芳香族カルボン酸誘導体は市販試薬や合成中間体として頻繁に見られる合成化学におけるユビキタス構造体である。芳香族カルボン酸誘導体は非常に安価であり、複素環合成法においては、原料にカルボン酸誘導体が用いられ、合成後の芳香環上にカルボン酸、およびエステル基は保持される。それらを他の官能基に変換することなく、直接、炭素骨格やヘテロ原子を含む化合物へ変換することは、工程数を低減させるのみならず、合成戦略を一新できる可能性がある。我々は芳香族カルボン酸誘導体の１つである芳香族エステルを標的として、ニッケル触媒を用いた脱カルボニル型反応を世界に先駆けて報告した。本年度は、エステルの非線形型の変換反応として、転移（メタセシス反応）、脱酸素型カップリング反応、エステルダンス反応という３つの新形式の反応を見いだすことに成功した。
脱酸素型カップリング反応：以前、ニッケル触媒存在下、芳香族エステルを用いた有機リン化合物との脱カルボニル型C－P結合形成反応を開発した。この反応では芳香族エステルがアリール化剤として機能し、対応する芳香族リン化合物が得られる。一方我々は、用いる金属触媒をパラジウムへと変えることで、芳香族エステルがベンジル化剤としてはたらき、ベンジルリン化合物が得られることを見いだした。本反応はパラジウム/dcypt、添加剤としてギ酸ナトリウムを用いることで効率的に進行する。
エステルダンス反応：パラジウム/dcypt触媒を用いることで、芳香族エステルのエステル骨格を結合位置のみ変えて、となりの炭素上に移動（1,2-転移）させる「エステルダンス反応」が進行することを見出した。有機化合物に頻出する構造の一つであるエステル骨格を芳香環上で1,2-転移させる反応は本例が初めてである。また、遷移金属触媒を用いることで効率的に進行する芳香族化合物の分子内転移反応は例が無いユニークな反応である。

パラジウム触媒を用いてベンジルホスファートやカーボナートに対して、アリルボラートを反応させることで目的とする脱芳香族的アリル化が進行することを見出した。 本反応は触媒的に、かつ一当量のベンジルホスファート類を用いることで進行する。ベンジル位の結合切断を促進する高い電子供与性の配位子をもつパラジウム触媒の適用が重要であり、金属上の電子密度を高くしていくにつれて反応の収率が向上した。生成する化合物の誘導化にも成功し、有用な脂環式ビルディングブロックを簡便に合成できた。さらに、本研究を基盤とし、ベンジル位炭素ー酸素結合切断に加え、他の炭素ーヘテロ結合切断をともなう脱芳香族的官能基化も見いだした。

本研究は炭素－炭素結合切断反応を起点とする、触媒的カップリング反応・付加反応に関する革新的な有機合成反応およびそれを促進する新規触媒の開発を目的とした。具体的には芳香族エステルの脱カルボニル型カップリング反応の拡張とシクロプロパンのsp3炭素-炭素結合に対する原子付加反応の開発に着手した。その結果、10種類以上の異なる求核剤を用いる芳香族エステルの脱カルボニル型カップリング反応を見いだすことができた。また、シクロプロパンに対するヒドロシリル化反応およびヒドロホウ素化反応を開発することに成功した。

本研究では、中分子化合物である複雑チオペプチド抗生物質の多様性合成を目指し、新規カップリング反応/環変換反応によるトリアリールピリジンの迅速合成と、2つの化学ライゲーション法を駆使したペプチド結合形成法を確立する。また、核となるマルチアリールヘテロ環の合成法を確立することを目的とした。
本年度は、多種類のアリール基で置換されたナフタレン、アントラセンおよび、機能性分子の重要骨格であるベンゾヘテロール化合物の合成に着手した。
1. 多種類のアリール基で置換されたナフタレン、アントラセンの自在合成：テトラアリールチオフェンオキシドとアラインとの [4+2]付加環化反応を用いることでオクタアリールナフタレン、オクタアリールアントラセン、デカアリールアントラセンを合成した。本手法に従えば、チオフェンに導入するアリール基の種類を変えることで、ナフタレン、アントラセンの望みの位置にアリール基が導入可能となる。
2. ヘプタアリールインドールの新規合成法の開発：多数の置換基を導入する多置換インドール合成に関しては未だ効率的な手法は限られ、特に３つ以上の異なる官能基を効率的に導入する手法は限られている。他のベンゾヘテロールの合成法に関しても同様の合成上の問題を抱えている。これらが多置換ベンゾヘテロール化学の化学的・物理学的性質・応用への進展を妨げているといっても過言ではない。今回、４つの簡便な部品（ジアリールインドール・アリールボロン酸・アリールブロモアセチレン・アリールアジリジン）を繋げイナミド中間体とした後に、逆電子要請型分子内[4+2]付加環化反応、続く酸化反応によるペンタアリールインドール(PAI)の合成、続く２度のアリール化反応によってヘプタアリールインドール(HAI: heptaarylindole)を合成することに成功した。

本研究では、先に見出していた2種類の芳香族エステルのカップリング反応（ニッケル触媒による脱エステル型C-Hアリール化反応・ニッケル触媒による鈴木ー宮浦型カップリング反応）を基盤とし、潜在的な求核剤を様々なヘテロ原子を含む化合物や炭素骨格へと大幅に拡大を試みた。すなわち、芳香族エステルから直接炭素―炭素結合形成、炭素―ヘテロ原子結合反応の開発を行った。昨年度は３つの新しい求核剤を見いだしたが、、今年度さらに3つの求核剤を用いた新規芳香族エステルの脱カップリング反応の開発に成功した
1. ヘテロ芳香環エステルとケトンのα-アリール化反応
2 芳香族エステルの脱カルボニル型炭素-;リン結合形成反応.
3. ニッケル触媒による芳香族エステルの脱カルボニル型アルキル化反応
1：用いるヘテロ芳香族エステルには、基質制限があるものの、ヘテロ芳香族エステルとケトンからクライゼン縮合が進行することなく、α-アリールケトンが得られる。独自に開発したdcypt[3,4-ビス(ジシクロヘキシルホスフィノ)チオフェン]が最も効果的である。2：広範な芳香族フェニルエステルで反応が進行し、リン求核剤としてはジアリールホスフィンオキシドやジアルキル亜リン酸が適用できる。3: 興味深いことにジアルキル塩化アルミが最も効率的なアルキル化剤として働く。本反応は、芳香族フェニルエステルに加えて、芳香族アルキルエステルに対しても適用可能である。
このように自身で開発した芳香族エステルのカップリング反応の可能性を大幅に拡張することに成功した。

天然物Fusicoccin A の全合成と各種誘導体合成および生物活性評価による構造活性相関研究を目指し、三環式炭素骨格の合成に挑戦した。ベンゼンに4炭素ユニットの側鎖を導入し、4-6-4炭素骨格を5-8-5縮環構造に変換するという極めて斬新な合成計画であった。すなわち、置換ベンゼンから連続的な環拡大反応で行い 、6員環を8員環に変換する。市販化合物から7工程で得られた置換ベンゼンに、Rh(II)触媒を作用させてBuchner反応を試みた。その結果、立体選択的なシクロプロパン化条件を見出し、続く中間体のジビニルシクロプロパン転位により、7員環をほぼ単一の生成物で定量的に得た。

