Steroidal enamines hydride reduction

A number of syntheses have been devised which lead to heterocyclic derivatives of cholestanes. 4-Aza-5a-sitostane (321 R = H, X = H2) and its N-methyl derivative (321 R = Me, X = H2) have been prepared by way of oxidative opening of ring A of 4-sitosten-3-one to give a 3,5-seco-5-oxo-3-oic acid which was cyclized by reaction with ammonium hydroxide or methylamine to give A5-enamine lactams these upon hydrogenation gave the lactams (321 R = H or Me, X = O) respectively. Hydride reduction completed the route to the required 4-aza-steroids.179... 

Enamines may be reduced by sodium borohydride to give saturated amines, but only if a protonating species is available to convert the enamine initially into the iminium cation (lo). Steroidal g-amino-g,5-dienes are unreactive to sodium boro-hydride alone, but addition of acetic acid leads to rapid reduction via the iminium ion (10) to give gj -amino-A -steroids [224], The possibility that diborane was the reactive species in the NaBHd/HOAc system was excluded by the virtual non-reactivity of the enamine to externally generated diborane. Reduction of the iminium ion derivative (3) of a 6-formyl enol ether has been exploited in a variant of the Vilsmeier synthesis of 6-methyl steroids [22 ], the reduction product was the 6-aminomethyl enol ether (ii) which suffered hydrogenolysis with Raney nickel to give the 6-methylated enol ether (12). 

Imines are formed by condensation of aldehydes or ketones with primary amines, but they form with more difficulty than enamines.84,85 A special case of enamine preparation was described with 20-oxo-steroids.86 Treatment of these ketones with a primary amine gives a 20-ketimine, which is acetylated with acetic anhydride, with migration of the double bond and formation of 20-(A-acetylalkylamino)-J17(20)-pregnene (14) reduction of 14 with lithium aluminum hydride affords the enamine. 

In a study of the reduction of steroidal imines with lithium aluminium hydride and sodium borohydride, Lusinchi9 found that with an excess of lithium aluminium hydride the methoxylated imine (8) afforded the two isomeric imines, (12) and (13), together with N-demethylconanine (14), in a ratio dependent on the time of the reaction. The absence of iV-demethylheteroconanine indicated that the reduction at position 20 was stereospecific. The imine (12) was found to result from initial reduction of the 20-N-imine, while the imine (13) was suggested to be derived from an enamine derivative, as in Scheme 1. 

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