Hiroki Shigehisa

Catalytic transformation of alkenes via the metal-hydride hydrogen atom transfer (MHAT) mechanism has notably advanced synthetic organic chemistry. This review focuses on MHAT/radical-polar crossover (MHAT/RPC) conditions, offering a novel perspective on generating electrophilic intermediates and facilitating various intramolecular reactions. Upon using cobalt hydrides, the MHAT mechanism displayed exceptional chemoselectivity and functional group tolerance, making it invaluable for the construction of complex biologically relevant molecules under mild conditions. Recent developments have enhanced regioselectivity and expanded the scope of MHAT-type reactions, enabling the formation of cyclic molecules via hydroalkoxylation, hydroacyloxylation, and hydroamination. Notably, the addition of an oxidant to traditional MHAT systems enables the synthesis of rare cationic alkylcobalt(IV) complexes, bridging radical mechanisms to ionic reaction systems. This review culminates with examples of natural product syntheses and exploration of asymmetric intramolecular hydroalkoxylation, highlighting the ongoing challenges and opportunities for future research to achieve higher enantioselectivity. This comprehensive study revisits the historical evolution of the MHAT mechanism and provides the groundwork for further innovations in the synthesis of structurally diverse and complex natural products.1 Introduction2 Intramolecular hydroalkoxylation and hydroacyloxylation reactions3 Intramolecular hydroamination reactions4 Intramolecular hydroarylation reactions5 Deprotective cyclization6 Asymmetric intramolecular hydroalkoxylation

This study demonstrates a novel method for synthesizing rare heterocyclic compounds, namely, cyclic isoureas using alkenoic ureas via cobalt-catalyzed metal-catalyzed hydrogen atom transfer/radical polar crossover (MHAT/RPC). This method successfully produces five-membered rings along with the rare six- and seven-membered cyclic isoureas. Density functional theory (DFT) calculations were performed to elucidate the reaction mechanism focusing on cyclization.

In this study, we investigated the metal-catalyzed hydrogen atom transfer (MHAT)/radical polar crossover (RPC) reaction, focusing on the influence of ligands on the cyclization selectivity by employing substrates containing two nucleophiles along with an alkene. We provide new insights into the importance of ligand optimization in the MHAT/RPC mechanism, particularly in hydroarylation reactions.

Copyright © 2020 American Chemical Society. The catalytic enantioselective synthesis of tetrahydrofurans, which are found in the structures of many biologically active natural products, via a transition-metal-catalyzed hydrogen atom transfer (TM-HAT) and radical-polar crossover (RPC) mechanism is described herein. Hydroalkoxylation of nonconjugated alkenes proceeded efficiently with excellent enantioselectivity (up to 94% ee) using a suitable chiral cobalt catalyst, N-fluoro-2,4,6-collidinium tetrafluoroborate, and diethylsilane. Surprisingly, the absolute configuration of the product was highly dependent on the steric hindrance of the silane. Slow addition of the silane, the dioxygen effect on the solvent, thermal dependence, and DFT calculation results supported the unprecedented scenario of two competing selective mechanisms. For the less-hindered diethylsilane, a high concentration of diffused carbon-centered radicals invoked diastereoenrichment of an alkylcobalt(III) intermediate by a radical chain reaction, which eventually determined the absolute configuration of the product. On the other hand, a more hindered silane resulted in less opportunity for a radical chain reaction, instead facilitating enantioselective kinetic resolution during the late-stage nucleophilic displacement of the alkylcobalt(IV) intermediate.

© 2020 American Chemical Society. Guided by the transition-metal hydrogen atom transfer and radical-polar crossover concepts, we developed a functional-group-tolerant and scalable method for the synthesis of cyclic carbamates and ureas, which are found in the structures of bioactive compounds. This method provides not only a common five-membered ring but also six-to-eight-membered ring products. The reaction proceeds through the intramolecular displacement of an alkylcobalt(IV) intermediate and dealkylation by 2,4,6-collidine; the activation energies of these steps were calculated by DFT.

Copyright © 2020 American Chemical Society. Herein we report a one-step, catalytic, Markovnikov-selective, and scalable method for the synthesis of saturated sulfur heterocycles, which are found in the structures of pharmaceuticals and natural products, from an alkenyl thioester. Unlike a potentially labile alkenyl thiol, an alkenyl thioester is stable and easy to prepare. Powerful catalysis via a cobalt hydride hydrogen atom transfer and radical-polar crossover mechanism enabled simultaneous cyclization and deprotection. The substrate scope was expanded by extensive optimization of the reaction conditions and tuning of the thioester unit. This is a rare instance of thioesters showing nucleophilic behavior. This method was also applicable to alkenyl selenoesters.