本研究では、分子結合活性化による直接的カップリング反応の新しい分子触媒を開発することを目的として研究を行った。合成した触媒を用いて、これまで達成できなかった、炭素－水素(結合、炭素－酸素結合、炭素-炭素結合を同時に活性化できる次世代カップリング法を開発した。直接的不斉カップリングも視野にいれ本手法を活用する事で生物活性物質の合成に応用することができた。

本研究では、不活性C-H結合、C-O結合およびC-C結合を活性化・官能基化できる新触媒・新反応を開発し、生物活性分子の超短工程合成を実現する。主に医薬品や天然物等の生物活性化合物に標的を設定し、反応開発研究と合成研究が連動するダイナミックな研究を行う。生物活性分子の迅速合成の為に必須である、具体的にはヘテロ芳香環、オレフィン、sp3炭素を含む最も理想的なC-H結合活性化、安定で豊富に存在するC-O結合活性化、さらにユビキタス官能基であるエステルのC-C結合活性化反応を合成化学的に実用的な反応に飛躍的に発展させる。今年度は、エステルのC-C結合活性化反応に注力し、ニッケル触媒を用いた有機ボロン酸との新規カップリング反応、脱エステル型カップリング反応を駆使した、トリチアゾリルペプチド抗生物質の合成に成功した。また、C-H結合及びC-O結合の活性化によりカルボニル化合物のα-アリール化反応や、イミダゾール類の触媒的直接的アリール化反応も見出した。

本研究では、不活性C-H結合を活性化・官能基化する新触媒・新反応を開発し、生物活性物質の超短工程合成を実現することを目的とした。昨年度に引き続き研究を行なった結果、ヘテロビアリール骨格を有する生物活性分子の合成を加速する新規芳香環直接アリール化反応を開発することができた。
1. Ni触媒を用いた脱エステル型カップリング反応 既にアリール化剤としてハロゲン化アリール、フェノール誘導体をもちいたNi触媒によるアゾール類の直接アリール化反応を見出していたが、今回芳香族エステルをアリール化剤とした新たなカップリング反応を発見した。本反応を応用したmuscoride Aの形式全合成も達成した
2.嵩高いビアリール合成を促進する新規パラジウム触媒の開発 独自に開発したパラジウム触媒によるチオフェン類とアリールボロン酸とのC4位選択的なC-Hアリール化反応を基盤として、嵩高いヘテロビアリール骨格の構築を様々な配位子を用いて検討を行なった。その結果、ビスオキサゾリン配位子を用いた場合、劇的な反応加速効果がみられ、嵩高いアリールボロン酸においても良好な収率でチオフェンやフラン、インドールなどのヘテロ芳香環と反応が進行することを見出した。さらにキラル配位子を用いた不斉反応へと展開し、不斉C-Hビアリールカップリング反応の開発にも成功した
3. C-Hアリール化のメディシナルケミストリーへの応用 σ1受容体として有効な化合物を探索した結果、スピロ環を有するアリールチオフェン骨格がσ1受容体として優れていることが明らかとなっている。今回、独自で開発したC5位およびC4位選択的チオフェンのアリール化反応を用いた、最終段階での直接C-Hアリール化反応を駆使する事でより幅広く誘導体を合成することに成功した

生物活性天然物や医農薬化合物に頻繁に見られるインドールーアジン骨格を最も理想的かつ直接的に構築する新規反応を開発した。開発した反応を駆使することでdragmacidin D, eudistomin Uなどの天然物有機化合物群合成への応用展開に成功した。

© 2018 Elsevier Ltd Lysine-specific demethylase 1 (LSD1) is an attractive molecular target for cancer therapy. We have previously reported potent LSD1-selective inhibitors (i.e., NCD18, NCD38, and their analogs) consisting of trans-2-phenylcyclopropylamine (PCPA) or trans-2-arylcyclopropylamine (ACPA) and a lysine moiety that could form a γ-turn structure in the active site of LSD1. Herein we report the design, synthesis and evaluation of γ-turn mimetic compounds for further improvement of LSD1 inhibitory activity and anticancer activity. Among a series of γ-turn mimetic compounds synthesized by a Mitsunobu-reaction-based amination strategy, we identified 1n as a potent and selective LSD1 inhibitor. Compound 1n induced cell cycle arrest and apoptosis through histone methylation in human lung cancer cells. The γ-turn mimetics approach should offer new insights into drug design for LSD1-selective inhibitors.

A decarbonylative aryl thioether synthesis by nickel catalysis is described. After optimization of the reaction conditions, two air-stable Ni catalytic systems [Ni(OAc)2/PnBu3 and Ni(OAc)2/dppb] were identified. Using these catalysts, various aryl thioesters can be converted to the corresponding aryl thioethers in decarbonylative fashion.

Multiply arylated (hetero) arenes are intriguing structural motifs in functional molecules, such as natural products, pharmaceuticals and functional organic materials. In recent decades, many synthesis methods of multiply arylated (hetero) arenes have been reported. As a subclass of multiply arylated arenes, fully arylated (hetero) arenes have also flourished as a unique structural class in functional organic materials and biologically active compounds. Despite the successful application of fully arylated (hetero) arenes with different aryl substituents, the synthesis of such (hetero) arenes has not been explored compared to partially arylated arenes due to the difficulty of synthesizing sterically hindered and highly unsymmetrical aromatic cores. This review reports the synthesis of fully arylated (hetero) arenes bearing more than two different aryl substituents and categorizes this emerging topic by the type of (hetero) arene core, focusing on the methods employing cross-coupling reaction including direct C-H arylation.

Transition metal-catalyzed cross-coupling reactions are a powerful method to form chemical bonds. Conventionally, haloarenes has been used as the most reliable aryl electrophiles in cross- coupling. Recent studies in the cross-coupling arena have enabled to employ unconventional but ubiquitous aryl electrophiles such as phenol and aniline. With this trend of organic synthesis, cross-coupling reactions using aromatic carboxylic acid derivatives such as esters as aryl electrophiles have gained considerable attention as a de novo and efficient method to construct C-C and C-heteroatom bonds. In order to realize this particular transformation, it is important to develop and design transition metal catalysts, those are active toward the scission of ester C-O bonds and decarbonylation. In this review, we describe the progress of catalytic decarbonylative cross- coupling of aromatic esters including chronological aspects and mechanistic considerations.

The first synthesis of heptaarylindole (HAI) has been accomplished using a coupling/ring transformation strategy. Four readily prepared modular units (diarylthiophenes, 2-arylaziridines, arylboronic acids, and arylalkynes) were joined together to provide key ynamide intermediates. Subsequent inverse electron-demand intramolecular [4 + 2] cycloaddition furnished pentaarylindoles (PAIs) regioselectively. This strategy was also applied to the synthesis of tetraarylazaindole with four different aryl substituents. PAIs underwent further arylations at the C2- and N1-positions, providing HAI with seven different aryl substituents with virtually complete regioselectivity.

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.

© 2018 The Chemical Society of Japan. In a novel disconnection of isoquinoline ring synthesis at the C7C8/C4aC8a bonds, these bonds can be formed by a [4+2] cycloaddition between thiophene S,S-dioxide and alkynes. With a subsequent CH arylation of the resulting hexaarylisoquinoline at the C3 position, the synthesis of a fully substituted isoquinoline has been achieved.

© Georg Thieme Verlag Stuttgart, New York. Heteroaromatic esters were found to be applicable as an arylating agent for the Pd-catalyzed α-arylation of ketones in a decarbonylative fashion. The use of our in-house ligand, dcypt, enabled this unique bond formation. Considering the ubiquity and low cost of aromatic esters, the present work will allow for rapid access to valuable α-aryl carbonyl compounds.

