Convergent and Scalable Second-Generation Synthesis of Fully Functionalized HIJKLMN-Ring Segment of Caribbean Ciguatoxin C-CTX-1
Makoto Sasaki,* Miyu Ohba, Ako Murakami, Atsushi Umehara
The Journal of Organic Chemistry, 2024, accepted. DOI: 10.1021/acs.joc.4c02723
プレスリリース from 東北大学大学院生命科学研究科 プレスリリース from 東北大学本部 報道 from 日本経済新聞 報道 from 産経ニュース A highly convergent and scalable second-generation synthesis of the fully functionalized HIJKLMN-ring segment of Caribbean ciguatoxin C-CTX-1, the primary toxin responsible for ciguatera fish poisoning in the Caribbean Sea and the Northeast Atlantic regions, has been accomplished. Key aspects of the synthetic approach include the efficient syntheses of the HI- and KLM-ring fragments on gram scales, a convergent fragment coupling toward the HIJKLM-ring skeleton based on the Suzuki–Miyaura coupling strategy, and optimized iron hydride-catalyzed hydrogen atom transfer-mediated olefin coupling conditions for constructing the N-ring.
Total Synthesis of (–)-Zearalenone and (–)-Zearalanone: A Macrocyclization Strategy by Ni/Zr/Cr-Mediated Reductive Ketone Coupling
Atsushi Umehara,* Ko-hei Kawakita, Makoto Sasaki*
The Journal of Organic Chemistry, 2024, 89, 13800-13805. DOI: 10.1021/acs.joc.4c01793
研究成果 from 東北大学大学院生命科学研究科 Selected as Most Read Articles(10/2024) The total synthesis of the resorcylic acid lactones (−)-zearalenone and (−)-zearalanone is described. Our synthetic strategy relies on Ni-, Zr-, and Cr-mediated intramolecular reductive ketone coupling to create 14-membered macrolactones. Notably, the use of CrCl
2 in addition to Ni/Zr-mediated reductive ketone coupling conditions was key for the success of the macrocyclization.
Total Synthesis of (–)-Irijimaside A Enabled by Ni/Zr-Mediated Reductive Ketone Coupling
プレスリリース from 東北大学大学院生命科学研究科 プレスリリース from 東北大学本部 報道 from 日本経済新聞 Selected as Most Read Articles(06/2024) The total synthesis of marine macrolide glycoside (−)-irijimaside A is described. Key to the synthesis is the convergent fragment assembly enabled by nickel/zirconocene-mediated one-pot reductive ketone coupling. At the last stage of the synthesis, Stille coupling and glycosylation led to the first total synthesis of (−)-irijimaside A.
DMAPO/Boc2O-Mediated One-Pot Direct N1-Acylation of Indazole with Carboxylic Acids: A Practical Synthesis of N1-Functionalized Alkyl Indazoles
Atsushi Umehara,* Shimizu Soma, Makoto Sasaki*
Europran Journal of Organic Chemistry 2024, e202400123. DOI: 10.1002/ejoc.202400123
プレスリリース from 東北大学大学院生命科学研究科 プレスリリース from 東北大学本部 報道 from 日本経済新聞 新聞記事 from 日刊工業新聞(2024.2.21) This report describes the one-pot direct
N-acylation of indazole with carboxylic acids using our previously developed 4-(
N,
N-dimethylamino)pyridine
N-oxide (DMAPO)/di-
tert-butyl dicarbonate (Boc
2O) system. This simple system provides
N1-acyl indazoles in high yield with high
N1 selectivities and does not require the use of activated derivatives of carboxylic acids or high temperatures. This new method exhibits a wide substrate scope (>40 examples). In addition, a new synthesis of
N1-functionalized alkyl indazoles utilizing
N1-acyl indazoles as starting materials was achieved. This stepwise protocol is useful for the selective synthesis of structurally diverse
N1-functionalized alkyl indazoles, which are difficult to synthesize by other methods such as the Mitsunobu reaction and classical S
N2 alkylation of indazole.
