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Intramolecular oxa-conjugate cyclization (IOCC) of α,β-unsaturated carbonyl compounds, triggered by deprotonation with a base, represents a straightforward method for the synthesis of tetrahydropyrans. However, it has been known that stereochemical outcome of IOCC depends on the local structure of substrates and sometimes requires harsh reaction conditions and/or prolonged reaction times for selective formation of 2,6-cis-substituted tetrahydropyrans. These shortcomings limit the feasibility of IOCC in the context of complex natural product synthesis. In this paper, we describe Brønsted acid-catalyzed IOCC of α,β-unsaturated ester surrogates (e.g., α,β-unsaturated thioesters, oxazolidinone imides, and pyrrole amides) under mild reaction conditions, which affords a series of synthetically versatile 2,6-cis-substiruted tetrahydropyran derivatives with good to excellent stereoselectrvity (dr from 7:1 to >20:1). These a^-unsaturated carbonyl compounds were found to be more reactive than the corresponding oxoesters that are generally unreactive toward Brønsted acid-catalyzed intramolecular oxa-conjugate additions. The product tetrahydropyrans could be transformed into various derivatives in an efficient manner, highlighting the usefulness of our methodology. [ABSTRACT FROM AUTHOR]

In this Account, we describe our efforts in the development of new synthetic strategies for the construction of N- and O-heterocycles by exploiting palladium-catalyzed reactions using enol phosphates as an electrophilic component. 1 Introduction 2 Suzuki-Miyaura Coupling of Lactone-Derived Enol Phosphates: A Convergent Synthetic Strategy toward trans-Fused Polycyclic Ether Marine Metabolites 3 Domino Intramolecular Heck/Diels-Alder Reaction of Imide-Derived Enol Phosphates toward the Synthesis of Fused N-Heterocycles 4 Strategies for the Synthesis of 2-Substituted Indoles and Indolines via Suzuki-Miyaura Coupling of Imide-Derived Enol Phosphates 5 Palladium-Catalyzed Reduction of Enol Phosphates: Total Synthesis of (�)-Lennoxamine and (�)-Chilenine 6 Suzuki-Miyaura Coupling of an Acetate-Derived Enol Phosphate: Total Synthesis of (+)-Neopeltolide 7 Concluding Remarks [ABSTRACT FROM AUTHOR]

New strategies for the synthesis of 2-substituted indoles and indolines using acyclic, imide-derived enol phosphates, which were readily prepared from o-haloanilides, have been developed based on Suzuki-Miyaura coupling-cyclization sequences. A highly chemoselective cross-coupling of imide-derived enol phosphates with boron nucleophiles under Suzuki-Miyaura conditions allowed for the efficient preparation of various N-(o-halophenyl)enecarbamates that served as useful precursors for subsequent 5-endo-trig Heck or 5-endo-trig aryl radical cyclizations to furnish 2-substituted indoles or indolines, respectively. Furthermore, a one-pot Suzuki-Miyaura coupling-cyclization cascade starting from enol phosphates has been developed, which was successfully applied to the efficient synthesis of an indol-2-yl-1H-quinolin-2-one KDR inhibitor. [ABSTRACT FROM AUTHOR]

Total synthesis of structure 1 originally proposed for brevenal, a nontoxic polycyclic ether natural product isolated from the Florida red tide dinoflagellate, Karenia brevis, was accomplished. The key features of the synthesis involved (i) convergent assembly of the pentacyclic polyether skeleton based on our developed Suzuki-Miyaura coupling chemistry and (ii) stereoselective construction of the multi-substituted (E,E)-dienal side chain by using copper(I) thiophen-2-carboxylate (CuTC)-promoted modified Stille coupling. The disparity of NMR spectra between the synthetic material and the natural product required a revision of the proposed structure. Detailed spectroscopic comparison of synthetic 1 with natural brevenal, coupled with the postulated biosynthetic pathway for marine polyether natural products, suggested that the natural product was most likely represented by 2, the C26 epimer of the proposed structure 1. The revised structure was finally validated by completing the first total synthesis of (—)-2, which also unambiguously established the absolute configuration of the natural product. [ABSTRACT FROM AUTHOR]

