Silver(I)/Dirhodium(II) Catalytic Platform for Asymmetric N-H Insertion Reaction of Heteroaromatics.

Transition-metal-catalyzed enantioselective N-H insertion reactions of carbene species offer a powerful and straightforward strategy to produce chiral nitrogen-containing compounds. Developing highly selective insertion reactions using indole variants can meet synthetic demand. Herein we present an asymmetric insertion reaction into N-H bonds of the aromatic heterocycles using donor/acceptor-substituted diazo compounds based on a heteronuclear catalytic platform. Although a previously developed catalysis comprising chiral silver catalyst or dirhodium(II,II) paddlewheel complexes with and without chiral phosphoric acid showed modest performance, a unique combination of widely available Rh2(OAc)4 and silver(I) phosphate dimer [(S)-TRIP-Ag]2 enabled asymmetric carbene insertion reactions (up to 98% ee). Moreover, the Ag/Rh catalytic system facilitated regioselective and enantioselective C-H functionalization of protic indoles. Mechanistic investigation based on density functional theory indicated that an in situ-generated Ag-Rh trimetallic enolate is protonated in a chiral environment.

Synthesizing Chiral Hydrocarbazoles with a Tetrasubstituted Carbon Using Holmium-Catalyzed Enantioselective [4 + 2] Cycloaddition: Mechanistic Insights from Luminescence and DFT Studies.

This study analyzes the feasibility of utilizing the catalytic and enantioselective [4 + 2] cycloaddition of sterically demanding heterocycle-incorporated siloxydienes to yield polycyclic skeletons with a tetrasubstituted carbon. A catalyst derived from lanthanide triflimide enabled the reaction. The mechanistic investigations and transformations of the adducts are also discussed. The proposed approach facilitates the synthesis of intricate polysubstituted skeletons, each with multiple contiguous chiral centers, thereby aiding in the production of diverse hydrocarbazoles for drug discovery purposes.

Systematic Studies of Functional Group Tolerance and Chemoselectivity in Carbene-Mediated Intramolecular Cyclopropanation and Intermolecular C-H Functionalization.

Generating reliable data on functional group compatibility and chemoselectivity is essential for evaluating the practicality of chemical reactions and predicting retrosynthetic routes. In this context, we performed systematic studies using a functional group evaluation kit including 26 kinds of additives to assess the functional group tolerance of carbene-mediated reactions. Our findings revealed that some intermolecular heteroatom-hydrogen insertion reactions proceed faster than intramolecular cyclopropanation reactions. Lewis basic functionalities inhibited rhodium-catalyzed C-H functionalization of indoles. While performing these studies, we observed an unexpected C-H functionalization of a 1-naphthol variant used as an additive.

Synthetic Study of Dragmacidin E: Enantioselective Construction of the Seven-Membered Ring-Fused Indole Skeleton with Contiguous Stereocenters.

We developed an enantioselective synthetic method of constructing a seven-membered ring-fused indole skeleton with contiguous stereocenters for the synthesis of dragmacidin E. Introduction of chirality at the benzylic position was achieved by Ir-catalyzed asymmetric hydrogenation. After construction of the tricyclic molecular framework using Pd-catalyzed cascade cyclization, the tetrasubstituted carbon center was created using the Ag nitrene-mediated C-H amination reaction. The developed method provided access to the functionalized seven-membered ring-fused indole skeleton with a hydroxymethyl branch in the tetrasubstituted carbon.

Development of Transition-Metal-Catalyzed Dearomatization Reactions.

To develop dearomatization reactions based on a nucleophilic activation of phenols, naphthols, and indoles, ipso-Friedel-Crafts-type C-alkylation must be selectively promoted over competitive O- or N-alkylation reactions. Resolving this chemoselectivity issue is essential for developing this class dearomatization reaction. We found that various dearomatization reactions could be developed using appropriately designed aromatic substrates with an electrophilic moiety for intramolecular reactions. This review describes the transition-metal-catalyzed dearomatization reactions developed by our group. π-Allylpalladium species, η3-propargylpalladium species, alkynes activated by Au(I) species, and silver carbene species could be applied as electrophiles in our reaction system, which provided access to a wide variety of dearomatized products from planar aromatic compounds in a highly chemoselective manner.

