Isolation and structure elucidation is a basic skill for natural product chemistry. The skill is a powerful tool to unveil cryptic diversity of natural products and see a beautiful world of organic molecules in nature. Based on isolation and structure elucidation skill, we have carried researches on natural product chemistry, chemical investigation of plant glandular trichome exudates, natural product discovery by epigenetically activating fungal silent biosynthetic gene clusters, semi-synthetically production of structurally diverse pseudo-natural polyketides. And, now we are working on “post-genomic natural product discovery based on Aspergillus oryzae heterologous expression system”. In this review, I show the research overviews of above topics including my experience and what I feel at that time.

Teleocidin B is a terpene indole isolated from bacteria. A methyltransfer enzyme in teleocidin B biosynthesis, TleD not only installs a methyl group on the geranyl moiety of the precursor, but also facilitates the nucleophilic attack from the electron-rich indole to the resultant cation, to form indole-fused cyclohexene ring. This study reports novel biosynthetic reaction in the field of terpene cyclization.

Recently, cinchona alkaloids such as quinine and quinidine were re-focused as next generation organocatalysts. Therefore, practical total syntheses of enantiomers of these alkaloids are required in current chemical society. Thus, efficient protocol for preparation of C4-alkyl substituted chiral piperidines using secondary amine catalyzed formal aza[3+3]cycloaddition reaction using aliphatic α,β-unsaturated aldehydes and thiomalonamate derivatives were discovered as key step in total synthesis. In our reaction system, thiomalonamate is excellent nucleophile, and the addition of suitable acid and it’s amounts are important factor for the acceleration effect in organocatalytic reaction. These efforts lead to only 0.1 mol% catalyst loading in multi-gram scale synthesis for suitable reaction time.

Since dimeric indole alkaloids possess architectural diversities and a wide range of biological activities, development of new synthetic strategies for construction of these structures has been one of the important topics in synthetic chemistry. Among these compounds, we focused on an architecturally intriguing dimeric monoterpene indole alkaloid, (+)-haplophytine, which had remained an unanswered challenge for more than a quarter century in the area of alkaloid synthesis. Our first total synthesis and the second generation synthesis of (+)-haplophytine are described. The synthesis of this dimeric compound features Ag-mediated coupling reaction between two polycyclic fragments. In addition, the characteristic diazabicyclo[3.3.1] skeleton in left segment was constructed by means of creative skeletal rearrangement including oxidation step.

This article introduces two topics regarding borderless natural product chemistry which has been conducted in our laboratory. The first theme presents the extraction and isolation of natural products from plant materials using ionic liquids that dissolve cellulose. Example of the study shows that shikimic acid was efficiently extracted from Ginkgo biloba leaves using [C₄mim]Cl. In the second topic, natural amino acid syntheses for clinical applications are shown. Desmosine and isodesmosine are tetrasubstituted pyridinium amino acids and are elastin crosslinkers as well as COPD biomarkers. The syntheses were achieved via palladium catalyzed cross-coupling reactions, or Pr(OTf)₃-promoted Chichibabin pyridinium synthesis.

Details for the total synthesis of omaezallene, an antifouling natural product obtained from Laurencia sp, are described. Toward the total synthesis, tasks to be solved by total synthesis were determinations of relative configurations between bromoallene and THF ring, and the absolute configuration at C9 position. The use of an aldehyde, prepared from d-glucose in 5 steps, as a starting material was envisioned to accomplish these tasks. Although reactions for construction of the bromoallene and the THF ring were successful, extensive efforts to install the bromodiene unit were essential to overcome unexpected results.

The stereoselectivity of the 7-endo radical cyclization in the syntheses of the complex terpenoids, resiniferatoxin and the model compound of puberulin C, was computationally examined. The DFT calculation of the transition states of the radical cyclizations provided the reasonable explanation for the stereoselective formation of the desired compounds. In the synthesis of the model compound of puberuline C, the energy profile of the radical reaction illustrated the favorable cascade process from the tricyclic intermediate to the pentacyclic compound.

The Amaryllidaceae alkaloid (+)-gracilamine, isolated from Galanthus gracilis, contains a characteristic pentacyclic ring system with seven consecutive stereogenic centers, including an all-carbon quaternary stereocenter. Recently we have achieved the enantioselective total synthesis of (+)-gracilamine. The synthesis features (i) asymmetric aza-Friedel-Crafts reaction of N-Boc aldimine with sesamol that allowed for constructing the stereocenter at C9a, (ii) a diastereoselective phenolic coupling reaction followed by a regioselective intramolecular aza-Michael reaction to construct the ABCE ring system. This synthesis reveals that the absolute configuration of (+)-gracilamine. Herein, we describe the details of the total synthesis of gracilamine.

A family of prenylated indole alkaloids, including notoamides and stephacidins, are secondary metabolites produced by various fungi, particularly Aspergillus and Penicillium spp. These alkaloids contain a diketopiperazine or a bicycle[2.2.2]diazaoctane ring, which is derived from tryptophan, proline, and one isoprene unit. Biosynthetically, this bicyclic core is believed to be the product of an intermolecular Diels-Alder reaction. We isolated various prenylated indole alkaloids, including some putative biosynthetic precursors, from Aspergillus protuberus, Aspergillus amoenus, and, Aspergillus taichungensis, and proposed possible biosynthetic pathways of the family.

