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Papers by Chihiro Tsukano

Research paper thumbnail of Optimization of the Linker Length in the Dimer Model of E22P-Aβ40 Tethered at Position 38

ACS Chemical Neuroscience

Research paper thumbnail of AI and computational chemistry-accelerated development of an alotaketal analogue with conventional PKC selectivity

Chemical Communications

We have designed and synthesized a new PKC ligand with a novel skeleton based on alotaketals thro... more We have designed and synthesized a new PKC ligand with a novel skeleton based on alotaketals through in silico screening, docking analysis, and molecular dynamics simulation. The new ligand has a higher affinity for PKCα-C1A than for PKCδ-C1B.

Research paper thumbnail of Synthetic Studies of Benzohopanes Based on Pd(0)-Catalyzed Benzylic C(sp3)-H Functionalization

Symposium on the Chemistry of Natural Products, Symposium papers, 2016

Research paper thumbnail of (-)-Aurantioclavineの不斉全合成とcommunesin類の全合成研究

Symposium on the Chemistry of Natural Products, Symposium papers, 2015

Research paper thumbnail of CCDC 1544731: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Research paper thumbnail of Development of a novel PKC ligand using machine learning model: synthesis and PKC surrogate binding of the simplified analogues of alotaketals

We have designed and synthesized a new PKC ligand with a novel skeleton based on alotaketals thro... more We have designed and synthesized a new PKC ligand with a novel skeleton based on alotaketals through in silico screening, docking analysis, and molecular dynamics simulation. We found that the new ligand has a higher affinity for PKCα-C1A than for PKCδ-C1B. This compound is expected to serve as the basis for developing PKC ligands with isozyme selectivity.

Research paper thumbnail of Total Synthesis of Lyconesidine B: Approach to a Three-Dimensional Tetracyclic Skeleton of Amine-Type Fawcettimine Core and Studies of Asymmetric Synthesis

Bulletin of the Chemical Society of Japan

Lyconesidine B, isolated from Lycopodium chinense, is characterized by an oxygenated amine core a... more Lyconesidine B, isolated from Lycopodium chinense, is characterized by an oxygenated amine core and a trans-fused CD ring with a hydroxymethyl group on the axial position. Because the oxidation level of C13 of this alkaloid is different from other fawcettimine-type alkaloids, we investigated a suitable strategy for its synthesis. As a result, we established a synthetic route to the CD ring decahydroquinoline via cyclopropanation followed by ring-opening and reduction, and the AB ring tetracyclic core by ene-yne metathesis. In the ene-yne metathesis, the use of a quaternary ammonium salt solved the issues of the conformation of the substrate as well as the deactivation of the catalyst. The first total synthesis was achieved by stereoselective derivatization of the tetracyclic skeleton. In addition, we investigated the asymmetric cyclopropanation, which introduces an initial chiral center and was found to be effective for a Ru catalyst with vinyloxazoline-type ligands.

Research paper thumbnail of Control of 6-Exo and 7-Endo Cyclizations of Alkynylamides using Platinum and Bismuth Catalysts

Chemistry - An Asian Journal, 2011

ABSTRACT In the presence of Bi(O-Tf)3 alkynylamides of type (I) are found to undergo 6-exo cycliz... more ABSTRACT In the presence of Bi(O-Tf)3 alkynylamides of type (I) are found to undergo 6-exo cyclization to afford piperazinones like (II).

Research paper thumbnail of Platinum catalyzed 7-endo cyclization of internal alkynyl amides and its application to synthesis of the caprazamycin core

Organic & Biomolecular Chemistry, 2012

The scope and limitations of the platinum catalyzed 7-endo cyclization of internal alkynyl amides... more The scope and limitations of the platinum catalyzed 7-endo cyclization of internal alkynyl amides were investigated. Substitution of the alkyne with an aryl group gave better results, presumably because it stabilized the transition state. Applying the reaction to a secondary amide, the caprazamycin core was successfully synthesized from commercially available material in eight steps.