A synthesis of multiply arylated naphthalenes and anthracenes with eight different substituents has been accomplished. The key intermediates are tetraarylthiophene S-oxides, which are synthesized through a method involving sequential C H arylation and cross-coupling from 3-methoxythiophene, followed by oxidation of the sulfur atom. The resulting tetraarylthiophene S-oxides can be converted into a tetraaryl benzynes or naphthalynes and then merged through [4+2] cycloaddition reaction with another tetraarylthiophene S-oxide, thereby resulting in the programmed synthesis of octaarylnaphthalenes and octaarylanthracenes.

Catalytic cross-coupling reactions of aromatic esters and amides have recently gained considerable attention from synthetic chemists as de novo and efficient synthetic methods to form C-C and C-heteroatom bonds. Esters and amides can be used as diversifiable groups in metal-catalyzed cross-coupling: in a decarbonylative manner, they can be utilized as leaving groups, whereas in a non-decarbonylative manner, they can form ketone derivatives. In this review, recent advances of this research topic are discussed.

© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Spirocyclic thiophene derivatives represent promising σ1ligands with high σ1affinity and selectivity over the σ2subtype. To increase ligand efficiency, the thiophene ring was replaced bioisosterically by a thiazole ring, and the pyran ring was opened. Late-stage diversification by regioselective C−H arylation of thiazoles 9 a–c resulted in a set of 53 compounds with high diversity. This set of compounds was analyzed with respect to σ1affinity, σ1/σ2selectivity, lipophilicity (logD7.4), lipophilicity-corrected ligand efficiency (LELP), and molecular target interactions. The most promising candidates were pyridyl-substituted thiazole derivatives 33 c (2-(1-benzyl-4-ethoxypiperidin-4-yl)-5-(pyridin-3-yl)thiazole) and 34 c (2-(1-benzyl-4-ethoxypiperidin-4-yl)-5-(pyridin-4-yl)thiazole), possessing low-nanomolar σ1affinity (Ki=1.3 and 1.9 nm), high σ1/σ2selectivity (>1500-fold), low lipophilicity (logD7.4=1.8) and very good ligand efficiency (LELP=5.5), indicating promising pharmacodynamics and pharmacokinetics. Molecular simulation studies, including docking and deconvolution of the free binding energy into its major components, led to decreased hydrophobic stabilization of pyridyl derivatives 33 c and 34 c, which was compensated by lower desolvation energy.

We have achieved a synthesis of multiply arylated pyridines by using a [4 + 2] cycloaddition of 2,4-diaryl-5-chloroxazoles and cinnamic acids as a key reaction. The resulting hydroxytriarylpyridines can be derivatized into triarylpyridines, tetraarylpyridines and pentaarylpyridines by sequential cross couplings. This synthetic method allows for facile and rapid access to highly arylated pyridines with different aryl substituents. (C) 2017 Elsevier Ltd. All rights reserved.

A Rh-catalyzed regiodivergent hydrosilylation of acyl aminocyclopropanes has been developed. Acyl aminocyclopropanes were reacted with hydrosilanes in the presence of Rh catalysts to afford ring-opened hydrosilylated adducts through carbon-carbon (C-C) bond cleavage of the cyclopropane ring. The regioselectivity of the addition of silanes (linear or branched) can be switched by changing the monophosphine ligand. This C-C bond cleavage/hydrosilylation methodology is applicable to the synthesis of silanediol precursors.

The mechanism of an aromatic C-H coupling reaction between heteroarenes and arylboronic acids using a Pd catalyst was theoretically and experimentally investigated. We identified the C-B transmetalation as the rate determining step. The (S)-catalyst-reactant complex was found to be stabilized by hyperconjugation between pi-orbitals on the tolyl group and the S-O sigma* antibonding orbital in the catalyst ligand. Our findings suggest routes for the design of new, improved Pd catalysts with higher stereoselectivity.

C-H (hetero) arylation of aromatic compounds using transition-metal catalysts has garnered much attention from the synthetic chemistry community as a next-generation coupling method for constructing (hetero) biaryl motifs. This account describes our recent achievements in transitionmetal-catalyzed aromatic C-H arylation and its applications to the synthesis of bioactive molecules.

Because diaryl ethers are present as an important motif in pharmaceuticals and natural products, extensive studies for the development of novel methods have been conducted. A conventional method for the construction of the diaryl ether moiety is the intermolecular cross-coupling reaction of aryl halides and phenols with a copper or palladium catalyst. We developed a catalytic decarbonylative etherification of aromatic esters using a palladium or nickel catalyst with our enabling diphosphine ligand to give the corresponding diaryl ethers. The present reaction can be conducted on grain scale in excellent yield. This reaction not only functions in an intramolecular setting but also allows for a crossetherification using other phenols.

The 2-arylcyclopropylamine (ACPA) motif is often seen in biologically active compounds. This review focuses on the synthesis of biologically active ACPAs and categorizes, by reaction type, the synthetic methods used toward such compounds.
1 Introduction
2 Cyclopropanation Using Diazo Compounds
2.1 Styrene
2.2 Cinnamate
2.3 Vinyl Phthalimide
2.4 Vinyl Acetamide
2.5 Oxazolone
2.6 Diketopiperazine
3 Cyclopropanation Using Ylides
3.1 Cinnamate
3.2 Nitrostyrene
3.3 Oxirane
3.4 Nitroacetate
4 Transformation of Cyclopropanes
4.1 Iodocyclopropane
4.2 Aminocyclopropane
5 Miscellaneous Methods
5.1 Kulinkovich Reaction
5.2 Three-Component Reaction
5.3 Intramolecular Nucleophilic Cyclization
5.4 Intramolecular Mitsunobu Reaction
5.5 Rearrangement from Cyclobutanone
6 Summary

A palladium-catalyzed decarbonylative alkynylation reaction of aromatic esters with terminal alkynes is reported. This reaction allows for halogen-free Sonogashira coupling, resulting in various aryl- and heteroarylalkynes. The utility of the reaction was demonstrated by orthogonal coupling reaction.

© The Royal Society of Chemistry. Multiply arylated arenes are privileged structures with highly useful functions and fascinating optoelectronic and biological properties. This feature article reports the synthesis of fully arylated (hetero)arenes bearing more than two different aryl substituents and categorizes this emerging topic by the type of (hetero)arene core and the type of chemistry employed to install the (hetero)aryl substituents.

The first palladium-catalyzed decarbonylative coupling of phenyl 2-azinecarboxylates and arylboronic acids is presented. The key for the development of this decarbonylative coupling is the use of Pd/dcype as a catalyst. A wide range of 2-azinecarboxylates can undergo the present coupling reaction to afford 2-arylazines. By combination with previously reported nickel-catalyzed decarbonylative coupling, we achieved a chemoselective sequential decarbonylative coupling of pyridine dicarboxylate to synthesize 2,4-diarylpyridine.

Generation of useful arylnitrile structures from simple aromatic feedstock chemicals represents a fundamentally important reaction in chemical synthesis. The first nickel-catalyzed cyanation of phenol derivatives with metal-free cyanating agents, aminoacetonitriles, is described. A nickel-based catalytic system consisting of a unique diphosphine ligand such as dcype or dcypt enables the cyanation of versatile phenol derivatives such as aryl carbamates and aryl pivalates. The use of aminoacetonitriles as a cyanating agent leads to an environmentally and easy-to-use method for arylnitrile synthesis.