The marine dinoflagellate Gambierdiscus toxicus produces highly lipophilic, polycyclic ether toxins that cause a seafood poisoning called ciguatera. Ciguatoxins (CTXs) and gambierol represent the two major causative agents of ciguatera intoxication, which include taste alterations (dysgeusiae). However, information on the mode of action of ciguatera toxins in taste cells is scarce. Here, we have studied the effect of synthetic CTX3C (a CTX congener) on mouse taste cells. By using the patch-clamp technique to monitor membrane ion currents, we found that CTX3C markedly affected the operation of voltage-gated Na+ channels but was ineffective on voltage-gated K+ channels. This result was the exact opposite of what we obtained earlier with gambierol, which inhibits K+ channels but not Na+ channels. Thus, CTXs and gambierol affect with high potency the operation of separate classes of voltage-gated ion channels in taste cells. Our data suggest that taste disturbances reported in ciguatera poisoning might be due to the ability of ciguatera toxins to interfere with ion channels in taste buds. [ABSTRACT FROM AUTHOR]

Ciguatera is a food poisoning caused by toxins of Gambierdiscus toxicus, a marine dinoflagellate. The neurological features of this intoxication include sensory abnormalities, such as paraesthesia, heightened nociperception, and also taste alterations. Here, we have evaluated the effect of gambierol, one of the possible ciguatera toxins, on the voltage-gated ion currents in taste cells. Taste cells are excitable cells endowed with voltage-gated Na+, K+, and Cl− currents (INa, IK, and ICl, respectively). By applying the patch-clamp technique to single cells in isolated taste buds obtained from the mouse vallate papilla, we have recorded such currents and determined the effect of bath-applied gambierol. We found that this toxin markedly inhibited IK in the nanomolar range (IC50 of 1.8 nM), whereas it showed no significant effect on INa or ICl even at high concentration (1 μM). The block of IK was irreversible even after a 50-min wash. In addition to affecting the current amplitude, we found that gambierol significantly altered both the activation and inactivation processes of IK. In conclusion, unlike other toxins involved in ciguatera, such as ciguatoxins, which affect the functioning of voltage-gated sodium channels, the preferred molecular target of gambierol is the voltage-gated potassium channel, at least in taste cells. Voltage-gated potassium currents play an important role in the generation of the firing pattern during chemotransduction. Thus, gambierol may alter action potential discharge in taste cells and this could be associated with the taste alterations reported in the clinical literature. [ABSTRACT FROM AUTHOR]

Abstract: The general synthesis and a novel intramolecular nucleophilic aromatic substitution (SNAr) reaction of 2-carboxamido-3-arylquinazolin-4-ones, a potentially useful scaffold in the field of medicinal chemistry, are described. The synthetic utility of the SNAr reaction as a tool for the synthesis of secondary aryl amines, including diaryl amines, is also demonstrated. [Copyright &y& Elsevier]

Stereoselective synthesis of the C18–C34 fragment of antascomicin A is described. Construction of the C27–C34 carbocycle moiety was achieved via catalytic Ferrier carbocylization and Johnson–Claisen rearrangement, which was converted to iodide by use of asymmetric alkylation and Sharpless epoxidation as key transformations. Coupling of iodide and sulfone furnished the C18–C34 fragment. [Copyright &y& Elsevier]

