Papers - Hanaya, Kengo

One-Step Maleimide-Based Dual Functionalization of Protein N-Termini.

Kengo Hanaya, Kazuaki Taguchi, Yuki Wada, Masaki Kawano

Angewandte Chemie International Edition (Wiley)     e202417134 2024.11

Research paper (scientific journal), Joint Work, Lead author, Corresponding author, Accepted,  ISSN  14337851

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Maleimide derivatives are privileged reagents for chemically modifying proteins through the Michael addition reaction with cysteine due to their selectivity, operational simplicity, and commercial availability. However, since accessible free cysteine is rarely found in natural proteins, it is highly desirable to find alternative targets to enable direct bioconjugation of proteins with maleimides. In this study, we have developed an operationally simple and straightforward method for the N-terminal modification of proteins without the need for mutagenesis via a copper(II)-mediated [3+2] cycloaddition reaction with maleimides and 2-pyridinecarboxaldehyde (2-PCA) derivatives under non-denaturing conditions at pH 6 and 37 °C in aqueous media. Our method utilizes commercially available maleimides to attach diverse functionalities to various N-terminal amino acids. We demonstrate the preparation of a ternary protein complex cross-linked at the N-termini and dually modified trastuzumab equipped with monomethyl auristatin E (MMAE), a cytotoxic agent, and a Cy5 fluorophore (MMAE-Cy5-trastuzumab). MMAE-Cy5-trastuzumab retained human epidermal growth factor receptor 2 (HER2) recognition activity and exerted cytotoxicity against HER2-positive cells. Furthermore, MMAE-Cy5-trastuzumab allowed successful visualization of HER2-positive cancer cells in mouse tumors. This straightforward method will expand the accessibility of protein conjugates with well-defined structures in a wide range of research fields.

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Dual delivery of carbon monoxide and doxorubicin using haemoglobin-albumin cluster: proof of concept for well-tolerated cancer therapy

Ito C., Taguchi K., Yamada T., Hanaya K., Enoki Y., Sugai T., Komatsu T., Matsumoto K.

Journal of Materials Chemistry B 12 ( 23 ) 5600 - 5608 2024.05

ISSN  2050750X

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A serious concern of doxorubicin (DOX) therapy is that it causes severe adverse effects, particularly cardiotoxicity. Carbon monoxide (CO) possesses powerful cytoprotective effects against drug-induced organ injury and is expected to ameliorate DOX-induced cardiotoxicity. In this study, a dual carrier of DOX and CO (CO-HemoAct-DOX) was fabricated based on a haemoglobin-albumin cluster (HemoAct), which is a protein cluster with a haemoglobin core structure wrapped by serum albumin. CO-HemoAct-DOX was synthesised by binding CO to a haemoglobin core and covalently conjugating (6-maleimidocaproyl)hydrazone derivative of DOX to an albumin shell. The average DOX/cluster ratio was about 2.6. In the in vitro cytotoxicity assay against cancer cells, the anti-tumour activity of CO-HemoAct-DOX was 10-fold lower than that of DOX in a 2D-cultured model, whereas CO-HemoAct-DOX suppressed the growth of tumour spheroids to the same extent as DOX in the 3D-cultured model. In colon-26 tumour-bearing mice, CO-HemoAct-DOX achieved DOX delivery to the tumour site and alleviated tumour growth more effectively than DOX. Furthermore, CO-HemoAct attenuated DOX-induced cardiomyocyte atrophy in H9c2 cells and elevated the levels of cardiac biomarkers in mice exposed to DOX. These results suggest that the dual delivery of CO and DOX using HemoAct is a promising strategy as an anti-tumour agent to realise well-tolerated cancer therapy with minimal cardiotoxicity.

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Synthesis and property of 2,2-difluoro-1,4-diazaborole

Nakahara M., Wada Y., Kawano M., Hanaya K., Sugai T., Higashibayashi S.

Chemistry Letters 53 ( 5 )  2024.05

ISSN  03667022

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The synthesis of 2,2-difluoro-1,4-diazaboroles was achieved through the condensation of aliphatic acyltrifluoroborates and amino-N-heteroarenes under acidic conditions. Various N-heteroarenes, including pyridine, pyrimidine, pyridazine, thiazole, and isoquinoline, were successfully employed in the reaction. Among the synthesized 2,2-difluoro-1,4-diazaboroles, the one with an isoquinoline structure exhibited the most intense light blue emission.

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Utilization of Lipase-Catalyzed Acetylation and Deacetylation in the Synthesis of a Natural Product with a Hydroquinone Skeleton

Sugai T., Honda K., Hashimoto R., Hanaya K., Higashibayashi S.

Asian Journal of Organic Chemistry 13 ( 12 )  2024

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Elaborated conditions for lipase-catalyzed preferential monoacetylation enabled the large-scale preparation of hydroquinone monoacetate. This product was then applied to the synthesis of tournefolin B, a highly oxygenated prenylated hydroquinone of plant origin (Tournefortia sarmentosa Lam.). During the course of the synthetic transformations, lipase-catalyzed deacetylation under mild conditions was demonstrated.

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Unified short syntheses of oxygenated tricyclic aromatic diterpenes by radical cyclization with a photoredox catalyst

Hashimoto R., Hanaya K., Sugai T., Higashibayashi S.

Communications Chemistry (Communications Chemistry)  6 ( 1 )  2023.12

Research paper (scientific journal), Joint Work, Accepted

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The biomimetic two-phase strategy employing polyene cyclization and subsequent oxidation/substitution is an effective approach for divergent syntheses of [6-6-6]-tricyclic diterpenes. However, this strategy requires lengthy sequences for syntheses of oxygenated tricyclic aromatic abietane/podocarpane diterpenes owing to the many linear oxidation/substitution steps after cyclization. Here, we present a new synthetic route based on a convergent reverse two-phase strategy employing a reverse radical cyclization approach, which enabled the unified short syntheses of four aromatic abietane/podocarpane diterpenes and the divergent short syntheses of other related diterpenes. Oxygenated and substituted precursors for cyclization were convergently prepared through Friedel-Crafts acylation and rhodium-catalyzed site-selective iodination. Radical redox cyclization using an iridium photoredox catalyst involving neophyl rearrangement furnished the thermodynamically favored 6-membered ring preferentially. (±)-5,6-Dehydrosugiol, salvinolone, crossogumerin A, and Δ5-nimbidiol were synthesized in only 8 steps. An oxygenated cyclized intermediate was also useful for divergent derivatization to sugiol, ferruginol, saprorthoquinone, cryptomeriololide, and salvinolone.

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Synthesis and luminescence properties of substituted benzils

Yasui M., Fujihara T., Ohtsu H., Wada Y., Shimada T., Zhu Y., Kawano M., Hanaya K., Sugai T., Higashibayashi S.

Communications Chemistry (Communications Chemistry)  6 ( 1 )  2023.12

Research paper (scientific journal), Accepted

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Photophysical properties of benzil (1,2-diphenylethane-1,2-dione) and its derivatives in the crystal state have recently attracted much attention. However, the study of substituted benzils has mostly been limited to para-substituted derivatives, which did not induce a significant effect on the emission wavelength compared to pristine benzil. The effects of ortho- and meta-substituents on the photophysical properties in the crystal state have not been investigated so far. Our recently developed organocatalytic pinacol coupling of substituted benzaldehydes allowed us to prepare various ortho-, meta-, and para-substituted benzil derivatives and to investigate their luminescence properties. Ortho- and meta-substituents affected the electronic states of benzils in the crystal state, resulting in differences in their luminescence properties. The luminescence wavelength and type, i.e., phosphorescence or fluorescence, were altered by these substituents. Fast self-recovering phosphorescence-to-phosphorescence mechanochromism by the para-CF3 substituent at room temperature was also discovered.

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Selective modification of tryptophan in polypeptides via C-N coupling with azoles using in situ-generated iodine-based oxidants in aqueous media

Watanabe S., Wada Y., Kawano M., Higashibayashi S., Sugai T., Hanaya K.

Chemical Communications (Chemical Communications)  59 ( 87 ) 13026 - 13029 2023.10

Research paper (scientific journal), Last author, Corresponding author, Accepted,  ISSN  13597345

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This study demonstrates the C-N coupling of tryptophan with azoles, promoted by an in situ-generated iodine-based oxidant. The protocol was successfully applied to the selective modification of tryptophan in nonprotected polypeptide bearing oxidatively sensitive residues in acidic aqueous media. The present method allows the attachment of reactive handles to polypeptides and the peptide stapling.

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Inversion of Diaza[5]Helicenes Through an N−N Bond Breaking Pathway

Kobayashi T., Ishiwari F., Fukushima T., Nojima Y., Hasegawa M., Mazaki Y., Hanaya K., Sugai T., Higashibayashi S.