© 2018 The Pharmaceutical Society of Japan. In this review, I tell the story of the cobalt chemistry that has been developed in my group since 2011. First, we achieved the total synthesis of polyketide natural product trichodermatide A, which involved a latestage Isayama-Mukaiyama hydration of an enol ether using cobalt(II) acetylacetonate (Co(acac)2) that gave the desired product chemo-, regio-, and diastereoselectively. After our report of this total synthesis in 2013, we were required to revise the originally reported structure of trichodermatide A following the accurate and important report from the Trauner group. Second, we found unique cobalt-catalyzed hydroelementation reactions of olefins involving a cobalt-salen complex, N-fluoro-2,4,6-trimethylpyridinium salt, and a silane reagent. Under these reaction conditions, a carbocationic or carbon radical species is generated from an olefin, and then C-X (X=O, N, C, F) bond formation occurs with good functional group tolerance for a broad substrate scope. This review also covers recent examples of switching chemistry and natural product synthesis involving my cobalt chemistry reported by several groups.

© 2017 The Japan Institute of Heterocyclic Chemistry Received. Two different kind of sequential cyclization-functionalization are developed. Namely, cyclization-chlorination of 2-ethynylaniline derivatives using CuCl2 gave 3-chloro- and 3,5-dichloroindole derivatives. The plausible mechanism for this reaction is also discussed. On the other hand, the reaction between 2-ethynylaniline derivatives and Cu(NO3)2·3H2O in THF provided C4-nitro compound. After being changed the solvent from THF to DMF, followed by heating, 5-nitroindole derivatives was afforded.

© 2016 American Chemical Society. A mild, general, and functional group tolerant intramolecular hydroalkoxylation and hydroacyloxylation of unactivated olefins using a Co(salen) complex, an N-fluoropyridinium salt, and a disiloxane reagent is described. This reaction was carried out at room temperature and afforded five- and six-membered oxygen heterocyclic compounds, such as cyclic ethers and lactones. The Co complex was optimized for previously rare medium ring formation by hydrofunctionalization of unactivated olefins. The powerful Co catalyst system also enables the deprotective hydroalkoxylation of O-protected alkenyl alcohol and hydroacyloxylation of alkenyl ester to afford cyclic ethers and lactones directly. The substrate scope and mechanistic proof of deprotection were investigated. The experimental evidence supports the concerted transition state of the bond-forming step involving a cationic Co complex.

© 2016 American Chemical Society. A mild, general, scalable, and functional group tolerant intramolecular hydroarylation of unactivated olefins using a Co(salen) complex, a N-fluoropyridinium salt, and a disiloxane reagent was reported. This method, which was carried out at room temperature, afforded six-membered benzocyclic compounds from mono-, 1,1- or trans-1,2-di, and trisubstituted olefins.

© 2016 The Pharmaceutical Society of Japan. We developed an addition reaction of fluorous solvents to olefins using salen-cobalt (Co) complex, Nfluoro- 2,4,6- Trimethylpyridinium tetrafluoroborate, and 1,1,3,3- Tetramethyldisiloxane. This reaction condition was found to activate olefins, which enabled them to be attacked by 2,2,2- Trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), both of which are electronically weak nucleophiles.

Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. A revised structure for trichodermatide A, which is a C10 epimer of the originally reported structure, is proposed. The revision is supported by the X-ray structure of a synthetic intermediate synthesized according to our previous route for trichodermatide A. The revised stereochemistry was also supported by NOESY experiment. Finally, we synthesized Trauner's compound corresponding to the originally reported structure from our synthetic intermediate of trichodermatide A through a Mitsunobu reaction at C10. A revised structure for trichodermatide A is proposed. The revision is supported by the X-ray structure of a synthetic intermediate synthesized according to our previous route for trichodermatide A. The revised stereochemistry was also supported by NOESY experiment. Finally, we synthesized Trauner's compound corresponding to the originally reported structure from our synthetic intermediate of trichodermatide A through a Mitsunobu reaction at C10.

© 2015 Georg Thieme Verlag Stuttgart, New York-Synlett. Recent developments in the Markovnikov-selective hydrofunctionalization of unactivated olefins are presented. Our group found that the use of a cobalt complex, an N-fluoropyridinium salt, and a siloxane facilitates hydrofunctionalization with excellent functional group tolerance. Mechanistically, this catalysis involves both a carbon radical and a carbocationic intermediate.

Recent developments of Markovnikov selective hydrofunctionalization of olefins are discussed. It is note that we realized hydrofunctionalization such as an intermolecular hydroalkoxylation, a hydrofluorination, and an intramolecular hydroamination with excellent functional group tolerance using cobalt complex, N-fluoropyridinium salt, and disiloxane. Mechanistically, this catalysis involves both carbon radical and carbocation intermediate.

© 2014 American Chemical Society. Functional group tolerance is one of the important requirements for chemical reactions, especially for the synthesis of complex molecules. Herein, we report a mild, general, and functional group tolerant intramolecular hydroamination of unactivated olefins using a Co(salen) complex, an N-fluoropyridinium salt, and a disiloxane reagent. This method, which was carried out at room temperature (or 0 °C), afforded three-, five-, six-, and seven-membered ring nitrogen-containing heterocyclic compounds and was compatible with diverse functional groups.