Synthesis of Bulky N-Acyl Heterocycles by DMAPO/Boc2O-Mediated One-Pot Direct N-Acylation of Less Nucleophilic N-Heterocycles with α-Fully Substituted Carboxylic Acids
プレスリリース from 東北大学 プレスリリース from 生命科学研究科 報道 from 日本経済新聞 Most Accessed Paper (07/2023) and (08/2023) This report describes a general method for the one-pot direct N-acylation of N-heterocycles using our previously developed 4-(N,N-dimethylamino)pyridine N-oxide (DMAPO)/di-tert-butyl dicarbonate (Boc2O) system. This system enables one-pot N-acylation reactions to provide bulky N-acyl heterocycles starting from a wide variety of less nucleophilic N-heterocycles and sterically hindered α-fully substituted carboxylic acids in high yield. Moreover, this one-pot method does not involve pre-activation of substrates. The protocol has been successfully extended to one-pot N-acylation of 7-azaindoles.
DMAPO/Boc2O-Mediated One-Pot Direct N-Acylation of Less Nucleophilic N-Heterocycles with Carboxylic Acids
Atsushi Umehara,* Soma Shimizu, Makoto Sasaki*
ChemCatChem 2023, 15, e202201596.
プレスリリース from 生命科学研究科プレスリリース from 東北大学本部 プレスリリース from 日本経済新聞 新聞記事 from 日刊工業新聞(2023.2.8) Research News from Tohoku Univ. TCIトピックス2023年 製品ハイライト from TCI Most Accessed Paper (02/2023), (04/2023), (05/2023), (06/2023), (07/2023), (08/2023), (09/2023), (10/2023), (11/2023), (12/2023), (01/2024), (02/2024), (04/2024), (05/2024), (06/2024), (07/2024) and (08/2024) In contrast to the considerable progress in the development of methodologies for amide bond formation in amines, the development of direct
N-acylation of less nucleophilic
N-heterocycles and amides with carboxylic acids is still challenging. In this report, we describe the direct
N-acylation of less nucleophilic heterocycles and amides with carboxylic acids promoted by the 4-(
N,
N-dimethylamino)pyridine
N-oxide (DMAPO)/di-
tert-butyl dicarbonate (Boc
2O) system. The new one-pot method, which does not involve pre-activation of substrates, enables the direct
N-acylation of a wide variety of nitrogen nucleophiles such as indole, carbazole, pyrrole, pyrazole, lactam, oxazolidinone, and anilide with carboxylic acids in high yield. The new method also exhibits excellent functional group tolerance and broad substrate scope. As the present method is practical, operationally simple, and scalable, it should find wide applications in both academic and industrial laboratories.
Convergent and Scalable Synthesis of the ABCDE-Ring Fragment of Caribbean Ciguatoxin C-CTX-1
Makoto Sasaki*, Miku Seida, Atsushi Umehara
J. Org. Chem. 2023, 88, 403-418
cover artが掲載されました。
研究科のHPで取りあげてもらいました。 Convergent and scalable synthesis of the ABCDE-ring fragment of Caribbean ciguatoxin C-CTX-1, the major causative toxin for ciguatera poisoning in the Caribbean Sea and the Northeast Atlantic areas, is described in detail. The key features of the synthesis include an iterative use of 2,2,6,6-tetramethyl piperidine 1-oxyl (TEMPO)/PhI(OAc)
2-mediated oxidative lactonization and Suzuki–Miyaura coupling en route to the DE-ring system and a convergent fragment coupling to form the ABCDE-ring skeleton via the Suzuki–Miyaura coupling strategy.
Convergent Synthesis of the HIJKLMN-Ring Fragment of Caribbean Ciguatoxin C-CTX-1 by a Late-Stage Reductive Olefin Coupling Approach
本研究のプレスリリースが掲載されました（2022/4/7） プレスリリース from 東北大院生命科学研究科 プレスリリース from 東北大本部 The convergent synthesis of the HIJKLMN-ring fragment of Caribbean ciguatoxin C-CTX-1, the major causative toxin for ciguatera fish poisoning in the Caribbean Sea and the Northeast Atlantic areas, is disclosed. The synthesis features a late-stage iron-catalyzed hydrogen atom transfer-initiated reductive olefin coupling to install the N-ring and a Suzuki–Miyaura coupling/thioacetalization strategy for the convergent assembly of the hexacyclic HIJKLM-ring skeleton.The convergent synthesis of the HIJKLMN-ring fragment of Caribbean ciguatoxin C-CTX-1, the major causative toxin for ciguatera fish poisoning in the Caribbean Sea and the Northeast Atlantic areas, is disclosed. Highlights of the synthesis are Suzuki–Miyaura coupling/thioacetalization strategy for convergent assembly of the HIJKLM-ring skeleton and a late-stage hydrogen atom transfer-initiated reductive olefin coupling to construct the terminal N-ring.
