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An 11-step synthesis of (+)-neopeltolide was developed. The C1-C7 carboxylic acid and the C8-C16 alcohol were prepared, each in six steps, from (

Collective asymmetric total synthesis of marine tricyclic alkaloids, cylindricines A–H, and the proposed structures of cylindricine I and J, was achieved in a concise manner from a single common spirocyclic pyrrolidine intermediate. A tandem chemoselective oxidation/intramolecular aza-Michael addition/epimerization was exploited to complete the tricyclic skeleton. This work provides a versatile synthetic entry to the cylindricine family of marine tricyclic alkaloids.

Site-selective introduction of multiple components into peptides is greatly needed for the preparation of densely functionalized peptides with uniform quality. In particular, N-terminal-selective peptide modification has attracted considerable attention in recent years for the purpose of single-site modification. In this work, an N-terminal selective [3+2] cycloaddition of peptide-based azomethine ylides with maleimides was developed. This reaction was catalyzed by Cu/Xantphos complex under mild conditions to afford the cycloadduct in excellent yield and with complete exo-diastereoselectivity, leaving the alkyl amine of a lysine residue untouched. Furthermore, the reaction forms an irreversible C–C bond, preventing the elimination of the introduced modules, which has been a major concern in previous methods. The reaction was applied to a convenient three-component assembly by a one-pot procedure using a peptide with aldehyde and maleimide. Furthermore, this method was efficiently applied to a single-site modification of oligopeptides. These results showcase the utility of this method for the single-site bi-functionalization of complex peptides.

A seven-step synthesis of (−)-atorvastatin calcium, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, has been developed. The key transformations of the present synthesis a...

A stereocontrolled synthetic entry to the southern hemisphere C3-C17 acyclic domain of neaumycin B, a highly potent cytotoxic macrolide natural product, has been developed. The present synthesis is based on (i) a tandem olefin cross-metathesis/hemiacetalization/intramolecular oxa-Michael addition, (ii) a regioselective reductive acetal opening for differential protection of the C14 hydroxy group, (iii) a Horner-Wadsworth-Emmons reaction for the stereoselective formation of the C8-C9 olefin, and (iv) a Corey-Bakshi-Shibata asymmetric reduction to create the C7 stereogenic center.

[RuCl2(p-cymene)]2/AgNO3-catalyzed intramolecular double hydrofunctionalization of internal alkynes having nitrogen and oxygen nucleophilic groups at appropriate positions provided a series of spir...

Cobalt-catalyzed Mukaiyama-type cyclization of γ-hydroxy olefins is known as an atom- and step-economical means for stereoselective synthesis of 2,5-trans-substituted tetrahydrofuran derivatives. In this study, we investigated the synthesis of a series of 2,5-substituted tetrahydrofuran derivatives by means of a cobalt-catalyzed Hartung-Mukaiyama cyclization. The stereochemical consequence of the reaction was found to be largely dependent on the substitution pattern and relative configuration of γ-hydroxy olefins. 2,5-cis-Substituted tetrahydrofuran derivatives could be obtained diastereoselectively from appropriately substituted γ-hydroxy olefins. Additionally, relatively bulky olefin substituents and unprotected hydroxy groups at non-interfering positions (e.g., α and δ) were well tolerated in the reaction. Finally, the synthetic versatility of the Hartung-Mukaiyama cyclization was demonstrated through a stereocontrolled synthesis of the tetrahydrofuran moiety of amphidinolide N, a potent cytotoxic macrolide of marine origin. This study expands the capacity of Mukaiyama-type cyclization in that it can be used in convergent assembly of complex tetrahydrofuran motifs from internal olefins.

The total synthesis of cytotoxic marine phosphomacrolides, (-)-enigmazole A and (-)-15-O-methylenigmazole A, is described in detail. The 2,6-cis-substituted tetrahydropyran ring was efficiently elaborated by using a tandem olefin cross-metathesis/intramolecular oxa-Michael addition reaction. The 18-membered macrolactone skeleton was forged via a Au-catalyzed propargylic benzoate rearrangement/macrocyclic ring-closing metathesis sequence. Late-stage diversification of a common intermediate enabled unified total synthesis of (-)-enigmazole A and (-)-15-O-methylenigmazole A.

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.