© 2016, Springer International Publishing Switzerland. Catalytic C–H functionalization using transition metals has received significant interest from organic chemists because it provides a new strategy to construct carbon–carbon bonds and carbon–heteroatom bonds in highly functionalized, complex molecules without pre-functionalization. Recently, inexpensive catalysts based on transition metals such as copper, iron, cobalt, and nickel have seen more use in the laboratory. This review describes recent progress in nickel-catalyzed aromatic C–H functionalization reactions classified by reaction types and reaction partners. Furthermore, some reaction mechanisms are described and cutting-edge syntheses of natural products and pharmaceuticals using nickel-catalyzed aromatic C–H functionalization are presented.

Catalytic C-H functionalization using transition metals has received significant interest from organic chemists because it provides a new strategy to construct carbon-carbon bonds and carbon-heteroatom bonds in highly functionalized, complex molecules without pre-functionalization. Recently, inexpensive catalysts based on transition metals such as copper, iron, cobalt, and nickel have seen more use in the laboratory. This review describes recent progress in nickelcatalyzed aromatic C-H functionalization reactions classified by reaction types and reaction partners. Furthermore, some reaction mechanisms are described and cutting-edge syntheses of natural products and pharmaceuticals using nickel-catalyzed aromatic C-H functionalization are presented.

Precise directional control of pollen-tube growth by pistil tissue is critical for successful fertilization of flowering plants [1-3]. Ovular attractant peptides, which are secreted from two synergid cells on the side of the egg cell, have been identified [4-6]. Emerging evidence suggests that the ovular directional cue is not sufficient for successful guidance but that competency control by the pistil is critical for the response of pollen tubes to the attraction signal [1, 3, 7]. However, the female molecule for this competency induction has not been reported. Here we report that ovular methyl-glucuronosyl arabinogalactan (AMOR) induces competency of the pollen tube to respond to ovular attractant LURE peptides in Torenia fournieri. We developed a method for assaying the response capability of a pollen tube by micromanipulating an ovule. Using this method, we showed that pollen tubes growing through a cut style acquired a response capability in the medium by receiving a sufficient amount of a factor derived from mature ovules of Torenia. This factor, named AMOR, was identified as an arabinogalactan polysaccharide, the terminal 4-O-methyl-glucuronosyl residue of which was necessary for its activity. Moreover, a chemically synthesized disaccharide, the β isomer of methyl-glucuronosyl galactose (4-Me-GlcA-β-(1→6)-Gal), showed AMOR activity. No specific sugar-chain structure of plant extracellular matrix has been identified as a bioactive molecule involved in intercellular communication. We suggest that the AMOR sugar chain in the ovary renders the pollen tube competent to the chemotropic response prior to final guidance by LURE peptides.

We have described a C-H arylation/ring-transformation strategy for the synthesis of triarylpyridines, which form the core structure of thiopeptide antibiotics. This synthetic method readily gave 2,3,6-triarylpyridines in a regioselective manner by a two-phase approach: C-H arylation (a nickel-catalyzed decarbonylative Suzuki-Miyaura cross-coupling and decarbonylative C-H coupling for the synthesis of 2,4-diaryloxazoles) and ring transformation ([4+2] cycloaddition of 2,4-diaryloxazoles with (hetero)arylacrylic acids). To showcase these methods, we have accomplished the formal synthesis of thiopeptide antibiotics GE2270s and amythiamicins.

The synthesis of natural products and pharmaceuticals, particularly those containing heterocyclic frameworks, can be dramatically simplified by using catalytic C-H functionalization. C-H functionalization has gathered significant interest from the organic synthesis community because it provides a new strategy to construct carbon-carbon and carbon-heteroatom bonds in highly functionalized, complex molecules without prefunctionalization. In this book chapter, methods in heterocycle substitution and synthesis using catalytic C-H functionalization are classified by heterocycle, with specific focus on the cutting-edge synthesis of natural products and pharmaceuticals.

© 2016 The Royal Society of Chemistry. We describe the structure-activity relationship of various arylcyclopropylamines (ACPAs), which are potent LSD1 inhibitors. More than 45 ACPAs were synthesized rapidly by an unconventional method that we have recently developed, consisting of a C-H borylation and cross-coupling sequence starting from cyclopropylamine. We also generated NCD38 derivatives, which are known as LSD1 selective inhibitors, and discovered a more effective inhibitor compared to the original NCD38.

© The Royal Society of Chemistry 2016. New thiazole analogues 2 of spirocyclic thiophenes 1, which are known to show high σ1receptor affinities, have been developed as potentially better σ1receptor ligands. To introduce an aryl group onto the thiazole core of 2 (C4 or C5 positions), we used Pd-catalyzed regioselective C-H arylation reactions. The Pd-catalyzed C5 arylation of 2a could be considerably improved by using microwave irradiation technique. The Pd-catalyzed C4 arylation of thiazole 2a with arylboronic acid 6 could be achieved in the presence of Pd(OAc)2, 1,10-phenanthroline, TEMPO, and LiBF4. Under these conditions, the tertiary amine and the tertiary alcohol were well-tolerated. The regioselective arylation of 2a led to new compounds 2b and 2c, with a 4-tolyl moiety in the C5- and C4-positions, displaying five to nine-fold increased σ1affinity. The same σ1affinity of the regioisomeric thiazoles 2b and 2c can be explained by fast rotation around the piperidine-thiazole bond. Compared to spirocyclic thiophenes 1, thiazoles 2 are considerably more polar.

The synthesis and functional analysis of KL001 derivatives, which are modulators of the mammalian circadian clock, are described. By using cutting-edge C-H activation chemistry, a focused library of KL001 derivatives was rapidly constructed, which enabled the identification of the critical sites on KL001 derivatives that induce a rhythm-changing activity along with the components that trigger opposite modes of action. The first period-shortening molecules that target the cryptochrome (CRY) were thus discovered. Detailed studies on the effects of these compounds on CRY stability implicate the existence of an as yet undiscovered regulatory mechanism.

The Suzuki-Miyaura cross-coupling is a metal-catalysed reaction in which boron-based nucleophiles and halide-based electrophiles are reacted to form a single molecule. This is one of the most reliable tools in synthetic chemistry, and is extensively used in the synthesis of pharmaceuticals, agrochemicals and organic materials. Herein, we report a significant advance in the choice of electrophilic coupling partner in this reaction. With a user-friendly and inexpensive nickel catalyst, a range of phenyl esters of aromatic, heteroaromatic and aliphatic carboxylic acids react with boronic acids in a decarbonylative manner. Overall, phenyl ester moieties function as leaving groups. Theoretical calculations uncovered key mechanistic features of this unusual decarbonylative coupling. Since extraordinary numbers of ester-containing molecules are available both commercially and synthetically, this new 'ester' cross-coupling should find significant use in synthetic chemistry as an alternative to the standard halide-based Suzuki-Miyaura coupling.

Since its discovery in 1825, benzene has served as one of the most used and indispensable building blocks of chemical compounds, ranging from pharmaceuticals and agrochemicals to plastics and those used in organic electronic devices. Benzene has six hydrogen atoms that can each be replaced by different substituents, which means that the structural diversity of benzene derivatives is intrinsically extraordinary. The number of possible substituted benzenes from n different substituents is (2n + 2n(2) + 4n(3) + 3n(4) + n(6))/12. However, owing to a lack of general synthetic methods for making multisubstituted benzenes, this potentially huge structural diversity has not been fully exploited. Here, we describe a programmed synthesis of hexaarylbenzenes using C-H activation, cross-coupling and [4+2] cycloaddition reactions. The present method allows for the isolation and structure-property characterization of hexaarylbenzenes with distinctive aryl substituents at all positions for the first time. Moreover, the established protocol can be applied to the synthesis of tetraarylnaphthalenes and pentaarylpyridines.

