Papers - Higashibayashi, Shuhei

Development of Catalytic Reactions Using Bis(pinacolato)diboron and Their Applications to Syntheses of Pharmaceuticals and Luminescent Dyes

Shuhei Higashibayashi

Journal of Synthetic Organic Chemistry 82 ( 11 ) 1052 - 1062 2024.11

Research paper (scientific journal), Single Work, Lead author, Corresponding author, Accepted,  ISSN  00379980

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We have developed three catalytic reactions involving borylation and C—C bond formation using bis(pinacolato)diboron (B2pin2), and have extended their use to the synthesis of pharmaceuticals and luminescent dyes. In addition, we have also elucidated the photophysical properties of those dyes. The first reaction is a Cu—catalyzed stereoselective borylation of glycosyl bromide to β—glycosyl trifluoroborates, which has been further expanded to synthesize aryl β—C—glycosides via Pd—catalyzed stereospecific cross—coupling with aryl bromides. These methods were applied to the stereospecific synthesis of the SGLT2 inhibitor, canagliflozin. The second reaction involves the copper—catalyzed borylation of acyl chlorides to form acyl trifluoroborates, which have further been applied to the synthesis of fluorescent C,N—chelated 2,2—difluoro—1,4—diazaboroles via condensation with various amino—heterocycles. The third reaction is an organocatalytic pinacol coupling of aryl aldehydes using B2pin2 as a reductant and a substituted pyridine catalyst. The resulting diols were converted to various substituted benzils, revealing the luminescent properties such as phosphorescence, fluorescence, and self—recovering phosphorescence—to—phosphorescence mechanochromism. These studies demonstrated the usefulness of the developed methods for producing pharmaceuticals, pharmaceutical candidates and novel materials, as well as making possible the investigation of the products physical properties.

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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 (Chemistry Letters)  53 ( 5 ) upae069 2024.05

Research paper (scientific journal), Joint Work, Accepted,  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    e202400303 2024

Research paper (scientific journal), Joint Work, Accepted

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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), 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), 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), 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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Transition-Metal-Free β-Selective C-Glycosylation of β-Glycosyl Boronates via Stereoretentive 1,2-Migration

Yasutomi H., Takeda D., Yoritate M., Higashibayashi S., Sugai T., Hirai G.

Synlett (Synlett)  34 ( 4 ) 347 - 352 2023.03

Research paper (scientific journal), Accepted,  ISSN  09365214

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C-Glycoside analogues of native glycans are useful molecular tools for medicinal chemistry and chemical biology due to their resistance to cellular glycoside hydrolases. We previously reported an α-selective direct C-glycosylation of 2-deoxy-β-glycosyl boronate through a Ni/photoredox-catalyzed stereoinvertive cross-coupling reaction. Here we report a complementary stereoretentive synthetic method for the preparation of β-C-glycosides from a similar boronate precursor through the addition of a C(sp2) anion followed by 1,2-migration of the glycosyl donor.

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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 2023

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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A double-helical S,C-bridged tetraphenyl-para-phenylenediamine and its persistent radical cation

Harada K., Hasegawa C., Matsumoto T., Sugishita H., Kitamura C., Higashibayashi S., Hasegawa M., Suzuki S., Kato S.I.

Chemical Communications (Chemical Communications)  59 ( 10 ) 1301 - 1304 2023

Research paper (scientific journal), Accepted,  ISSN  13597345

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A structurally constrained, double-helical S,C-bridged tetraphenyl-para-phenylenediamine (TPPD) has been synthesized. The stable radical cation of the S,C-bridged TPPD was generated by chemical oxidation, and the electron spin was found to be delocalized over the entire π-conjugated framework. The excellent conformational stability of the neutral molecule facilitated the separation of its enantiomers.

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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), 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), 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), 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), 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), 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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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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Single-molecule electric switching induced by acid-base reaction

Yoshihara Y., Fujii S., Higashibayashi S., Kiguchi M., Nishino T.

Chemistry Letters (Chemistry Letters)  50 ( 6 ) 1271 - 1273 2021.06

Research paper (scientific journal), Accepted,  ISSN  03667022

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Electric switches are one of the most fundamental electric circuitries. Recent developments in single-molecule techniques allow us to study various electric-switching phenomena on the single-molecule scale. In this study, the switch of the current through a single molecule of a biphenothiazine derivative was investigated using the break junction technique. The biphenothiazine derivative undergoes acid-base reaction-induced electronic modulation due to the reversible structural transformation between a closed shell and an open shell, resulting in a change in the electronic gap and effective tunneling barrier height. We succeeded in controlling the single-molecule electric conductivity of the biphenothiazine derivative wired to two Au electrodes by allowing the reaction to proceed reversibly on the electrode.

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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 85 ( 3 ) 476 - 480 2021.02

Research paper (scientific journal), Joint Work, Accepted

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© The Author(s) 2020. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry. 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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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 2021 ( 3 ) 449 - 451 2021.01

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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