Publishing type：Research paper (scientific journal)   Publisher：Georg Thieme Verlag KG  

<title>Abstract</title>
C
1-Symmetric chiral ammonium salt catalysts induced a kinetic resolution of racemic α-nitrolactones through an asymmetric ester–amide exchange reaction. The corresponding amides were obtained with high enantioselectivities and high S (= k
fast/k
slow) values. This reaction system is a useful approach for obtaining carbocyclic quaternary α-nitroamides as chiral building blocks.

DOI： 10.1055/s-0040-1707303

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Publishing type：Research paper (scientific journal)   Publisher：Georg Thieme Verlag KG  

<title>Abstract</title>An enantioselective Diels–Alder reaction of 3-nitrocoumarins has been developed. A tryptophan-derived C
1-symmetric organoammonium thiourea catalyst promoted the reaction of 3-nitrocoumarins with Danishefsky’s diene to give the corresponding adducts with good enantioselectivity (up to 94% ee). One of the resulting adducts was converted into a chiral carbocyclic quaternary β-amino alcohol.

DOI： 10.1055/s-0040-1707302

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Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

To achieve both structural changes and rapid synthesis of the tetracyclic scaffold relevant to artemisinins, we explored two kinds of de novo synthetic approaches that generate both skeletally diversified tetracyclic peroxides and 6-aza-artemisinins. The anti-malarial activities of the tetracyclic peroxides with distinct skeletal arrays, however, were moderate and far inferior to artemisinins. Given the privileged scaffold of artemisinins, we next envisioned element implantation at the C6 position with a nitrogen without the trimmings of substituents and functional groups. This molecular design allowed the deep-seated structural modification of the hitherto unexplored cyclohexane moiety (C-ring) while keeping the three-dimensional structure of artemisinins. Notably, this approach induced dramatic changes of retrosynthetic transforms that allow an expeditious catalytic asymmetric synthesis with generation of substitutional variations at three sites (N6, C9, and C3) of the 6-aza-artemisinins. These de novo synthetic approaches led to the lead discovery with substantial intensification of the in vivo activities, which undermine the prevailing notion that the C-ring of artemisinins appears to be merely a structural unit but to be a functional area as the anti-malarial pharmacophore. Furthermore, we unexpectedly found that racemic 6-aza-artemisinin (33) exerted exceedingly potent in vivo efficacies superior to the chiral one and the first-line drug, artesunate.

DOI： 10.1021/acs.joc.0c01017

PubMed

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Royal Society of Chemistry (RSC)  

<p>A procedure converting tribromocyclopropane to densely functionalized β-selenocyclopropylboronic ester using the 1,2-metallate rearrangement of a boron ate-complex has been developed.</p>

DOI： 10.1039/d0cc07134j

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Language：English   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：GEORG THIEME VERLAG KG  

Organoammonium salts of dipeptide-derived chiral tri-amines or diamines with TfOH catalyzed the enantioselective 1,3-dipolar cycloaddition reactions of alpha-acyloxyacroleins with nitrones to give the corresponding adducts in good yields (up to 96%) and with high diastereo- and enantioselectivities (up to 89% ee). Although alpha-(p-methoxybenzoyloxy)acrolein is rather unstable under the reaction conditions, alpha-(3-pyrroline-1-carbonyloxy)acrolein is stable enough to be smoothly converted into the corresponding adducts with the aid of the chiral organoammonium salt catalysts.

DOI： 10.1055/s-0039-1690133

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Thioureas bearing electron-deficient aryl groups show high catalytic activity in the biomimetic bromocyclization of geranyl derivatives. The reaction of geranyl derivatives with N-bromosuccinimide (NBS) proceeds rapidly in CH2Cl2 to give the corresponding bromocyclization products in high yields as a ca. 1:1 mixture of endo- and exo-isomers. The reactivity of geranyl derivatives highly depends on the terminal substituent: electron-donating substituents increase the reactivity, while electron-withdrawing substituents decrease the reactivity.

