Aza-noradamantane

With the aza-adamantyl prototype in hand, we undertook a systematic effort to probe for subtle variations in 1) scaffold bulk, and 2) spatial orientation of the bridgehead nitrogen with respect to the benzamide attachment site. Additionally, the syn/anf/-epimeric analog relationship at the attachment site was further developed. Figure 4 illustrates the target aza-noradamantane scaffolds 1-5. Each of these scaffolds is the... 

Removal of the enantiotopic methano bridges 1 and 2 produced the corresponding aza-noradamantanes as shown in table 3. Compound SC-52491 of Type 1 is very potent in the ratTMM assay, EC50 = 51 nM [15]. However, the enantiomer SC-52490 of Type 2 is 70-fold less active. This indicated that the combination of removal of the C-1 methano bridge and retention of the C-2 methano bridge leads to an aza-noradamantane with a... 

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]. 

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