C5 methylation confers accessibility, stability and selectivity to picrotoxinin.

Minor changes to complex structures can exert major influences on synthesis strategy and functional properties. Here we explore two parallel series of picrotoxinin (PXN, 1) analogs and identify leads with selectivity between mammalian and insect ion channels. These are the first SAR studies of PXN despite its >100-year history and are made possible by advances in total synthesis. We observe a remarkable stabilizing effect of a C5 methyl, which completely blocks C15 alcoholysis via destabilization of an intermediate twist-boat conformer; suppression of this secondary hydrolysis pathway increases half-life in plasma. C5 methylation also decreases potency against vertebrate ion channels (γ-Aminobutyric acid type A (GABAA) receptors) but maintains or increases antagonism of homologous invertebrate GABA-gated chloride channels (resistance to dieldrin (RDL) receptors). Optimal 5MePXN analogs appear to change the PXN binding pose within GABAARs by disruption of a hydrogen bond network. These discoveries were made possible by the lower synthetic burden of 5MePXN (2) and were illuminated by the parallel analog series, which allowed characterization of the role of the synthetically simplifying C5 methyl in channel selectivity. These are the first SAR studies to identify changes to PXN that increase the GABAA-RDL selectivity index.

Asymmetric Syntheses of (+)- and (-)-Collybolide Enable Reevaluation of kappa-Opioid Receptor Agonism.

The fungal metabolite collybolide has attracted attention as a non-nitrogenous, potent, and biased agonist of the kappa-opioid receptor (KOR). Here, we report a 10-step asymmetric synthesis of this complex sesquiterpene that enables facile access to either enantiomer. The synthesis relies on a diastereoselective α-benzoyloxylation to install the buried C6 benzoate and avoid irreversible translactonization of the congested, functionally dense core. Neither enantiomer, however, exhibited KOR agonism, indicating that collybolide has been mischaracterized as a KOR agonist. Given the pharmaceutical, medical, and societal interest in collybolide as a next-generation antipruritic and analgesic, this refutation of KOR activity has important ramifications for ongoing studies. Classification of collybolide as a new non-nitrogenous, KOR-selective, potent agonist with the same clinical potential as salvinorin A seems to have been premature.

Revision of the Unstable Picrotoxinin Hydrolysis Product.

The plant metabolite picrotoxinin (PXN) is a widely used tool in neuroscience for the identification of GABAergic signaling. Its hydrolysis in weakly alkaline media has been observed for over a century and the structure of the unstable hydrolysis intermediate was assigned by analogy to the degradation product picrotoxic acid. Here we show this assignment to be in error and we revise the structure of the hydrolysis product by spectroscopic characterization in situ. Counterintuitively, hydrolysis occurs at a lactone that remains closed in the major isolable degradation product, which accounts for the longstanding mistake in the literature.

Balancing skeleton and functional groups in total syntheses of complex natural products: a case study of tigliane, daphnane and ingenane diterpenoids.

Total synthesis of natural products has greatly contributed to natural product research, organic synthesis and drug discovery and development. However, in most cases, the efficiency of total synthesis is far from sufficient for direct practical industrial application. Thus, designing a concise and efficient synthetic route with balanced efforts between building the complex skeleton and introducing functional groups is highly desirable. In this critical review, we first present an introduction of this issue and a philosophical framework that cover possible synthetic approaches. Next, we have chosen the biogenetically closely related, biologically important and synthetically extremely challenging natural products, tiglianes, daphnanes and ingenanes as the particular case for the discussion, since in the past 40 years many synthetic approaches have been reported. The successes and pitfalls included therefore serve as the basis to draw some conclusions that may inspire future development in this area.

Change the channel: CysLoop receptor antagonists from nature.

Vertebrate and invertebrate ligand-gated ion channels (LGICs) exhibit significant structural homology and often share ligands. As a result, ligands with activity against one class can be brought to bear against another, including for development as insecticides. Receptor selectivity, metabolism and distribution must then be optimized using chemical synthesis. Here we review natural products (NPs) that ligate and inhibit the Cys-loop family of LGICs, which benefit from the unique physicochemical properties of natural product space but often present a high synthetic burden. Recent advances in chemical synthesis, however, have opened practical entries into these complex structures, several of which are highlighted. © 2020 Society of Chemical Industry.

Synthesis of (-)-Picrotoxinin by Late-Stage Strong Bond Activation.

We report a concise, stereocontrolled synthesis of the neurotoxic sesquiterpenoid (-)-picrotoxinin (1, PXN). The brevity of the route is due to regio- and stereoselective formation of the [4.3.0] bicyclic core by incorporation of a symmetrizing geminal dimethyl group at C5. Dimethylation then enables selective C-O bond formation in multiple intermediates. A series of strong bond (C-C and C-H) cleavages convert the C5 gem-dimethyl group to the C15 lactone of PXN.

Total Synthesis of Prostratin, a Bioactive Tigliane Diterpenoid: Access to Multi-Stereocenter Cyclohexanes from a Phenol.

Tiglianes such as prostratin and related diterpenoids are biologically significant natural molecules and long-standing targets for organic synthesis community. Due to the complex polycyclic scaffolds, high oxygenation level, and dense functional groups and stereocenters, their de novo chemical syntheses still face formidable challenges despite extensive efforts in the past 40 years. This account details the development of a modular and concise synthesis of prostratin, a potent anti-HIV and anticancer agent. The key approach in this synthesis involved a sequence of oxidative dearomatization and sequential stereoselective installation of peripheral groups to rapidly build the contiguously substituted cyclohexane C-ring. Inspired by Wender's work, an acid- and solvent-controlled stereodivergent formation of cyclopropane D-ring was developed. Mechanistic investigations by computational methods revealed that the competition between intra- and intermolecular hydrogen bonding led to different conformations, thus favoring different protonation processes. The designed and unexpected chemistry along this campaign reflected the uniqueness of the natural structures and should be amenable to future chemical syntheses of related complex polycyclic molecules.

Stereocontrolled construction of the tricyclic framework of tiglianes and daphnanes by an oxidative dearomatization approach.

An appropriately functionalized [5-7-6] tricyclic framework of tigliane and daphnane diterpenes containing seven contiguous stereocenters has been prepared in 10 steps from very simple building blocks in a modular and stereocontrolled fashion. The key features of this approach involve an efficient visible light-induced singlet oxygen oxidative dearomatization and an array of substrate-controlled highly diastereoselective transformations. This work provides a model strategy for rapid and diverted synthesis of natural and unnatural molecules sharing the common skeleton.

Highly enantio- and diastereoselective allylic alkylation of Morita-Baylis-Hillman carbonates with allyl ketones.

The asymmetric allylic alkylation of Morita-Baylis-Hillman (MBH) carbonates with allyl ketones has been developed. The α-regioselective alkylation adducts, containing a hexa-1,5-diene framework with important synthetic value, were achieved in up to 83% yield, >99% ee, and 50:1 dr by using a commercially available Cinchona alkaloid as the catalyst. From the allylic alkylation adduct, a cyclohexene bearing two adjacent chiral centers was readily prepared.