DOI： 10.1021/acs.orglett.9b00352

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Language：English   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Densely functionalized tetrahydropyridines were stereoselectively synthesized from 1,6-dihydropyridines. Exploiting a carbonyl group installed at the C3 position of the 1,6-dihydropyridine system, we devised a strategy for cyanomethylation at C2/C6 and subsequent divergent installation of an allyl group at C3/C5 in a highly regio- and stereo-controlled manner. This versatile protocol for programmable functionalization of the 1,6-dihydropyridine system allows the divergent and streamlined synthesis of multiply-substituted tetrahydropyridines as an important class of biologically and medicinally relevant scaffolds. Two of the N-heterocyclic compounds bearing an alkyl nitrile group showed anti-hepatitis C virus (HCV) activity. (C) 2017 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmc.2017.03.011

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

A convergent coupling reaction is described that enables the stereoselective construction of angularly substituted trans-fused decalins from acyclic precursors. The process builds on our alkoxide-directed titanium-mediated alkyne-alkyne coupling and employs a 1,7-enyne coupling partner. Overall, the reaction is thought to proceed through initial formation of a tetrasusbstituted metallacyclopentadiene, stereoselective intramolecular [4+2] cycloaddition, elimination, isomerization, and regio- and stereoselective protonation. Distinct from our early studies directed at the synthesis of trans-fused hydrindanes, the current annulative coupling reveals an important effect of TMSCl in controlling the final protonation-the event that establishes the stereochemistry of the ring fusion.

DOI： 10.1002/anie.201606962

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Language：Japanese  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Investigation of titanium-centered metallacycle-mediated cross-coupling between unsymmetrical internal alkynes has led to the discovery that TMSCl significantly accelerates the C-C bond forming event. We report a collection of results that compare the efficiency of this reaction employing Ti(Oi-Pr)(4)/2n-BuLi in PhMe with and without TMSCl, demonstrating in every case that the presence of TMSCl has a profound impact on efficiency. While relevant in the context of developing this fundamental bond-forming process as an entry to more complex organometallic transformations, these modified reaction conditions allow coupling processes to be run at &gt;10 times the concentrations previously possible [in 2.4 M n-BuLi (hexanes)], without the requirement of additional solvent. Finally, we demonstrate the effectiveness of these modified reaction conditions for the annulative cross-coupling between TMS-alkynes and 1,6-enynes leading to the formation of angularly substituted hydrindanes with, now well appreciated, high levels of regio- and stereoselection. (C) 2016 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2016.07.045

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

LiOOt-Bu is an effective oxidant for converting the penultimate organometallic intermediate generated in a titanium alkoxide-mediated [2+2+2] reaction cascade to an allylic alcohol. Oxidation of the presumed allylic titanium species is highly regioselective, providing direct access to substituted hydrindanes containing a primary allylic alcohol. In addition to demonstrating the feasibility of this oxidation process, we document the ability to convert the primary allylic alcohol products to angularly substituted cis-fused hydrindanes. (C) 2015 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2015.01.029

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Bridged bicyclic metallacyclopentenes generated from the [4 + 2] cycloaddition of metallacyclopentadienes with alkenes have been proposed as reactive intermediates in the course of [2 + 2 + 2] annulation reactions. Recently a collection of alkoxide-directed Ti-mediated [2 + 2 + 2] annulation reactions have been discovered for the synthesis of densely functionalized hydrindanes, where the bridged bicyclic metallacyclopentenes from intramolecular [4 + 2] were treated as fleeting intermediates en route to cyclohexadiene products formed by formal cheletropic extrusion of Ti(Oi-Pr)(2). In studies aimed at understanding the course of these organometallic cascade reactions it was later discovered that these bridged bicyclic intermediates can be trapped by various elimination processes. Here, we have realized metallacycle-mediated annulation reactions for the assembly of angularly substituted decalins-structural motifs that are ubiquitous in natural products and molecules of pharmaceutical relevance. In addition to defining the basic annulation reaction we have discovered a surprising stability associated with the complex organometallic intermediates generated in the course of this coupling process and document here the ability to control the fate of such species. Ligand-induced cheletropic extrusion of the titanium center delivers cyclohexadiene-containing products, while several distinct protonation events have been identified to realize polycyclic products that contain three new stereocenters (one of which is the angular quaternary center that is a hallmark of alkoxide-directed titanium-mediated [2 + 2 + 2] annulation reactions). Examples of this metallacycle-mediated annulation reaction are provided to demonstrate that a range of stereodefined fused bicyclo[4.4.0]decanes are accessible, including those that contain aromatic and aliphatic substituents, and an empirical model is presented to accompany the observations made.

