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Palladium-catalyzed transformations of salvinorin A, a neoclerodane diterpene from Salvia divinorum.

ABSTRACT: Transformations that selectively modify the furan ring present in a variety of naturals products would be useful in the synthesis of biological probes but remain largely underexplored. The neoclerodane diterpene salvinorin A, isolated from Salvia divinorum, is an example of a furan-containing natural product. Following selective bromination of salvinorin A, Suzuki-Miyaura and Sonogashira couplings were accomplished in moderate to good yields without hydrolyzing the labile C-2 acetate or altering the stereochemistry of the epimerizable centers.

SUBMITTER: Riley AP

PROVIDER: S-EPMC3946488 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Palladium-catalyzed transformations of salvinorin A, a neoclerodane diterpene from Salvia divinorum.

Riley Andrew P AP Day Victor W VW Navarro Hernán A HA Prisinzano Thomas E TE

Organic letters 20131118 23

Transformations that selectively modify the furan ring present in a variety of naturals products would be useful in the synthesis of biological probes but remain largely underexplored. The neoclerodane diterpene salvinorin A, isolated from Salvia divinorum, is an example of a furan-containing natural product. Following selective bromination of salvinorin A, Suzuki-Miyaura and Sonogashira couplings were accomplished in moderate to good yields without hydrolyzing the labile C-2 acetate or altering ...[more]

PMID: 24246026

Similar Datasets

Salvinicins A and B, new neoclerodane diterpenes from Salvia divinorum.

Project description:[reaction: see text] Two new neoclerodane diterpenes, salvinicins A (4) and B (5), were isolated from the dried leaves of Salvia divinorum. The structures of these compounds were elucidated by spectroscopic techniques, including (1)H and (13)C NMR, NOESY, HMQC, and HMBC. The absolute stereochemistry of these compounds was assigned on the basis of single-crystal X-ray crystallographic analysis of salvinicin A (4) and a 3,4-dichlorobenzoate derivative of salvinorin B.

| S-EPMC2535573 | biostudies-literature

Synthetic studies of neoclerodane diterpenes from Salvia divinorum: exploration of the 1-position.

Project description:Modification of the C-1 ketone of salvinorin A (2a) produces analogues with opioid antagonist properties. Of particular significance is the finding that 1-deoxo-1,10-dehydrosalvinorin A (11a) is a moderately potent antagonist at all three opioid receptor subtypes, and that herkinorin (2b), a mu agonist, is converted to a weak antagonist by removal of the C-1 ketone (3b and 11b). These observations suggest that the ketone of 2b is a key structural feature responsible for mu agonist activity.

| S-EPMC2111044 | biostudies-literature

Synthetic studies of neoclerodane diterpenes from Salvia divinorum: role of the furan in affinity for opioid receptors.

Project description:Further synthetic modification of the furan ring of salvinorin A (1), the major active component of Salvia divinorum, has resulted in novel neoclerodane diterpenes with opioid receptor affinity and activity. A computational study has predicted 1 to be a reproductive toxicant in mammals and is suggestive that use of 1 may be associated with adverse effects. We report in this study that piperidine 21 and thiomorpholine 23 have been identified as selective partial agonists at kappa opioid receptors. This indicates that additional structural modifications of 1 may provide ligands with good selectivity for opioid receptors but with reduced potential for toxicity.

| S-EPMC3025038 | biostudies-literature

A (-)-kolavenyl diphosphate synthase catalyzes the first step of salvinorin A biosynthesis in Salvia divinorum.

Project description:Salvia divinorum (Lamiaceae) is an annual herb used by indigenous cultures of Mexico for medicinal and ritual purposes. The biosynthesis of salvinorin A, its major bioactive neo-clerodane diterpenoid, remains virtually unknown. This investigation aimed to identify the enzyme that catalyzes the first reaction of salvinorin A biosynthesis, the formation of (-)-kolavenyl diphosphate [(-)-KPP], which is subsequently dephosphorylated to afford (-)-kolavenol. Peltate glandular trichomes were identified as the major and perhaps exclusive site of salvinorin accumulation in S. divinorum. The trichome-specific transcriptome was used to identify candidate diterpene synthases (diTPSs). In vitro and in planta characterization of a class II diTPS designated as SdKPS confirmed its activity as (-)-KPP synthase and its involvement in salvinorin A biosynthesis. Mutation of a phenylalanine into histidine in the active site of SdKPS completely converts the product from (-)-KPP into ent-copalyl diphosphate. Structural elements were identified that mediate the natural formation of the neo-clerodane backbone by this enzyme and suggest how SdKPS and other diTPSs may have evolved from ent-copalyl diphosphate synthase.

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Localization of salvinorin A and related compounds in glandular trichomes of the psychoactive sage, Salvia divinorum.