CCR2 and CCR5 receptors play a key role in the development and progression of several inflammatory, cardiovascular and autoimmune diseases. Therefore, dual targeting of both receptors appeals as a promising strategy for the treatment of such complex, multifactorial disorders. Herein we report on the design, synthesis and biological evaluation of benzo[7] annulene- and [7] annulenothiophene-based selective and dual CCR2 and CCR5 receptor antagonists. Intermediates were designed in such a way that diversification could be introduced at the end of the synthesis. Starting from the lead compound TAK-779 (1), the quaternary ammonium moiety was exchanged by different non-charged moieties, the 4-methylphenyl moiety was extensively modified and the benzo[7]annulene core was replaced bioisosterically by the [7]annulenothiophene system. The naphthyl derivative 9h represents the most promising dual antagonist (K-i (CCR2) = 25 nM, IC50 (CCR5) = 17 nM), whereas the 6-isopropoxy-3-pyridyl and 4-methoxycarbonylphenyl derivatives 9k and 9r show more than 20-fold selectivity for the CCR2 (K-i = 19 nM) over the CCR5 receptor.

The first nickel-catalyzed C-H arylations and alkenylations of imidazoles with phenol and enol derivatives are described. Under the influence of Ni(OTf)(2)/dcype/K3PO4 (dcype: 1,2-bis(dicyclohexylphosphino) ethane) in t-amyl alcohol, imidazoles can undergo C-H arylation with phenol derivatives. The C-H arylation of imidazoles with chloroarenes as well as that of thiazoles and oxazoles with phenol derivatives can also be achieved with this catalytic system. By changing the ligand to dcypt (3,4-bis(dicyclohexylphosphino) thiophene), enol derivatives could also be employed as coupling partners achieving the C-H alkenylation of imidazoles as well as thiazoles and oxazoles. Thus, a range of C2-arylated and alkenylated azoles can be synthesized using this newly developed nickel-based catalytic system. The key to the success of the C-H coupling of imidazoles is the use of a tertiary alcohol as solvent. This also allows the use of an air-stable nickel(II) salt as the catalyst precursor.

A step-economical and stereodivergent synthesis of privileged 2-arylcyclopropylamines (ACPAs) through a C-(sp(3))-H borylation and Suzuki-Miyaura coupling sequence has been developed. The iridium-catalyzed C-H borylation of N-cyclopropylpivalamide proceeds with cis selectivity. The subsequent B-cyclopropyl Suzuki-Miyaura coupling catalyzed by [PdCl2(dppf)]/Ag2O proceeds with retention of configuration at the carbon center bearing the Bpin group, while epimerization at the nitrogen-bound carbon atoms of both the starting materials and products is observed under the reaction conditions. This epimerization is, however, suppressed in the presence of O-2. The present new ACPA synthesis results in not only a significant reduction in the steps required for making ACPA derivatives, but also the ability to access either isomer (cis or trans) by simply changing the atmosphere (N-2 or O-2) in the coupling stage.

© The Royal Society of Chemistry. A nickel-catalyzed α-arylation of esters and amides with phenol derivatives has been accomplished. In the presence of our unique nickel catalyst, prepared in situ from Ni(cod)2, 3,4-bis(dicyclohexylphosphino)thiophene (dcypt), and K3PO4, various esters and amides undergo α-arylation with O-arylpivalates or O-arylcarbamates to afford the corresponding coupling products. The thus obtained α-aryl esters and amides are useful precursors of privileged motifs such as α-arylcarboxylic acids and β-arylamines. This journal is

Syntheses of dictyodendrins A and F have been achieved using a sequential C-H functionalization strategy. The N-alkylpyrrole core is fully functionalized by means of a rhodium(I)-catalyzed C-H arylation at the C3-position, a rhodium(II)-catalyzed double C-H insertion at the C2- and C5-positions, and a Suzuki-Miyaura cross-coupling reaction at the C4-position. The syntheses of dictyodendrins A and F were completed by formal 6p-electrocyclization to generate the pyrrolo[2,3-c]carbazole core of the natural products.

The mechanism of the Ni-dcype-catalyzed C-H/C-O coupling of benzoxazole and naphthalen-2-yl pivalate was studied. Special attention was devoted to the base effect in the C-O oxidative addition and C-H activation steps as well as the C-H substrate effect in the C-H activation step. No base effect in the C(aryl)-O oxidative addition to Ni-dcype was found, but the nature of the base and C-H substrate plays a crucial role in the following C-H activation. In the absence of base, the azole C-H activation initiated by the C-O oxidative addition product Ni(dcype)(Naph)(PivO), 1B, proceeds via Delta G = 34.7 kcal/mol barrier. Addition of Cs2CO3 base to the reaction mixture forms the Ni(dcype)(Naph)[PivOCs.CsCO3], 3_Cs_clus, cluster complex rather than undergoing PivO(-) -> CsCO3(-) ligand exchange. Coordination of azole to the resulting 3_Cs_clus complex forms intermediate with a weak Cs-heteroatom(azole) bond, the existence of which increases acidity of the activated C-H bond and reduces C-H activation barrier. This conclusion from computation is consistent with experiments showing that the addition of Cs2CO3 to the reaction mixture of 1B and benzoxazole increases yield of C-H/C-O coupling from 32% to 67% and makes the reaction faster by 3-fold. This emerging mechanistic knowledge was validated by further exploring base and C-H substrate effects via replacing Cs2CO3 with K2CO3 and benzoxazole (1a) with 1H-benzo[d]imidazole (1b) or quinazoline (1c). We proposed the modified catalytic cycle for the Ni(cod)(dcype)-catalyzed C-H/C-O coupling of benzoxazole and naphthalen-2-yl pivalate.

© 2014 American Chemical Society. The first general β-selective C-H arylation of pyrroles has been developed by using a rhodium catalyst. This C-H arylation reaction, which is retrosynthetically straightforward but results in unusual regioselectivity, could result in de novo syntheses of pyrrole-derived natural products and pharmaceuticals. As such, we have successfully synthesized polycyclic marine pyrrole alkaloids, lamellarins C and I, by using this β-selective arylation of pyrroles with aryl iodides (C-H/C-I coupling) and a new double C-H/C-H coupling as key steps.

A ligand-controlled branch-selective allylic C-H carboxylation through Pd catalysis is described. The developed catalytic system, which consists of Pd(OAc)(2), sulfoxide oxazoline (sox) as a ligand and benzoquinone as an oxidant, couples terminal alkenes and carboxylic acids to furnish the corresponding branched allylic esters with high regioselectivity.

Life-threatening infections caused by bacteria that have developed resistance to common antibiotics, such as methicillin-resistant Staphylococcus aureus (MRSA), have become a serious problem in hospitals and other areas all over the world. Thus, the development of an effective class of antibiotics against these bacteria is an urgent subject. Herein, we report a step-economical and diversity-oriented synthesis of a series of 2-arylidenehydrazinyl-4-arylthiazole and 2-arylidenehydrazinyl-5-arylthiazole analogues that utilizes C-H coupling methodologies. A library of 54 new congeners were synthesized and tested for their biological potential. Moreover, new knowledge regarding the structure-activity relationships (SARs) of these heterobiaryl compounds was collected.