Theoretical Investigation of Chemoselectivity between C-H Insertion and Amide Insertion in Intramolecular Rhodium-Carbene Reactions.

C-H insertion and amide insertion reactions using metal-carbene species provide a powerful synthetic method for direct functionalization of kinetically inert or thermodynamically stable chemical bonds. Our group previously developed an amide insertion reaction using a rhodium-dimer complex, constructing an array of nitrogen-bridged heterocycles. Another research group reported C-H insertion reactions using structurally related substrates and rhodium catalysts. Detailed mechanistic studies were not provided, however, and therefore, the origin of the chemoselectivity was ambiguous. Here we describe our theoretical investigation of the chemoselectivity between the amide insertion reaction and C-H functionalization. An energy gap of the identified transition states in the reaction coordinates could support the reported experimental results and the observed chemoselectivity. Moreover, frontier molecular orbital analysis revealed that functionalities adjacent to the metal-carbene species could affect orbital populations and their energy levels, resulting in the construction of a completely distinctive ring system.

Computation-Guided Total Synthesis of Vitisinol G.

Computational chemistry is useful in synthetic organic chemistry, as it can be used not only to analyze reaction mechanisms, but also to calculate biosynthetic pathways and to plan and evaluate strategies for total syntheses. Here we report the computation-guided total synthesis of vitisinol G, a resveratrol dimer.

Synthesis of Visible-Light-Activated Hypervalent Iodine and Photo-oxidation under Visible Light Irradiation via a Direct S0→Tn Transition.

Heavy atom-containing molecules cause a photoreaction by a direct S0 → Tn transition. Therefore, even in a hypervalent iodine compound with a benzene ring as the main skeleton, the photoreaction proceeds under 365-400 nm wavelength light, where UV-visible spectra are not observed by usual measurement method. Some studies, however, report hypervalent iodine compounds that strongly absorb visible light. Herein, we report the synthesis of two visible light-absorbing hypervalent iodines and their photooxidation properties under visible light irradiation. We also demonstrated that the S0 → Tn transition causes the photoreaction to proceed under wavelengths in the blue and green light region.

Asymmetric Intramolecular Dearomatization of Nonactivated Arenes with Ynamides for Rapid Assembly of Fused Ring System under Silver Catalysis.

Arene dearomatization is a straightforward method for converting an aromatic feedstock into functionalized carbocycles. Enantioselective dearomatizations of chemically inert arenes, however, are quite limited and underexplored relative to those of phenols and indoles. We developed a method for diazo-free generation of silver-carbene species from an ynamide and applied it to the dearomatization of nonactivated arenes. Transiently generated norcaradiene could be trapped by intermolecular [4 + 2] cycloaddition, synthesizing polycycles with five consecutive stereogenic centers. This protocol constitutes the first highly enantioselective reaction based on the diazo-free generation of silver-carbene species. Mechanistic investigations revealed a dearomatization followed by two different classes of pericyclic reactions, as well as the origin of the chemo- and enantioselectivity.

Mechanistic Studies of the Pd- and Pt-Catalyzed Selective Cyclization of Propargyl/Allenyl Complexes.

Following the discovery of an unusual transition-metal-catalyzed reaction, the elucidation of the underlying mechanism is essential to understand the characteristic reactivity of the metal. We previously reported a synthetic method for tricyclic indoles using Pt-catalyzed Friedel-Crafts-type C-H coupling. In this reaction, the Pt catalyst selectively formed a seven-membered ring, but the Pd catalyst only afforded a six-membered ring. However, the reasons for the different selectivities caused by Pd and Pt were unclear. We performed density functional theory (DFT) calculations and experimental studies to reveal the origin of the different behaviors of the two metals. The calculations revealed that the formation of the six- and seven-membered rings proceeds via η1-allenyl and η3-propargyl/allenyl complexes, respectively. A molecular orbital analysis of the η3-propargyl/allenyl complex revealed that, for the platinum complex, the energy required to convert the unoccupied molecular orbital on the reactive carbon into the lowest unoccupied molecular orbital (LUMO) was lower than that for the palladium complex. In addition, DFT calculations revealed that the combination of platinum and bis[2-(diphenylphosphino)phenyl] ether (DPEphos) reduced the activation energy of the seven-membered cyclization in comparison with palladium or PPh3. Additional experimental studies, including NMR studies and stoichiometric reactions, support the aforementioned examination.

