5«-Spirostan

The side chain in spirostan derivatives (44) can undergo certain exchange reactions which are characteristic for this skeleton. In general, this spiro-ketal moiety is quite stable under alkaline or neutral conditions, but in acidic media it undergoes a reversible opening of ring F (45 and 46). In... 

When the exchange is carried out on a (25S)-spirostan derivative (50) the compound undergoes epimerization at C-25. During this inversion about 20 % deuterium is incorporated" at C-25 [(51), R = D]. This observation is consistent with the various mechanisms which have been proposed for this... 

The reduction of the 16-keto function in kryptogenin (66) is a good example for the selectivity of sodium borodeuteride. The resulting 16a-di-16y -hydroxy analog (67) can then be cyclized to give a Iba-d -spirostane derivative (68). ... 

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. 

Homogeneous catalytic deuteration of various unsaturated 5a-spirostane derivatives is an excellent method for the preparation of side chain labeled analogs. Thus, saturation of the double bonds at positions 20(21), 23 and 24 provided the corresponding deuterated compounds (144), (145) and (146) in high isotopic purity. The preparation of (146) is a rare example of the saturation of an isolated trisubstituted double bond in the steroid field. 

Similar treatment of (25R)-5a-spirost-14-ene with deuteriodiborane and subsequent hydrolysis with propionic acid lead to 14jS-di-(25R)-spirostane in 79% isotopic purity. ... 

Bromine can also be displaced with powdered zinc in ethanol-OD but this reaction is much slower and usually takes several days of heating under reflux. Nevertheless, this method is very useful in certain cases where neutral conditions are required as shown by the preparation of 23 -di-(25R)-5a-spirostan (222). Due to the sensitivity of the spirostan system to acid (see section II-F), removal of the 23-equatorial bromide in (221) was carried out with zinc in ethanol-OD yielding the deuterated product (222) in 93%... 

A mixture of lithium aluminum deuteride and aluminum chloride is a more powerful reducing agent than lithium aluminum deuteride itself. This is well illustrated by the opening of ring F in 5a-spirostan [(230) (231)] which otherwise is quite stable to lithium aluminum deuteride. The resulting 22-di-26-hydroxy-5a-furostan (231) exhibits better than 97% isotopic purity. 

Thus, the model compound 5a, 6a-epoxy-6j -methyltigogenin acetate (103) affords 3)5-hydroxy-6)5-methyl-10(5 6)crZ)eo-(25S)-spirostan-5-one acetate (104) in 90 % yield. As expected, the j9-acetoxy ketone (104) loses the elements of acetic acid on passing through a column of alumina to give 6)5-methyl-10(5 -> 6)-flZ>eo-(25S)-spirost-3-en-5-one (105). 

In systems which preclude retro-aldol condensations, benzilic acid rearrangement of 11,12-diketones affords normal C-norsteroids in fair yields. For example, 11,12-diketotigogenin (82) is converted to the C-nor-(5oc,9(, 22a)-spirostane (83) in 65 % yield by barium oxide in boiling aqueous methyl-cellosolve. ... 

Spirostane (83) was converted to C-norpregnane-3,ll,20-trione (84) with uncertain stereochemistry at C-9 (but probably B/C trans). ... 

Of the two competing pathways (44 -+ 45) and (44 -> 46) the one leading to C-23 deuteration (44-+45) is favored. Thus, when 5a-spirostan (44) is heated under reflux for 1 hour in acetic acid-OD or in ethanol-OD solution containing deuteriochloric acid, the 23,23-d2-analog (47, R = D) is obtained containing 90% of d2-species.78 Prolonged heating leads to the trideuterated... 

---