The nickel-catalyzed α-arylation of ketones with readily available phenol derivatives (esters and carbamates) provides access to useful α-arylketones. For this transformation, 3,4-bis(dicyclohexylphosphino) thiophene (dcypt) was identified as a new, enabling, air-stable ligand for this transformation. The intermediate of an assumed C-O oxidative addition was isolated and characterized by X-ray crystal-structure analysis. The nickel-catalyzed α-arylation of ketones with readily available phenol derivatives (esters and carbamates) provides access to useful α-arylketones. The use of 3,4-bis(dicyclohexylphosphino)thiophene (dcypt) as an air-stable ligand enables this transformation. The intermediate of an assumed C-O oxidative addition was isolated and characterized by X-ray crystal-structure analysis. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

We previously reported the discovery of NCH-31, a potent histone deacetylase (HDAC) inhibitor. By utilizing our C-H coupling reaction, we rapidly synthesized 16 analogues (IYS-1 through IYS-15 and IYS-Me) of NCH-31 with different aryl groups at the C4-position of 2-aminothiazole core of NCH-31. Subsequent biological testing of these derivatives revealed that 3-fluorophenyl (IYS-10) and 4-fluorophenyl (IYS-15) derivatives act as potent pan-HDAC inhibitor. Additionally, 4-methylphenyl (IYS-1) and 3-fluoro-4-methylphenyl (IYS-14) derivatives acted as HDAC6-insensitive inhibitors. The present work clearly shows the power of the late-stage C-H coupling approach to rapidly identify novel and highly active/selective biofunctional molecules. © 2014 American Chemical Society.

A programmed synthesis of privileged arylthiazoles via sequential C-H couplings catalyzed by palladium or nickel catalysts has been accomplished. This versatile protocol can supply all possible arylthiazole substitution patterns (2-aryl, 4-aryl, 5-aryl, 2,4-diaryl, 2,5-diaryl, 4,5-diaryl, and 2,4,5-triaryl) from an unfunctionalized thiazole platform by 11 distinct synthetic routes. We have generated over 150 arylthiazoles by using this methodology. We have applied this method to the rapid synthesis of fatostatin (SREBP inhibitor), and the gram-scale synthesis of triarylthiazoles has been demonstrated.

Chemokine receptor 5 (CCR5) antagonists provide a new therapeutic approach in the treatment of HIV-1 (AIDS). TAK-779 displays high affinity and selectivity for the CCR5 receptor and serves as a lead compound for the development of further antagonists. In order to increase the oral bioavailability replacement of the quaternary ammonium structure by a tertiary amine and modification of the 4-methylphenyl moiety were envisaged. Herein, a new synthetic strategy for the development of TAK-779 analogs by late stage diversification is reported. The Suzuki-Miyaura cross-coupling reactions allowed various modifications of the central amide building block 3 at the end of the synthesis leading to compounds 2f and 2h with a promising CCR5 binding affinity.

Manganese-catalyzed intermolecular C-H/C-H coupling of carbonyls and heteroarenes has been developed. The presence of NaIO4 as an oxidant is crucial for the catalytic reaction. These new, inexpensive reaction conditions allow the gram-scale synthesis of a-heteroaryl carboxylic acids.

We describe mechanistic studies of a C-H/C-O biaryl coupling of 1,3-azoles and aryl pivalates catalyzed by Ni(cod)2/dcype. This study not only supports a catalytic cycle consisting of C-O oxidative addition, C-H nickelation, and reductive elimination but also provides insight into the dramatic ligand effect in C-H/C-O coupling. We have achieved the first synthesis, isolation and structure elucidation of an arylnickel(II) pivalate, which is an intermediate in the catalytic cycle after oxidative addition of a C-O bond. Furthermore, kinetic studies and kinetic isotope effect investigations reveal that the C-H nickelation is the turnover-limiting step in the catalytic cycle. © 2013 American Chemical Society.

Rather u(Ni)que: Two new C-H alkenylation reactions, that is C-H/CO alkenylation and decarbonylative C-H alkenylation, of azoles are uniquely catalyzed by Ni/dcype. These azole alkenylation reactions are successfully applied to the convergent formal synthesis of siphonazoleB. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Nickel-catalyzed cross-coupling reactions have recently been receiving significant attention from the synthetic community as a way to construct carbon-carbon or carbon-heteroatom bonds, because nickel catalysts are less expensive and less toxic than palladium catalysts.We herein describe our recent developments in nickel-catalyzed biaryl coupling methodology, along with mechanistic studies and applications to the synthesis of natural products and pharmaceuticals. In particular, we focus on nickel-catalyzed direct coupling reactions in which "unreactive" bonds such as C-H, C-O, and C-C bonds are converted into biaryl moieties.

The direct C-H-bond arylation of the complex spirocyclic lactones 13, 14, and 18 allows the introduction of diverse aryl moieties in the last step of the synthesis. A selective α-arylation of the thiophene moiety was performed with the catalytic system PdCl2/2,2′-bipyridyl/Ag2CO3, whereas the β-position of the thiophene ring was addressed by using the alternative catalytic system PdCl2/ P[OCH(CF3)2]3/Ag2CO3. Due to electronic and steric reasons the arylation of the five-membered lactone 18 occurred in both α-positions providing 4′-mono-, 6′-mono- and 4′,6′-diarylated thiophenes 22-26a-c. Compounds with an additional aryl moiety at the 'upper left (top)' position (1′-position of 13, 3′-position of 14, 4′-position of 18) showed increased σ1affinity compared to the non-arylated parent compounds. A phenyl moiety at the 'left' position (2′-position in 20a) also increased the σ1affinity but to a lower extent. A considerable reduction of σ1affinity was observed after introducing an aryl moiety in 6′-position of 18, which might result from shielding the tertiary amine, which is crucial for interaction with the σ1receptor. The discussion of the experimental results is supported by high-level quantum chemical DFT-calculations of the NBO-charges of 13 and 18 and the relative energies of the related arylated products. © 2013 Elsevier Ltd. All rights reserved.

Nickel catalysis for biaryl coupling reactions has received significant attention as a less expensive and less toxic alternative to "standard" palladium catalysis. Here we describe recent developments in nickel-catalyzed biaryl coupling methodology, along with mechanistic studies and applications. In particular we focus on nickel-catalyzed coupling reactions in which "unreactive" bonds such as C-H, C-O, and C-C bonds are converted into biaryl moieties.

A rapid synthesis of thiophene-based TAK-779 analogues 1 is reported using a late-stage diversification strategy. At the end of the synthesis, the key building block 2, which was prepared in six steps from thiophene, was arylated regioselectively at the α-position directly with iodoarenes. Since 2 offers several reactive positions, various established catalyst systems were tested. It was found that Crabtree catalyst (an Ir catalyst) converted efficiently and selectively the thiophene system 2 into 2-aryl-substituted compounds 9. The direct C-H arylation of 2 with electron-rich iodoarenes led to high yields, whereas electron-deficient iodoarenes required longer reaction times for complete conversion. A small set of diverse amides 1 was synthesized by hydrolysis of 9 and subsequent HATU coupling with primary amines 4. © 2013 American Chemical Society.