Chemistry - A European Journal (Chemistry - A European Journal)  29 ( 43 )  2023.08

Research paper (scientific journal), Joint Work, Accepted,  ISSN  09476539

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1,1’,10,10’-Biphenothiazine and its S,S,S’,S’-tetroxide are diaza[5]helicenes with N−N linkages. Kinetic experiments on racemization together with DFT calculations revealed that they undergo inversion through the N−N bond breaking pathway rather than the general conformational pathway. In these diaza[5]helicenes with this inversion mechanism, the reduction of electronic repulsion in the N−N bond by modification of S to SO2 at the outer position of the helix led to a significantly higher inversion barrier, 35.3 kcal/mol, compared to [5]helicene. 1,1’,10,10’-Biphenothiazine S,S,S’,S’-tetroxide was highly resistant to acid-mediated N−N bond breaking and racemization under acidic conditions.

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Single-Step N-Terminal Modification of Proteins via a Bio-Inspired Copper(II)-Mediated Aldol Reaction

Hanaya K., Yamoto K., Taguchi K., Matsumoto K., Higashibayashi S., Sugai T.

Chemistry - A European Journal (Chemistry - A European Journal)  28 ( 47 )  2022.08

Research paper (scientific journal), Lead author, Corresponding author, Accepted,  ISSN  09476539

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The chemical modification of proteins is an effective technique for manipulating the properties and functions of proteins, and for creating protein-based materials. The N-terminus is a promising target for single-site modification that provides modified proteins with uniform structures and properties. In this paper, a copper(II)-mediated aldol reaction with 2-pyridinecarboxaldehyde (2-PC) derivatives is proposed as an operationally simple method to selectively modify the N-terminus of peptides and proteins at room temperature and physiological pH. The copper(II) ion activates the N-terminal amino acids by complexation with an imine of the N-terminal amino acid and 2-PCs, realizing the selective formation of the nucleophilic intermediate at the N-terminus. This results in a stable carbon-carbon bond between the 2-PCs and the α-carbon of various N-terminal amino acids. The reaction is applied to four different proteins, including biopharmaceuticals such as filgrastim and trastuzumab. The modified trastuzumab retains the human epidermal growth factor receptor 2 recognition activity.

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One-Step Synthesis of Acylborons from Acyl Chlorides through Copper-Catalyzed Borylation with Polystyrene-Supported PPh<inf>3</inf>Ligand

Nakahara M., Kurahayashi K., Hanaya K., Sugai T., Higashibayashi S.

Organic Letters (Organic Letters)  24 ( 30 ) 5596 - 5601 2022.08

Research paper (scientific journal), Joint Work, Accepted,  ISSN  15237060

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We developed a one-step synthesis of acylborons from both readily available acyl chlorides and bis(pinacolato)diboron through copper(I)-catalyzed borylation. Under the reaction conditions using tBuOLi, polystyrene-supported triphenylphosphine as a copper ligand was found to promote the borylation of acyl chlorides while suppressing alcoholysis. This method enables the facile synthesis of potassium acyltrifluoroborates.

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Synthesis of 1H-2-Benzopyran-5,8-dione Skeleton through a Cascade Reaction between Benzoquinone and β-Ketoester

Nakahara M., Ohtsu H., Kawano M., Hanaya K., Sugai T., Higashibayashi S.

Chemistry Letters (Chemistry Letters)  51 ( 4 ) 356 - 359 2022.04

Research paper (scientific journal), Joint Work, Accepted,  ISSN  03667022

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The 1H-2-benzopyran-5,8-dione structure was synthesized by a cascade reaction through Michael addition, elimination of HBr, and O-alkylation between a dibromobenzoquinone derivative and β-ketoesters under basic conditions. The reaction using potassium carbonate and 18-crown-6 in THF was the best condition, giving 1H-2-benzopyran-5,8-dione derivatives in good yields. The UV-vis absorption spectrum and cyclic voltammogram of the synthesized 1H-2-benzopyran-5,8-dione derivative were measured, clarifying the photophysical and redox properties.

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1,2-Rearrangement from o-Quinols to Multisubstituted Catechols via Retro Diels-Alder Reaction of o-Quinol Dimers

Hashimoto R., Hanaya K., Sugai T., Higashibayashi S.

Bulletin of the Chemical Society of Japan (Bulletin of the Chemical Society of Japan)  95 ( 4 ) 663 - 672 2022

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00092673

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The 1,2-rearrangement of o-quinols has been a long-standing unsolved problem since 1958. Although the rearrangement is expected to be useful for syntheses of catechol derivatives, it is hampered by many competing reactions and has not been developed as a useful methodology. Here, we succeeded in settling this problem by a first systematic thorough investigation, establishing the 1,2-rearrangement as a cascade reaction with a retro Diels-Alder reaction from o-quinol dimers. This is a useful strategy for syntheses of substituted catechols used as synthetic building blocks for bioactive compounds and material molecules. o-Quinol dimers were synthesized by improved oxidative hydroxylation of substituted phenols followed by spontaneous Diels-Alder reaction. The dimers then underwent the retro Diels-Alder reaction to regenerate the o-quinols followed by 1,2-rearrangement under neutral heating conditions at an appropriate temperature depending on the migratory substituent, furnishing substituted catechols in good yields. The competing reactions such as an elimination of a substituent or α-ketol rearrangement were minimized by controlling the reaction temperature.

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Copper-Catalyzed Stereoselective Borylation and Palladium-Catalyzed Stereospecific Cross-Coupling to Give Aryl C-Glycosides

Kurahayashi K., Hanaya K., Sugai T., Hirai G., Higashibayashi S.

Chemistry - A European Journal (Chemistry - A European Journal)  29 ( 6 )  2022

Research paper (scientific journal), Joint Work, Accepted,  ISSN  09476539

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Metabolically stable C-glycosides are an essential family of compounds in bioactive natural products, therapeutic agents, and biological probes. For their application, development of synthetic methods by connecting glycosides and aglycons with strict stereocontrol at the anomeric carbon, as well as with high functional-group compatibility and environmental compatibility is a pivotal issue. Although Suzuki–Miyaura-type C(sp3)−C(sp2) cross-coupling using glycosyl boronates is a potential candidate for the construction of C-glycosides, neither the cross-coupling itself nor the facile synthesis of the coupling precursor, glycosyl boronates, have been achieved to date. Herein, it was succeeded to develop a copper-catalyzed stereoselective one-step borylation of glycosyl bromides to glycosyl boronates and palladium-catalyzed stereospecific cross-coupling of β-glycosyl borates with aryl bromides to give aryl β-C-glycosides, in which the β-configuration of the anomeric carbon of the glycosyl trifluoroborates is stereoretentively transferred to that of the resulting aryl C-glycosides.

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Intramolecular cyclization of m-homoprenylphenols through oxidative nucleophilic aromatic substitution

Deguchi H., Hanaya K., Sugai T., Higashibayashi S.

Chemical Communications (Chemical Communications)  59 ( 6 ) 748 - 751 2022

Research paper (scientific journal), Accepted,  ISSN  13597345

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We developed an intramolecular cyclization of m-homoprenylphenols and related m-prenylphenols to bicyclic skeletons by hypervalent iodine reagents through an oxidative nucleophilic aromatic substitution using the prenyl group as a carbon nucleophile. The reaction was applicable for the syntheses of 5/6-, 6/6-, and 7/6-fused ring systems.

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Chemoselectivity-independent Cu-mediated coupling to construct the hydroquinoline skeleton of symbioimine

Fujita R., Hanaya K., Sugai T., Higashibayashi S.

Scientific Reports (Scientific Reports)  11 ( 1 )  2021.12

Research paper (scientific journal), Accepted

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Construction of the hydroquinoline skeleton of symbioimine by Cu-mediated N-alkenylation or O-alkenylation of an allyl aminoalcohol, in which either chemoselectivity could lead to the target compound, was investigated. O-alkenylation followed by Claisen rearrangement was favored with high selectivity under a ligand-free condition. Subsequent intramolecular condensation furnished the hydroquinoline skeleton of symbioimine.

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Metal-free thermal organocatalytic pinacol coupling of arylaldehydes using an isonicotinate catalyst with bis(pinacolato)diboron

Yasui M., Hanaya K., Sugai T., Higashibayashi S.

RSC Advances (RSC Advances)  11 ( 40 ) 24652 - 24655 2021.07

Research paper (scientific journal), Accepted

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The metal-free thermal organocatalytic pinacol coupling of arylaldehydes has been developed. The intermolecular coupling of arylaldehydes catalyzed byt-butyl isonicotinate with bis(pinacolato)diboron as the co-reducing agent afforded 1,2-diphenylethane-1,2-diols. This reaction was also applicable to the intramolecular coupling of 1,1′-biphenyl-2,2′-dicarbaldehydes to afford 9,10-dihydrophenanthrene-9,10-diols. Various functional groups were tolerated under this coupling condition.

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Chemoenzymatic semisynthesis of caffeic acid β-phenethyl ester, an antioxidative component in propolis, from raw coffee bean extract

Hashimoto R., Iai H., Fujita R., Hanaya K., Higashibayashi S., Inoue H., Sugai T.

