Advanced Structure Analysis Reveals a Transient Portimine B Hydrate.

Portimine B was isolated from an extract derived from the dinoflagellate Vulcanodinium rugosum, a known producer of the closely related portimine A. Initial molecular characterization studies of portimine B suggested an open tetrahydrofuranyl ring isomer, contrary to the intact ring moiety found in portimine A. In 2023, the Baran lab synthesized both portimines A and B suggesting that both macrocyclic analogs contained the intact tetrahydrofuranyl ring. In this note, we utilize newly acquired NMR data, the i-HMBC NMR experiment, and advanced density functional theory calculations to define the structural divergence, originating from the presence of a transient hydrate.

Synthesis of portimines reveals the basis of their anti-cancer activity.

Marine-derived cyclic imine toxins, portimine A and portimine B, have attracted attention because of their chemical structure and notable anti-cancer therapeutic potential1-4. However, access to large quantities of these toxins is currently not feasible, and the molecular mechanism underlying their potent activity remains unknown until now. To address this, a scalable and concise synthesis of portimines is presented, which benefits from the logic used in the two-phase terpenoid synthesis5,6 along with other tactics such as exploiting ring-chain tautomerization and skeletal reorganization to minimize protecting group chemistry through self-protection. Notably, this total synthesis enabled a structural reassignment of portimine B and an in-depth functional evaluation of portimine A, revealing that it induces apoptosis selectively in human cancer cell lines with high potency and is efficacious in vivo in tumour-clearance models. Finally, practical access to the portimines and their analogues simplified the development of photoaffinity analogues, which were used in chemical proteomic experiments to identify a primary target of portimine A as the 60S ribosomal export protein NMD3.

Total Synthesis of (+)-Haperforin G.

A concise chemical synthesis of (+)-haperforin G in 20 steps from commercially available starting materials is achieved with the integration of the Co-catalyzed intramolecular Pauson-Khand reaction for the stereoselective construction of cyclopentanone bearing an all-carbon quaternary stereogenic center at the bridge-head position and the light-initiated photocatalysis for convergent and asymmetric cross-coupling of the unstabilized C(sp3)-radical with an enone. The developed chemistry paves the way to synthesizing structurally diverse analogs of haperforin G (6).