Project description:Background and aimsSalvia divinorum produces several closely related neoclerodane diterpenes. The most abundant of these, salvinorin A, is responsible for the psychoactive properties of the plant. To determine where these compounds occur in the plant, various organs, tissues and glandular secretions were chemically analysed. A microscopic survey of the S. divinorum plant was performed to examine the various types of trichomes present and to determine their distribution.MethodsChemical analyses were performed using thin layer chromatographic and histochemical techniques. Trichomes were examined using conventional light microscopy and scanning electron microscopy.Key resultsIt was found that neoclerodane diterpenes are secreted as components of a resin that accumulates in peltate glandular trichomes, specifically in the subcuticular space that exists between the trichome head cells and the cuticle that encloses them. Four main types of trichomes were observed: peltate glandular trichomes, short-stalked capitate glandular trichomes, long-stalked capitate glandular trichomes and non-glandular trichomes. Their morphology and distribution is described. Peltate glandular trichomes were only found on the abaxial surfaces of the leaves, stems, rachises, bracts, pedicles and calyces. This was consistent with chemical analyses, which showed the presence of neoclerodane diterpenes in these organs, but not in parts of the plant where peltate glandular trichomes are absent.ConclusionsSalvinorin A and related compounds are secreted as components of a complex resin that accumulates in the subcuticular space of peltate glandular trichomes.

| S-EPMC4242294 | biostudies-literature

Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Identification of a Potent and Centrally Acting ? Opioid Analgesic with Reduced Abuse Liability.

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| S-EPMC5189922 | biostudies-literature

Inhibitory effect of salvinorin A, from Salvia divinorum, on ileitis-induced hypermotility: cross-talk between kappa-opioid and cannabinoid CB(1) receptors.

Project description:Salvinorin A, the active component of the hallucinogenic herb Salvia divinorum, inhibits intestinal motility through activation of kappa-opioid receptors (KORs). However, this compound may have target(s) other than the KORs in the inflamed gut. Because intestinal inflammation upregulates cannabinoid receptors and endogenous cannabinoids, in the present study we investigated the possible involvement of the endogenous cannabinoid system in salvinorin A-induced delay in motility in the inflamed gut.Motility in vivo was measured by evaluating the distribution of a fluorescent marker along the small intestine; intestinal inflammation was induced by the irritant croton oil; direct or indirect activity at cannabinoid receptors was evaluated by means of binding, enzymic and cellular uptake assays.Salvinorin A as well as the KOR agonist U-50488 reduced motility in croton oil treated mice. The inhibitory effect of both salvinorin A and U-50488 was counteracted by the KOR antagonist nor-binaltorphimine and by the cannabinoid CB(1) receptor antagonist rimonabant. Rimonabant, however, did not counteract the inhibitory effect of salvinorin A on motility in control mice. Binding experiments showed very weak affinity of salvinorin A for cannabinoid CB(1) and CB(2) and no inhibitory effect on 2-arachidonoylglycerol and anandamide hydrolysis and cellular uptake.The inhibitory effect of salvinorin A on motility reveals a functional interaction between cannabinoid CB(1) receptors and KORs in the inflamed--but not in the normal--gut in vivo.

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Heck Transformations of Biological Compounds Catalyzed by Phosphine-Free Palladium.

Project description:The development and optimization of synthetic methods leading to functionalized biologically active compounds is described. Two alternative pathways based on Heck-type reactions, employing iodobenzene or phenylboronic acid, were elaborated for the arylation of eugenol and estragole. Cinnamyl alcohol was efficiently transformed to saturated arylated aldehydes in reaction with iodobenzene using the tandem arylation/isomerization sequential process. The arylation of cinnamyl alcohol with phenylboronic acid mainly gave unsaturated alcohol, while the yield of saturated aldehyde was much lower. Catalytic reactions were carried out using simple, phosphine-free palladium precursors and water as a cosolvent, following green chemistry rules as much as possible.

| S-EPMC6225119 | biostudies-literature

Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Design, Synthesis, and Evaluation of Analogues with Improved Potency and G-protein Activation Bias at the μ-Opioid Receptor.

Project description:Previous structure-activity relationship (SAR) studies identified the first centrally acting, non-nitrogenous μ-opioid receptor (MOR) agonist, kurkinorin (1), derived from salvinorin A. In an effort to further probe the physiological effects induced upon activation of MORs with this nonmorphine scaffold, a variety of analogues were synthesized and evaluated in vitro for their ability to activate G-proteins and recruit β-arrestin-2 upon MOR activation. Through these studies, compounds that are potent agonists at MORs and either biased toward β-arrestin-2 recruitment or biased toward G-protein activation have been identified. One such compound, 25, has potent activity and selectivity at the MOR over KOR with bias for G-protein activation. Impressively, 25 is over 100× more potent than morphine and over 5× more potent than fentanyl in vitro and elicits antinociception with limited tolerance development in vivo. This is especially significant given that 25 lacks a basic nitrogen and other ionizable groups present in other opioid ligand classes.

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The enantioselective construction of tetracyclic diterpene skeletons with Friedel-Crafts alkylation and palladium-catalyzed cycloalkenylation reactions.

Project description:Due to the profound extent to which natural products inspire medicinal chemists in drug discovery, there is demand for innovative syntheses of these often complex materials. This article describes the synthesis of tricarbocyclic natural product architectures through an extension of the enantioselective Birch-Cope sequence with intramolecular Friedel-Crafts alkylation reactions. Additionally, palladium-catalyzed enol silane cycloalkenylation of the tricarbocyclic structures afforded the challenging bicyclo[3.2.1]octane C/D ring system found in the gibberellins and the ent-kauranes, two natural products with diverse medicinal value. In the case of the ent-kaurane derivative, an unprecedented alkene rearrangement converted four alkene isomers to one final product.

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