Bioscience, biotechnology, and biochemistry (Bioscience, biotechnology, and biochemistry)  85 ( 3 ) 476 - 480 2021.02

Research paper (scientific journal), Accepted,  ISSN  09168451

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Caffeic acid β-phenethyl ester (CAPE), an antioxidative bioactive catechol isolated from propolis, was semisynthesized from chlorogenic acid and related compounds in an extract of raw (unroasted) Robusta coffee (Coffea canephora) beans in 5 steps and a total yield of 31%. Oxidative degradation of the intermediates and target molecule was prevented by alkaline hydrolysis of the chlorogenic acids in the presence of sodium dithionite (Na2S2O4) and deprotection of the catecholic diacetate precursor by Candida antarctica lipase B-mediated transesterification as the final step.

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Selective capture and non-invasive release of cells using a thermoresponsive polymer brush with affinity peptides

Nagase K., Shimura M., Shimane R., Hanaya K., Yamada S., Akimoto A.M., Sugai T., Kanazawa H.

Biomaterials Science (Biomaterials Science)  9 ( 3 ) 663 - 674 2021.02

Research paper (scientific journal), Accepted,  ISSN  20474830

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Tissue engineering and cell transplantation therapy have become promising therapies for intractable diseases. These approaches require cell separation technology without cell modification. Accordingly, in this study, we developed a novel cell separation method using a thermoresponsive block copolymer brush with an affinity peptide. A block copolymer brush with bottom poly(2-hydroxyethyl methacrylate [HEMA]-co-propargyl acrylate) and top poly(N-isopropylacrylamide-co-HEMA) segments was prepared through two steps of atom transfer radical polymerization. Then, cell affinity peptides were conjugated to the bottom segment of the copolymer brush through a click reaction. Using cRGD as a cell-Affinity peptide, enhancement of cell adhesion with rapid adhesion on the copolymer brush was observed at 37 °C, whereas the copolymer brush without cRGD did not exhibit cell adhesion. Temperature-modulated cell adhesion and detachment were performed with a relatively long upper segment because the affinity between peptides and cells was modulated by the swelling and shrinking of the upper thermoresponsive segment. Selective endothelial cell adhesion was performed at 37 °C using GGGREDV as an affinity peptide. Smooth muscle cells and fibroblasts did not adhere to the copolymer brush. Adhered human umbilical vein endothelial cells (HUVECs) were successfully recovered by reducing the temperature to 20 °C. Based on the properties of the copolymer brush, HUVECs could be purified using a mixture of cells simply by changing the temperature. These results demonstrated that the prepared copolymer brush with cell affinity peptides could be a useful cell separation tool because the cells could be separated with specificity and without cell modification using a simple procedure.

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Semisynthesis of prunetin, a bioactive O-methylated isoflavone from naringenin, by the sequential deacetylation of chalcone intermediates and oxidative rearrangement

Sugai T., Hanaya K., Higashibayashi S.

Bioscience, biotechnology, and biochemistry (Bioscience, biotechnology, and biochemistry)  85 ( 1 ) 143 - 147 2021.01

Research paper (scientific journal), Accepted,  ISSN  09168451

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Prunetin (4',5-dihydroxy-7-methoxyisoflavone) was semisynthesized in 8 steps from readily available naringenin in 26% total yield. The key reaction was chemoenzymatic sequential deacetylation to 6'-acetoxy-2',4″-dihydroxy-4'-methoxychalcone, the in situ-formed precursor for thallium(III) nitrate-mediated oxidative rearrangement.

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Theoretical Analysis of the Heterocyclic [4+2] Cycloaddition Between Pyridinium Ion and Enol Ether

Nakahara M., Hanaya K., Sugai T., Higashibayashi S.

ChemistryOpen (ChemistryOpen)  10 ( 6 ) 627 - 629 2021

Research paper (scientific journal), Accepted

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© 2021 The Authors. Published by Wiley-VCH GmbH Dearomative heterocyclic [4+2] cycloaddition between the N-(2,4-dinitrophenyl)pyridinium ion of nicotinamide and an enol ether was analyzed by Density Functional Theory (DFT) calculations. The calculation revealed that the reaction undergoes stepwise bond formation rather than occurring in a concerted manner. The experimental products were found to be both kinetically and thermodynamically favored. The calculated transition states and intermediate suggested that the high diastereoselectivity is derived from the electrostatic interaction between the 2-nitro group of the pyridinium ion and the hydrogen of the enol ether.

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Nickel(II)‐Mediated C‐S Cross‐Coupling Between Thiols and ortho‐Substituted Arylboronic Acid

Kengo Hanaya, Hiroyoshi Ohtsu, Masaki Kawano, Shuhei Higashibayashi, Takeshi Sugai

Asian Journal of Organic Chemistry (Wiley)  10 ( 3 ) 582 - 587 2020.12

Research paper (scientific journal), Joint Work, Accepted,  ISSN  21935807

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© 2020 Wiley-VCH GmbH Herein, we report a C−S cross-coupling reaction between alkyl thiols or aryl thiols and ortho-substituted arylboronic acids that proceeds in the presence of an inexpensive and ligand-free NiCl2 ⋅ 6H2O salt and N-methylmorpholine, a weak base, at 25 °C in air. The presence of coordinating and electron-withdrawing groups at the ortho-position of the arylboronic acids played a crucial role in determining the efficiency of the reaction. X-ray crystallographic analysis revealed that the [NiCl2(DMF)2(H2O)2] complex was formed in-situ. The complex is an excellent precursor of the active nickel species. The reaction offers an extremely mild and operationally convenient method to access a wide variety of alkyl aryl sulfides and diaryl sulfides without using expensive transition metals, such as palladium, gold, and rhodium, and specialized and expensive ligands.

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Copper-mediated peptide arylation selective for the N-terminus

Mary K. Miller, Haopei Wang, Kengo Hanaya, Olivia Zhang, Alex Berlaga and Zachary T. Ball

Chemical Science (ROYAL SOCIETY OF CHEMISTRY)  11 ( 38 ) 10501 - 10505 2020.09

Research paper (scientific journal), Joint Work, Accepted,  ISSN  20416520

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© The Royal Society of Chemistry 2020. Polypeptides present remarkable selectivity challenges for chemical methods. Amino groups are ubiquitous in polypeptide structure, yet few paradigms exist for reactivity and selectivity in arylation of amine groups. This communication describes the utilization of boronic acid reagents bearing certaino-electron withdrawing groups for copper-mediated amine arylation of the N-terminus under mild conditions and primarily aqueous solvent. The method adds to the toolkit of boronic acid reagents for polypeptide modification under mild conditions in water that shows complete selectivity for the N-terminus in the presence of lysine side chains.

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Improved preparation of vitexin from hot water extract of Basella alba, the commercially available vegetable Malabar spinach (“Tsurumurasaki” in Japanese) and the application to semisynthesis of chafuroside B

Kurahayashi K., Hanaya K., Higashibayashi S., Sugai T.

Bioscience, Biotechnology and Biochemistry (Bioscience, Biotechnology and Biochemistry)  84 ( 8 ) 1554 - 1559 2020.08

Research paper (scientific journal), Accepted,  ISSN  09168451

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© 2020, © 2020 Japan Society for Bioscience, Biotechnology, and Agrochemistry. Hot water extraction of D-arabinofuranosylvitexin from the raw leaves of commercially available Basella alba “Tsurumurasaki” and subsequent acidic hydrolysis was improved to be a procedure using a high-pressure steam sterilizer to afford vitexin. The amount was estimated to be 14.1 mg from 1 g of dry weight of the raw leaves, whose recovery was calculated to be 95% based on the estimated content of D-arabinofuranosylvitexin in B. alba raw leaves. The product was dehydratively cyclized between hydroxy groups on the carbohydrate and flavone skeletons under modified Mitsunobu reaction conditions in N,N-dimethylformamide to give chafuroside B, which is known to be a bioactive Oolong tea polyphenol. Through these transformations, 10.2 mg of chafuroside B could be semisynthesized from 1 g of dry weight of the raw leaves, and the efficiency was improved compared to that from the extraction from Oolong tea (3.4 μg from 1 g of dry weight).

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Comprehensive semisyntheses of catathelasmols C, D, and E from D-glutamic acid, utilizing lipase-catalyzed site-selective reactions on intermediates

Hashiba R., Hashimoto R., Nishiguchi M., Kobayashi T., Hanaya K., Higashibayashi S., Sugai T.

