α-Functionalization of Spirocyclic Imines Related to the Marine Natural Product Portimine

Abstract

Portimines are a family of spirocyclic imine natural products. They hold great potential in drug development with significant anticancer, antifouling and anti-HIV-1 activities. It is noteworthy that portimines A and B (34-35) are the only spirocyclic imine natural products to date, which possess an oxidized carbon alpha to the imine functionality (highlighted in blue). Installation of the hydroxyl or carbonyl group alpha to the imine is a key step in the total synthesis of portimines. Although the 5,6-spirocyclic imine scaffold (highlighted in red) plays important role for the bioactivity of portimines, this pharmacophore was rarely studied and the viability of the oxidation at its alpha carbon position was unclear at the outset of this project. In this research, we established an efficient strategy for the synthesis of the 5,6-spirocyclic imine moiety. The strategy hinged on an organolithium-induced intramolecular cyclization of nitrile chloride 82 to generate the 5,6-spirocyclic imine 80. Oxidation at the methylene alpha to the imine was also investigated. Direct oxidation of spirocyclic imine 80 to α-keto imine 118 was realized using a Riley-type reaction. A bromination and substitution sequence successfully afforded α-acetoxy imine 117. Interestingly, deprotection of the acetyl group at 117 led to isolation of α-keto imine 118 instead of the expected α-hydroxy imine 85. The mechanism of this unexpected transformation was investigated. It was proposed that α-hydroxy imine 85 was prone to tautomerize to α-keto amine 131, which was unstable under air and oxidized to α-keto imine 118 spontaneously. Addition of TFA efficiently inhibited the oxidation and enabled isolation of ammonium salt 133, which supported the proposed mechanism. Furthermore, other analogues such as oxaziridine, phenolic derivative were also generated. Spirocyclic imine 80, bromide 111 and α-acetoxy imine 117 were subjected to antifouling tests. Bromide 111 exhibited potent antifouling activity against Mytilus galloprovincialis with a minimum inhibitory concentration (MIC) of 0.1 μg/mL.