Visible Light-Induced Direct S0 → Tn Transition of Benzophenone Promotes C(sp3)-H Alkynylation of Ethers and Amides.

Benzophenone has an S0 → S1 absorption band at 365 nm. However, the rarely reported S0 → Tn transition occurs upon irradiation at longer wavelengths. Herein, we employed benzophenone as a catalyst and exploited its S0 → Tn transition in C(sp3)-H alkynylations with hypervalent iodine reagents. The selective benzophenone excitation prevented alkynylating reagent decomposition, enabling the reaction to proceed under mild conditions. The reaction mechanism was investigated by spectroscopic and computational studies.

Silver-Catalyzed, Chemo- and Enantioselective Intramolecular Dearomatization of Indoles to Access Sterically Congested Azaspiro Frameworks.

An asymmetric dearomatization of indoles bearing α-diazoacetamide functionalities was developed for synthesizing high-value spiro scaffolds. A silver phosphate chemoselectively catalyzed the sterically challenging dearomatization, whereas more typically used metal catalysts for carbene transfer reactions, such as a rhodium complex, were not effective and instead resulted in a Büchner ring expansion or cyclopropanation. Mechanistic studies indicated that the spirocyclization occurred through a silver-assisted asynchronous concerted process and not via a silver-carbene intermediate. Analyses based on natural bond orbital population and a distortion/interaction model indicated that the degree of C-Ag mutual interaction is crucial for achieving a high level of enantiocontrol. In addition, an oxidative disconnection of a C(sp3)-C(sp2) bond in the product provided unconventional access to the corresponding chiral spirooxindole.

Computational Study on the Synergic Effect of Brønsted Acid and Hydrogen-Bonding Catalysis for the Dearomatization Reaction of Phenols with Diazo Functionality.

Catalytic dearomative transformations of phenol variants via an ipso-Friedel-Crafts reaction could provide a straightforward method for the rapid assembly of functionalized spiromolecules as versatile synthetic scaffolds. We previously reported a dearomative spirocyclization reaction by merging Brønsted acid and hydrogen-bonding catalysis. However, it was unclear how the reaction proceeded and how the synergic effect was triggered. Described herein are the computational studies used to elucidate the reaction mechanism. Such calculations indicated that the applied catalysts, maleic acid and Schreiner's thiourea, work cooperatively. The synergic effect enabled the chemoselectivity to interconvert between phenol dearomatization and O-H insertion, which is a major side reaction. This investigation also revealed that not only does the Schreiner's thiourea catalyst serve as a hydrogen bonding donor, but the sulfur atom in thiourea possesses a general base function. The dual functional support of the thiourea along with maleic acid would thus realize the chemoselective prioritization of dearomatization over the O-H insertion reaction under mild conditions.

A Direct S0 →Tn Transition in the Photoreaction of Heavy-Atom-Containing Molecules.

According to the Grotthuss-Draper law, light must be absorbed by a substrate to initiate a photoreaction. There have been several reports, however, on the promotion of photoreactions using hypervalent iodine during irradiation with light from a non-absorbing region. This contradiction gave rise to a mystery regarding photoreactions involving hypervalent iodine. We demonstrated that the photoactivation of hypervalent iodine with light from the apparently non-absorbing region proceeds via a direct S0 →Tn transition, which has been considered a forbidden process. Spectroscopic, computational, and synthetic experimental results support this conclusion. Moreover, the photoactivation mode could be extended to monovalent iodine and bromine, as well as bismuth(III)-containing molecules, providing new possibilities for studying photoreactions that involve heavy-atom-containing molecules.

Chemoselective Intramolecular Formal Insertion Reaction of Rh-Nitrenes into an Amide Bond Over C-H Insertion.

