Synthesis of the cyclic prenylguanidine nitensidine E using a palladium-catalyzed carbenylative amination

We demonstrate the utility of carbenylative aminations in the synthesis of the cyclic alkaloid nitensidine E involving both protected and un-protected guanidine moieties. The alkylguanidine substrate is generated using a Mitsunobu reaction and we show that NH chemical shifts correlate with the regiochemistry and tautomeric structure of N-alkyl-bis-N,N′-Boc-guanidines. When the doubly-protected guanidine is used as a substrate in the palladium reaction, the catalyst assembles the heterocyclic ring and quaternary center of nitensidine E but with concomitant loss of one of the Boc groups. The reaction also works with an un-protected guanidine leading directly to nitensidine E.