Research paper thumbnail of Total Synthesis of Lyconesidine B, a Lycopodium Alkaloid with an Oxygenated, Amine-Type Fawcettimine Core

Organic Letters

This report describes the total synthesis of the complex, oxygenated tetracyclic alkaloid, lycone... more This report describes the total synthesis of the complex, oxygenated tetracyclic alkaloid, lyconesidine B. The key synthetic challenge involves diastereoselective generation of a decahydroquinoline ring with a quaternary carbon at the angular position via domino cyclopropanation, ring-opening, and reduction. Another crucial step is the domino ene-yne metathesis involving a quaternary ammonium ion, leading to the construction of a decahydroazaazulen framework.

Research paper thumbnail of Total Synthesis of Avenaol, non-Canonical Strigolactone

Journal of Synthetic Organic Chemistry, Japan

Research paper thumbnail of Ellagic acid, extracted from Sanguisorba officinalis , induces G1 arrest by modulating PTEN activity in B16F10 melanoma cells

Genes to Cells

In Chinese medicine, herbal medicine is commonly used to treat individuals suffering from many ty... more In Chinese medicine, herbal medicine is commonly used to treat individuals suffering from many types of diseases. We thus expected that some herbal medicines would contain promising compounds for cancer chemotherapy. Indeed, we found that Sanguisorba officinalis extracts strongly inhibit the growth of B16F10 melanoma cells, and we identified ellagic acid (EA) as the responsible ingredient. B16F10 cells treated with EA exhibited strong G1 arrest accompanied by accumulation of p53, followed by inactivation of AKT. Addition of a PTEN inhibitor, but not a p53 inhibitor, abrogated the EA‐induced AKT inactivation and G1 arrest. The PTEN inhibitor also diminished EA‐induced p53 accumulation. Furthermore, EA apparently increased the protein phosphatase activity of PTEN, as demonstrated by the reduced phosphorylation level of FAK, a protein substrate of PTEN. Furthermore, an in vitro PTEN phosphatase assay on PIP3 showed the direct modulation of PTEN activity by EA. These results suggest that EA functions as an allosteric modulator of PTEN, enhancing its protein phosphatase activity while inhibiting its lipid phosphatase activity. It is notable that a combination of EA and cisplatin, a widely used chemotherapy agent, dramatically enhanced cell death in B16F10 cells, suggesting a promising strategy in chemotherapy.

Research paper thumbnail of Synthetic Studies towards Communesins: Diastereoselective Oxidative Rearrangement of Aurantioclavine Derivatives

European Journal of Organic Chemistry, 2015

Communesins are a heptacyclic class of indole alkaloids bearing two aminal moieties and two conti... more Communesins are a heptacyclic class of indole alkaloids bearing two aminal moieties and two contiguous quaternary carbon centers. We have investigated the construction of the pentacyclic skeleton of communesins via the oxidative rearrangement of aurantioclavine derivatives, because aurantioclavine is believed to be a biosynthetic intermediate of the polycyclic communesin alkaloids. The C7 quaternary carbon center was constructed in a stereoselective manner, while the installation of the C11 stereocenter required an epimerization process. The isolation of 2ethoxyindolenine prior to the reduction of the nitro group and cyclization was found to be critical to the success of this strategy.

Research paper thumbnail of Dearomatization Reactions of Electron-Deficient Aromatic Rings

Asymmetric Dearomatization Reactions, 2016

Research paper thumbnail of Construction of the ACDE Ring System of Calyciphylline A-type Alkaloids via Intramolecular Diels–Alder Reaction of a Tetrasubstituted Olefin

Synlett

A concise synthesis of the ACDE tetracyclic ring system of calyciphylline A-type alkaloids was in... more A concise synthesis of the ACDE tetracyclic ring system of calyciphylline A-type alkaloids was investigated. The intramolecular Diels–Alder reaction of a tetrasubstituted olefin with furan enabled the construction of the ACD ring system bearing two contiguous quaternary carbons in one step, and subsequent intramolecular [3+2] cycloaddition successfully gave the E ring.