DOI： 10.1021/jacs.5b02107

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROYAL SOC CHEMISTRY  

Copper-catalyzed 6-endo cyclization of N-propargylic beta-enaminocarbonyls was developed for the synthesis of oxidation-labile 1,6-dihydropyridines. This synthetic method allows flexible and regio-defined assembly of various substituents at the N1, C2, C3, C4, and C6 positions of 1,6-dihydropyridines under mild conditions.

DOI： 10.1039/c5ob00356c

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Angularly substituted trans-fused hydroindanes are now accessible by the direct and convergent union of trimethylsilyl (TMS)-alkynes with 4-hydroxy-1,6-enynes by a process that forges three C C bonds, one C H bond, and two new stereocenters. The annulation is proposed to proceed by initial formation of a Ti-alkyne complex (with a TMS-alkyne) followed by regioselective alkcodde-directed coupling with the enyne, stereoselective intramolecular cycloaddition, elimination of phenoxide, 1,3-metallotropic shift, and stereoselective protonation of the penultimate allylic organometallic intermediate. Several examples are given to demonstrate the compatibility of this reaction with substrates bearing aromatic and aliphatic substituents, and an empirical model is presented to accompany the stereochemical observations.

DOI： 10.1021/ja504374j

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

To access architecturally complex natural products, chemists usually devise a customized synthetic strategy for constructing a single target skeleton. In contrast, biosynthetic assembly lines often employ divergent intramolecular cyclizations of a polyunsaturated common intermediate to produce diverse arrays of scaffolds. With the aim of integrating such biogenetic strategies, we show the development of an artificial divergent assembly line generating unprecedented numbers of scaffold variations of terpenoid indole alkaloids. This approach not only allows practical access to multipotent intermediates, but also enables systematic diversification of skeletal, stereochemical and functional group properties without structural simplification of naturally occurring alkaloids. Three distinct modes of [412] cyclizations and two types of redox-mediated annulations provided divergent access to five skeletally distinct scaffolds involving iboga-, aspidosperma-, andranginine- and ngouniensine-type skeletons and a non-natural variant within six to nine steps from tryptamine. The efficiency of our approach was demonstrated by successful total syntheses of (+/-)-vincadifformine, (+/-)-andranginine and (2)-catharanthine.

DOI： 10.1038/NCHEM.1798

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BEILSTEIN-INSTITUT  

By emulating the universal biosynthetic strategy, which employs modular assembly and divergent cyclizations, we have developed a four-step synthetic process to yield a collection of natural-product-inspired scaffolds. Modular assembly of building blocks onto a piperidine-based manifold 6, having a carboxylic acid group, was achieved through Ugi condensation, N-acetoacetylation and diazotransfer, leading to cyclization precursors. The rhodium-catalyzed tandem cyclization and divergent cycloaddition gave rise to tetracyclic and hexacyclic scaffolds by the appropriate choice of dipolarophiles installed at modules 3 and 4. A different piperidine-based manifold 15 bearing an amino group was successfully applied to demonstrate the flexibility and scope of the unified four-step process for the generation of structural diversity in the fused scaffolds. Evaluation of in vitro antitrypanosomal activities of the collections and preliminary structure-activity relationship (SAR) studies were also undertaken.

DOI： 10.3762/bjoc.8.105

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROYAL SOC CHEMISTRY  

We have developed a unique catalytic protocol for direct gem-vinylation of tryptamine derivatives employing Hg(OTf)(2) as the optimum catalyst. The intermolecular vinylations with a series of aromatic acetylenes proceeded under ambient temperature at the C2 positions of indoles with high functional group tolerance. Based on the mechanistic insights, we further developed the tandem reactions successfully constructing a quaternary center.

