Published papers

加水分解酵素であるリパーゼの有機合成への応用に関して、著者らの研究を中心に概説した。

有機溶媒中の酵素反応、特にリパーゼやプロテアーゼを利用した光学分割について解説した。

有機合成に微生物をどう利用するか、という課題について実験技術を中心に初心者向けに解説した。

天然物合成における微生物や酵素の利用について、著者らの研究を中心に概説した。

対称ジエステルを微生物酵素で不斉加水分解し、有用天然生物活性物質に導くアプローチについて解説した。

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.

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.

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.

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.

Caffeic acid ß-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.

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.

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.

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.

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.

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.