The first total synthesis of (-)-gambierol (1), a marine polycyclic ether toxin, has been achieved. Key features of the successful synthesis include (1) a convergent union of the ABC and EFGH ring fragments (5 and 6, respectively) via our developed B-alkyl Suzuki-Miyaura cross-coupling strategy leading to the octacyclic polyether core 4 and (2) a late-stage introduction of the sensitive triene side chain by use of Pd(PPh[sub 3])[sub 4]/CuCl/LiCl-promoted Stille coupling. The ABC ring fragment 5 was synthesized in a linear manner (B → AB → ABC), wherein the A ring was formed by intramolecular hetero-Michael reaction and the C ring was constructed via 6-endo cyclization of hydroxy epoxide 7. An improved synthetic entry to the EFGH ring fragment 6 is also described, in which Sml[sub 2]-induced reductive cyclization methodology was applied to the stereoselective construction of the F and H rings, leading to 6 with remarkable overall efficiency. Stereoselective hydroboration of 5 and subsequent Suzuki-Miyaura coupling with 6 provided endocyclic enol ether 45 in high yield, which was then converted to octacyclic polyether core 4. Careful choice of the global deprotection stage was a key element for the successful total synthesis. Functionalization of the H ring and global desilylation gave (Z)-vinyl bromide 2. Finally, cross-coupling of 2 with (Z)-vinyl stannane 3 under Corey's Pd(PPh[sub 3])[sub 4]/CuCl/LiCl-promoted Stille conditions completed the total synthesis of (-)-gambierol (1). [ABSTRACT FROM AUTHOR]

Marine polycyclic ether natural products have gained significant interest from the chemical community due to their impressively huge molecular architecture and diverse biological functions. The structure assignment of this class of extraordinarily complex natural products has mainly relied on NMR spectroscopic analysis. However, NMR spectroscopic analysis has its own limitations, including configurational assignment of stereogenic centers within conformationally flexible systems. Chemical shift deviation analysis of synthetic model compounds is a reliable means to assign the relative configuration of "difficult" stereogenic centers. The complete configurational assignment must be ultimately established through total synthesis. The aim of this review is to summarize the indispensable role of organic synthesis in stereochemical assignment of marine polycyclic ethers. [ABSTRACT FROM AUTHOR]

The asymmetric total synthesis of four diastereomers of laingolide A was achieved, which led to the unambiguous assignment of the stereochemistry of the natural product. The salient features of the convergent, fully stereocontrolled approach were a copper-catalysed stereospecific Kumada-type coupling, a Julia-Kocienski olefination and an RCM/alkene migration sequence to access the desired macrocyclic enamide. [ABSTRACT FROM AUTHOR]

In this study, stereoisomeric aspergillide A/neopeltolide chimeras were synthesized in a parallel manner, and their antiproliferative activity was evaluated to demonstrate the potential utility of the 14-membered macrolactone structure embedded with a tetrahydropyran substructure as a template for developing natural product-like antiproliferative agents. [ABSTRACT FROM AUTHOR]

The article offers information about a study conducted to explore the synthetic strategies of Brevenal, a pentacyclic polyether natural product isolated from red tide-forming dinoflagellates or Karenia brevis. The study arrived at the first total synthesis of the proposed structure of Brevenal through the use of the Suzuki-Miyaura coupling strategy. The synthesis started with the construction of a pentacylic polyether core built in a highly convergent and stereo-controlled manner.

Highlights from the article: Synthesis and detailed NMR spectroscopic analyses of candidate diastereomers enabled correction of the relative configuration of the proposed structure. Chiral HPLC analysis of a synthetic pair of enantiomers with authentic reference finally established the absolute configuration of iriomoteolide-2 a. Biological assessment of the synthetic compounds was carried out to test the potency of this natural product.

Invited for the cover of this issue is the group of Haruhiko Fuwa at Tohoku University. The image depicts a puzzle of lyngbyaloside B, a complex macrolide natural product. Read the full text of the article at . [ABSTRACT FROM AUTHOR]

Structural reassignment: Total synthesis of the proposed and correct structures of (−) ‐ lyngbyaloside B (see figure), a marine macrolide glycoside, has been achieved. The synthesis entailed an Abiko – Masamune aldol reaction, a vinylogous Mukaiyama aldol reaction, and an acyl ketene macrocyclization to forge the 14 ‐ membered macrolactone. The present work established the complete stereostructure of this natural product in an unambiguous manner. More information can be found in the Full Paper by H. Fuwa et al. on page 6815 ff. [ABSTRACT FROM AUTHOR]

