Enantioselective Total\nSynthesis of (−)-Caulamidine\nA

Abstract

Marine bryozoans continue to provide architecturally\nfascinating\nhalogenated alkaloids that pose unique challenges for chemical synthesis.\nThe antimalarial alkaloids caulamidines A and B, recently isolated\nfrom <i>Caulibugula intermis</i>, contain an intricate bis-amidine\ncore and a chlorine-bearing neopentylic stereocenter. Compared to\ntopologically similar C₂₀ bis­(cyclotryptamine) alkaloids,\ncaulamidines possess an additional carbon atom of unknown biosynthetic\norigins, which renders their entire skeleton nonsymmetric and nondimeric.\nHerein, we report the first total synthesis of caulamidine A and confirm\nits absolute configuration. Key chemical findings include the exploitation\nof glycol bistriflate to facilitate a rapid, diastereoselective ketone-amidine\nannulation reaction and a highly diastereoselective hydrogen atom\ntransfer to correctly establish the key chlorine-bearing stereogenic\ncenter.