Synthesis-Driven Stereochemical Assignment of Marine Polycyclic Ether Natural Products.

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.

Stereoselective Synthesis of the I-L Fragment of the Pacific Ciguatoxins.

The I-L ring system found in all the Pacific ciguatoxins has been prepared from a tricyclic precursor in a highly stereoselective manner. Subtle differences in the reactivity of the enones present in the seven- and eight-membered rings of the tricyclic ether starting material have been exploited to allow selective protection of the enone in the eight-membered ring. Subsequent distereoselective allylation of the seven-membered ring has been accomplished by a palladium-mediated Tsuji-Trost reaction. The K-ring methyl and hydroxyl groups have been installed in a highly stereoselective manner by sequential conjugate reduction and enolate oxidation reactions. Ring L has been constructed by a use of a novel relay ring-closing metathesis reaction to complete the tetracyclic framework, which possesses the functionality necessary for elaboration of rings I and L and the introduction of ring M.

Synthesis of the A-D Ring System of the Gambieric Acids.

The A-D fragment of gambieric acids A and C has been synthesized using an asymmetric Tsuji-Trost allylation reaction to couple the two key segments. The A ring fragment has been prepared by a short and highly efficient route involving diastereoselective Lewis acid mediated alkylation of an acetal. Iterative ring-closing metathesis reactions have been used to construct cyclic ethers and assemble the tricyclic B-D fragment.

Synthetic ciguatoxin CTX 3C induces a rapid imbalance in neuronal excitability.

Ciguatera is a human global disease caused by the consumption of contaminated fish that have accumulated ciguatoxins (CTXs), sodium channel activator toxins. Symptoms of ciguatera include neurological alterations such as paraesthesiae, dysaesthesiae, depression, and heightened nociperception, among others. An important issue to understand these long-term neurological alterations is to establish the role that changes in activity produced by CTX 3C represent to neurons. Here, the effects of synthetic ciguatoxin CTX 3C on membrane potential, spontaneous spiking, and properties of synaptic transmission in cultured cortical neurons of 11-18 days in vitro (DIV) were evaluated using electrophysiological approaches. CTX 3C induced a large depolarization that decreased neuronal firing and caused a rapid inward tonic current that was primarily GABAergic. Moreover, the toxin enhanced the amplitude of miniature postsynaptic inhibitory currents (mIPSCs), whereas it decreased the amplitude of miniature postsynaptic excitatory currents (mEPSCs). The frequency of mIPSCs increased, whereas the frequency of mEPSCs remained unaltered. We describe, for the first time, that a rapid membrane depolarization caused by CTX 3C in cortical neurons activates mechanisms that tend to suppress electrical activity by shifting the balance between excitatory and inhibitory synaptic transmission toward inhibition. Indeed, these results suggest that the acute effects of CTX on synaptic transmission could underlie some of the neurological symptoms caused by ciguatera in humans.

Practical route to the left wing of CTX1B and total syntheses of CTX1B and 54-deoxyCTX1B.

Ciguatoxins, the principal causative agents of ciguatera seafood poisoning, are extremely large polycyclic ethers. We report herein a reliable route for constructing the left wing of CTX1B, which possesses the acid/base/oxidant-sensitive bisallylic ether moiety, by a 6-exo radical cyclization/ring-closing metathesis strategy. This new route enabled us to achieve the second-generation total synthesis of CTX1B and the first synthesis of 54-deoxyCTX1B.

Total synthesis and complete structural assignment of gambieric acid A, a large polycyclic ether marine natural product.

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.

Total synthesis and biological evaluation of (+)-gambieric acid A and its analogues.

