some advantages of this reaction are high yield if the tosylate is in a sterically accessible position excellent isotopic purity of the product (usually higher than-95%) and perhaps most important, access to stereospecifically labeled methylene derivatives. For example, deuteride displacement of 3j -tosylates (183) yields the corresponding Sa-d derivative (185) in 96-98% isotopic purity. Application of this method to the labeled sulfonate (184), obtained. by lithium aluminum deuteride reduction of a 3-ketone precursor (see section HI-A) followed by tosylation, provides an excellent synthesis of 3,3-d2 labeled steroids (186) without isotopic scrambling at the adjacent positions. The only other method which provides products of comparable isotopic purity at this position is the reduction of the tosyl-hydrazone derivative of 3-keto steroids (section IV-B). 

The displacement of homoallylic tosylates follows an entirely different course with a strong tendency for the formation of cyclo steroids. Thus, when the 3/ -tosylate of a A -steroid (187) is treated with lithium aluminum deuteride, the product consists mainly of a 3l3-di-A -steroid (188) and a 6c-dj-3,5a-cyclo steroid (189). The incorporation of deuterium at the 3 -position in (188) indicates that this reaction proceeds via a 3,5-cyclo cholesteryl cation instead of the usual S, 2 type displacement sequence. This is further substantiated by the formation of the cyclo steroid (189) in which the deuterium at C-6 is probably in the p configuration. ... 

There are three methods which are commonly used in the steroid field to replace a halogen atom by deuterium. These methods involve treatment of the halides— generally chloride, bromide or iodide—(a) with lithium aluminum deuteride, (b) with deuterium gas and a surface catalyst or (c) with zinc in O-deuterated acids or alcohols. 

Only one of these methods, namely the reaction of halides with lithium aluminum deuteride, is a true displacement reaction, following the same course as the previously discussed displacement of sulfonate esters (section Vl-A). Thus, lithium aluminum deuteride treatment of 7a- and 7jS-bromo-3 -benzoyloxy-5a-cholestanes (195) and (196) gives the corresponding deuterium labeled cholestanols (197) and (198) respectively." ... 

Lithium aluminum deuteride treatment of 3j -benzoyloxy-A" -6j -chloro steroids (204) provides another example of double bond migration. This... 

A mixture of 6/l-chloroandrost-4-ene-3/ ,17/l-diol dibenzoate (223 1.5 g) and lithium aluminum deuteride (0.5 g) in anhydrous ether (75 ml) is heated under reflux for 2 hr and then stirred overnight at room temperature. The excess hydride is decomposed by the careful addition of saturated sodium sulfate solution, and the inorganic salts are removed by filtration and washed with... 

A facile method for the stereospecific labeling of carbon atoms adjacent to an oxygenated position is the reductive opening of oxides. The stereospecificity of this reaction is due to virtually exclusive diaxial opening of steroidal oxides when treated with lithium aluminum hydride or deuteride. The resulting /ra/w-diaxial labeled alcohols are of high stereochemical and isotopic purity, with the latter property depending almost solely on the quality of the metal deuteride used. (For the preparation of m-labeled alcohols, see section V-D.)... 

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