Bioscience, Biotechnology and Biochemistry (Bioscience, Biotechnology and Biochemistry)  84 ( 7 ) 1339 - 1344 2020.07

Research paper (scientific journal), Accepted,  ISSN  09168451

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© 2020, © 2020 Japan Society for Bioscience, Biotechnology, and Agrochemistry. Catathelasmols C, D, and E, which had been isolated from Catathelasma imperiale as inhibitors for 11-hydroxysteroid dehydrogenases, were comprehensively semisynthesized from commercially available D-glutamic acid. The key synthetic intermediate, (R)-pentane-1,2,5-triol, was site-selectively acetylated by treatment with vinyl acetate and Candida antarctica lipase B (Novozym 435) in tetrahydrofuran (THF) at 25°C to furnish 1,5-diacetate (catathelasmol E, quantitative). The acetylation occurred site-selectively on the primary alcohols at the C-1 and C-5 positions over the secondary alcohol at the C-2 position. Dichromic acid oxidation provided 2-oxopentane-1,5-diyl diacetate (catathelasmol C, 78%). Burkholderia cepacia lipase-catalyzed transesterification with methanol in THF at–5°C proceeded preferentially on the acetate at C-1 located adjacent to the C-2 carbonyl group over the other terminal acetate at the C-5 position. 5-Hydroxy-4-oxopentyl acetate (catathelasmol D) was obtained in 53% yield.

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Accumulation of major linezolid metabolites in patients with renal impairment

Souza E., Crass R.L., Felton J., Hanaya K., Pai M.P.

Antimicrobial Agents and Chemotherapy (Antimicrobial Agents and Chemotherapy)  64 ( 5 )  2020.05

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00664804

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© 2020 American Society for Microbiology. All Rights Reserved. In patients with renal impairment (n=22 of 39), the median serum concentrations of linezolid, PNU-142300, and PNU-142586 were 1.6-, 3.3-, 2.8-fold higher, respectively, than in patients without renal impairment. Metabolite concentrations in paired samples were poorly correlated with linezolid concentrations (r2 = 0.26 for PNU-142300 and 0.06 for PNU-142586). Linezolid and its metabolites share potential toxicophores that deserve characterization to mitigate higher myelosuppression risk in patients with renal impairment.

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Stepwise approach for sterically hindered C<inf>sp³</inf>-C<inf>sp³</inf> bond formation by dehydrogenative: O -alkylation and Lewis acid-catalyzed [1,3]-rearrangement towards the arylalkylcyclopentane skeleton of sesquiterpenes

Fujitani B., Hanaya K., Sugai T., Higashibayashi S.

Chemical Communications (Chemical Communications)  56 ( 25 ) 3621 - 3624 2020.03

Research paper (scientific journal), Joint Work, Accepted,  ISSN  13597345

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This journal is © The Royal Society of Chemistry. A stepwise dehydrogenative cross-coupling method was developed for the formation of sterically hindered Csp3-Csp3 bonds. Intramolecular dehydrogenative O-alkylation of a β-ketoester by 2,3-dichloro-5,6-dicyano-p-benzoquinone to form an oxolane followed by Lewis acid-catalyzed [1,3]-rearrangement furnished the sesquiterpene arylmethylcyclopentane skeleton. The formal syntheses of herbertane-type β-herbertenol, cuparane-type enokipodins A and B were also achieved.

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Development of a sensitive LC–MS/MS method for quantification of linezolid and its primary metabolites in human serum

Souza E., Felton J., Crass R., Hanaya K., Pai M.

Journal of Pharmaceutical and Biomedical Analysis (Journal of Pharmaceutical and Biomedical Analysis)  178 2020.01

Research paper (scientific journal), Joint Work, Accepted,  ISSN  07317085

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© 2019 Elsevier B.V. Linezolid (LZD) is a widely used antimicrobial that is active against a broad range of disease-causing bacteria. Myelosuppression is major treatment-limiting toxicity of LZD that occurs more frequently in patients with renal insufficiency. Quantification of LZD and its two primary metabolites (PNU-142300 and PNU-142586), which undergo significant renal elimination, may support design of improved dosing strategies to mitigate the risk of myelosuppression. In this study, we established the first liquid chromatography-tandem mass spectrometry (LC–MS/MS) method for the simultaneous quantification of LZD and its main metabolites in human serum. Proteins in serum samples were precipitated with acetonitrile containing a deuterated internal standard. Chromatographic separation of analytes was performed with Waters X-bridge column (C18, 150 × 4.6 mm, 3.5 μm) at 25 °C and subjected to mass analysis using positive electro-spray ionization. The mobile phase A was water with 0.1% formic acid, and mobile phase B was acetonitrile with 0.1% formic acid at a flow rate of 0.6 mL/min, within a 15 min run time. Standard curves were linear and correlation coefficients (r2) were ≥0.99 for concentration ranges of 0.1–50 μg/mL for LZD and PNU-142300, and 0.1–25 μg/mL for PNU-142586. The inter- and intra-assay precisions were <15% for all analytes in quality control samples, and the accuracies ranged from 97 to 112%. Extraction recoveries ranged from 78 to 103% for all analytes, and there was no significant matrix effect. Samples from 10 patients (5 with renal impairment) were assayed. Mean (SD) LZD, PNU-142300 and PNU-142586 trough concentrations were 19.4(6.8), 11.6(6.8), 25.7(16.4) μg/mL, respectively, in patients with renal impairment. These values were 2.5-, 5.8-, and 6.8-fold higher for LZD, PNU-142300 and PNU-142586, respectively compared to patients without renal impairment. The method was effectively applied in the determination of LZD and its main metabolites in human serum.

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Syntheses of indirubins by aldol condensation of isatins with indoxyl anion generated in situ by lipase-catalyzed deacetylation of indoxyl acetate

Sugai T., Hanaya K., Higashibayashi S.

Heterocycles (Heterocycles)  100 ( 1 ) 129 - 136 2020

Research paper (scientific journal), Joint Work, Accepted,  ISSN  03855414

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© 2020 The Japan Institute of Heterocyclic Chemistry. The syntheses of indirubin (76% yield), 6-bromoindirubin (82% yield), and 6-bromoindirubin-3′-oxime (78% yield in two steps) were achieved via the lipase-triggered aldol condensation between isatins and an indoxyl anion in tetrahydrofuran under anhydrous and anaerobic conditions as the key step. The aldol donor was generated in situ by Burkholderia cepacia lipase (Amano PS-IM)-catalyzed deacetylation of commercially available and stable indoxyl acetate in the presence of triethylamine and with 2-propanol as the transesterification reagent. The scale-up of the presently developed reactions is easier than that in the previously reported chemical aldol condensations, because of the simplicity of the isolation procedure and suppression of the oxidative byproduct formation from indoxyl acetate.

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Analysis of Interconversion between Atropisomers of Chiral Substituted 9,9’-Bicarbazole

Kobayashi T., Ishiwari F., Fukushima T., Hanaya K., Sugai T., Higashibayashi S.

European Journal of Organic Chemistry (European Journal of Organic Chemistry)  2021 ( 3 ) 449 - 451 2020

Research paper (scientific journal), Joint Work, Accepted,  ISSN  1434193X

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© 2020 Wiley-VCH GmbH Interconversion of atropisomers of chiral 3,3’-di-tert-butyl-9,9’-bicarbazole linked by a single N−N bond was analyzed by DFT calculations and experiments. The calculations revealed that the trans transition state has a lower energy for the interconversion than the cis transition state. The lowest transition state of interconversion between natural dixiamycins A and B containing a 9,9’-bicarbazole structure was found to be the trans transition state. The calculations also indicated that degradation through N−N bond cleavage was faster than racemization. Atropisomeric enantiomers of 3,3’-di-tert-butyl-9,9’-bicarbazole were resolved by chiral HPLC for the first time, and then racemization and N−N bond cleavage were investigated by heating experiments, showing that racemization did not take place below the degradation temperature.

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Nickel(II)-promoted amide N-H arylation of pyroglutamate-histidine with arylboronic acid reagents

Hanaya K., Miller M., Ball Z.

Organic Letters (Organic Letters)  21 ( 7 ) 2445 - 2448 2019.04

Research paper (scientific journal), Joint Work, Lead author, Accepted,  ISSN  15237060

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© 2019 American Chemical Society. Small and simple bioorthogonal reactive handles that can be readily encoded by natural processes are important for bioconjugation. A rapid nickel-promoted N-H arylation of pyroglutamate-histidine sequences with 2-nitroarylboronic acids proceeds under mild aqueous conditions. Chemoselective activation of a lactam amide N-H within a peptide or protein provides a new approach to selective conjugation in polyamide structures.

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Rapid nickel(ii)-promoted cysteine: S -arylation with arylboronic acids

Hanaya K., Ohata J., Miller M., Mangubat-Medina A., Swierczynski M., Yang D., Rosenthal R., Popp B., Ball Z.

Chemical Communications (Chemical Communications)  55 ( 19 ) 2841 - 2844 2019.02

Research paper (scientific journal), Accepted,  ISSN  13597345

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© 2019 The Royal Society of Chemistry. S-Arylation of cysteine residues is an increasingly powerful tool for site-specific modification of proteins, providing novel structure and electronic perturbation. The present work demonstrates an operationally-simple cysteine arylation reaction 2-nitro-substituted arylboronic acids, promoted by a simple nickel(ii) salt. The process exhibits strikingly fast reaction rates under physiological conditions in purely aqueous media with excellent selectivity toward cysteine residues. Cysteine arylation of natural proteins and peptides allows attachment of useful reactive handles for stapling, imaging, or further conjugation.