In this review, two marine natural products, durinskiol A, a huge polyol compound from the cultured symbiotic dinoflagellate Durinskia sp., and aplyronine A, an antitumor macrolide from the sea hare Aplysia sp., are highlighted. We have developed a fluorescent labeling method for MS/MS analysis to establish the planar structure of durinskiol A. We also discovered 6-amidopyrene as a highly detectable tag for label-assisted laser desorption/ionization mass spectrometry (LA-LDI MS) without matrixes. Two amidopyrene derivatives of aplyronine A were synthesized, and their LA-LDI MS and MS/MS analyses to determine the binding position of the target protein actin are described.

Andranginine, a pentacyclic monoterpenoid indole alkaloid having hexahydroquinoline-ring and azepine fused structure, was first isolated as a racemate from Craspidospermum verticillatum in 1974. On the other hand, our andranginine isolated from Kopsia arborea exhibited optical activity. In order to find out the mystery on absolute configuration of andranginine, we carried out the asymmetric total synthesis. The first asymmetric total synthesis of andranginine utilizing asymmetric Morita-Baylis-Hillman reaction and diastereoselective intramolecular Diels-Alder reaction has revealed that natural andranginine isolated from K. arborea existed as a scalemic mixture.

Nucleic acids are biomolecules which living organisms universally possess. Since the function of nucleic acid is basically defined by its sequence, the changes and the differences in its sequence are often closely related to diseases and individual differences. Furthermore, in recent years, medicinal use of nucleic acids is increasing. Responding to these needs, the importance of studies on nucleic acid related compounds continues to increase in many fields. In this review, we introduce some eventful synthetic studies on nucleic acid related compounds in my research life.

How do you increase total yield in natural product synthesis? This is a permanent question for organic chemists. I would like to propose one answer for the question in this article.

Endeavors toward natural product synthesis could always be a potential source of inspiration and an opportunity for the discovery of new chemical transformations. Topics from three total syntheses are reviewed to illustrate these valuable aspects of total synthesis study.

(+)-Iso-A82775C is one of the proposed biosynthetic precursors of chloropupukeananin and an important intermediate for related bioactive natural products. The first enantioselective total synthesis of (+)-iso-A82775C toward the eventual biomimetic total synthesis of chloropupukeananin has been achieved. The key steps of the total synthesis are the enantioselective Diels-Alder reaction of 4-bromo-3-hydroxy-2-pyrone with methyl 2-chloroacrylate catalyzed by cinchona alkaloids and the anti-selective Cu-mediated S_N2' reaction to afford the axially chiral vinylallene moiety. Herein the details and inside stories are disclosed.

Design and synthesis of ester bond-containing, unique precursor polypeptides opened the door for efficient chemical synthesis of aggregative amyloid peptides and human insulin. Peptide oligomers, derived from the aggregation of monomeric peptide, play important roles both in physiological and pathological events. The functions and higher-order structures of the oligomers are elusive, however, due to the transient, unstable properties of the oligomer states. We propose chemical synthesis of a stable oligomer model, which offers unexplored insight into the structure-function relationships of the peptide oligomers.

In this mini-review article, di(4-fluoro)phenylborinic acid (3c) catalyzed 1,2-cis-α and β-stereoselective glycosylations using 1,2-anhydroglucose donor 8 and 1,2-anhydromannose donor 11, respectively, that have recently been developed in our laboratory, are introduced. In addition, representative applications of these glycosylation methods to the stereoselective synthesis of biologically active natural products, GSL-1 and acremomannolipin A, are also introduced.

Stereoselective synthesis of the proposed C79-C104 fragment of symbiodinolide, a polyol marine natural product, revealed that the stereochemistry of the C91-C99 carbon chain domain of this natural product needs to be reassigned. Next, stereodivergent synthesis of eight possible diastereomers corresponding to the C79-C97 and C94-C104 fragments resulted in the proposal of two candidate stereostructures, respectively. The synthesis of four candidate compounds of the C79-C104 fragment and comparison of their ¹³C NMR data with those of the natural product allowed stereostructural revision of this fragment of symbiodinolide.

Herein, our synthetic strategies toward polyketide-derived polycyclic compounds are described. Our approaches are based on the construction of isoxazole-fused polycyclic structure with an angular hydroxy group via (1) annulation via benzonitrile oxide and (2) benzoin cyclization. Also described is the stereocontrolled introduction of angular substituents via pinacol-type 1,2-shift and N-methylation/hydroxylation, paving a way to advanced intermediates. The synthetic utility has been highlighted by successful total syntheses of some structurally complex, polycyclic natural products, such as BE-43472B, pleospdione, and tetracenomycin C.