Abstract: Total synthesis of (−)‐enigmazole A, a marine macrolide natural product with cytotoxic activity, has been accomplished. The tetrahydropyran moiety was constructed by means of a domino olefin cross‐metathesis/intramolecular oxa‐Michael addition of a δ‐hydroxy olefin. After coupling of advanced intermediates, the macrocycle was formed through gold‐catalyzed rearrangement of a propargylic benzoate, followed by ring‐closing metathesis of the resultant α,β‐unsaturated ketone. [ABSTRACT FROM AUTHOR]

Total synthesis of (−)‐enigmazole A, a marine macrolide natural product with cytotoxic activity, has been accomplished. The tetrahydropyran moiety was constructed by means of a domino olefin cross‐metathesis/intramolecular oxa‐Michael addition of a δ‐hydroxy olefin. After coupling of advanced intermediates, the macrocycle was formed through gold‐catalyzed rearrangement of a propargylic benzoate, followed by ring‐closing metathesis of the resultant α,β‐unsaturated ketone. [ABSTRACT FROM AUTHOR]

A number of α-substituted medium sized cyclic ethers are prepared in an efficient and stereoselective manner. [ABSTRACT FROM AUTHOR]

More than thirty years after the discovery of polycyclic ether marine natural products, they continue to receive intense attention from the chemical, biological, and pharmacological communities because of their potent biological activities and highly complex molecular architectures. Gambieric acids are intriguing polycyclic ethers that exhibit potent antifungal activity with minimal toxicity against mammals. Despite the recent advances in the synthesis of this class of natural products, gambieric acids remain unconquered due to their daunting structural complexity, which poses a formidable synthetic challenge to organic chemists. This paper reviews our long-term studies on the total synthesis, complete configurational reassignment, and structure-activity relationships of gambieric acid A over the last decade. [ABSTRACT FROM AUTHOR]

The article presents a chemical structure related to the article "Total Synthesis and Structure Revision of Didemnaketal B" by H. Fuwa and others, published in the "Chemistry-A European Journal" in 2014.

via a silver-catalyzed endo-cyclization of hydroxy ynone (II) as a key step [ABSTRACT FROM AUTHOR]

The first total synthesis of (+)‐gambieric acid A, a potent antifungal marine polycyclic ether, has been accomplished by H. Fuwa, M. Sasaki et al. in their Full Paper on page 5276 ff. in a convergent manner by relying on Suzuki–Miyaura reaction for the assembly of the A/BCD‐ and F′GHIJ‐ring fragments and a ring‐closing metathesis for formation of the nonacyclic backbone. The total synthesis unambiguously establishes the structure of this extraordinary complex molecule, thus demonstrating the important role of organic synthesis in the structural elucidation of natural products. [ABSTRACT FROM AUTHOR]

Auto-tandem as well as orthogonal-tandem catalysis (OTC) are investigated in the preparation of the title compounds. [ABSTRACT FROM AUTHOR]

involving the Stille-type coupling of thioester (II) with vinylstannane (III) and spiroacetalization of diol mixture (V)/(VI) as the key steps [ABSTRACT FROM AUTHOR]

Review: 301 refs. [ABSTRACT FROM AUTHOR]

Treatment of α,β-unsaturated thioesters, oxazolidinone imides, and pyrrole amides with CSA allows a mild, effective, and stereoselective access to biologically important 2,6-cis-substituted tetrahydropyrans. [ABSTRACT FROM AUTHOR]

A synthesis of the C8-C29 fragment of amphidinolide N, a potent cytotoxic macrolide isolated from the marine dinoflagellate Amphidinium sp., has been achieved. The key features of the synthesis involve a convergent union of the C9-C15 and C16-C29 fragments by Steglich esterification and the construction of a pyran unit through a Tebbe methylenation/ring-closing metathesis sequence. [ABSTRACT FROM AUTHOR]