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Synthesis of 5-Hydroxy-3′,4′,7-trimethoxyflavone and Related Compounds and Elucidation of Their Reversal Effects on BCRP/ABCG2-Mediated Anticancer Drug Resistance

Tsunekawa R., Katayama K., Hanaya K., Higashibayashi S., Sugimoto Y., Sugai T.

ChemBioChem (ChemBioChem)  20 ( 2 ) 210 - 220 2019.01

Research paper (scientific journal), Joint Work, Accepted,  ISSN  14394227

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© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3′,4′,7-Trimethoxyflavone (TMF) has been reported to show a potent reversal effect on drug resistance mediated by breast cancer resistance protein (BCRP)/ATP-binding cassette subfamily G member 2 (ABCG2). In this study, we designed and synthesized five derivatives with either a hydroxy group or a fluorine atom at C-5 and several kinds of capping moiety at the C-7 hydroxy group, on the same 3′,4′-dimethoxy-substituted flavone skeleton. We subsequently evaluated the efficacies of these compounds against BCRP-expressing human leukaemia K562/BCRP cells. Reversal of drug resistance was expressed as the concentration of compound causing a twofold reduction in drug sensitivity (RI 50 ). Of the synthesized compounds, the reversal effect of 5-hydroxy-3′,4′,7-trimethoxyflavone (HTMF, RI 50 7.2 nm) towards 7-ethyl-10-hydroxycamptothecin (SN-38) was stronger than that of TMF (RI 50 18 nm). Fluoro-substituted 5-fluoro-3′,4′,7-trimethoxyflavone (FTMF, RI 50 25 nm) and monoglycosylated 7-(β-glucosyloxy)-5-hydroxy-3′,4′-dimethoxyflavone (GOHDMF, 91 nm) also exhibited reversal effects, whereas the di- and triglycoside derivatives did not. TMF, HTMF and FTMF at 0.01–10 μm upregulated the K562/BCRP cellular accumulation of Hoechst 33342 nuclear staining dye. In addition, western blotting revealed that treatment of K562/BCRP cells with 0.1 μm TMF, HTMF or FTMT suppressed the expression of BCRP. HTMF showed the strongest inhibition of BCRP-mediated efflux and suppression of BCRP expression of the three effective synthesized flavones.

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Syntheses of Englerin A, a Potent Renal Cancer Inhibitor

Hagihara S., Hanaya K., Sugai T., Shoji M.

Asian Journal of Organic Chemistry (Asian Journal of Organic Chemistry)  8 ( 1 ) 48 - 62 2019.01

Research paper (scientific journal), Joint Work, Accepted,  ISSN  21935807

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© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Mankind has been searching for anticancer drugs from nature and artificial compounds. Since the discovery of englerin A, a guaiane sesquiterpene possessing the characteristic tricyclic 5–6-5 fused ring framework with contiguous seven stereogenic centers and isolated from Phyllanthus engleri, many synthetic groups have enthusiastically launched and accomplished its the chemical synthesis. All the synthetic groups focused on how to efficiently construct the tricyclic framework containing oxygen bridge with various approaches. In this review, the total and formal syntheses of englerin A reported to date are summarized.

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Site-selective synthesis of acacetin and genkwanin through lipase-catalyzed deacetylation of apigenin 5,7-diacetate and subsequent methylation

Fujita R., Mandal S., Hanaya K., Shoji M., Higashibayashi S., Sugai T.

Heterocycles (Heterocycles)  99 ( 1 ) 638 - 648 2019

ISSN  03855414

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© 2019 The Japan Institute of Heterocyclic Chemistry. Candida antarctica lipase B-catalyzed deacetylation proceeded with high site-selectivity on the C-4′ acetyl group in apigenin triacetate to give apigenin 5,7-diacetate. Methylation of the liberated hydroxy group with the combination of trimethyloxonium tetrafluoroborate (Meerwein reagent) and 1,8-bis(dimethylamino)naphthalene (proton sponge) in CH2Cl2 proceeded in a quantitative manner to give the product methylated at the C-4′ hydroxy group (acacetin 5,7-diacetate). Even with the same precursor, a different methylation product at the C-7 hydroxy group (genkwanin 4′,5-diacetate) was obtained in 86% yield by applying iodomethane and Cs2CO3 in dimethyl sulfoxide (DMSO). The methylated products were deprotected to form acacetin and genkwanin. We inferred that the latter unexpected methylation was ascribable to the intermolecular migration of an acetyl group from C-7 to C-4′. DFT calculations indicated that the C-7 phenoxide ion was 12.6 kJ/mol more stable than the initially formed C-4′ phenoxide ion.

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Lipase-catalyzed site-selective deacetylation of sterically hindered naphthohydroquinone diacetate and its application to the synthesis of a heterocyclic natural product

Hashimoto R., Sakakura A., Hanaya K., Higashibayashi S., Sugai T.

Heterocycles (Heterocycles)  99 ( 1 ) 625 - 632 2019

ISSN  03855414

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© 2019 The Japan Institute of Heterocyclic Chemistry. Lipase-catalyzed site-selective deacetylation of 2,5-dimethylnaphthalene-l,4-diol diacetate was examined. With Candida antarctica lipase B, the suppressing effect of a methyl substituent at the peri-position of the a-naphthyl ester over that at the ortho-position was significant. This site-selectivity was in contrast to that of chemical hydrolysis reported to date. From the resulting monoacetate, mansonone F, a physiologically active heterocyclic orthoquinone, was synthesized in 38% yield in as few as three steps.

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Chemoenzymatic synthesis of hydroxytyrosol monoesters and their suppression effect on nitric oxide production stimulated by lipopolysaccharides

Sakakura A., Pauze M., Namiki A., Funakoshi-Tago M., Tamura H., Hanaya K., Higashibayashi S., Sugai T.

Bioscience, Biotechnology and Biochemistry (Bioscience, Biotechnology and Biochemistry)  83 ( 2 ) 185 - 191 2019

ISSN  09168451

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© 2018 Japan Society for Bioscience, Biotechnology, and Agrochemistry. Fatty acid monoesters of hydroxytyrosol [2-(3,4-dihydroxyphenyl)ethanol] were synthesized in two steps from tyrosol (4-hydroxyphenylethanol) by successive Candida antarctica lipase B-catalyzed chemoselective acylation on the primary aliphatic hydroxy group over phenolic hydroxy group in tyrosol, and 2-iodoxybenzoic acid (IBX)-mediated hydroxylation adjacent to the remaining free phenolic hydroxy group. Examination of their suppression effects on nitric oxide production stimulated by lipopolysaccharides in RAW264.7 cells showed that hydroxytyrosol butyrate exhibited the highest inhibition (IC 50 7.0 μM) among the tested compounds.

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Synthesis and Properties of Hydrazine-Embedded Biphenothiazines and Application of Hydrazine-Embedded Heterocyclic Compounds to Fluorescence Cell Imaging

Shindo Y., Nomura S., Saikawa Y., Nakata M., Tanaka K., Hanaya K., Sugai T., Higashibayashi S.

Asian Journal of Organic Chemistry (Asian Journal of Organic Chemistry)  7 ( 9 ) 1797 - 1801 2018.09

ISSN  21935807

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© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Hydrazine-embedded unsubstituted butterfly-shaped biphenothiazine and its sulfoxides were synthesized by dimerization of 1,9-dibromophenothiazine, which was prepared by realizing selective debromination at the 3,7-positions of 1,3,7,9-tetrabromophenothiazine. cis/trans-Biphenothiazine sulfoxide was selectively prepared by changing the oxidation temperature to control the inversion rate of the butterfly shape of the intermediate. Their butterfly-shapes, conformations, photophysical properties (UV-vis absorption, fluorescence), and redox properties were elucidated by X-ray analysis, DFT calculations, spectral and electrochemical measurements. Fluorescent hydrazine-embedded biphenothiazine sulfoxides and bicarbazoles were applied to cell imaging of HeLa cells. The bicarbazoles exhibited high fluorescence signals in the cells with low toxicity.

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Recent examples of the use of biocatalysts with high accessibility and availability in natural product synthesis

Sugai T., Higashibayashi S., Hanaya K.

Tetrahedron (Tetrahedron)  74 ( 27 ) 3469 - 3487 2018.07

ISSN  00404020

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© 2018 Elsevier Ltd Utilization of biocatalysts with high accessibility and availability, which have recently been applied in the preparation of enantiomerically enriched starting materials and synthetic intermediates for natural product syntheses (mainly 2013–2017) are summarized in this review. The main contents are as follows: 1) recruitment of biocatalysts for the transformation of organic compounds; 2) special precautions for preparative-scale biocatalytic synthetic experiments; 3) asymmetric reduction of carbonyl substrates; 4) kinetic resolution of alcohol and carboxylate enantiomers; 5) desymmetrization of multifunctional alcohol and carboxylate substrates; and 6) recognition of remote and non-central chirality.

