Rare Caulamidine Hexacyclic Alkaloids from the Marine Ascidian Polyandrocarpa sp.

Abstract

Two new caulamidines C (2) and D (4) and three isocaulamidines B, C, and D (1, 3, and 5) along with the known compound caulamidine B (6) were isolated from the marine ascidian Polyandrocarpa sp. Their structures were elucidated by analysis of nuclear magnetic resonance (NMR) and electronic circular dichroism (ECD) data. Isocaulamidines have an altered pattern of N-methyl substitution (N-15 vs N-13 in the caulamidines) with a concomitant double-bond rearrangement to provide a new C-14/N-13 imine functionality. Caulamidine C (2) and isocaulamidine C (3) are the first members of this alkaloid family with two chlorine substituents in the core 6H-2,6naphthyridine ring system.

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

“…The polyhalogenated alkaloids caulamidines B–D ( 1 , 3 , and 5 ) and isocaulamidines B–D ( 2 , 4 , and 6 ) (Figure a) were isolated from ascidians Polyandrocarpa sp. near Palau by Gustafson and co-workers . Compared to their previously reported caulamidine A ( 7 ) and trace amount of caulamidine B ( 1 ) isolated from bryozoan Caulibugula intermis, the ascidian-derived congeners possessed even more diverse halogenation patterns as well as unprecedented isomerization of amidine motifs across the D–E–F rings in isocaulamidines B–D (purple and blue in Figure a).…”

“…When we compared the NMR spectra of our synthetic (−)-isocaulamidine D ( 6 ) with the reported data, an astonishing observation was that they did not match at all. Neither did the data for (−)-caulamidine ( 5 ).…”

“…Compared to their previously reported caulamidine A ( 7 ) and trace amount of caulamidine B ( 1 ) isolated from bryozoan Caulibugula intermis, the ascidian-derived congeners possessed even more diverse halogenation patterns as well as unprecedented isomerization of amidine motifs across the D–E–F rings in isocaulamidines B–D (purple and blue in Figure a). 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 .…”