Aza-Achmatowicz rearrangement coupled with intermolecular aza-Friedel-Crafts enables total syntheses of uleine and aspidosperma alkaloids.

Aspidosperma and uleine alkaloids belong to the large family of monoterpene indole alkaloids with diverse biological activities and thus have attracted extensive synthetic interest. Reported is the development of a new synthetic strategy that allows direct C3-C2' linkage of indoles with functionalized 2-hydroxypiperidines to construct the core common to all aspidoserma and uleine alkaloids. Such indole-piperidine linkage is enabled by coupling aza-Achmatowicz rearrangement (AAR) with indoles via an intermolecular aza-Friedel-Crafts (iAFC) reaction. This AAR-iAFC reaction proceeds under mild acidic conditions with wide tolerance of functional groups (33 examples). The synthetic application of the AAR-iAFC method was demonstrated with collective total syntheses of 3 uleine-type and 6 aspidosperma alkaloids: (+)-3-epi-N-nor-dasycarpidone, (+)-3-epi-dasycarpidone, (+)-3-epi-uleine, 1,2-didehydropseudoaspidospermidine, 1,2-dehydroaspidospermidine, vincadifformine, winchinine B, aspidospermidine, and N-acetylaspidospermidine. We expect that this AAR-iAFC strategy is applicable to other monoterpene indole alkaloids with the C3-C2' linkage of indoles and piperidines.

BiBr3 -Mediated Intramolecular Aza-Prins Cyclization of Aza-Achmatowicz Rearrangement Products: Asymmetric Total Synthesis of Suaveoline and Sarpagine Alkaloids.

An intramolecular aza-Prins cyclization of aza-Achmatowicz rearrangement products was developed in which bismuth tribromide (BiBr3 ) plays a dual role as an efficient Lewis acid and source of the bromide nucleophile. This approach enables the facile construction of highly functionalized 9-azabicyclo[3.3.1]nonanes (9-ABNs), which are valuable synthetic building blocks and a powerful platform for the synthesis of a variety of alkaloid natural products and drug molecules. Suitable substrates for the aza-Prins cyclization include 1,1-disubstituted alkenes, 1,2-disubstituted alkenes, alkynes, and allenes, with good to excellent yields observed. Finally, we showcase the application of this new approach to the enantioselective total synthesis of six indole alkaloids: (-)-suaveoline (1), (-)-norsuaveoline (2), (-)-macrophylline (3), (+)-normacusine B (4), (+)-Na -methyl-16-epipericyclivine (5) and (+)-affinisine (6) in a total of 9-14 steps. This study significantly expands the synthetic utility of the aza-Achmatowicz rearrangement, and the strategy (aza-Achmatowicz/aza-Prins) is expected to be applicable to the total synthesis of other members of the big family of macroline and sarpagine indole alkaloids.

Marine Alkaloid Lepadins E and H Induce Ferroptosis for Cancer Chemotherapy.

Induction of ferroptosis emerges as an effective method for cancer treatment. With massive efforts to elucidate the ferroptosis mechanism, the development of new ferroptosis inducers proceeds rather slowly, with only a few small molecules identified. Herein, we report our discovery of marine alkaloid lepadins E and H as a new class of ferroptosis inducers. Our in vitro studies show that lepadins E and H exhibit significant cytotoxicity, promote p53 expression, increase ROS production and lipid peroxides, reduce SLC7A11 and GPX4 levels, and upregulate ACSL4 expression, all of which consistently support induction of ferroptosis through the classical p53-SLC7A11-GPX4 pathway. Our animal model study of lepadin H confirms its in vivo antitumor efficacy with negligible toxicity to normal organs. This work elucidates the mode of action of lepadins (E and H) and verifies their in vivo efficacy as a new class of ferroptosis inducers for anticancer therapy with translational potential.

Electrochemical oxidative rearrangement of tetrahydro-ß-carbolines in a zero-gap flow cell.

Oxidative rearrangement of tetrahydro-ß-carbolines (THßCs) is one of the most efficient methods for the synthesis of biologically active spirooxindoles, including natural products and drug molecules. Here, we report the first electrochemical approach to achieve this important organic transformation in a flow cell. The key to the high efficiency was the use of a multifunctional LiBr electrolyte, where the bromide (Br-) ion acts as a mediator and catalyst and lithium ion (Li+) acts as a likely hydrophilic spectator, which might considerably reduce diffusion of THßCs into the double layer and thus prevent possible nonselective electrode oxidation of indoles. Additionally, we build a zero-gap flow cell to speed up mass transport and minimize concentration polarization, simultaneously achieving a high faradaic efficiency (FE) of 96% and an outstanding productivity of 0.144 mmol (h-1 cm-2). This electrochemical method is demonstrated with twenty substrates, offering a general, green path towards bioactive spirooxindoles without using hazardous oxidants.