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A vinylogous photocleavage strategy allows direct photocaging of backbone amide structure.

MAGUBAT-MEDINA Alicia E,MARTIN Samuel C,HANAYA Kengo, BALL Zachary T

Journal of the American Chemical Society (American Chemical Society)  140 ( 27 ) 8401 - 8404 2018.06

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00027863

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© 2018 American Chemical Society. Side-chain modifications that respond to external stimuli provide a convenient approach to control macromolecular structure and function. Responsive modification of backbone amide structure represents a direct and powerful alternative to impact folding and function. Here, we describe a new photocaging method using histidine-directed backbone modification to selectively modify peptides and proteins at the amide N-H bond. A new vinylogous photocleavage method allows photorelease of the backbone modification and, with it, restoration of function.

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Formal total synthesis of (−)-hamigeran B from a chemo-enzymatically prepared building block with quaternary chiral center

KUWATA Kazuaki, FUJITA Rie, HANAYA Kengo, HIGASHIBAYASHI Shuhei, SUGAI Takeshi

Tetrahedron (Tetrahedron)  74 ( 7 ) 740 - 745 2018.02

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00404020

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© 2017 Elsevier Ltd A formal total synthesis of (−)-hamigeran B was achieved in 17 steps from commercially available ethyl 2-oxocyclopentanecarboxylate. Carbonyl reductase-catalyzed asymmetric reduction and the subsequent chemical transformations furnished an enantiomerically pure synthetic intermediate, (R)-5-formyl-2-isopropyl-5-methylcyclopent-1-en-1-yl trifluoromethylsulfonate. Suzuki-Miyaura coupling with Gao's arylboronate [2-(2-formyl-3-methoxy-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane], under PdCl2(dppf)•CH2Cl2 catalysis, and the subsequent cyclization by way of intramolecular reductive SmI2-mediated 1,2-diol formation provided a tricyclic skeleton with a tetrasubstituted double bond between C-1 and C-9b. Upon hydrogenation of this double bond, the proper stereochemistry of the remaining chiral centers was established. Exclusive addition of the hydrogen atom from the β-face occurred, owing to the shielding of the α-face with a bulky TBS protective group on the C-4 alcohol. The hydrogenation products were transformed into Clive's synthetic precursor for (−)-hamigeran B.

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Chemoenzymatic approaches to the synthesis of the (1S,2R)-isomer of benzyl2-hydroxycyclohexanecarboxylate

TSUNEKAWA Ryuji, HANAYA Kengo, HIGASHIBAYASHI Shuhei, SHOJI Mitsuru, SUGAI Takeshi

Mol. Catal. 444   84 - 89 2018

Research paper (scientific journal), Joint Work, Accepted

Synthesis of trilobatin from naringin via prunin as the key intermediate: acidic hydrolysis of the α-rhamnosidic linkage in naringin under improved conditions

KURAHAYASHI Kazuki, HANAYA Kengo, HIGASHIBAYASHI Shuhei, SUGAI Takshi

Bioscience, Biotechnology, and Biochemistry (Bioscience, Biotechnology and Biochemistry)  82 ( 9 ) 1463 - 1467 2018

Research paper (scientific journal), Joint Work, Accepted,  ISSN  09168451

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© 2018 Japan Society for Bioscience, Biotechnology, and Agrochemistry Trilobatin [4-(β-D-glucopyranosyloxy)-2,4”,6-trihydroxydihydrochalcone] was synthesized from commercially available naringin in three steps with an overall yield of 30%. The key step was the acid-catalyzed site-selective hydrolysis of terminal α-rhamnopyranosidic linkage in neohesperidose involved in naringin under controlled conditions, by applying a high-pressure steam sterilizer.

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Synthesis of fisetin and 2',4',6'-trihydroxydihyrochalcone 4'-O-β-neohesperidoside based on site-selective deacetylation and deoxygenation

TSUNEKAWA Ryuji, HANAYA Kengo, HIGASHIBAYASHI Shuhei, SUGAI Takeshi

Bioscience, Biotechnology, and Biochemistry (Bioscience, Biotechnology and Biochemistry)  82 ( 8 ) 1316 - 1322 2018

Research paper (scientific journal), Joint Work, Accepted,  ISSN  09168451

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© 2018 Japan society for Bioscience, Biotechnology, and Agrochemistry. Fisetin and 2′,4′,6′-trihydroxydihyrochalcone 4′-O-β-neohesperidoside were synthesized from commercially available quercetin and naringin in five steps. The key steps are site-selective deacetylation and subsequent deoxygenation. The target molecules were obtained in 37% and 23% yields from the starting materials, respectively.

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Synthesis of 3β-tert-Butyldimethylsiloxy-22-phenylthio-23,24-bisnorchola-5,9(11)-diene and Reductive Nucleophilic Attack on a Branched Aliphatic Aldehyde

NAGAI Toshiya, HANAYA Kengo, HIGASHIBAYASHI Shuhei, SHOJI, Mitsuru, SUGAI Takeshi

CHEMICAL and PHARMACEUTICAL BULLETIN (Chemical and Pharmaceutical Bulletin)  66 ( 3 ) 334 - 338 2018

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00092363

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© 2018 The Pharmaceutical Society of Japan. 3β-tert-Butyldimethylsiloxy-22-phenylthio-23,24-bisnorchola-5,9(11)-diene, which has a double bond between C-9 and C-11 and a phenylsulfenyl group on the terminus of the side chain, is a potential synthetic intermediate for steroids with 9,11-unsaturation or 9,11-seco skeletons. We describe here the synthesis of the title compound from 17-ethylenedioxy-3-acetoxyandrosta-3,5-dien-11-one. The introduction of an ethylene unit to 3β-tert-butyldimethylsiloxyandrosta-5,9(11)-dien-17-one by the action of ethyltriphenylphosphonium bromide under basic conditions resulted in an inseparable mixture of two stereoisomeric products (5 : 1). However, in the subsequent step, only the (Z)-isomer was susceptible to the Lewis acid-catalyzed ene reaction with formaldehyde, giving a stereochemically pure product with the desired configuration. Within three steps, the ene-product was derivatized to the title compound, with a total yield of 53% over seven steps. Reductive terminal anion formation by treatment with lithium di-tert-butylbiphenyl (LiDBB) and subsequent nucleophilic attack on a branched aliphatic aldehyde was demonstrated, with an eye toward the introduction of side chains, especially for steroids with oxygen functionality at C-23.

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Dearomative Oxidative Rearrangement of [3]Cyclo-1,8-carbazolylene

Yasui M., Ohtsu H., Kawano M., Hanaya K., Sugai T., Higashibayashi S.

Chemistry Letters (Chemistry Letters)  47 ( 11 ) 1357 - 1359 2018

ISSN  03667022

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© 2018 The Chemical Society of Japan. [3]Cyclo-1,8-carbazolylene was found to undergo oxidative rearrangement by oxidation with 2,3-dichloro-5,6-dicyano-pbenzoquinone, giving a 9a-substituted carbazol-1-one derivative. This is the first example of a dearomative oxidative rearrangement of a carbazole or aniline derivative. The geometrical and electronic structures were elucidated by X-ray analysis, UV-vis absorption spectroscopy, and DFT calculations.

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Synthesis of oroxylin A starting from naturally abundant baicalin

Fujita R., Hanaya K., Higashibayashi S., Sugai T.

Heterocycles (Heterocycles)  97 ( 2 ) 1165 - 1174 2018

ISSN  03855414

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© 2018 The Japan Institute of Heterocyclic Chemistry – A new approach to oroxylin A, a monomethylated trihydroxyflavone, is described. The starting material was baicalin, a representative naturally abundant flavonoid glucuronide. First, conditions for the cleavage of the glycosidic bond were established, using a mixture of water and conc. sulfuric acid (5:2) at 121 °C for 40 min. The hydrolysis was performed in a high-pressure steam sterilizer so that the temperature and reaction time were precisely controlled. Subsequent acetylation of the crude material furnished baicalein 6,7-diacetate on a preparative scale and in a reproducible manner. Next, the C-7 position was protected site-selectively with a methoxymethyl (MOM) group, taking advantage of an unexpected sequential migration of the two acetyl groups among the C-5, C-6, and C-7 positions under basic conditions. The removal of the two remaining acetyl groups followed by site-selective methylation of the C-6 position furnished 5-hydroxy-6-methoxy-7-methoxymethoxyflavone (oroxylin A C-7 MOM ether). Finally, by the deprotection of the MOM ether, oroxylin A was obtained in 6 total steps and 62% overall yield from baicalin.

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Construction of 2,6,9,11-tetraoxatricyclo[6.2.1.03,8]undecane containing 4-keto-d-glucose skeleton

FUJITANI Ban, HANAYA Kengo, HIGASHIBAYASHI Shuhei, SHOJI Mitsuru, SUGAI Takeshi

Tetrahedron 73 ( 51 ) 7217 - 7222 2017.12

Research paper (scientific journal), Joint Work, Accepted

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Chemoenzymatic approaches to the synthesis of the (1S,2R)-isomer of benzyl 2-hydroxycyclohexanecarboxylate.