Triplex DNA is a powerful tool for the genome researches and genome targeting technologies. However, there is an intrinsic limitation to form the stable triplex DNA at any duplex DNA sequence. Recently, we have developed the artificial nucleoside analogue to recognize the CG base pair that cannot be stabilized by natural nucleic acids. Interestingly, the artificial nucleic acid was designed on the basis of the natural T-CG triplex formation. Consequently, we succeeded in expanding the triplex DNA recognition code and achieved the inhibition of the gene expression by the novel antigene triplex forming oligonucleotides.

The first total synthesis of avenaol, which is the first reported natural C₂₀ germination stimulant structurally related to strigolactones, was achieved using a new robust strategy involving all-cis-substituted cyclopropane formation via an alkylidencyclopropane. The keys to success for the total synthesis were (i) Rh-catalyzed intramolecular cyclopropanation of an allene, (ii) Ir-catalyzed stereoselective double-bond isomerization, and (iii) regioselective oxidation of tetrahydropyran. This strategy effectively avoids cyclopropane ring opening and undesired formation of a cage structure.

Colibactin, a secondary metabolite produced by a commensal Escherichia coli harboring pks island, exhibits a genotoxicity to mammalian cells and progresses to colorectal cancer. Regardless of potential risk for the promotion of cancer by colibactin, which shows neither a biological mechanism of action nor determination of chemical structure. Analysis of a genetic mutant of colibactin-producing E. coli enabled us to provide biosynthetic intermediates and shunt products associated with a partial structure of colibactin. This review covers the recent findings of the biosynthesis and implication of chemical structure of colibactin.

There have been a lot of scientific issues and their solutions found through the total synthesis of complex and synthetically challanging natural products. Ryanodine, a potent modulator of intracellular calcium release channels, is one of the most highly oxygenated molecules in all terpenoids, and its total synthesis is an exceptionally challenging task. Here, I will introduce the extreme synthetic difficulty and its solution focusing on the C15-hemiacetal construction from our total synthesis of ryanodine. We developed a new combination of cobalt-catalyzed hydroperoxidation and NfF-promoted elimination that enabled conversion of the hindered olefin into the corresponding ketone.

Asymmetric total syntheses and structure revision of dihydroisocoumarin-type natural products, eurotiumide A and eurotiumide B have been described. Key features of these total syntheses are the asymmetric Shi epoxidation, regioselective epoxide opening, and Pd-catalyzed CO insertion-lactonization cascade reaction to construct 4-methoxyisochroman-1-one skeleton. X-ray crystallographic analysis of the key intermediate revealed the absolute configuration and relative structure of eurotiumides, and it revised the reported structures of eurotiumide A and B, respectively. These natural products also exhibited highly fluorescence with several solvents with large Stokes shift.

Asparagine-linked oligosaccharides (N-glycans) have high diversity and are involved in a variety of important physiological events. To reveal the molecular basis of N-glycans functions, we synthesized N-glycans. We employed convergent synthetic route: two non-reducing end donors were connected to the reducing-end acceptor at the blanched mannose. Intermolecular hydrogen bonds involving acetamide were discovered to reduce the reactivity in glycosylations: the protection of NHAc as NAc₂ improved the reactivity. We also found that ether solvents enhanced the yields of key glycosylations between large fragments by stabilization of the oxocarbenium ion intermediate. To improve the α-selectivity of these glycosylations, we manipulated the remote participation because neighbouring group participation from 2 position of donor was not available.

Azadirachtin is a complex natural product, which possesses sixteen contiguous stereogenic centers as well as various oxygen-containing functional groups. Completing the synthesis of this compound is one of the greatest challenges for synthetic chemists. It took about twenty-six years for us to achieve the second synthesis of azadirachtin in the world. In this article, I wish to describe the details of our synthetic studies on azadirachtin.

In 2048, the vast majority of occupations have been replaced by artificial intelligence (AI), we do not do the routine work anymore. In the research of natural product synthesis, it is scenery completely different from the research environment 30 years ago. Here, I anticipate how the synthesis of natural products changed in 30 years.

Limonin, the flagship congener of the limonoid tetranortriterpenoids, is a highly oxygenated natural product. Here, the author reports a personal account on the total synthesis of limonin.

To conjugate two azide molecules easily, I recently developed a transient protection method of cyclooctynes from cycloaddition with an azide via 1 : 1 complexation with a cationic copper(I) salt. Protection of a cyclooctyne bearing a terminal alkyne with a copper salt enabled the selective copper-catalyzed click conjugation with an azide at the terminal alkyne moiety, facilitating easy preparation of cyclooctyne derivatives.

Cyclic peptides have been emerged as novel candidates for recent drug discovery, because cyclization or introduction of unnatural amino acid residues significantly improve physicochemical properties such as metabolic stability and cell permeability. Toward elucidation of the mode of action of cyclic peptides, we intensely investigated the structure-activity relationships study based on the total synthesis of naturally occurring cyclic peptides and its analogues utilizing solid-phase. Herein, we describe the details of total synthesis of spiruchostatin A, a potent histone deacetylase inhibitor, using a macrolactonization on the silyl-linked polymer-support.