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.

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.

Total Synthesis of (+)-Shearilicine.

Herein we report the first total synthesis of the indole diterpenoid natural product shearilicine by an 11-step sequence via a generalizable precursor to the highly oxidized subclass of indole diterpenoids. A native chiral auxiliary strategy was employed to access the target molecule in an enantiospecific fashion. The formation of the key carbazole substructure was achieved through a mild intramolecular Heck cyclization, wherein a computational study revealed noncovalent substrate-ligand and ligand-ligand interactions that promoted migratory insertion.

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.

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.

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.

Cost analysis of transcatheter versus surgical aortic valve replacement in octogenarians: analysis from a single Japanese center.

Transcatheter aortic valve replacement (TAVR) has revolutionized the prognosis of intermediate- or high-risk patients with severe aortic stenosis, particularly among older adults. However, in possible candidates for surgical aortic valve replacement (SAVR), the implantation of expensive prostheses may be questionable in an era when healthcare costs are becoming a major concern. In this retrospective analysis of a single Japanese center, we focused on patients aged over 80 years; the objectives of this study were: (1) to compare TAVR and SAVR in terms of total hospitalization costs and (2) to describe the itemized cost of TAVR and SAVR to identify patients aged over 80 years in whom TAVR or SAVR would be cost-effective. A total of 146 patients aged over 80 years who underwent TAVR or SAVR for severe aortic stenosis were included. These patients were divided into a high-risk group (Society of Thoracic Surgeons [STS] mortality score > 8%; 36: TAVR and 12: SAVR) with 48 patients and a non-high-risk group (STS mortality score < 8%; 45: TAVR and 53 SAVR) with 98 patients. No 30-day mortality was observed in either group. In both groups, postoperative intensive care unit stay and hospital stay were longer with SAVR than with TAVR. In the non-high-risk group, the total cost was comparable for TAVR and SAVR; however, in the high-risk group, the total cost was significantly higher with SAVR than that with TAVR. A breakdown analysis of the total cost in the high-risk group showed both pre- and postoperative costs to be significantly higher with SAVR than with TAVR; however, operative costs were higher with TAVR. Up to 3 years, the overall survival in both groups did not significantly differ between TAVR and SAVR. Our findings suggest that from the perspective of total medical costs, TAVR is more suitable than SAVR for high-risk older adults.

Development of Novel Methodology Using Diazo Compounds and Metal Catalysts.

The ability to control the reactions of highly active chemical species to enable straightforward synthesis of valuable compounds such as bioactive natural products and pharmaceuticals is a continuing challenge in synthetic organic chemistry. This review describes the development of a methodology using reactive metal-carbene species and its synthetic application in our laboratory. First, regioselective synthesis of γ-amino acid equivalents to take advantage of their metal-dependent reactivities and the mechanistic rationale are presented. Chemoselective and enantioselective dearomatization reactions of several arenes with silver-carbene are also discussed. In the second half of the review, we discuss a carbene-insertion reaction into an amide and urea C-N bond for the assembly of nitrogen-bridged cyclic molecules.

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.

Tolvaptan can limit postoperative paroxysmal atrial fibrillation occurrence after open-heart surgery.

PURPOSE: Tolvaptan administration in the early postoperative period after cardiac surgery rapidly treats fluid retention without affecting the renal function. Tolvaptan also has the benefit of not stimulating the renin-angiotensin and sympathetic nervous systems, which are risk factors for postoperative paroxysmal atrial fibrillation. In this study, we examined the hypothesis that tolvaptan administration reduces postoperative paroxysmal atrial fibrillation and worsening of the renal function incidence in patients who have undergone open-heart surgery. METHODS: From our previous randomized study, we selected 166 open-heart surgery patients, divided them into 2 groups [tolvaptan group, 83 patients; control (non-tolvaptan) group, 83 patients], and compared the incidence of postoperative paroxysmal atrial fibrillation and worsening of the renal function in the postoperative period between the groups. RESULTS: The incidence of worsening of the renal function was significantly lower in the tolvaptan group than in the control group (4.8% vs. 15.7%; P = 0.04). The incidence of postoperative paroxysmal atrial fibrillation within 14 days was also significantly lower in the tolvaptan group than in the control group (26.5% vs. 42.2%; P = 0.011). CONCLUSION: Tolvaptan administration in the early postoperative period after open-heart surgery may reduce the incidence of postoperative paroxysmal atrial fibrillation and worsening of the renal function.