TSUNEKAWA Ryuji, HANAYA Kengo, HIGASHIBAYASHI Shuhei, SHOJI Mitsuru, SUGAI Takeshi

MolecularCatalysis (ELSEVIER)  444   84 - 89 2017.11

Research paper (scientific journal), Joint Work, Accepted

Synthesis of the 1,2-seco fusicoccane diterpene skeleton by Stille coupling reaction between the highly functionalized A and C ring segments of cotylenin A

KUWATA Kazuaki, HANAYA Kengo, HIGASHIBAYASHI Shuhei, SUGAI Takeshi, SHOJI Mitsuru

Tetrahedron 73 ( 41 ) 6039 - 6045 2017.10

Research paper (scientific journal), Joint Work, Accepted

Formal synthesis of englerin A utilizing regio- and diastereoselective [4+3] cycloaddition

HAGIHARA Shuichi,HANAYA Kengo, SUGAI Takeshi, SHOJI Mitsuru

The Journal of Antibiotics (Journal of Antibiotics)  71 ( 2 ) 257 - 262 2017.08

Research paper (scientific journal), Joint Work, Accepted,  ISSN  00218820

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© 2018 Japan Antibiotics Research Association All rights reserved. Englerin A, a guaiane sesquiterpene isolated from Phyllanthus engleri, showed highly potent and selective growth inhibitory activities against renal cancer cell lines. We synthesized the key tricyclic intermediate from commercially available 2,2-dimethyl-1,3-dioxan-5-one via regio- and diastereoselective [4+3] cycloaddition between the formyl enol silyl ether and the disubstituted furan, in 4.8% total yield over 10 steps.

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Chemo-enzymatic synthesis of (R)-5-hydroxymethyl-2-isopropyl-5-methylcyclopent-1-en-1-yl trifluoromethylsulfonate, a potential chiral building block for multicyclic terpenoids

KUWATA Kazuaki, HANAYA Kengo, SUGAI Takeshi, SHOJI Mitsuru

Tetrahedron: Asymmetry 28 ( 7 ) 964 - 968 2017.07

Research paper (scientific journal), Accepted

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Synthesis of trans,trans,cis-fused tetracyclic skeleton via radical domino cyclization

FURUTA Miyu, HANAYA Kengo, SUGAI Takeshi, SHOJI Mitsuru

Tetrahedron 73 ( 16 ) 2316 - 2322 2017.04

Research paper (scientific journal), Accepted

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Synthesis of enantiomerically enriched drug precursors and an insect pheromone via reduction of ketones using commercially available carbonyl reductase screening kit "Chiralscreen® OH".

NAGAI Toshiya,SAKURAI Saki,NATORI Naoki, HATAOKA Manaka, KINOSHITA Takako, INOUE Hiroyoshi, HANAYA Kengo, SHOJI Mitsuru, SUGAI Takeshi

Bioorganic & Medicinal Chemistry (Bioorganic and Medicinal Chemistry)  26 ( 7 ) 1304 - 1313 2017.04

Accepted,  ISSN  09680896

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© 2017 Elsevier Ltd Commercially available “Chiralscreen® OH” starter kit containing five types of carbonyl reductases (E001, E007, E031, E039, and E078) was used for the reduction of several aromatic and aliphatic ketones to obtain enantiomerically enriched drug precursors and an insect pheromone. Almost stereochemically pure secondary alcohols, used in the synthesis of drugs such as (R)-rasagiline mesylate, (S)-rivastigmine, (R)-chlorphenesin carbamate, and (R)-mexiletine, and the insect pheromone (4S,5R)-sitophilure, were conveniently obtained. The enzymes worked well with ketones containing at least one non-bulky substituent at the carbonyl group. The diverse stereochemical preference of the above five carbonyl reductases was clarified.

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Short-step syntheses of naturally occurring polyoxygenated aromatics based on site-selective transformation

YAMASHITA Yasunobu, BIARD Alan, HANAYA Kengo, SHOJI Mitsuru, SUGAI Takeshi

Bioscience, Biotechnology, and Biochemistry 81 ( 7 ) 1279 - 1284 2017.03

Research paper (scientific journal), Accepted

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Synthesis of linezolid metabolites PNU-142300 and PNU-142586 toward the exploration of metabolite-related events

HANAYA Kengo, Matsumoto Kazuaki, Yokoyama Yuta, Kizu Junko, Shoji Mitsuru, Sugai Takeshi

CHEMICAL and PHARMACEUTICAL BULLETIN 65   194 - 199 2017

Research paper (scientific journal), Accepted

Synthesis of benzyltetra-O-acetyl-α-L-glucopyranoside from benzyl 2,3-dideoxy-β -D-erythro-hex-2-enopyranoside

OKAZAKI Hayato, UEDA Yuji, HANAYA Kengo, SHOJI Mitsuru, SUGAI Takeshi

Heterocycles 95   862 - 871 2016.11

Research paper (scientific journal), Accepted

Preparation of (R)-3-Hydroxy-N-methylpiperidine, a Synthetic Key Intermediate of (R)-Mepenzolate, Based on the Lipase-Catalyzed Resolution of the Racemic Form

Yamashita Yasunobu, HANAYA Kengo, Shoji Mitsuru, Sugai Takeshi

Heterocycles  2016

Research paper (scientific journal), Accepted

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Development of a Novel Sulfonate Ester-Based Prodrug Strategy

Hanaya, K.; Yoshioka, S.; Ariyasu, S.; Aoki, S.; Shoji, M.; Sugai, T.

Bioorganic & Medicinal Chemistry Letters 26   545 - 550 2016

Accepted

Simple Synthesis of Sakuranetin and Selinone via a Common Intermediate, Utilizing Complementary Regioselectivity in the Deacetylation of Naringenin Triacetate

YAMASHITA Yasunobu, HANAYA Kengo, SHOJI Mitsuru, SUGAI Takeshi

CHEMICAL and PHARMACEUTICAL BULLETIN 64 ( 7 ) 961 - 965 2016

Research paper (scientific journal), Joint Work, Accepted

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Ex Situ Enantioconvergent Approaches for the Effective Use of Undesired­ Isomers: Stereochemical Convergence of a Substrate with Multiple Chiral Centers and Recycling of a Decarboxylated Byproduct

YAMASHITA Yasunobu, KURIHARA Tohru, HORIGUCHI Takenobu, MIKI Atsushi, SHOJI Mitsuru, SUGAI Takeshi, HANAYA Kengo

Synthesis 48 ( 14 ) 2191 - 2200 2016

Research paper (scientific journal), Joint Work, Accepted

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Synthesis of acacetin and resveratrol 3,5-di-O-β-glucopyranoside using lipase-catalyzed regioselective deacetylation of polyphenol glycoside peracetates as the key step

HANAMURA Shun, HANAYA Kengo, SHOJI Mitsuru, SUGAI Takeshi

Journal of Molecular Catalysis B Enzymatic 128   19 - 26 2016

Research paper (scientific journal), Joint Work, Accepted

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Chemical Reactions of 8-Quinolinol Derivatives and Their Applications to Biochemical Tools and Enzyme Inhibitors

AOKI Shin, ARIYASU Shinya, HANAYA Kengo, HISAMATSU Yosuke, SUGAI Takeshi

Journal of Synthetic Organic Chemistry Japan 74 ( 5 ) 482 - 493 2016

Joint Work, Accepted

New synthesis of artepillin C, a prenylated phenol, utilizing lipase-catalyzed regioselective deacetylation as the key step

Yashiro, K.; Hanaya, K.; Shoji, M.; Sugai, T.

BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY 79 ( 12 ) 1926 - 1930 2015.12

Research paper (scientific journal),  ISSN  0916-8451

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Upregulation of cellular glutathione levels in human ABCB5- and murine Abcb5-transfected cells

Kondo, S.; Hongama, K.; Hanaya, K.; Yoshida, R.; Kawanobe, T.; Katayama, K.; Noguchi K.; Sugimoto, Y.

BMC Pharmacology and Toxicology 16 ( 37 )  2015

Research paper (scientific journal), Accepted

Recognition of the remote chiral center in lipase-catalyzed kinetic resolution of [2-methyl-2-(2 '-naphthyl)-1,3-benzodioxol-4-yl]methyl acetate, the precursor of 2-methyl-2-(2 '-naphthyl)-1,3-benzodioxole-4-carboxylic acid (MNB carboxylic acid)

Natori, Naoki, Nakagawara, Kaoruko, Shoji, Mitsuru, Sugai, Takeshi, Hanaya, Kengo

JOURNAL OF MOLECULAR CATALYSIS B-ENZYMATIC 109   130 - 135 2014.11

Research paper (scientific journal),  ISSN  1381-1177

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Design and synthesis of 8-hydroxyquinoline-based radioprotective agents

Ariyasu, S.; Sawa, A.; Morita, A.; Hanaya, K.; Hoshi, M.; Takahashi, I.; Wang, B.; Aoki, S.

