Chiral nitriles and their derivatives are prevalent in pharmaceuticals and bioactive compounds. Enantioselective alkene hydrocyanation represents a convenient and efficient approach for synthesizing these molecules. However, a generally applicable method featuring a broad substrate scope and high functional group tolerance remains elusive. Here, we address this long-standing synthetic problem using an electrocatalytic strategy. Electrochemistry allows for the seamless combination of two classic radical reactions-cobalt-mediated hydrogen-atom transfer and copper-promoted radical cyanation-to accomplish highly enantioselective hydrocyanation without the need for stoichiometric oxidant. We harness electrochemistry's unique feature of precise potential control to optimize the chemoselectivity of challenging substrates. Computational analysis sheds light on the origin of enantioinduction, for which the chiral catalyst imparts a combination of attractive and repulsive non-covalent interactions that direct the enantio-determining C-CN bond formation. This discovery demonstrates the power of electrochemistry in accessing new chemical space and providing solutions to pertinent challenges in synthetic chemistry. File list (2) download file view on ChemRxiv 01_Lin_MS.pdf (1.70 MiB) download file view on ChemRxiv 00_Lin_TOC.png (333.52 KiB)

The unprecedented structure of the marine natural product brevetoxin B was elucidated by the research group of Nakanishi and Clardy in 1981. The ladderlike molecular architecture of this fused polyether molecule, its potent toxicity, and fascinating voltage-sensitive sodium channel based mechanism of action immediately captured the imagination of synthetic chemists. Synthetic endeavors resulted in numerous new methods and strategies for the construction of cyclic ethers, and culminated in several impressive total syntheses of this molecule and some of its equally challenging siblings. Of the marine polyethers, maitotoxin is not only the most complex and most toxic of the class, but is also the largest nonpolymeric natural product known to date. This Review begins with a brief history of the isolation of these biotoxins and highlights their biological properties and mechanism of action. Chemical syntheses are then described, with particular emphasis on new methods developed and applied to the total syntheses. The Review ends with a discussion of the, as yet unfinished, story of maitotoxin, and projects into the future of this area of research.

Azaspiracids (AZAs) are marine phycotoxins with an unknown mechanism of action, implicated in human intoxications. We investigated the effect of azaspiracid-1 (AZA-1) on the cytosolic calcium concentration ([Ca2+]c), intracellular pH (pHi), and neuron viability in neuronal cultures. AZA-1 increased [Ca2+]c and decreased neuronal viability. The effects of several fragments of the AZA-1 molecule (13 different chemical structures) were examined. The ent-ABCD-azaspiracid-1 (2) showed similar potency to AZA-1 (1) in increasing [Ca2+]c but higher cytotoxity than AZA-1. The chemical structures containing only the ABCD or the ABCDE ring domains (3-8) caused a [Ca2+]c increase but did not alter cell viability. The compounds containing only the FGHI ring domain of AZA-1 (9-14) did not modify the [Ca2+]c or the cell viability. Therefore, the effect of AZA-1 on [Ca2+]c depends on the presence of the ABCD or the ABCDE-ring structure, but the complete chemical structure is needed to produce neurotoxic effects.

Azaspiracids (AZAs) are a novel group of marine phycotoxins that have been associated with severe human intoxication. We found that AZA-1 exposure increased lactate dehydrogense (LDH) efflux in murine neocortical neurons. AZA-1 also produced nuclear condensation and stimulated caspase-3 activity with an half maximal effective concentration (EC(50)) value of 25.8 nM. These data indicate that AZA-1 triggers neuronal death in neocortical neurons by both necrotic and apoptotic mechanisms. An evaluation of the structure-activity relationships of AZA analogs on LDH efflux and caspase-3 activation demonstrated that the full structure of AZAs was required to produce necrotic or apoptotic cell death. The similar potencies of AZA-1 to stimulate LDH efflux and caspase-3 activation and the parallel structure-activity relationships of azaspiracid analogs in the two assays are consistent with a common molecular target for both responses. To explore the molecular mechanism for AZA-1-induced neurotoxicity, we assessed the influence of AZA-1 on Ca(2+) homeostasis. AZA-1 suppressed spontaneous Ca(2+) oscillations (EC(50) = 445 nM) in neocortical neurons. A distinct structure-activity profile was found for inhibition of Ca(2+) oscillations where both the full structure as well as analogs containing only the FGHI domain attached to a phenyl glycine methyl ester moiety were potent inhibitors. The molecular targets for inhibition of spontaneous Ca(2+) oscillations and neurotoxicity may therefore differ. The caspase protease inhibitor Z-VAD-FMK produced a complete elimination of AZA-1-induced LDH efflux and nuclear condensation in neocortical neurons. Although the molecular target for AZA-induced neurotoxicity remains to be established, these results demonstrate that the observed neurotoxicity is dependent on a caspase signaling pathway.

A copper-catalyzed new C-N bond formation involving a sp-hybridized carbon is described here leading to a facile entry for syntheses of chiral ynamides. This direct N-alkynylation of amides should have a significant impact on the future development of synthetic methodologies employing ynamides.

The chase for the structure of azaspiracid‐1 has ended with a revised structure (see picture). The total synthesis of this challenging target has closed another chapter in this intriguing chemical detective story and allowed the assignment of the relative and absolute configuration of the molecule.

Azaspiracid-1 (AZA-1) is a marine toxin discovered 10 years ago. Since then, toxicologic studies have demonstrated that AZA-1 targets several organs in vivo, including the intestine, lymphoid tissues, lungs, and nervous system; however, the mechanism of action of AZA-1 remains unknown. Studies in vitro suggest that AZA-1 affects the actin cytoskeleton in nonadherent cells. We characterized the effects of AZA-1 on the cytoskeleton of adherent cells and on cell growth, an adhesion-dependent process in many cell types, and analyzed the structure dependency of this toxicity. Confocal and TIRF imaging of fluorescently labeled cytosketon showed that AZA-1 induced the rearrangement of stress fibers (actin filament bundles) and the loss of focal adhesion points in neuroblastoma and Caco-2 cells, without affecting the amount of polymerized actin. AZA-1 did not seem to alter the microtubule cytoskeleton, but it changed the cell shape and internal morphology observed by phase contrast imaging. Cell growth of lung carcinoma and neuroblastoma cells was inhibited by the toxin, as measured by a sulforhodamine B assay and BrdU incorporation to newly synthesized DNA. Fifteen different fragments and/or stereoisomers of AZA-1 were tested for cytoskeletal rearrangement and cell growth inhibition. Results showed that no fragment or stereoisomer had any activity, except for ABCD-epi-AZA-1, which conserved toxicity. AZA-1-induced reorganization of the actin cytoskeleton concurred with detachment and growth inhibition, three events that are probably related.

As the largest secondary metabolite to be discovered as of yet, the polyether marine neurotoxin maitotoxin constitutes a major structural and synthetic challenge. After its originally proposed structure ( 1) had been questioned on the basis of biosynthetic considerations, we provided computational and experimental support for structure 1. In an effort to provide stronger experimental evidence of the molecular architecture of maitotoxin, its GHIJKLMNO ring system 3 was synthesized. The (13)C NMR chemical shifts of synthetic 3 matched closely those corresponding to the same domain of the natural product providing strong evidence for the correctness of the originally proposed structure of maitotoxin ( 1).