Research paper thumbnail of Frontispiz: Asymmetric Total Synthesis of Shagenes A and B

Research paper thumbnail of Frontispiece: Asymmetric Total Synthesis of Shagenes A and B

Angewandte Chemie International Edition

Research paper thumbnail of Synthesis of Alkyl Bridged‐Tris‐α‐Amino Acids as C 3 ‐Symmetric and Linear Linkers

European Journal of Organic Chemistry

Research paper thumbnail of Asymmetric Total Synthesis of Shagenes A and B

Angewandte Chemie International Edition

We report the first total synthesis of shagenes A and B, which are tricyclic terpenoids containin... more We report the first total synthesis of shagenes A and B, which are tricyclic terpenoids containing a cis -substituted cyclopropane, via ring-closing metathesis of an enamide and Ir-catalyzed double-bond isomerization of an alkylidenecyclopropane. Chemo- and diastereoselectivity in the distorted cis -substituted structures were controlled by the alkylidenecyclopropane reactivity and using the ketone functionality as a remote directing group for the Ir catalyst, respectively. The total synthesis suggested the absolute configuration of shagenes.

Research paper thumbnail of Enantioselective Acetalization by Dynamic Kinetic Resolution for the Synthesis of γ‐Alkoxybutenolides by Thiourea/Quaternary Ammonium Salt Catalysts: Application to Strigolactones

Angewandte Chemie International Edition

Although acetalization is a fundamental transformation in organic synthesis, intermolecular asymm... more Although acetalization is a fundamental transformation in organic synthesis, intermolecular asymmetric acetalization remains an unsolved problem. In this study, a thiourea-ammonium hybrid catalyst was revealed to promote the O-alkylation of enols with a racemic γ-chlorobutenolide via dynamic kinetic resolution to give chiral acetals with good enantioselectivity. The catalyst simultaneously activates both the nucleophile and electrophile in a multifunctional manner. This method was applied to the asymmetric synthesis of several strigolactones. DFT calculations suggest that hydrogen bonding interaction between the chlorine of γ-chlorobutenolide and the Ts amide hydrogen of the catalyst, as well as other types of noncovalent catalyst-substrate interactions are crucial for achieving high stereoselectivity.

Research paper thumbnail of Optimization of the Linker Length in the Dimer Model of E22P-Aβ40 Tethered at Position 38

ACS Chemical Neuroscience

Research paper thumbnail of AI and computational chemistry-accelerated development of an alotaketal analogue with conventional PKC selectivity

Chemical Communications

We have designed and synthesized a new PKC ligand with a novel skeleton based on alotaketals thro... more We have designed and synthesized a new PKC ligand with a novel skeleton based on alotaketals through in silico screening, docking analysis, and molecular dynamics simulation. The new ligand has a higher affinity for PKCα-C1A than for PKCδ-C1B.

Research paper thumbnail of Synthetic Studies of Benzohopanes Based on Pd(0)-Catalyzed Benzylic C(sp3)-H Functionalization

Symposium on the Chemistry of Natural Products, Symposium papers, 2016

Research paper thumbnail of (-)-Aurantioclavineの不斉全合成とcommunesin類の全合成研究

Symposium on the Chemistry of Natural Products, Symposium papers, 2015

Research paper thumbnail of CCDC 1544731: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Research paper thumbnail of Development of a novel PKC ligand using machine learning model: synthesis and PKC surrogate binding of the simplified analogues of alotaketals

We have designed and synthesized a new PKC ligand with a novel skeleton based on alotaketals thro... more We have designed and synthesized a new PKC ligand with a novel skeleton based on alotaketals through in silico screening, docking analysis, and molecular dynamics simulation. We found that the new ligand has a higher affinity for PKCα-C1A than for PKCδ-C1B. This compound is expected to serve as the basis for developing PKC ligands with isozyme selectivity.