In this study, we report the first total synthesis and complete stereostructure of gambieric acid A, a potent antifungal polycyclic ether metabolite, in detail. The A/B-ring exocyclic enol ether 32 was prepared through a Suzuki-Miyaura coupling of the B-ring vinyl iodide 18 and the alkylborate 33 and subsequent closure of the A-ring by using diastereoselective bromoetherification as the key transformation. Suzuki-Miyaura coupling of 32 with acetate-derived enol phosphate 49, followed by ring-closing metathesis of the derived diene, produced the D-ring. Subsequent closure of the C-ring through a mixed thioacetalization completed the synthesis of the A/BCD-ring fragment 8. The A/BCD- and F'GHIJ-ring fragments (i.e., 8 and 9) were assembled through Suzuki-Miyaura coupling. The C25 stereogenic center was elaborated by exploiting the intrinsic conformational property of the seven-membered F'-ring. After the oxidative cleavage of the F'-ring, the E-ring was formed as a cyclic mixed thioacetal (i.e., 70) and then stereoselectively allylated by using glycosylation chemistry. Ring-closing metathesis of the diene 3 thus obtained closed the F-ring and completed the polycyclic ether skeleton. Finally, the J-ring side chain was introduced by using a Julia-Kocienski olefination in the presence of CeCl3 to complete the total synthesis of gambieric acid A (1), thereby unambiguously establishing its complete stereostructure. The present total synthesis enabled us to evaluate the antifungal and antiproliferative activities of 1 and several synthetic analogues.

Total synthesis and complete stereostructure of gambieric acid A.

Total synthesis of gambieric acid A, a potent antifungal polycyclic ether metabolite, has been accomplished for the first time, which firmly established the complete stereostructure of this natural product.

Design and synthesis of skeletal analogues of gambierol: attenuation of amyloid-ß and tau pathology with voltage-gated potassium channel and N-methyl-D-aspartate receptor implications.

Gambierol is a potent neurotoxin that belongs to the family of marine polycyclic ether natural products and primarily targets voltage-gated potassium channels (K(v) channels) in excitable membranes. Previous work in the chemistry of marine polycyclic ethers has suggested the critical importance of the full length of polycyclic ether skeleton for potent biological activity. Although we have previously investigated structure-activity relationships (SARs) of the peripheral functionalities of gambierol, it remained unclear whether the whole polycyclic ether skeleton is needed for its cellular activity. In this work, we designed and synthesized two truncated skeletal analogues of gambierol comprising the EFGH- and BCDEFGH-rings of the parent compound, both of which surprisingly showed similar potency to gambierol on voltage-gated potassium channels (K(v)) inhibition. Moreover, we examined the effect of these compounds in an in vitro model of Alzheimer's disease (AD) obtained from triple transgenic (3xTg-AD) mice, which expresses amyloid beta (Aß) accumulation and tau hyperphosphorylation. In vitro preincubation of the cells with the compounds resulted in significant inhibition of K(+) currents, a reduction in the extra- and intracellular levels of Aß, and a decrease in the levels of hyperphosphorylated tau. In addition, pretreatment with these compounds reduced the steady-state level of the N-methyl-D-aspartate (NMDA) receptor subunit 2A without affecting the 2B subunit. The involvement of glutamate receptors was further suggested by the blockage of the effect of gambierol on tau hyperphosphorylation by glutamate receptor antagonists. The present study constitutes the first discovery of skeletally simplified, designed polycyclic ethers with potent cellular activity and demonstrates the utility of gambierol and its synthetic analogues as chemical probes for understanding the function of K(v) channels as well as the molecular mechanism of Aß metabolism modulated by NMDA receptors.

Convergent synthesis of the HIJKLM ring system of ciguatoxin CTX3C.

The HIJKLM ring system of ciguatoxin CTX3C was synthesized in a convergent manner. The key steps were a conjugate addition/alkylation sequence, spiroacetalization, intramolecular allylation, ring-closing metathesis, and hydrogenation to form the 36-α-methyl substituent.

Stereoselective 6-exo radical cyclization using cis-vinyl sulfoxide: practical total synthesis of CTX3C.

Ciguatoxins, the principal causative toxins of ciguatera seafood poisoning, are large ladder-like polycyclic ethers. We report a highly stereoselective 6-exo radical cyclization/ring-closing olefin metathesis sequence to construct the syn/trans-fused polyether system. The new method was applied to the practical synthesis of ciguatoxin CTX3C.

Studies toward the total synthesis of gambieric acids: stereocontrolled synthesis of a DEFG-ring model compound.