Gambierol inhibits voltage-gated K

Ciguatoxins (CTXs) which are produced by dinoflagellates of the genus Gambierdiscus and Fukuyoa and share a ladder-shaped polyether structure, are causative compounds of one of the most frequent foodborne illness disease known as ciguatera fish poisoning (CFP). CFP was initially found in tropical and subtropical areas but nowadays the dinoflagellates producers of ciguatoxins had spread to European coasts. Therefore, this raises the need of establishing toxicity equivalency factors for the different compounds that can contribute to ciguatera fish poisoning, since biological methods have been replaced by analytical techniques. Thus, in this work, the effects of six compounds causative of ciguatera, on their main target, the human voltage-gated sodium channels have been analyzed for the first time. The results presented here led to the conclusion that the order of potency was CTX1B, CTX3B, CTX4A, gambierol, gambierone and MTX3. Furthermore, the data indicate that the activation voltage of sodium channels is more sensitive to detect ciguatoxins than their effect on the peak sodium current amplitude The research leading to these results has received funding from the following FEDER cofunded-grants. From Conselleria de Cultura, Educacion e Ordenación Universitaria, Xunta de Galicia, GRC (ED431C 2021/01). From Ministerio de Ciencia e Innovación IISCIII/PI19/001248, PID 2020-11262RB-C21. From European Union Interreg AlertoxNet EAPA-317-2016, Interreg Agritox EAPA-998-2018, and H2020 778069-EMERTOX SI

Stereoselective tandem synthesis of syn-1,3-diol motifs, abundantly present in polyketide natural products and relevant pharmaceuticals, was achieved from homoallylic alcohols, α,β-unsaturated ketones, and aldehydes. Olefin cross-metathesis of homoallylic alcohols with α,β-unsaturated ketones, hemiacetalization of the resultant alcohols with aldehydes, and subsequent intramolecular oxa-Michael addition of the derived hemiacetals furnished syn-1,3-dioxane derivatives in good to excellent yields without isolation of any intermediates. The acetal moiety of the resultant syn-1,3-dioxanes could be cleaved chemoselectively/regioselectively under mild conditions in subsequent transformations.

Amphirionin-2 is a linear polyketide metabolite that exhibits potent and selective cytotoxic activity against certain human cancer cell lines. We disclose herein the first total synthesis of amphirionin-2 and determination of its absolute configuration. Our synthesis featured an extensive use of cobalt-catalyzed Mukaiyama-type cyclization of γ-hydroxy olefins for stereoselective formation of all the tetrahydrofuran rings found in the natural product, and a late-stage Stille-type coupling for convergent assembly of the entire carbon backbone. Four candidate diastereomers of amphirionin-2 were synthesized in a unified, convergent manner, and their spectroscopic/chromatographic properties were compared with those of the authentic material. The present study culminated in the reassignment of the C5/C7 relative configuration, assignment of the C12/C18 relative configuration, and determination of the absolute configuration of amphirionin-2., An extensive application of cobalt-catalyzed Mukaiyama-type cyclization of γ-hydroxy olefins and a late-stage Stille-type reaction enabled syntheses of four diastereomers of amphirionin-2 to establish its absolute configuration.

International audience; 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.

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.

The development of efficient methods for stereocontrolled synthesis of polyol derivatives has been of continuing interest for the synthetic community. We describe herein tandem olefin cross-metathesis/hemiacetalization/intramolecular oxa-Michael addition of allylic/homoallylic alcohols, α,β-unsaturated ketones, and aldehydes, which enabled the synthesis of syn-1,2- and syn-1,3-diol derivatives in a step-economical manner. A series of differentially protected polyol derivatives could be obtained in subsequent transformations via chemoselective/regioselective cleavage of the acetal moiety of the tandem reaction products.

Design, synthesis and functional analysis of fluorescent derivatives of neopeltolide, an antiproliferative marine macrolide, are reported herein. Live cell imaging using the fluorescent derivatives showed rapid cellular uptake and localization within the endoplasmic reticulum as well as the mitochondria.

Gambierol is a marine polycyclic ether toxin, first isolated from cultured Gambierdiscus toxicus dinoflagellates collected in French Polynesia. The chemical synthesis of gambierol permitted the analyses of its mode of action which includes the selective inhibition of voltage-gated K+ (KV) channels. In the present study we investigated the action of synthetic gambierol at vertebrate neuromuscular junctions using conventional techniques. Gambierol was studied on neuromuscular junctions in which muscle nicotinic ACh receptors have been blocked with d-tubocurarine (postsynaptic block), or in junctions in which quantal ACh release has been greatly reduced by a low Ca2+–high Mg2+ medium or by botulinum neurotoxin type-A (BoNT/A) (presynaptic block). Results show that nanomolar concentrations of gambierol inhibited the fast K+ current and prolonged the duration of the presynaptic action potential in motor nerve terminals, as revealed by presynaptic focal current recordings, increased stimulus-evoked quantal content in junctions blocked by high Mg2+–low Ca2+ medium, and by BoNT/A, reversed the postsynaptic block produced by d-tubocurarine and increased the transient Ca2+ signals in response to nerve-stimulation (1–10 Hz) in nerve terminals loaded with fluo-3/AM. The results suggest that gambierol, which on equimolar basis is more potent than 3,4-diaminopyridine, can have potential application in pathologies in which it is necessary to antagonize pre- or post-synaptic neuromuscular block, or both. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.

