Enantioselective Total Synthesis of (−)-Caulamidine A

Abstract

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 C 20 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 chlorinebearing stereogenic center.

Asymmetric Synthesis and Biological Evaluation of Platensilin, Platensimycin, Platencin, and Their Analogs via a Bioinspired Skeletal Reconstruction Approach

“…The subsequent synthetic challenge involved the diastereoselective hydrogenation of the planar alkene to complete C8 epimerization and deliver the thermodynamically stable trans -decalin ring system. Recently, MHAT hydrogenation, pioneered by Shenvi, has emerged as a powerful solution to afford thermodynamically stable products . Diene (15 R )- 17 was first converted into tetra-substituted olefin (15 R )- 22 using Pd/C and H 2 .…”

Pd-Catalysed asymmetric allylic alkylation of heterocycles: a user's guide

“…More recently, Maimone and co-workers applied the method in their enantioselective synthesis of (−)-caulamidine A (Scheme 35B). 42…”

Enantioselective Total Syntheses of (−)-Caulamidine D and (−)-Isocaulamidine D and Their Absolute Configuration Reassignment

“…More importantly, caulamidines A and B displayed selective inhibition at low-micromolar concentrations toward chloroquine-resistant strains of Plasmodium falciparum, and the rest of this family of congeners possessed moderate cytotoxicity in the NCI-60 cell lines. , The promising biological activity rendered (iso)­caulamidines as potential antiplasmodial drug leads, together with their unprecedented molecular frameworks that drew attention from both synthetic and pharmaceutical communities. During the preparation of this Letter, Zhu and Maimone reported the first elegant total synthesis of caulamidine A ( 7 ) over 11 steps (longest linear sequence) starting from methyl 5-chloroindole-3-acetate based on three key reactions (Figure b), namely, You’s Ir-catalyzed asymmetric dearomative prenylation, the Staudinger aza-Wittig reaction, and hydrogen atom transfer (HAT) reduction . However, the structures and absolute configurations of newly reported (iso)­caulamidines B–D ( 1 – 6 ) have not been rigorously determined, although contemporary NMR techniques and DFT calculations have been applied.…”