Research paper thumbnail of Total Synthesis of Lyconesidine B: Approach to a Three-Dimensional Tetracyclic Skeleton of Amine-Type Fawcettimine Core and Studies of Asymmetric Synthesis

Bulletin of the Chemical Society of Japan

Lyconesidine B, isolated from Lycopodium chinense, is characterized by an oxygenated amine core a... more Lyconesidine B, isolated from Lycopodium chinense, is characterized by an oxygenated amine core and a trans-fused CD ring with a hydroxymethyl group on the axial position. Because the oxidation level of C13 of this alkaloid is different from other fawcettimine-type alkaloids, we investigated a suitable strategy for its synthesis. As a result, we established a synthetic route to the CD ring decahydroquinoline via cyclopropanation followed by ring-opening and reduction, and the AB ring tetracyclic core by ene-yne metathesis. In the ene-yne metathesis, the use of a quaternary ammonium salt solved the issues of the conformation of the substrate as well as the deactivation of the catalyst. The first total synthesis was achieved by stereoselective derivatization of the tetracyclic skeleton. In addition, we investigated the asymmetric cyclopropanation, which introduces an initial chiral center and was found to be effective for a Ru catalyst with vinyloxazoline-type ligands.

Research paper thumbnail of Control of 6-Exo and 7-Endo Cyclizations of Alkynylamides using Platinum and Bismuth Catalysts

Chemistry - An Asian Journal, 2011

ABSTRACT In the presence of Bi(O-Tf)3 alkynylamides of type (I) are found to undergo 6-exo cycliz... more ABSTRACT In the presence of Bi(O-Tf)3 alkynylamides of type (I) are found to undergo 6-exo cyclization to afford piperazinones like (II).

Research paper thumbnail of Platinum catalyzed 7-endo cyclization of internal alkynyl amides and its application to synthesis of the caprazamycin core

Organic & Biomolecular Chemistry, 2012

The scope and limitations of the platinum catalyzed 7-endo cyclization of internal alkynyl amides... more The scope and limitations of the platinum catalyzed 7-endo cyclization of internal alkynyl amides were investigated. Substitution of the alkyne with an aryl group gave better results, presumably because it stabilized the transition state. Applying the reaction to a secondary amide, the caprazamycin core was successfully synthesized from commercially available material in eight steps.

Research paper thumbnail of Total Synthesis of Lyconesidine B, a Lycopodium Alkaloid with an Oxygenated, Amine-Type Fawcettimine Core

Organic Letters

This report describes the total synthesis of the complex, oxygenated tetracyclic alkaloid, lycone... more This report describes the total synthesis of the complex, oxygenated tetracyclic alkaloid, lyconesidine B. The key synthetic challenge involves diastereoselective generation of a decahydroquinoline ring with a quaternary carbon at the angular position via domino cyclopropanation, ring-opening, and reduction. Another crucial step is the domino ene-yne metathesis involving a quaternary ammonium ion, leading to the construction of a decahydroazaazulen framework.

Research paper thumbnail of Total Synthesis of Avenaol, non-Canonical Strigolactone

Journal of Synthetic Organic Chemistry, Japan

Research paper thumbnail of Ellagic acid, extracted from Sanguisorba officinalis , induces G1 arrest by modulating PTEN activity in B16F10 melanoma cells

Genes to Cells

In Chinese medicine, herbal medicine is commonly used to treat individuals suffering from many ty... more In Chinese medicine, herbal medicine is commonly used to treat individuals suffering from many types of diseases. We thus expected that some herbal medicines would contain promising compounds for cancer chemotherapy. Indeed, we found that Sanguisorba officinalis extracts strongly inhibit the growth of B16F10 melanoma cells, and we identified ellagic acid (EA) as the responsible ingredient. B16F10 cells treated with EA exhibited strong G1 arrest accompanied by accumulation of p53, followed by inactivation of AKT. Addition of a PTEN inhibitor, but not a p53 inhibitor, abrogated the EA‐induced AKT inactivation and G1 arrest. The PTEN inhibitor also diminished EA‐induced p53 accumulation. Furthermore, EA apparently increased the protein phosphatase activity of PTEN, as demonstrated by the reduced phosphorylation level of FAK, a protein substrate of PTEN. Furthermore, an in vitro PTEN phosphatase assay on PIP3 showed the direct modulation of PTEN activity by EA. These results suggest that EA functions as an allosteric modulator of PTEN, enhancing its protein phosphatase activity while inhibiting its lipid phosphatase activity. It is notable that a combination of EA and cisplatin, a widely used chemotherapy agent, dramatically enhanced cell death in B16F10 cells, suggesting a promising strategy in chemotherapy.