A stereocontrolled convergent synthesis of a DEFG-ring model compound of gambieric acids, highly potent antifungal marine polycyclic ether natural products, has been achieved based on Suzuki-Miyaura coupling. Conformational analysis of the model compound revealed that the nine-membered F-ring exists exclusively as a single stable conformer, as opposed to that of ciguatoxins.

SmI2-induced cyclizations and their applications in natural product synthesis.

Since the isolation of brevetoxin-B, a red tide toxin, many bioactive marine natural products featuring synthetically challenging trans-fused polycyclic ether ring systems have been reported. We have developed SmI(2)-induced cyclization of beta-alkoxyacrylate with aldehyde, affording 2,6-syn-2,3-trans-tetrahydropyran (THP) or 2,7-syn-2,3-trans-oxepane with complete stereoselection, as a key reaction of efficient iterative and bi-directional strategies for the construction of these polycyclic ethers. This reaction is also applicable to the synthesis of 3-, 5-, and 6-methyl-THPs and 3,5-dimethyl-THP. The synthesis of 2-methyl- and 2,6-dimethyl-THPs was accomplished by means of a unique methyl insertion. Recently, the SmI(2)-induced cyclization was extended to similar reactions using beta-alkoxyvinyl sulfone and sulfoxide. Reaction of (E)- and (Z)-beta-alkoxyvinyl sulfone-aldehyde afforded 2,6-syn-2,3-trans- and 2,6-syn-2,3-cis- THPs, respectively. Reaction of (E)-beta-alkoxyvinyl (R)- and (S)-sulfoxides gave 2,6-anti-2,3-cis- and 2,6-syn-2,3-trans-THPs, respectively. Reaction of (Z)-beta-alkoxyvinyl (R)-sulfoxides gave 2,6-syn-2,3-cis-THP and an olefinic product, while that of (Z)-beta-alkoxyvinyl (S)-sulfoxide afforded a mixture of many products. These SmI(2)-induced cyclizations have been applied to the total syntheses of various natural products, including brevetoxin-B, mucocin, pyranicin, and pyragonicin. Synthetic studies on gambierol and maitotoxin are also introduced.

Total synthesis of gambierol by using oxiranyl anions.

Gambierol was isolated as a neurotoxin from the cultured cells of the ciguatera causative dinoflagellate Gambierdiscus toxicus and classified as a member of the polycyclic ether family of marine toxins. The structure consists of a ladder-shaped trans-fused octacyclic ring system that includes 18 stereogenic centers, two 1,3-diaxial dimethyl-substituted tetrahydropyranyl rings, and a partially conjugated triene side chain. The total synthesis of gambierol has been achieved by utilizing an oxiranyl anion strategy in an iterative manner. Synthetic highlights of this route include direct carbon-carbon formation on epoxides, sulfonyl-assisted 6-endo cyclization, and an expansion reaction of the tetrahydropyranyl rings to oxepanes to forge the polycyclic architecture of the target molecule.

The first F-ring modified ciguatoxin analogue showing significant toxicity.

Ciguatoxins, the principal causative toxins of ciguatera seafood poisoning, are potent neurotoxic polycyclic ethers. We report herein the total synthesis of a 10-membered F-ring analogue of 51-hydroxyCTX3C, which constitutes the first example of an F-ring modified ciguatoxin that exhibits potent cytotoxicity as well as mouse acute toxicity.

Synthesis of natural products containing spiroketals via intramolecular hydrogen abstraction.

Although known for over a quarter of a century, the oxidative radical cyclisation route to spiroketals has found limited use in natural product synthesis in comparison to classical approaches. Its successful application in this field of research forms the subject of this perspective.

Total synthesis of gambierol.

The total synthesis of gambierol has been achieved utilizing an oxiranyl anion strategy in an iterative manner. Synthetic highlights of this route include direct carbon-carbon formation on epoxides, sulfonyl-assisted 6-endo cyclization, and expansion reaction of tetrahydropyranyl rings to oxepanes to forge the polycyclic architecture of the target molecule.

Total synthesis of ciguatoxin.

Something fishy: Ciguatoxin (see structure) is one of the principal toxins involved in ciguatera poisoning and the target of a total synthesis involving the coupling of three segments. The key transformations in this synthesis feature acetylene-dicobalthexacarbonyl complexation.