Enantioselective Total Synthesis of (-)-Caulamidine A

Marine bryozoans continue to provide architecturally fascinating halogenated alkaloids that pose unique challenges for chemical synthesis. The antimalarial alkaloids caulamidines A and B, recently isolated from Caulibugula intermis, contain an intricate bis-amidine core and a chlorine-bearing neopentylic stereocenter. Compared to topologically similar C₂₀ bis(cyclotryptamine) alkaloids, caulamidines possess an additional carbon atom of unknown biosynthetic origins, which renders their entire skeleton nonsymmetric and nondimeric. Herein, we report the first total synthesis of caulamidine A and confirm its absolute configuration. Key chemical findings include the exploitation of glycol bistriflate to facilitate a rapid, diastereoselective ketone-amidine annulation reaction and a highly diastereoselective hydrogen atom transfer to correctly establish the key chlorine-bearing stereogenic center.