Catalytic hydrofluorination of olefins using a cobalt catalyst was developed. The exclusive Markovnikov selectivity, functional group tolerance, and scalability of this reaction make it an attractive protocol for the hydrofluorination of olefins. A preliminary mechanistic experiment showed the involvement of a radical intermediate. © 2013 American Chemical Society.

A unique Markovnikov hydroalkoxylation of unactivated olefins with a cobalt complex, silane, and N-fluoropyridinium salt is reported. Further optimization of reaction conditions yielded high functional group tolerance and versatility of alcoholic solvent employed, including methanol, i-propanol, and t-butanol. Use of trifluorotoluene as a solvent made the use of alcohol in stoichiometric amount possible. Mechanistic insight into this novel catalytic system is also discussed. Experimental results suggest that catalysis involves both carbon radical and carbocation intermediates. © 2013 American Chemical Society.

Hard core made easy: The pentacyclic core of trichodermatide A was stereoselectively synthesized from a bis(1,3-cyclohexanedione) derivative by a ring-closing reaction followed by an intramolecular ketal formation (see scheme; PPTS=pyridinium p-toluenesulfonate). The first total synthesis of trichodermatide A was then completed by the introduction of three hydroxy groups. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Full details are provided for an improved synthesis of cortistatin A and related structures as well as the underlying logic and evolution of strategy. The highly functionalized cortistatin A-ring embedded with a key heteroadamantane was synthesized by a simple and scalable five-step sequence. A chemoselective, tandem geminal dihalogenation of an unactivated methyl group, a reductive fragmentation/trapping/elimination of a bromocyclopropane, and a facile chemoselective etherification reaction afforded the cortistatin A core, dubbed "cortistatinone". A selective δ16-alkene reduction with Raney Ni provided cortistatin A. With this scalable and practical route, copious quantities of cortistatinone, δ16-cortistatin A (the equipotent direct precursor to cortistatin A), and its related analogues were prepared for further biological studies. © 2011 American Chemical Society.

One stereocenter makes all the difference: The synthesis and biological evaluation of 17-epi-cortistatin A is reported from a common intermediate used to procure natural cortistatin A. The synthesis features a unique stereocontrolled Raney-Ni reduction process that can be employed to reliably produce both α- and β-configured Dring aryl steroids. Biological evaluations of these "cortalogs" are reported for the first time. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.

Optically pure N-Boc-norpandamarilactonine-B was diastereoselectively synthesized starting from L-serine by employing a double ring closing metathesis (RCM) of a tetraene derivative as a key reaction. N-Boc-norpandamarilactonine-B obtained was further converted to pandamarilactonine-A. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA.

An exceptional intramolecular palladium-catalyzed alkenylation of silyl enol ether in the absence of a fluoride additive was developed, and this reaction led to the construction of bicyclo[3.3.1]nonane ring system in reasonable yield. In this type of reactions, trialkylamines were employed as additives instead of previously indispensable fluoride additives. © 2008 Elsevier Ltd. All rights reserved.

8',9'-Dimethoxy-1',5',6',10b'-tetrahydro-4H-spiro(cyclohexa-2,5-diene-1,2'-pyrrolo[2,1-a]isoquinoline)-3',4-dione 2 with a basic skeleton of a natural product, annnosqualine, exhibited unique behavior in a dienone-phenol rearrangement. Treatment of 2 with trifluoroacetic acid gave a simple 1-benzylisoquinoline alkaloid, norarmepavine 4. Plausible reaction mechanism for the observed transformation is also described. © 2008 The Japan Institute of Heterocyclic Chemistry.

The first total synthesis of a spiro-isoquinoline alkaloid, (±)-annosqualine, was established by employing an enamide-phenol coupling of a 1-methylene-1,2,3,4-tetrahydroisoquinoline derivative with a hypervalent iodine reagent, where the formation of the phenoxide was recognized to be an essential step for the reaction of the phenolic hydroxyl group with the hypervalent iodine reagent leading to the formation of the desired product. © 2006 Elsevier Ltd. All rights reserved.

A novel synthetic path to proaporphine alkaloids was established by employing aromatic oxidation with a hypervalent iodine reagent, where an unprecedented carbon-carbon bond forming reaction between the para-position of a phenol group and an enamide-carbon took place smoothly to give the desired spiro-cyclohexadienone. © 2006 American Chemical Society.

A catalytic process for the synthesis of optically active C4-substituted tetrahydroindandiones using an asymmetric intramolecular aldol condensation reaction was developed. When 30 mol% of phenylalanine and 50 mol% of pyridinium p-toluenesulfonate were used under highly concentrated conditions, a variety of C4-substituted tetrahydroindandiones and octahydronaphthalenediones were obtained in high yield (up to 89% yield) and high enantiomeric excess (up to 94% ee). One of the products was successfully transformed into the key intermediate for the synthesis of the phosphatidylinositol 3-kinase inhibitor wortmannin, achieving formal total synthesis of (+)-wortmannin. © 2005 Elsevier Ltd. All rights reserved.