Noradamantane synthesis

Protoadamantanone is a versatile intermediate for the synthesis of not only protoadamantane derivatives,but also 1,2- and 2,4-disubstituted adamantanes, ° 2-substituted noradamantanes," and 4(5)-substituted 4-homoprotoadamantanes. ... 

An extremely easy synthesis of 3-substituted noradamantanes is derived from the cleavage of the 2-methyl-2-adamantyloxy radical. Pyrolysis of 2-... 

Protoadamantanone is a versatile intermediate for the synthesis of not only protoadamantane derivatives,but also 1,2- and 2,4-disubstituted adamantanes, 2-substituted noradamantanes, and 4(5)-substituted 4-homoprotoadamantanes. 4-Protoadamantanone has been prepared by the nitrous acid deamination of 2-amino-l-adamantanol (77%), by aprotic diazo-tization of endo-7-aminomethylbicyclo[3.3.1]nonan-3-one in benzene with an equivalent amount of acetic acid (67%), and by thermolysis of 1-adamantyl hypohalites followed by base-promoted cyclization of the resulting halo ketones (32-37%).In spite of low and erratic yields, the last reaction sequence has provided the most convenient route to the protoadamantanes, since the other two approaches require lengthy syntheses of the starting materials. 

Given the desired 5-HT4/5-HT3 receptor profile and pharmacological efficacy of SC-52491, a scalable synthesis was developed. The aza-noradamantane ring system found in this agent possesses four contiguous chiral centers within its tricyclic framework. An asymmetric route was deemed to be superior to resolution of racemates, as previous efforts along the latter pathway resulted in difficult separations of fairly end-stage intermediates [22]. 

Noradamantanes.—The synthesis of 2- and 9-noradamantanone has been achieved by an enamine route in which the key intermediate (726) is obtained the imminium function if readily replaced by a selective carbonyl protecting group, and ring closure is then achieved by base-catalysed elimination of the analogous mesylate esters. Homoketonization of 2-acetoxytriaxane (727) in deuteriated media produces[4- H]-noradamantan-2-one (728) with almost complete retention in acid solution and with... 

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