Valence-isomer selective cycloaddition reaction of cycloheptatrienes-norcaradienes.

The rapid and precise creation of complex molecules while controlling multiple selectivities is the principal objective in synthetic chemistry. Combining data science and organic synthesis to achieve this goal is an emerging trend, but few examples of successful reaction designs are reported. We develop an artificial neural network regression model using bond orbital data to predict chemical reactivities. Actual experimental verification confirms cycloheptatriene-selective [6 + 2]-cycloaddition utilizing nitroso compounds and norcaradiene-selective [4 + 2]-cycloaddition reactions employing benzynes. Additionally, a one-pot asymmetric synthesis is achieved by telescoping the enantioselective dearomatization of non-activated benzenes and cycloadditions. Computational studies provide a rational explanation for the seemingly anomalous occurrence of thermally prohibited suprafacial [6 + 2]-cycloaddition without photoirradiation.

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.

Molecular Reconstruction with Stereochemical Relay: An Investigation into the Rearrangement of Spiro[4.5]decadienone to Benzoxepane.

Herein, we report the unusual skeletal rearrangement of spiro[4.5]decadienone to benzoxepane. In particular, Lewis acid-promoted epoxide-opening ipso-cyclization of aryl epoxides afforded spiro[4.5]decadienone intermediates. Subsequent thermal activation assembled a benzoxepane core via rearomative molecular reorganization. The sequence was high-yielding and highly diastereoselective but sensitive to the aromatic substitution pattern and the epoxide side chain. Mechanistic studies suggested that the rearrangement proceeded via an uncommon intramolecular enolate attack onto the electrophilic O of p-quinone oxonium zwitterion. DFT calculations helped rationalize the product distribution and the origin of diastereoselectivity. Initial investigation into the application of this chemical transformation is also presented.

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.

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.

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.

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 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.

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.

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.

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.

Atypical Dearomative Spirocyclization of ß-Naphthols with Diazoacetamides Using a Silver Catalyst.

A chemoselective dearomatization of the less reactive benzenoid unit in ß-naphthol was developed. Spirocyclization with a reductant constructs a pivotal structure for drug candidates. One-pot oxidative conversion enabled the tandem dearomatization of ß-naphthol, producing conjugated tetraenone variants. The potential utility of the product as an F--selective anion sensor was also demonstrated. Theoretical studies revealed the intermediacy of silver-carbenoid species leading to chemoselective spirocyclization over arene cyclopropanation.

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.

Debranching thoracic endovascular aortic repair for distal aortic arch aneurysm in elderly patients aged over 75 years old.

BACKGROUND: We examined the outcome of debranching thoracic endovascular aortic repair (d-TEVAR) without sternotomy for distal aortic arch aneurysm in patients aged ≥75 years. METHODS: Patients who underwent d-TEVAR or TAR for aortic arch aneurysm between 2008 and 2015 at our hospital and aged ≥75 years were included. Age, sex, left ventricular ejection fraction, preoperative creatinine level, diabetes, cerebrovascular disease, and chronic obstructive pulmonary disease were matched using PS. RESULTS: Among 74 patients (d-TEVAR: 51, TAR: 23), 17 patients in each group were matched. No difference in surgical outcome was detected between the d-TEVAR and TAR groups, including 30-day death (0% vs. 0%), hospital death (5.8% vs. 0%: p = 0.31) and incidence of cerebral infarction (5.8% vs. 7.6%: p = 0.27) as well as the long-term outcomes of 5-year survival (92.8% vs. 74.8%: p = 0.30) and 5-year aorta-related event-free rate (88.2% vs. 100%: p = 0.15). Average duration of ICU stay (1.3 ± 1.1 days vs. 5.6 ± 1.3 days: p = 0.025) and hospital stay (16.5 ± 5.2 days vs. 37.7 ± 19.6 days: p = 0.017) were significantly shorter in the d-TEVAR group. CONCLUSION: Our results indicated that d-TEVAR is less invasive without affecting long-term outcome up to 5 years. Although the number of the patients included in the study was small, debranching TEVAR could be one of the treatments of the choice in the elderly, especially with comorbidities.

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.

Asymmetric Formal Synthesis of (+)-Catharanthine via Desymmetrization of Isoquinuclidine.

Although (+)-catharanthine is an attractive alkaloid for both clinical research and organic synthetic chemistry, only a limited number of approaches for its catalytic asymmetric synthesis exist. Herein, we describe a novel strategy for synthesizing a chiral intermediate of (+)-catharanthine via phosphoric acid-catalyzed asymmetric desymmetrization of a meso-isoquinuclidine possessing a 1,3-diol unit that was synthesized by a formal amide insertion reaction.

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.

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.

Lack of deuterium isotope effects in the antidepressant effects of (R)-ketamine in a chronic social defeat stress model.

RATIONALE: (R,S)-ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, exhibits rapid and long-lasting antidepressant effects and anti-suicidal ideation in treatment-resistant patients with depression. However, the precise mechanisms underlying the antidepressant actions of (R,S)-ketamine are unknown. Although the previous report demonstrated the deuterium isotope effects in the antidepressant actions of (R,S)-ketamine, the deuterium isotope effects in the antidepressant actions of (R)-ketamine, which is more potent than (S)-ketamine, are unknown. METHODS: We examined whether deuterium substitution at the C6 position could affect antidepressant effects of (R)-ketamine in a chronic social defeat stress (CSDS) model. RESULTS: Pharmacokinetic studies showed that levels of (2R,6R)-d1-hydroxynorketamine [(2R,6R)-d1-HNK], a final metabolite of (R)-d2-ketamine, in the plasma and brain after administration of (R)-d2-ketamine (10 mg/kg) were lower than those of (2R,6R)-HNK from (R)-ketamine (10 mg/kg), indicating deuterium isotope effects in the production of (2R,6R)-HNK. In contrast, levels of (R)-ketamine and its metabolite (R)-norketamine in the plasma and brain were the same for both compounds. In a CSDS model, both (R)-ketamine (10 mg/kg) and (R)-d2-ketamine (10 mg/kg) showed rapid and long-lasting (7 days) antidepressant effects, indicating no deuterium isotope effect in the antidepressant effects of (R)-ketamine. CONCLUSIONS: The present study suggests that deuterium substitution of hydrogen at the C6 position slows the metabolism from (R)-ketamine to (2R,6R)-HNK in mice. In contrast, we did not find the deuterium isotope effects in terms of the rapid and long-lasting antidepressant effects of (R)-ketamine in a CSDS model. Therefore, it is unlikely that (2R,6R)-HNK is essential for antidepressant effects of (R)-ketamine.