Gambierol Blocks a K+ Current Fraction without Affecting Catecholamine Release in Rat Fetal Adrenomedullary Cultured Chromaffin Cells
Gambierol inhibits voltage-gated K
+ (K
V) 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 K
V 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
+ (K
Ca) and ATP-sensitive K
+ (K
ATP) channels. The gambierol concentration necessary to inhibit 50% of the K
+ current-component sensitive to the polyether (IC
50) 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 K
Ca 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 K
Ca channels in the control of exocytosis from fetal (F19–F20) adrenomedullary chromaffin cells.
Determination of the Toxicity Equivalency Factors for Ciguatoxins using Human Sodium Channels
Sandra Raposo-Garcia, M. Carmen Louzao, Haruhiko Fuwa, Makoto Sasaki, Carmen Vale, Luis M. Botana
Food Chem. Toxicol. 2022, 160, 112812
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.
Synthesis and Structural Implication of the JKLMN-Ring Fragment of Caribbean Ciguatoxin C-CTX-1
Makoto Sasaki*, Kotaro Iwasaki, and Keisuke Arai
J. Org. Chem. 2021. 86, 4580
Synthesis of the JKLMN-ring fragment of Caribbean ciguatoxin C-CTX-1, the causative toxin of ciguatera fish poisoning in the Caribbean Sea and the Northeast Atlantic areas, is described in detail. Key to the synthesis are a [2,3]-sigmatropic rearrangement to construct a seven-membered α-hydroxy
exo-enol ether, stereoselective construction of an angular tetrasubstituted stereogenic center on the seven-membered M-ring by a hydrogen atom transfer-based reductive olefin coupling, Suzuki–Miyaura coupling of the KLMN-ring enol phosphate with a highly congested M-ring, and silica gel-mediated epoxide ring opening to form the J-ring. Comparison of the nuclear magnetic resonance spectroscopic data for the synthesized fragment with those for the natural product provided support for the formerly assigned structure of the N-ring in the right-hand terminal of C-CTX-1.
Synthesis of leuconoxine, leuconodine B, and rhazinilam by transformation of melodinine E via 6-hydro-21-dehydroxyleuconolam
Synthesis of monoterpene indole alkaloids, leuconoxine, leuconodine B, and rhazinilam, by transformation of melodinine E via 6-hydro-21-dehydroxyleuconolam was established. The pivotal intermediate, 6-hydro-21-dehydroxyleuconolam, was prepared from melodinine E via a ring-opening
N,
S-acetal formation of the diaza[5.5.6.6]fenestrane skeleton and subsequent chemoselective reduction. These results demonstrate that 6-hydro-21-dehydroxy-leuconolam is a useful synthetic precursor of these related monoterpene indole alkaloids.
Unified Total Synthesis of (−)-Enigmazole A and (−)-15-O-Methylenigmazole A
Keisuke Sakurai, Keita Sakamoto, Makoto Sasaki and Haruhiko Fuwa
Chem. Asian J. 2020, 15, 3494.
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.
Gambierol Potently Increases Evoked Quantal Transmitter Release and Reverses Pre- and Post-Synaptic Blockade at Vertebrate NeuromuscularJunctions
Jordi Molgó, Sébastien Schlumberger, Makoto Sasaki, Haruhiko Fuwa, M. Carmen Louzao, Luis M. Botana, Denis Servent, and Evelyne Benoit
Neuroscience 2020, 439, 106–116.
Gambierol is a marine polycyclic ether toxin,first isolated from culturedGambierdiscus toxicusdinoflagel-lates collected in French Polynesia. The chemical synthesis of gambierol permitted the analyses of its mode of actionwhich includes the selective inhibition of voltage-gated K+(KV) channels. In the present study we investigated theaction of synthetic gambierol at vertebrate neuromuscular junctions using conventional techniques. Gambierol wasstudied on neuromuscular junctions in which muscle nicotinic ACh receptors have been blocked withd-tubocurarine (postsynaptic block), or in junctions in which quantal ACh release has been greatly reduced by alow Ca2+–high Mg2+medium or by botulinum neurotoxin type-A (BoNT/A) (presynaptic block). Results show thatnanomolar concentrations of gambierol inhibited the fast K+current and prolonged the duration of the presynapticaction 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 postsy-naptic block produced by d-tubocurarine and increased the transient Ca2+signals in response to nerve-stimulation(1–10 Hz) in nerve terminals loaded withfluo-3/AM. The results suggest that gambierol, which on equimolar basis ismore potent than 3,4-diaminopyridine, can have potential application in pathologies in which it is necessary to antagonizepre- or post-synaptic neuromuscular block, or both
Fluorescence-labeled neopeltolide derivatives for subcellular localization imaging
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 reti- culum as well as the mitochondria.