BIOORGANIC & MEDICINAL CHEMISTRY 22 ( 15 ) 3891 - 3905 2014.08

Research paper (scientific journal),  ISSN  0968-0896

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Design, Synthesis and Photochemical Reactivation of Caged Prodrugs of 8-Hydroxyquinoline-Based Enzyme Inhibitors

Ariyasu, S.; Mizuseda, Y.; Hanaya, K.; Aoki, S.

CHEMICAL and PHARMACEUTICAL BULLETIN 62 ( 7 ) 642 - 648 2014.07

Research paper (scientific journal),  ISSN  0009-2363

Synthesis and biological comparison of enantiomers of mepenzolate bromide, a muscarinic receptor antagonist with bronchodilatory and anti-inflammatory activities.

Yamashita Y, Tanaka K, Asano T, Yamakawa N, Kobayashi D, Ishihara T, Hanaya K, Shoji M, Sugai T, Wada M, Mashimo T, Fukunishi Y, Mizushima T*.

Bioorg Med Chem 22   3488-97 2014.06

Research paper (scientific journal), Joint Work, Accepted

Divergent synthesis of pseudoenantiomers for ABC-ring moiety of steroids

Furuta, M.; Hanaya, K.; Sugai, T.; Shoji, M.

TETRAHEDRON LETTERS 55 ( 20 ) 3189 - 3191 2014.05

Research paper (scientific journal),  ISSN  0040-4039

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Stereoselective synthesis of scyphostatin hydrophilic moiety

Kuwata, K.; Suzuki, M.; Inami, Y.; Hanaya, K.; Sugai, T.; Shoji, M.

TETRAHEDRON LETTERS 55 ( 17 ) 2856 - 2858 2014.04

Research paper (scientific journal),  ISSN  0040-4039

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Structure-activity relationship of celecoxib and rofecoxib for the membrane permeabilizing activity

Yamakawa N.; Suzuki, K.; Yamashita, Y.; Katsu, T.; Hanaya, K.; Shoji, M.; Sugai, T.; Mizushima, T.

Bioorganic & Medicinal Chemistry 22 ( 8 ) 2529 - 2534 2014.04

Research paper (scientific journal),  ISSN  0968-0896

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Whole-cell Yeast-mediated Preparation of (R)-2-Chloro-1-(3-nitrophenyl)ethanol as a Synthetic Precursor for (R)-Phenylephrine.

Tokoshima D, Hanaya K, Shoji M, Sugai T.

Journal of Molecular Catalysis. B: Enzymatic 97   95-99 2013.12

Research paper (scientific journal), Joint Work, Accepted

Synthesis of (R)-bambuterol based on asymmetric reduction of 1-[3,5-Bis(dimethylcarbamoyloxy)phenyl]-2-chloroethanone with Incubated Whole Cells of W. californica.

Asami K, Machida T, Jung S, Hanaya K, Shoji M, Sugai T.

Journal of Molecular Catalysis. B: Enzymatic 97   106-109 2013.12

Research paper (scientific journal), Joint Work, Accepted

(-)-Benzyl 2,3-Dideoxy-β-D-erythro-hex-2-enopyranoside.

Ohba S, Okazaki H, Ueda Y, Hanaya K, Shoji M, Sugai T.

Acta Crystallographica Section E 69   o1811 2013.12

Research paper (scientific journal), Joint Work, Accepted

Evaluation of Zinc (II) chelators for inhibiting p53-mediated apoptosis

Morita, A.; Ariyasu, S.; Ohya, S.; Takahashi, I.; Wang, B.; Tanaka, K.; Uchida, T.; Okazaki, H.; Hanaya, K.; Enomoto, A.; Nenoi, M.; Ikekita, M.; Aoki, S.; Hosoi, Y.

ONCOTARGET 4 ( 12 ) 2439 - 2450 2013.12

Research paper (scientific journal),  ISSN  1949-2553

A New Route toward 2-Acetamido-4-O-methyl-2-deoxy-D-mannopyranose from a Ferrier Derivative of tri-O-Acetyl-D-glucal, Which Contributes to Aldolase-catalyzed Synthesis of Laninamivir (CS-8958).

Okazaki H, Hanaya K, Shoji M, Hada N, Sugai T.

Tetrahedron 69   7931-7935 2013.09

Research paper (scientific journal), Joint Work, Accepted

Chemo-enzymatic Enantioconvergent Approach toward Ethyl Shikimate from Ethyl 5-Hydroxy-3,4-isopropylidenedioxycyclohex-1-enecarboxylate.

Yamashita Y, Hanaya K, Sugai T, Mizushima T, Shoji M.

Tetrahedron 61   6527-6532 2013.08

Research paper (scientific journal), Joint Work, Accepted

Synthesis of Okicamelliaside, a Glucoside of Ellagic Acid with Potent Anti-Degranulation Activity

Kobayashi, R.; Hanaya, K.; Shoji, M.; Ohba, S.; Sugai, T.

BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY 77 ( 4 ) 810 - 813 2013.04

Research paper (scientific journal),  ISSN  0916-8451

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微生物酵素触媒を高度に活用する―合成経路デザインにおける、基質分子工学と触媒探索の重要性―.

古田未有, 花屋賢悟, 庄司満, 須貝威.

有機合成化学協会誌 71   237-246 2013.03

Research paper (scientific journal), Joint Work, Accepted

Towards the Integrated Exploitation of Microbial and Enzymatic Catalysis - Importance of Substrate Molecular Technology and Quest of Biocatalysts, for Designing Synthetic Plans

Furuta, M.; Hanaya, K.; Shoji, M.; Sugai, T.

JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN 71 ( 3 ) 237 - 246 2013.03

Research paper (scientific journal),  ISSN  0037-9980

A Chemo-enzymatic Expeditious Route to Racemic Dihexanoyl (2R*,3R*,4R*)-Dehydroxymethylepoxyquinomycin (DHMEQ), the Precursor for Lipase-catalyzed Synthesis of the Potent Nuclear Factor-κB Inhibitor, (2S,3S,4S)-DHMEQ.

Kobayashi R, Hanaya K, Shoji M, Umezawa K, Sugai T.

Chemistry and Pharmaceutical Bulletin 60   1220-1223 2012.12

Research paper (scientific journal), Joint Work, Accepted

Selective Capture and Collection of Live Target Cells Using a Photoreactive Silicon Wafer Device Modified with Antibodies via a Photocleavable Linker

Ariyasu, S.; Hanaya, K.; Watanabe, E.; Suzuki, T.; Horie, K.; Hayase, M.; Abe, R.; Aoki, S.

LANGMUIR 28 ( 36 ) 13118 - 13126 2012.09

Research paper (scientific journal),  ISSN  0743-7463

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Reduction of Acetophenones with Methyl Fluorines and a Bulky Group on the Aromatic Ring Using Microorganisms and Related Enzymes.

Abe C, Sugawara T, Machida T, Higashi T, Hanaya K, Shoji M, Cao C, Yamamoto Y, Matsuda T, Sugai T.

Journal of Molecular Catalysis. B: Enzymatic 82   86-91 2012.08

Research paper (scientific journal), Joint Work, Accepted

Potent inhibition of dinuclear zinc(II) peptidase, an aminopeptidase from Aeromonas proteolytica, by 8-quinolinol derivatives: inhibitor design based on Zn2+ fluorophores, kinetic, and X-ray crystallographic study

Hanaya, K.; Suetsugu, M.; Saijo, S.; Yamato, I.; Aoki, S.

JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY 17 ( 4 ) 517 - 529 2012.04

Research paper (scientific journal),  ISSN  0949-8257

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Photochemical Cleavage Reaction of 8-Quinolinyl Sulfonates That Are Halogenated and Nitrated at the 7-Position

Ariyasu, S.; Hanaya, K.; Tsunoda, M.; Kitamura, M.; Hayase, M.; Abe, R.; Aoki, S.

CHEMICAL and PHARMACEUTICAL BULLETIN 59 ( 11 ) 1355 - 1362 2011.11

Research paper (scientific journal),  ISSN  0009-2363

DESIGN AND SYNTHESIS OF PHOTOCLEAVABLE BIOTINYLATED-DOPAMINE WITH POLYETHYLENEOXY PHOTOCLEAVABLE LINKERS

Hanaya, K.; Kageyama, Y.; Kitamura, M.; Aoki, S.

HETEROCYCLES 82 ( 2 ) 1601 - + 2011.03

Research paper (scientific journal),  ISSN  0385-5414

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Design and synthesis of a photocleavable biotin-linker for the photoisolation of ligand-receptor complexes based on the photolysis of 8-quinolinyl sulfonates in aqueous solution

Aoki, S.; Matsuo, N.; Hanaya, K.; Yamada, Y.; Kageyama, Y.

BIOORGANIC & MEDICINAL CHEMISTRY 17 ( 9 ) 3405 - 3413 2009.05

Research paper (scientific journal),  ISSN  0968-0896

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