Steroids stereoselective reduction

The properties of chlorine azide resemble those of bromine azide. Pon-sold has taken advantage of the stronger carbon-chlorine bond, i.e., the resistance to elimination, in the chloro azide adducts and thus synthesized several steroidal aziridines. 5a-Chloro-6 -azidocholestan-3 -ol (101) can be converted into 5, 6 -iminocholestan-3l -ol (102) in almost quantitative yield with lithium aluminum hydride. It is noteworthy that this aziridine cannot be synthesized by the more general mesyloxyazide route. Addition of chlorine azide to testosterone followed by acetylation gives both a cis- and a trans-2iddMct from which 4/S-chloro-17/S-hydroxy-5a-azidoandrostan-3-one acetate (104) is obtained by fractional crystallization. In this case, sodium borohydride is used for the stereoselective reduction of the 3-ketone... 

For steroidal ketones and a-ketols, stereoselective cathodic reductions have been described [343]. The stereoselective reductive ring opening of epoxyketones to a ke-toalcohol has been used in the conversion of the corresponding steroids [344, 345]. 

Stereoselective reductions of cyclic ketones have immense importance in the chemistry of steroids where either a or 5 epimers can be obtained. A few... 

Stereoselective reduction of a chiral a-methylpropargyl ketone. (R)-l, prepared from (-l-)-a-pinene, reduces the steroidal propargyl ketone 2 to 3 and 4 with higher than expected diastereoselectivity (24 1). In contrast, (S)-l reduces 2 slowly and incompletely, with low cnantioselectivity. 

Although reductions of ketones by active metals in alcohols have been largely supplanted by other procedures in modem synthetic chemistry, these methods still find occasional use. A modification employing K in r-butyl or r-pentyl alcohol has been used for the stereoselective reduction of 7-keto steroids in high yield,and the Li-ethanol and Na-ethanol reductions of 16-keto steroids have been investigated. Both traditional Na-ethanol °" reductions and a variation using Na-propan-2-ol in toluene - have also been used recently in selected systems. 

The side chain of brassinolide, (205,22R), can be stereoselectively introduced by alkylation (5n2) of the (20/ )-tosyloxy steroid with a protected cyanohydrin followed by the stereoselective reduction of the resulting 23-en-22-one. ... 

Iridium is little used, but gives satisfactory results when stereoselective reduction of steroids is required, e.g., the methylene compound, 4, is transformed to the 16j8-methyl compound, 5, by the use of Ir deposited on BaS04 or CaC03. ... 

An efficient stereoselective reduction of 22-keto-23-acetylenic steroid to anti-Cram product 22-(R)-hydroxy-23-acetylenic steroid and Cram product 22-(S)- hydroxy-23-acetylenic steroid has been achieved using (R)-Alpine-Borane [(-i-)-a-pinene, 92% ee] (125 1, R-.S) and L-selectride (lithium tri-sec-butylboro-hydride) (1 11, R S), respectively [19] (Chart 26.7). (S)-Alpine-Borane (2 M in THE) prepared from (-)-a-pinene (92% ee) provides unexpectedly low 1 2.7, R S ratio due to the influence of the a-chiral center at C-20 of the steroid, and also the reduction is much slower than with (R)-Alpine-Borane. 

An illustrative example of a stereoselective reduction with diimide is the conversion of the steroid derivative 82 into 83 as the only observed isomer (Equation 19) [61]. This transformation was used as a convenient stereo-and regioselective method for isotopic labeling of 83. Use of diimide avoided the formation of diastereomeric mixtures and prevented partial unwanted isotopic labeling at the allylic position, both of which had otherwise been observed with use of standard heterogeneous catalytic hydrogenations. 

In polycyclic systems the Birch reduction of C—C double bonds is also highly stereoselective, e.g. in the synthesis of the thermodynamically favored trans-fused steroidal skeletons (see p. 104 and p. 278). 

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). 

Lithium-ammonia reductions of most steroidal enones of interest create one or two new asymmetric centers. Such reductions are found to be highly stereoselective and this stereoselectivity constitutes the great utility of the reaction. For conjugated enones of the normal steroid series, the thermodynamically most stable products are formed predominantly and perhaps exclusively. Thus the following configurations are favored 5a, 8/ , 9a, and in certain cases 14a (see page 35). Starr has listed numerous examples illustrating these facts and Smith " and Barton have tabulated similar data. 

Greater stereoselectivity for the formation of equatorial amines has been found in the reduction of enamines with formic acid or formamides (553-559). The selective formation of 3-a-amino-5- -steroids by this method and of 3- 3-amino-5- 3-steroids by catalytic reduction (5<50) of the corresponding enamines is of interest. 

Although estrone and estradiol (26) have both been isolated from human urine, it has recently been shown that it is the latter that is the active compound that binds to the so-called estrogen receptor protein. Reduction of estrone with any of a large number of reducing agents (for example, any of the complex metal hydrides) leads cleanly to estradiol. This high degree of stereoselectivity to afford the product of attack at the alpha side of the molecule is characteristic of many reactions of steroids. 

The metal tends to orient itself such that it is on the less sterically hindered side of the steroid. The bulk of the metal atom then directs subsequent reduction or oxidation, thus making these reactions quite stereoselective (76, 77). 

A stereoselective reaction on the other hand is one in which the stereo-electronic requirement of the reaction mechanism is such that two equally valid alternative pathways are available for the same mechanistic interaction between reactant and reagent. However, either the free energies of activation of the alternative reactions or the thermodynamic stabilities of the products differ, so that one isomer is formed in preference to the other selection has occurred. An example is provided by the reduction of cholestan-3-one (32). Equatorial attack (i) or axial attack (ii) of the hydride ion is mechanistically equally feasible and stereoelectronically defined. However, steric interactions between the hydride ion source and the conformationally fixed steroid molecule, together with considerations as to whether the reaction was under kinetic or thermodynamic control, would determine that the reaction is proceeding in a stereoselective manner. 

Reductive desulfonylation.1 A stereocont rolled method for addition of the steroid side chain to a 17-keto steroid is outlined in scheme (I). The various steps proceed selectively to the sulfone 5. Reductive desulfonylation of 5 with Na/Hg, Na2HP04 in CH3OH gives the desired 6 (57% yield) and the undesired alkene in a 2 1 ratio. The desired stereoselectivity was obtained with lithium in ethylamine. The final step was hydrogenation of the 17(20)-double bond to give a protected cholesterol (7). 

Kabasakalian and coworkers 87) have achieved the cathodic reduction of steroidal ketones in ethanol-20% H20 with 0.2 M (C4H9)4NC1 as the supporting electrolyte. The reactions proceeded with very high chemical yield and were rather stereoselective. Electrolysis of androstane-17 3-ol-3-one (64) at —2.6 V(SCE) gave the 3p-equatorial alcohol 65 quantitatively. Under identical conditions the exocyclie carbonyl of 66 was also reduced and the corresponding alcohol was obtained in 92% yield. But, the reaction was less stereoselective and the ratio of the 2O0-/2Oa epimers was 74/26. 

Cathodic reduction of nonconjugated steroidal ketones has been found to give the equatorial alcohols with a high degree of stereoselectivity and in very good yields 134 These reactions were run at -2.6 V in aqueous ethanol-tetrabutyl-ammonium bromide. a-Methyldesoxybenzoin gave only the erythro form of 1,2-diphenylpropanol-1 on reduction at mercury in 40 % ethanol at pH 8 (veronal buffer) at -1.85 V (SCE) 13S>. 

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