Research paper thumbnail of Synthetic Studies towards Communesins: Diastereoselective Oxidative Rearrangement of Aurantioclavine Derivatives

European Journal of Organic Chemistry, 2015

Communesins are a heptacyclic class of indole alkaloids bearing two aminal moieties and two conti... more Communesins are a heptacyclic class of indole alkaloids bearing two aminal moieties and two contiguous quaternary carbon centers. We have investigated the construction of the pentacyclic skeleton of communesins via the oxidative rearrangement of aurantioclavine derivatives, because aurantioclavine is believed to be a biosynthetic intermediate of the polycyclic communesin alkaloids. The C7 quaternary carbon center was constructed in a stereoselective manner, while the installation of the C11 stereocenter required an epimerization process. The isolation of 2ethoxyindolenine prior to the reduction of the nitro group and cyclization was found to be critical to the success of this strategy.

Research paper thumbnail of Dearomatization Reactions of Electron-Deficient Aromatic Rings

Asymmetric Dearomatization Reactions, 2016

Research paper thumbnail of Construction of the ACDE Ring System of Calyciphylline A-type Alkaloids via Intramolecular Diels–Alder Reaction of a Tetrasubstituted Olefin

Synlett

A concise synthesis of the ACDE tetracyclic ring system of calyciphylline A-type alkaloids was in... more A concise synthesis of the ACDE tetracyclic ring system of calyciphylline A-type alkaloids was investigated. The intramolecular Diels–Alder reaction of a tetrasubstituted olefin with furan enabled the construction of the ACD ring system bearing two contiguous quaternary carbons in one step, and subsequent intramolecular [3+2] cycloaddition successfully gave the E ring.

Research paper thumbnail of Frontispiz: Asymmetric Total Synthesis of Shagenes A and B

Research paper thumbnail of Frontispiece: Asymmetric Total Synthesis of Shagenes A and B

Angewandte Chemie International Edition

Research paper thumbnail of Synthesis of Alkyl Bridged‐Tris‐α‐Amino Acids as C 3 ‐Symmetric and Linear Linkers

European Journal of Organic Chemistry

Research paper thumbnail of Asymmetric Total Synthesis of Shagenes A and B

Angewandte Chemie International Edition

We report the first total synthesis of shagenes A and B, which are tricyclic terpenoids containin... more We report the first total synthesis of shagenes A and B, which are tricyclic terpenoids containing a cis -substituted cyclopropane, via ring-closing metathesis of an enamide and Ir-catalyzed double-bond isomerization of an alkylidenecyclopropane. Chemo- and diastereoselectivity in the distorted cis -substituted structures were controlled by the alkylidenecyclopropane reactivity and using the ketone functionality as a remote directing group for the Ir catalyst, respectively. The total synthesis suggested the absolute configuration of shagenes.

Research paper thumbnail of Enantioselective Acetalization by Dynamic Kinetic Resolution for the Synthesis of γ‐Alkoxybutenolides by Thiourea/Quaternary Ammonium Salt Catalysts: Application to Strigolactones

Angewandte Chemie International Edition

Although acetalization is a fundamental transformation in organic synthesis, intermolecular asymm... more Although acetalization is a fundamental transformation in organic synthesis, intermolecular asymmetric acetalization remains an unsolved problem. In this study, a thiourea-ammonium hybrid catalyst was revealed to promote the O-alkylation of enols with a racemic γ-chlorobutenolide via dynamic kinetic resolution to give chiral acetals with good enantioselectivity. The catalyst simultaneously activates both the nucleophile and electrophile in a multifunctional manner. This method was applied to the asymmetric synthesis of several strigolactones. DFT calculations suggest that hydrogen bonding interaction between the chlorine of γ-chlorobutenolide and the Ts amide hydrogen of the catalyst, as well as other types of noncovalent catalyst-substrate interactions are crucial for achieving high stereoselectivity.