The past few decades have witnessed extensive efforts to disclose the unique reactivity of metal-nitrenes, because they could be a powerful synthetic tool for introducing the amine functionality into unactivated chemical bonds. The reactivity of metal-nitrenes, however, is currently mainly confined to aziridination (an insertion into a C=C bond) and C-H amination (an insertion into a C-H bond). Nitrene insertion into an amide C-N bond, however, has not been reported so far. In this work we have developed a rhodium-catalyzed one-nitrogen insertion into amide C-N and sulfonamide S-N bonds. Experimental and theoretical analyses based on density functional theory indicate that the formal amide insertion proceeds via a rhodium-coordinated ammonium ylide formed between the nitrene and the amide nitrogen, followed by acyl group transfer concomitant with C-N bond cleavage. Mechanistic studies have allowed rationalization of the origin of the chemoselectivity observed between the C-H and amide insertion reactions. The methodology presented herein is the first example of an insertion of nitrene into amide bonds and provides facile access to unique diazacyclic systems with an N-N bond linkage.

Silver-Catalyzed Asymmetric Insertion into Phenolic O-H Bonds using Aryl Diazoacetates and Theoretical Mechanistic Studies.

An enantioselective insertion reaction of silver carbenes generated from donor-acceptor-substituted diazo compounds into the O-H bond of phenols was developed. A homobinuclear silver complex with a chiral phosphorous ligand was created in situ from AgNTf2 and (S)-XylylBINAP (in a 2:1 mole ratio). Detailed mechanistic studies using combined experimental and computational techniques revealed that one silver atom center of the catalyst forms a silver carbene and another one works as a Lewis acid for the nucleophilic addition of a phenol. Two counter-anions, two water molecules, and two silver atoms cooperatively mediate the subsequent protonation event to lower the activation energy and control enantioselectivity, affording an array of valuable α-aryl-α-aryloxy esters.

Synthesis of 3,4-Fused Tricyclic Indoles Using 3-Alkylidene Indolines as Versatile Precursors.

In this personal account, our recent studies of novel synthetic methods of 3,4-fused tricyclic indole derivatives using 3-alkylidene indoline derivatives as versatile precursors are discussed. Two types of cascade reactions producing 3,4-fused tricyclic 3-alkylidene indolines were developed based on a palladium-catalyzed intramolecular Heck insertion to an allene-allylic amination cascade and a platinum-catalyzed intramolecular Friedel-Crafts type C-H coupling-allylic amination cascade. Furthermore, three types of 3,4-fused tricyclic indoles were accessible from a single 3-alkylidene indoline precursor via acid-promoted olefin isomerization or oxidative treatments. The application of the developed methods to the synthesis of natural products bearing a 3,4-fused tricyclic indole skeleton, (-)-aurantioclavine, fargesine, and synthetic studies of dragmacidin E are also highlighted.

Catalytic asymmetric synthesis of α-methyl-p-boronophenylalanine.

p-Boronophenylalanine (l-BPA) is applied in clinical settings as a boron carrier for boron neutron capture therapy (BNCT) to cure malignant melanomas. Structural modification or derivatization of l-BPA, however, to improve its uptake efficiency into tumor cells has scarcely been investigated. We successfully synthesized (S)-2-amino-3-(4-boronophenyl)-2-methylpropanoic acid in enantioenriched form as a novel candidate molecule for BNCT. Key steps to enhance the efficiency of this synthesis were enantioselective alkylation of N-protected alanine tert-butyl ester with a Maruoka catalyst and Miyaura borylation reaction to install the boron functionality.

Silver-catalyzed regioselective hydroamination of alkenyl diazoacetates to synthesize γ-amino acid equivalents.

A simple protocol to directly access γ-amino acid derivatives by intermolecular regioselective hydroamination of trichloroethyl alkenyldiazoacetates with carbamate using a silver tetrafluoroborate catalyst is described. Density functional theory (DFT) calculations to analyze the reaction mechanism revealed that multiple attractive interactions occur in a transition state to promote the vinylogous addition of nitrogen nucleophiles.