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.

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.

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.

Can Tolvaptan Protect Renal Function in the Early Postoperative Period of Cardiac Surgery?　- Results of a Single-Center Randomized Controlled Study.

BACKGROUND: Oral administration of tolvaptan, a vasopressin V2receptor antagonist, significantly reduces deterioration of renal function, which has recently been highlighted as an exacerbating factor for adverse events in patients with acute heart failure. In the present study we tested the hypothesis that concomitant administration of tolvaptan with a conventional diuretic is beneficial for perioperative body fluid management in patients who have undergone cardiac surgery.Methods and Results:In all, 280 patients who underwent cardiac surgery were prospectively randomized to concomitant treatment with tolvaptan and a conventional diuretic (tolvaptan group; 147 patients) or treatment with a conventional diuretic alone (control group; 133 patients). Groups were compared in terms of the time required to restore preoperative body weight and the incidence of worsening renal function (WRF), defined as an increase in the serum creatinine level ≥0.3 mg/dL. The time required to restore preoperative body weight was significantly shorter in the tolvaptan than control group (mean [±SD] 3.97±1.95 vs. 5.02±2.83 days, respectively; P<0.001). The incidence of WRF was significantly lower in the tolvaptan than control group (n=11 [7.5%] vs. n=25 [18.8%], respectively; P=0.011). CONCLUSIONS: Administration of tolvaptan with conventional diuretics in the early postoperative period after cardiac surgery could be beneficial in maintaining urine output without affecting renal function and may thus help avoid WRF.

Urea Insertion Reaction of Rhodium-Carbenoid.

We developed the first carbenoid insertion reaction into the urea C-N bond. The urea insertion reaction proceeded smoothly using Rh2(NHPiv)4, a rhodium catalyst previously designed by our group, to construct a diazabicyclic system. Highly functionalized bridged molecules with three adjacent stereocenters were diastereoselectively synthesized via the urea insertion reaction followed by hydride reduction or nucleophilic addition sequences in one-pot.

Chemoselective Asymmetric Intramolecular Dearomatization of Phenols with α-Diazoacetamides Catalyzed by Silver Phosphate.

We report asymmetric dearomatization of phenols using Ag carbenoids from α-diazoacetamides. The Ag catalyst promoted intramolecular dearomatization of phenols, whereas a Rh or Cu catalyst caused C-H insertion and a Büchner reaction. Studies indicated Ag carbenoids have a carbocation-like character, making their behavior and properties unique. Highly enantioselective transformations using Ag carbenoids have not been reported. We achieved a Ag carbenoid-mediated chemo- and highly enantioselective phenol dearomatization with substrate generality for the first time.

Rhodium-Catalyzed Stereospecific C-H Amination for the Construction of Spiroaminal Cores: Reactivity Difference between Nitrenoid and Carbenoid Species against Amide Functionality.

Metal nitrenoids and metal carbenoids exhibit similar reactivity for insertion into a C-H bond and a C=C double bond. These reactions have attracted the attention of organic chemists due to their unusual bond-forming ability, but the reactivity difference between these chemical species has not been studied. In this paper, we examined the reactivity difference using the corresponding Rh nitrenoid and Rh carbenoid precursors. The Rh nitrenoid inserted into an intramolecular C(sp3 )-H bond adjacent to an amide nitrogen, affording functionalized spiroaminals that are ubiquitous in natural products, while the Rh carbenoid inserted into an amide C-N bond. The totally different reactivity was rationalized by the relatively low energy barrier for the C-H insertion reaction of the Rh nitrenoid. Computational analysis suggests that the origin of the discrepancy is the electrophilicity of the coordinating atoms to the Rh complex.

Synthetic Study of Dragmacidin E: Construction of the Core Structure Using Pd-Catalyzed Cascade Cyclization and Rh-Catalyzed Aminoacetoxylation.

We developed a novel synthetic method of the core structure of dragmacidin E bearing a 7-membered ring-fused bis(indolyl)pyrazinone skeleton. Formation of the 7-membered ring-fused tricyclic indole skeleton was accomplished using a palladium-catalyzed Heck insertion-allylic amination cascade. Vicinal difunctionalization of the 7-membered ring was realized via a rhodium-catalyzed aminoacetoxylation.