Further Studies on Ni/Zr-mediated One-pot Ketone Synthesis: Use of a Mixture of NiI- and NiII-catalysts Greatly Improves the Molar Ratio of Coupling Partners
Atsushi Umehara and Yoshito Kishi
Chem. Lett. 2019, 48, 947–950
Selected as Editor's Choice A new Ni/Zr-mediated one-pot ketone synthesis is developed, with use of a mixture of (Me)
3tpy·Ni
II- and py-(Me)imid·Ni
IICl
2-catalysts. The Ni
I-catalyst selectively activates iodides, whereas the Ni
II-catalyst activates thio-pyridine esters. An adjustment of a relative loading of the two catalysts allows to tune the relative rate of the two activations and trap a short-lived radical intermediate(s) efficiently. Thus, the new method makes one-pot ketone synthesis highly effective even with a 1:1 mixture of the coupling partners. The synthetic value of the new method is demonstrated with the C-C bond formation at the final stage of a convergent halichondrin-synthesis.
Studies toward the Total Synthesis of Caribbean Ciguatoxin C‐CTX-1: Synthesis of the LMN-Ring Fragment through Reductive Olefin Cross-Coupling
Makoto Sasaki, Kotaro Iwasaki, and Keisuke Arai
Org. Lett. 2018, 20, 7163−7166
Synthesis of the LMN-ring fragment of Car- ibbean ciguatoxin C-CTX-1, the principal causative toxin for ciguatera fish poisoning around the Caribbean Sea areas, is described. The key feature of the synthesis is the stereoselective introduction of an angular methyl group on the sterically encumbered seven-membered M-ring by the application of a hydrogen atom transfer-based reductive olefin coupling.
Total Synthesis of (−)‐Enigmazole A
Keisuke Sakurai, Makoto Sasaki, and Haruhiko Fuwa
Angew. Chem. Int. Ed. 2018, 57, 5143 –5146
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 d-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 a,b- unsaturated ketone.
Total Synthesis of Polycavernosides A and B, Two Lethal Toxins from Red Alga
Kotaro Iwasaki, Satori Sasaki, Yusuke Kasai, Yuki Kawashima, Shohei Sasaki, Takanori Ito, Mari Yotsu-Yamashita, and Makoto Sasaki
J. Org. Chem. 2017, 82, 13204−13219
Polycavernosides A and B are glycosidic macrolide natural products isolated as the toxins causing fatal human poisoning by the edible red alga
Gracilaria edulis (
Polycavernosa tsudai). Total synthesis of polycavernosides A and B has been achieved via a convergent approach. The synthesis of the macrolactone core structure is highlighted by the catalytic asymmetric syntheses of the two key fragments using hetero-Diels–Alder reaction and Kiyooka aldol reaction as the key steps, their union through Suzuki–Miyaura coupling, and Keck macrolactonization. Finally, glycosylation with the
l-fucosyl-
d-xylose unit and construction of the polyene side chain through Stille coupling completed the total synthesis of polycavernosides A and B.
Tetracyclic Truncated Analogue of the Marine Toxin Gambierol Modifies NMDA, Tau, and Amyloid β Expression in Mice Brains: Implications in AD Pathology
Eva Alonso, Andreś C. Vieira, Ineś Rodriguez, Rebeca Alvariño, Sandra Gegunde, Haruhiko Fuwa, Yuto Suga, Makoto Sasaki, Amparo Alfonso, José Manuel Cifuentes, and Luis M. Botana
ACS Chem. Neurosci. 2017, 8, 1358−1367
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 β
1–42 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-methyl-
d-aspartate (NMDA) receptor. The combined effect of this compound on amyloid β
1–42 and tau phosphorylation represents a multitarget therapeutic approach for AD which might be more effective for this multifactorial and complex neurodegenerative disease than the current treatments.