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.

This paper describes a concise synthesis of six- to eight-membered α,α'-substituted cyclic ethers by exploiting diastereoselective ring-closing metathesis (RCM) of 1,4-pentadien-3-yl ether derivatives. The RCM precursors could be efficiently prepared via a vinylation of the corresponding α-acetoxy ether derivatives using divinylzinc. Diastereoselective RCM of 1,4-pentadien-3-yl ether derivatives afforded a series of six- to eight-membered α,α'-substituted cyclic ethers with moderate to good diastereoselectivity. The stereochemical consequence of the diastereoselective RCM appeared to be dependent on the structure of the ring being forged. The diastereoselectivity of six- and seven-membered cyclic ethers appeared to be largely under kinetic control irrespective of the catalyst reactivity, whereas that of an eight-membered cyclic ether could be controlled by the catalyst reactivity. Finally, the diastereoselective RCM chemistry was applied to the synthesis of a biotin-tagged photoactivatable derivative of gambierol.

Okadaic acid (OA), a product of dinoflagellate Prorocentrum spp., is transformed into 7- O -acyl OA in various bivalve species. The structural transformation proceeds enzymatically in vitro in the presence of the microsomal fraction from the digestive gland of bivalves. We have been using LC–MS/MS to identify OA-transforming enzymes by detecting 7- O -acyl OA, also known as dinophysistoxin 3 (DTX3). However, an alternative assay for DTX3 is required because the OA-transforming enzyme is a membrane protein, and surfactants for solubilizing membrane proteins decrease the sensitivity of LC–MS/MS. The present study examined saturated fatty acyl CoAs with a carbon chain length of 10 (decanoyl), 12 (dodecanoyl), 14 (tetradecanoyl), 16 (hexadecanoyl) and 18 (octadecanoyl) as the substrate for the in vitro acylation reaction. Saturated fatty acyl CoAs with a carbon chain length of 14, 16 and 18 exhibited higher yields than those with a carbon chain length of 10 or 12. Acyl CoAs with carbon chain lengths from 14 to 18 and containing either a diene unit, an alkyne unit, or an azide unit in the carbon chain were synthesized and shown to provide the corresponding DTX3 with a yield comparable to that of hexadecanoyl CoA. The three functional units can be conjugated with fluorescent reagents and are applicable to the development of a novel assay for DTX3.

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.

Iriomoteolide-2a is a marine macrolide metabolite isolated from a cultured broth of the benthic dinoflagellate Amphidinium sp. HYA024 strain. This naturally occurring substance was reported to show remarkable cytotoxic activity against human cancer cell lines HeLa and DG-75 and in vivo antitumor activity against murine leukemia P388 cell line. Herein, the total synthesis, stereochemical revision, and biological assessment of iriomoteolide-2a are reported in detail. Total synthesis of the proposed structure 1 of iriomoteolide-2a featured a late-stage convergent assembly of three components by a Suzuki-Miyaura coupling, an esterification, and a ring-closing metathesis. However, the NMR data of synthetic 1 were not identical to those of the natural product. Careful analysis of the NMR data of the authentic material and synthesis/NMR analysis of appropriately designed model compounds led to consideration of four possible stereoisomers 2-5 as candidates for the correct structure. Accordingly, total syntheses of 2-5 were achieved by taking advantage of the convergent strategy, and comparison of the NMR spectra of synthetic 2-5 with those of the natural product led to the conclusion that 5 shows the correct relative configuration of iriomoteolide-2a. The absolute configuration of this natural product was finally established through chiral HPLC analysis of synthetic 5/ent-5 with the authentic sample. The antiproliferative activity of the synthetic compounds was assessed against HeLa and A549 cells to show that, in contrast to expectation, synthetic 5 and ent-5 were only marginally active in these cell lines. This work clearly underscores the vital role of total synthesis in the establishment of the structure and biological activity of natural products.