An aerobic oxidative coupling of arenes/alkenes with arylboronic acids (C-H/C-B coupling) using catalytic Pd(II)-sulfoxide-oxazoline (sox) ligand and iron-phthalocyanine (FePc) has been developed. This dual catalyst system enables the synthesis of sterically hindered heterobiaryls and styrene derivatives under air without stoichiometric co-oxidants. Additionally, this chemistry demonstrated an advance toward an enantioselective biaryl coupling through C-H functionalization.

Direct C-H bond arylation in the α- and β-positions of spirocyclic thiophenes containing various functional groups (amine, ether, acetal, lactone) was accomplished. Selective phenylation in the α-position of the thiophene ring was achieved by using the catalytic system PdCl 2/bipy/Ag 2CO 3. The introduction of phenyl moieties to the β-position was performed with the catalytic system PdCl 2/P[OCH(CF 3) 2] 3/Ag 2CO 3. Even the five-membered lactone 10 with an electron-withdrawing carbonyl moiety directly attached to the thiophene ring was arylated. Spirocyclic thiophenes substituted with a phenyl moiety in position A (top position) or B (left position) display low nanomolar Ï 1 affinities (e.g., 4a: K i = 1.6 nM; 5a: K i = 2.4 nM), indicating an additional hydrophobic pocket on the complementary Ï 1 receptor protein. A phenyl moiety in position C (at the bottom position) is not tolerated by the Ï 1 receptor (e.g., 12: K i = 483 nM). However, an additional phenyl moiety in position A is able to compensate at least partially the unfavorable effects of the phenyl moiety in position C. Diverse spirocyclic thiophenes were synthesized regioselectively by direct C-H bond arylation using the catalytic systems PdCl 2/bipy/Ag 2CO 3 and PdCl 2/ P[OCH(CF 3) 2] 3/Ag 2CO 3. Compounds bearing the phenyl moiety at the top position and the sulfur atom in left position show the highest Ï 1 affinity. © 2012 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

The palladium- and copper-catalyzed C-H arylation reactions of 1H- and 2H-indazoles with haloarenes are described. A PdCl2/phen/Ag2CO3/K3PO4 catalytic system is effective for the C-H arylation of 1H- and 2H-indazoles with haloarenes, whereas a less expensive CuI/phen/LiOt-Bu catalytic system is applicable to the C H coupling of substituted 2H-indazoles and iodoarenes. The utility of newly developed catalyst was demonstrated in the rapid synthesis of YC-1 (an antitumor agent) and YD-3 (platelet anti-aggregating agent). These new reactions represent important direct functionalization tools of indazoles, well-known bioisosteres of pharmaceutically important indole core. (C) 2012 Elsevier Ltd. All rights reserved.

To explore the hydrophobic binding region of the σ1receptor protein, regioisomeric spirocyclic thiophenes 9-11 were developed as versatile building blocks. Regioselective α- and β-arylation using the catalyst systems PdCl2/bipy/Ag2CO3and PdCl2/P[OCH(CF3)2]3/Ag2CO3allowed the introduction of various aryl moieties at different positions in the last step of the synthesis. The increasing σ1affinity in the order 4 < 5/6 < 7/8 indicates that the positions of the additional aryl moiety and the S atom in the spirocyclic thiophene systems control the σ1affinity. The main features of the pharmacophore model developed for this class of σ1ligands are a positive ionizable group, a H-bond acceptor group, two hydrophobic moieties, and one hydrophobic aromatic group. Docking of the ligands into a σ13D homology model via molecular mechanics/Poisson-Boltzmann surface area calculations led to a very good correlation between the experimentally determined and estimated free energy of receptor binding. These calculations support the hypothesis of a reverse binding mode of ligands bearing the aryl moiety at the "top" (compounds 2, 3, 7, and 8) and "left" (compounds 4, 5, and 6) positions, respectively. © 2012 American Chemical Society.

A nickel-catalyzed decarbonylative C-H biaryl coupling of azoles and aryl esters is described. The newly developed catalytic system does not require the use of expensive metal catalysts or silver- or copper-based stoichiometric oxidants. We have successfully applied this new C-H arylation reaction to a convergent formal synthesis of muscoride A.

The first nickel-catalyzed C-H bond arylation of azoles with phenol derivatives is described. The new Ni(cod)(2)/dcype catalytic system is active for the coupling of various phenol derivatives such as esters, carbamates, carbonates, sulfamates, triflates, tosylates, and mesylates. With this C-H/C-O biaryl coupling, we synthesized a series of privileged 2-arylazoles, including biologically active alkaloids. Moreover, we demonstrated the utility of the present reaction for functionalizing estrone and quinine.

A new Pd-catalyzed C-H/C-B coupling of sterically hindered heteroarenes and arylboronic acids has been identified. The newly established Pd(OAc)(2)/bisoxazoline/TEMPO system not only enables the synthesis of sterically hindered heterobiaryls but also offers an opportunity for enantioselective biaryl coupling through C-H functionalization.

The direct functionalization of C-H bonds in organic compounds has recently emerged as a powerful and ideal method for the formation of carbon-carbon and carbon-heteroatom bonds. This Review provides an overview of C-H bond functionalization strategies for the rapid synthesis of biologically active compounds such as natural products and pharmaceutical targets. The ideal case: The direct functionalization of C-H bonds in organic compounds has recently emerged as a powerful and ideal method for the formation of carbon-carbon and carbon-heteroatom bonds. This Review provides an overview of C-H functionalization strategies for the rapid synthesis of biologically active compounds such as natural products and pharmaceutical targets. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Dimeric pyrrole-imidazole alkaloids represent a rich and topologically unique class of marine natural products. This full account will follow the progression of efforts that culminated in the enantioselective total syntheses of the most structurally ornate members of this family: the axinellamines, the massadines, and palau'amine. A bio-inspired approach capitalizing on the pseudo-symmetry of the members of this class is recounted, delivering a deschloro derivative of the natural product core. Next, the enantioselective synthesis of the chlorocyclopentane core featuring a scalable, catalytic, enantioselective Diels-Alder reaction of a 1-siloxydiene is outlined in detail. Finally, the successful divergent conversion of this core to each of the aforementioned natural products, and the ensuing methodological developments, are described.

We have developed a palladium-catalyzed C-H/C-H coupling reaction of indoles or pyrroles with azine N-oxides. The reaction proceeds selectively at the C3 position of indoles/pyrroles and the C2 position of azine N-oxides. Furthermore, we have accomplished the synthesis of marine indole alkaloid eudistomin U by utilizing this newly developed C-H/C-H coupling reaction.

The hypothesis that the σ 1 receptor will tolerate an additional aryl moiety in position 1 of the spirocyclic system was based on spirocyclic pyrazole derivatives, pharmacophore models of σ 1 receptor ligands and DFT calculations. The strategy of introducing the aryl residue at the final step of the synthesis allowed the preparation of a large set of diverse ligands for the exploitation of the hydrophobic pocket of the σ 1 receptor protein. The catalyst system PdCl 2/2,2′-bipyridyl/Ag 2CO 3 is able to introduce various aryl groups onto the α-positions of spirocyclic thiophene derivatives 5 and 6 to afford the target aryl-appended spirocyclic thiophenes 3 and 4. Although the σ 1 affinity of the 1-phenyl substituted spirocyclic thiophenes 3a and 4a is slightly reduced compared with the σ 1 affinity of the non-arylated compounds 5 and 6, both compounds represent very potent σ 1 receptor ligands (3a: K i = 4.5 nM; 4a: K i = 1.0 nM). This result indicates that an aryl moiety in position 1 is well tolerated by the σ 1 receptor protein. The substitution pattern of the additional phenyl moiety has only weak effects on the σ 1 affinity. Even ligands 3f and 4h with extended naphthyl residue show high σ 1 affinity. However, decrease of σ 1 affinity by extension of the π-system to a biphenylyl substituent (4j: K i = 30 nM) indicates that the biphenylyl residue is too large for the primary hydrophobic binding pocket of the σ 1 receptor. © The Royal Society of Chemistry 2011.