Gambierol and its heptacyclic and tetracyclic analogs were tested for inhibitory activity against the human voltage-gated potassium channel K v 1.2 (hK v 1.2), which was stably expressed in Chinese hamster ovary (CHO) cells. Gambierol, the heptacyclic analog, and the tetracyclic analog inhibited the potassium current evoked by a step pulse from −80 mV to 40 mV. The IC 50 values for the three compounds were 0.75 ± 0.15 nM, 7.6 ± 1.2 nM, and 28 ± 4.0 nM (the mean ± SEM, n = 3), respectively. The cytotoxic activity was examined in order to assess a relationship between cytotoxicity and inhibition of the hK v 1.2. The IC 50 values for gambierol, the heptacyclic analog, and the tetracyclic analog in the wild-type CHO cells were 95 ± 7.1 μM, 6.5 ± 0.8 μM (the mean ± SEM, n = 3), and >100 μM ( n = 3), respectively, whereas those in the CHO cells stably expressing hK v 1.2 were 78 ± 5.8 μM, 6.0 ± 1.0 μM (the mean ± SEM, n = 3), and >100 μM ( n = 3). These results suggested that cytotoxicity is not triggered by inhibition of the human K v 1.2. The electrophysiological recording at the resting potential in the presence of gambierol, the heptacyclic analog, and the tetracyclic analog revealed the dose-dependent leak current, which was largest when the heptacyclic analog was administered to the cells. We thus propose that the leak current induced by these compounds might cause a fatal effect on the cultured cells. [ABSTRACT FROM AUTHOR]

Tetrahydropyran‐containing macrolactones were synthesized by integrating Meyer–Schuster rearrangement, macrocyclic ring‐closing metathesis, and transannular oxa‐Michael addition under gold and ruthenium catalysis. Single‐step access to a variety of 14‐ to 20‐membered macrolactones containing a tetrahydropyran ring was possible from readily available linear precursors in good yields and with moderate to excellent diastereoselectivity. A 13‐step synthesis of (−)‐exiguolide, an anticancer marine macrolide, showcased the feasibility of our tandem reaction sequence for macrolactone synthesis and also demonstrated the power of transannular reactions for rapid assembly of the tetrahydropyran rings of the target natural product. [ABSTRACT FROM AUTHOR]

Gambierol inhibits voltage-gated K+ (KV) channels in various excitable and non-excitable cells. The purpose of this work was to study the effects of gambierol on single rat fetal (F19–F20) adrenomedullary cultured chromaffin cells. These excitable cells have different types of KV channels and release catecholamines. Perforated whole-cell voltage-clamp recordings revealed that gambierol (100 nM) blocked only a fraction of the total outward K+ current and slowed the kinetics of K+ current activation. The use of selective channel blockers disclosed that gambierol did not affect calcium-activated K+ (KCa) and ATP-sensitive K+ (KATP) channels. The gambierol concentration necessary to inhibit 50% of the K+ current-component sensitive to the polyether (IC50) was 5.8 nM. Simultaneous whole-cell current-clamp and single-cell amperometry recordings revealed that gambierol did not modify the membrane potential following 11s depolarizing current-steps, in both quiescent and active cells displaying repetitive firing of action potentials, and it did not increase the number of exocytotic catecholamine release events, with respect to controls. The subsequent addition of apamin and iberiotoxin, which selectively block the KCa channels, both depolarized the membrane and enhanced by 2.7 and 3.5-fold the exocytotic event frequency in quiescent and active cells, respectively. These results highlight the important modulatory role played by KCa channels in the control of exocytosis from fetal (F19–F20) adrenomedullary chromaffin cells. [ABSTRACT FROM AUTHOR]

Abstract: A stereocontrolled synthesis of a fully elaborated GHIJ-ring fragment of gambieric acids, which are potent antifungal polycyclic ether natural products, has been accomplished. The synthesis features convergent assembly of the tetracyclic polyether skeleton through aldol coupling/cyclodehydration/reductive etherification processes and stereoselective construction of the J-ring side chain by a CeCl3-promoted Julia–Kocienski olefination. [Copyright &y& Elsevier]