Intramolecular double hydroalkoxylation of internal alkynes could be achieved using a Grubbs-type ruthenium carbene complex or its modified species to deliver a series of bridged- and spiroacetal derivatives in moderate to good yields. This study represents a new example of nonmetathetic reactions catalyzed by Grubbs-type ruthenium carbene complexes.

Goniodomin A is a marine polyether macrolide natural product isolated from the dinoflagellate Alexandrium hiranoi. In this paper, we report stereocontrolled, convergent synthesis of a fully functionalized C12-C36 fragment of goniodomin A. The synthesis of the C12-C25 vinylstannane involved a Wittig reaction and a reductive cycloetherification for the construction of the dihydropyran ring. The C26-C36 thioester was synthesized via a Nozaki-Hiyama-Kishi reaction of an aldehyde and an iodoalkyne, the former of which was easily prepared from (R)-malic acid as a chiral source by taking advantage of substrate-controlled diastereoselective reactions. Finally, a palladium-catalyzed coupling of the C12-C25 vinylstannane and the C26-C36 thioester completed the synthesis of the target compound.

A marine polyether natural product okadaic acid is known to be a potent and specific inhibitor of protein phosphatases 1 and 2A. Herein, concise synthesis of the C15–C38 fragment of okadaic acid is reported. We investigated two different strategies for the construction of two spiroacetal substructures found in the target compound. The first strategy involved Suzuki–Miyaura coupling for the synthesis of endocyclic enol ethers and subsequent spiroacetalization. The second strategy exploited Suzuki–Miyaura coupling for the synthesis of exo-olefins as the precursor of spiroacetals. An alkynylaluminum–anomeric sulfone coupling effectively assembled the key spiroacetal substructures and completed the target compound.

Total syntheses of the proposed and correct structures of iriomoteolide-2a, a cytotoxic marine macrolide natural product with an unusual 23-membered macrolactone skeleton, have been accomplished for the first time. The synthesis of the correct structure involves an asymmetric epoxidation/diepoxide cyclization cascade for the construction of the bis(tetrahydrofuran) moiety, a Suzuki-Miyaura coupling for the fragment assembly, and a ring-closing metathesis for the closure of the macrocyclic backbone. In addition, the original stereochemical assignment of iriomoteolide-2a was revised.

A concise synthetic entry to the C15-C38 fragment of okadaic acid by exploiting a Suzuki-Miyaura reaction for the rapid assembly of the spiroacetal substructures has been developed. The present synthesis was completed in 19 linear steps from a commercially available material, showcasing the efficiency of our synthetic strategy.

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.

We describe the synthesis and biological evaluation of (+)-neopeltolide analogues with structural modifications in the oxazole-containing side chain. Evaluation of the antiproliferative activity of newly synthesized analogues against A549 human lung adenocarcinoma cells and PANC-1 human pancreatic carcinoma cells have shown that the C19-C20 and C26-C27 double bonds within the oxazole-containing side chain and the terminal methyl carbamate group are essential for potent activity.

Stereoselective synthesis of α,α'-substituted medium-sized cyclic ethers has been achieved by means of nucleophilic substitution of the corresponding lactone-derived thioacetals and their sulfone counterparts. Nucleophilic substitution of medium-sized lactone-derived thioacetals could be achieved efficiently either by (i) activation with NIS/TMSOTf in the presence of allyltrimethylsilane or TMSCN or by (ii) oxidation to the corresponding sulfones followed by treatment with an appropriate organometallic species such as divinylzinc or dimethyl(2-phenylethynyl)aluminum. Interestingly, the stereochemical consequence was found to be largely dependent on the local structure of substrates. In some cases, the gauche steric interaction developed in the transition state was considered to be responsible for the observed diastereoselectivity. The present method enables an efficient synthesis of a variety of α,α'-substituted seven- to nine-membered cyclic ethers from readily accessible lactone precursors.

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 of 13-demethyllyngbyaloside B, an unnatural analogue of a marine macrolide glycoside lyngbyaloside B, has been achieved. The 14-membered macrocyclic backbone was constructed in a convergent manner via esterification and ring-closing metathesis. The bromodiene side chain was introduced by means of a Stille-type reaction and a subsequent bromodesilylation. Finally, the rhamnopyranose unit was stereoselectively introduced by glycosylation under Schmidt conditions.

