Trials and tribulations of the cubane paradigm in biomolecule discovery highlight synthetic limitations, culminating in a continuing guide for practitioners, which includes cyclooctatetraene.

1-Azahomocubane has been prepared 56 years after the parent hydrocarbon. Introduction of a nitrogen atom into this constrained polycyclic environment resulted in minimal changes to the framework geometry, with s-character of the nitrogen lone pair increasing due to strain.

Cubane was recently validated as a phenyl ring (bio)isostere, but highly strained caged carbocyclic systems lack π character, which is often critical for mediating key biological interactions. This electronic property restriction associated with cubane has been addressed herein with cyclooctatetraene (COT), using known pharmaceutical and agrochemical compounds as templates. COT either outperformed or matched cubane in multiple cases suggesting that versatile complementarity exists between the two systems for enhanced bioactive molecule discovery.

Synthesis of the 6-aza[1.0]­triblattane skeleton and the unexpected construction of the 7-azatetracyclo­[4.2.1.02,5.03,7]­nonane framework are reported, as inspired by the Wilder–Culberson 1-aza[1.1]­triblattane ring system. The key steps to assess the 6-aza[1.0]­triblattane include accessing the 1,6-cycloaddition product from reaction of chlorosulfonyl isocyanate with cyclohept-1,3,5-triene followed by intramolecular electrocyclization and aminium radical cyclization.

The only reported synthesis of a [n]-azacubane, 1,4-diazacubane, on re-examination revealed a disordered piperazine that constitutes the previously reported Ni2+ Kagome metal organic framework (MOF).