(Figure Presented) Worth the wait: The long anticipated total synthesis of palau'amine has been accomplished by a route featuring highly chemoselective transformations, cascade reactions, and a remarkable transannular cyclization to secure the unprecedented trans-5,5 ring junction (shown in red). © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.

Ni-based catalytic systems for the arylation of heteroarenes with aryl halides and triflates have been established. Ni(OAc)(2)/bipy is a general catalyst for aryl bromides/iodides, and Ni(OAC)(2)/dppf is effective for aryl chlorides/triflates. Thiazole, benzothiazole, oxazole, benzoxazole, and benzimidazole are applicable as heteroarene coupling partners. A rapid synthesis of febuxostat, a drug for gout and hyperuricemia, is also demonstrated.

Catalytic enantioselective stereoablative reactions represent a unique approach to the preparation of enantioenriched materials, wherein a catalytic method destroys, at least temporarily, stereogenic elements of a molecule. This review introduces a recent example of novel approaches in asymmetric catalytic methods for stereoablation, as well as the use of a new stereoablative reaction in a concise synthesis of the marine diterpenoid (-)-cyanthiwigin F.

trans-tert-Butyldimethylsiloxy-l-proline displays greater catalytic activity and affords higher enantioselectivity than the parent proline in the a-amination reaction of carbonyl compounds with azodicarboxylate. A quantum mechanical calculation reveals the structure of the transition state. In the presence of a catalytic amount of siloxyproline and water (3-9 equiv), α-amino carbonyl derivatives, which are important synthetic intermediates, are obtained in good yield and with excellent enantioselectivity. © 2008 Wiley-VCH Verlag GmbH&Co. KGaA.

(Chemical Equation Presented) A biomimetic pathway to lucilactaene (1) from NG-391 has been developed which involves stereoselective reactions under very mild conditions. It was demonstrated that 1 racemizes rapidly, and the conditions under which racemization occurs were elucidated. Lucilactaene (1) isolated under neutral conditions is racemic, which suggests that either the natural product is racemized rapidly in the mycelia, or racemic 1 is biosynthesized. © 2005 Wiley-VCH Verlag GmbH & Co. KGaA.

The direct proline-catalyzed asymmetric α-aminoxylation of aldehydes and ketones has been developed using nitrosobenzene as an oxygen source, affording α-anilinoxy-aldehydes and -ketones with excellent enantioselectivity. Reaction conditions have been optimized, and low temperature (-20 °C) was found to be a key for the successful α-aminoxylation of aldehydes, while slow addition of nitrosobenzene is essential for that of ketones. The scope of the reaction is presented.

Nitrosobenzene is the oxygen source in the direct catalytic enantioselective α-aminoxylation of ketones catalyzed by L-proline [Eq. (1)]. Versatile α-aminoxylated ketones are obtained in high yield and with excellent enantioselectivities.

The direct catalytic enantioselective α-aminooxylation of aldehydes has been developed using nitrosobenzene as the oxygen source and L-proline as catalyst, affording versatile α-aminooxylated aldehydes in high yield with excellent enantioselectivities. © 2003 Elsevier Ltd. All rights reserved.

The stereocontrolled total synthesis of (+)-NG-391, a neuronal cell-protecting molecule, is described along with the determination of its absolute stereochemistry. The following reactions in this synthesis are particularly noteworthy: (1) The stereoselective construction of the conjugated (E,E,E,E,E)-pentaene from an (E,E,E)-alcohol using an IBX oxidation followed by stereoselective Horner-Emmons reaction. (2) The (E)-selective Knoevenagel condensation of a beta-ketonitrile with a chiral 2-alkoxyaldehyde prepared from (S)-malic acid. (3) A diastereoselective epoxidation. (C) 2002 Elsevier Science Ltd. All rights reserved.

本研究では、植物CK１阻害剤として我々が発見した三種類の分子を武器に、サブタイプ選択性を向上させた新規阻害剤を創製し、植物概日時計制御におけるCK1 タンパク質の詳細な役割の解明を目指す。はじめに植物概日リズム調整剤PHA のSAR 研究と標的タンパク質の同定に着手した。また高活性な部分構造を組み合わせたハイブリッド体(AMI-331)が、PHA と比較して約100 倍の活性を示した。その結果、AMI-331 をもとにした分子プローブを合成し、プルダウンアッセイを行ったところCK選択性が格段に向上した。また、植物CK1 阻害剤PHA とB-AZ[6]の構造を基にin silico スクリーニングで見いだした化合物DB8およびDB9 の合成に成功した。

芳香族化合物の官能基化はそれらの機能を十分に発揮するために必須な装飾である。従って、芳香族化合物の官能基化反応は有機合成化学において古くより検討が行われている。芳香族求電子置換反応や求核置換反応などにより、位置優先的・選択的に置換基を導入した置換芳香族化合物が合成できる。最近では触媒的な芳香族化合物の官能基化反応が研究され、例えば、触媒量の遷移金属存在下、炭素-水素結合を直裁的に変換する手法（芳香環C–H結合直接変換反応）の開発が盛んである。我々はごく最近、研究室で開発している「芳香族エステルの脱カルボニル型カップリング反応」反応開発中、思いがけず「触媒的エステルダンス反応」を発見した。本研究ではこの反応の最適化、基質一般性を検討した。

本研究では、安価なケミカルフィードストックが有する汎用官能基を切断し様々な求核剤とのカップリング反応を行う。具体的には①フェノール誘導体、②芳香族チオエステル、③芳香族カルボン酸誘導体、そして④芳香族ニトロ化合物を対象とした。。切断—置換反応の足がかりとなるのは触媒サイクルのあらゆる段階を促進する、基質に含まれる無痕跡配向基と精密にデザインされた配位子である。①ー④すべての官能基を活性化することに成功し、脱カルボニル型エーテル化反応・チオエーテル化反応、C-P結合形成、アルキル化反応を見いだした。分子内C-H結合も同様に活性化し、ジベンゾフラン誘導体も合成することに成功した。

芳香族化合物群は、機能性分子における最重要骨格のひとつである。特にアリール基で置換された芳香族化合物群は、光電子機能性材料や生体機能性材料に頻繁に見られる。導入するアリール基の性質に起因して分子全体の構造あるいは電子的性質は大きく変化するため、分子の機能を発現する上でアリール基は重要な役割を担っている。そのため、アリール基を芳香族化合物に自在に導入することが出来れば、分子の機能を自在に操ることが可能となる。我々は既にチオフェンやチアゾールが有するC–H結合を望みの位置かつ望みの様式でアリール基に変換することで、アリール化された5員環芳香族ヘテロ環の自在合成を可能としてた。また、得られた5員環からの環変換反応によりアリール基がすべて異なるヘキサアリールベンゼン、ヘキサアリールピリジンの合成を達成してた。さらに、アリール化された5員環ヘテロ芳香族化合物の環変換反応により、マルチアリール化アセン・ヘテロールの自在合成法を開発した。