Gambierol and its two, tetra- and heptacyclic, analogues have been previously proved as promising molecules for the modulation of Alzheimer’s disease (AD) hallmarks in primary cortical neurons of 3xTg-AD fetuses. In this work, the effect of the tetracyclic analogue of gambierol was tested in vivo in 3xTg-AD mice (10 months old) after 1 month of weekly treatment with 50 μg/kg. Adverse effects were not reported throughout the whole treatment period and no pathological signs were observed for the analyzed organs. The compound was found in brain samples after intraperitoneal injection. The tetracyclic analogue of gambierol elicited a decrease of amyloid β1–42 levels and a dose-dependent inhibition of β-secretase enzyme-1 activity. Moreover, this compound also reduced the phosphorylation of tau at the 181 and 159/163 residues with an increase of the inactive isoform of the glycogen synthase kinase-3β. In accordance with our in vitro neuronal model, this compound produced a reduction in the N2A subunit of the N...

Campechic acids A and B are anti-invasive polyketide antibiotics isolated from Streptomyces sp. CHI93 strain. Herein we describe stereoselective synthesis of the C-16–C-30 fragment of campechic acids A and B via a biosynthesis-inspired epoxide-opening cascade and its NMR spectroscopic comparison with the authentic degradation product, resulting in configurational assignment of the C-21, C-24, C-25, and C-28 stereogenic centers and reassignment of the C-18 stereogenic center.

Stereoselective synthesis of the C1–C16 fragment of the antifungal marine polyether macrolide goniodomin A is described. A Stille-type coupling of organostannanes and thioesters was exploited as th...

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-substituted tetrahydropyran derivatives with good to excellent stereoselectivity (dr from 7:1 to20:1). These α,β-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.

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 CeCl 3 -promoted Julia–Kocienski olefination.

In this paper, we describe a new strategy for the synthesis of substituted dihydropyrones and tetrahydropyrones. By exploiting palladium-catalyzed coupling of thioesters with terminal alkynes or alkenylboronic acids, a variety of β-hydroxy ynones or enones, respectively, could be prepared in an efficient manner under mild conditions. AgOTf-promoted intramolecular oxa-conjugate cyclization of β-hydroxy ynones provided 2,6-substituted dihydropyrones in excellent yields. On the other hand, acid-catalyzed cyclization of β-hydroxy enones caused racemization of the product 2,6-substituted tetrahydropyrones due to its reversible nature. Eventually, stereoselective hydrogenation of substituted dihydropyrones was found to be a solid and efficient approach for the synthesis of 2,6-cis-substituted tetrahydropyrone derivatives.

We describe herein an enantioselective total synthesis of (-)-exiguolide, the natural enantiomer. The methylene bis(tetrahydropyran) substructure was efficiently synthesized by exploiting olefin cross-metathesis for the assembly of readily available acyclic segments and intramolecular oxa-conjugate cyclization and reductive etherification for the formation of the tetrahydropyran rings. The 20-membered macrocyclic framework was constructed in an efficient manner by means of Julia-Kocienski coupling and Yamaguchi macrolactonization. Finally, the (E,Z,E)-triene side chain was introduced stereoselectively via Suzuki-Miyaura coupling to complete the total synthesis. Assessment of the growth inhibitory activity of synthetic (-)-exiguolide against a panel of human cancer cell lines elucidated for the first time that this natural product is an effective antiproliferative agent against the NCI-H460 human lung large cell carcinoma and the A549 human lung adenocarcinoma cell lines. Moreover, we have investigated structure-activity relationships of (-)-exiguolide, which elucidated that the C5-methoxycarbonylmethylidene group and the length of the side chain are important for the potent activity.

A stereocontrolled convergent synthesis of the C15–C36 segment of goniodomin A, a potent anti-angiogenic marine polyether macrolide, has been achieved using Stille-type cross-coupling reaction of a vinylstannane and a thioester as a key segment assembly process.

A stereocontrolled synthesis of the GHIJ-ring fragment having a side chain of gambieric acids, which are potent antifungal polycyclic ether natural products, has been achieved. The synthesis features convergent assembly of the tetracyclic polyether skeleton by using aldol coupling and stereoselective construction of the J-ring side chain by a cerium chloride-promoted Julia–Kocienski reaction.

The ladder-shaped polycyclic ether marine natural products present formidable and challenging synthetic targets due to their structural complexity, and exceptionally potent biological activities. Over the past decade, however, the limited availability of these substances from natural sources has precluded detailed biological studies. There has been an urgent need for means to supply useful quantities of these natural products and their analogues by total synthesis. We have developed a highly convergent strategy for the rapid and efficient assembly of polycyclic ether arrays, which relies on the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction of cyclic enol triflates or phosphates. The utility of this strategy has been demonstrated by its application to the convergent total synthesis of the polycyclic ether class of natural products.