DOI： 10.1039/c2ob25236h

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Language：Japanese   Publisher：Symposium on the chemistry of natural products  

Indole alkaloids composed of elaborated cyclic arrays have been one of the most valuable resources for discovering biologically active substances. To gain concise and flexible access to alkaloid analogs possessing natural and unexploited skeletons, we are developing a synthetic process based on divergent cyclizations inspired by the biogenic strategy generating structural diversity of natural products. With intentions to emulate the biosynthetic proposal of iboga and aspidosperma alkaloids, we designed a common dihydropyridine precursor 3 for divergent Diels-Alder reactions in either of two ways: (1) the dihydropyridine reacts as a diene leading to the iboga-type skeleton; (2) the dihydropyridine serves as a dienophile to form the aspidosperma-type skeleton. First of all, we developed an original protocol for constructing sensitive 1,6-dihydropyridine (DHP) rings employing a cationic Cu(I) catalyst. Next, the key precursor 21 for the Cu(I)-catalyzed DHP synthesis was successfully prepared through conjugate addition of the common intermediate 25 with methyl propiolate 20 and concomitant Hofmann elimination. The Cu(I)-catalyzed 1,6-DHP cyclization and subsequent Diels-Alder cycloaddition under mild conditions (45℃) allowed a cascade synthesis of iboga-type skeleton 28. Meanwhile, divergent cyclization proceeded to furnish ngouniensine-type skeleton 29 by the simple modification of reaction temperature (100℃). Furthermore, the reaction site of 25 with 20 was altered depending on the solvents to produce a distinct precursor for the Cu(I)-catalyzed cyclization, which allowed successful construction of a novel tetracyclic skeleton 31. We also achieved total synthesis of (±)-catharanthine 34 through protecting group-free 9-step sequence in order to demonstrate applicability and potential of the currently developed synthetic process efficiently generating complexity and diversity of natural product relevant scaffolds in a programmable fashion.

DOI： 10.24496/tennenyuki.53.0_193

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

We report the development of a divergent synthetic process entailing four-step access to the elaborate fused skeletons reminiscent of aspidophytines and transtaganolides. A variety of branched precursors were synthesized on the basis of Ugl condensations and installation of diazoimide and subjected to rhodium-catalyzed tandem reactions. Switching of cyclization modes was demonstrated by the choice of the amine building blocks installed at site C.

DOI： 10.1021/ol901020a

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Language：Japanese   Publishing type：Book review, literature introduction, etc.   Publisher：SOC SYNTHETIC ORGANIC CHEM JPN  

Polyoxygenated steroids cardenolides, typified by ouabagenin, possess a broad spectrum of biological activity such as inotropic activity. Due to their unique structure, including unusual cis-fused A/B- and C/D ring junction, and a number of beta-configured oxygenated functional group, they have been an attractive target in chemical synthesis. In this review, recent developments in the practical synthetic strategies toward these cardenolides are described.

DOI： 10.5059/yukigoseikyokaishi.75.253

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Language：Japanese   Publishing type：Book review, literature introduction, etc.   Publisher：SOC SYNTHETIC ORGANIC CHEM JPN  

With intention to formulate a potentially general synthetic strategy generating a collection of skeletally diverse scaffolds without simplifying a structural feature of natural products, we devised an artificial assembly line of terpenoid indole alkaloids and its variants. Inspired by the key biosynthetic intermediate, dehydrosecodine, responsible for divergent intramolecular cyclizations, a "multipotent intermediate" with improved stability and versatile reactivity was designed to establish a streamlined divergent synthetic process. A newly developed copper-catalyzed cyclization protocol allowed rapid formation of the sensitive dihydropyridine system. By harnessing the versatile reactivity of the multipotent intermediate, three types of bioinspired [4+2] cycloadditions as well as two types of oxidation-triggered cyclizations were successfully implemented to generate five distinct scaffolds involving iboga-, aspidosperma-, andranginine- and ngouniensine-type skeletons and unnatural tetracyclic framework within 6-9 steps from tryptamine. Furthermore, simple manipulations of the [4+2] products allowed total synthesis of (-)-catharanthine, (+/-)-vincadifformine and (+/-)-andranginine, demonstrating a structural relevance of our compound collections to the natural products.

DOI： 10.5059/yukigoseikyokaishi.74.854

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)  

DOI： 10.1271/kagakutoseibutsu.53.345

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (trade magazine, newspaper, online media)   Publisher：化学同人  

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Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン開催  

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Venue：COVID-19のため学会中止，講演予稿集の発行により発表成立  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：COVID-19のため学会中止，講演予稿集の発行により発表成立  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：COVID-19のため学会中止，講演予稿集の発行により発表成立  

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