Revised Mechanism of Gold-Catalyzed Thioallylation of Propiolates.

Gold-catalyzed enantioselective thioallylation of propiolates proved effective in delivering highly enantio-enriched α-allyl-ß-thioacrylates. In this work, we report a revised mechanism for this process based on the new mechanistic experiments and kinetic data in the presence of a competitive inhibitor. The employment of thioethers as nucleophiles inevitably involves their competitive binding to the only catalytic site of the Au(I) catalyst, which may inhibit the activity. We developed a modified Hammett plot in the presence of a dummy thioether inhibitor, which revealed a true kinetic profile, excluding the effect of inhibition. A revised mechanism suggested that the conjugate addition of thioethers to the Au(I)-activated alkynes is the turnover-limiting step, and the subsequent [3,3]-rearrangement occurs quickly, suggesting the efficacy of the sulfonium-based approach in accelerating Claisen rearrangement. In addition, the enantioselectivity was suggested to be determined during the sigmatropic rearrangement by discriminating the prochiral olefin faces of the allyl group in the σ-bound Au(I) complex.

Recent Progress in Enolonium Chemistry under Metal-Free Conditions.

Umpolung approach through inversion of the polarity of conventional enolates, has opened up an unprecedented opportunity in the cross-coupling via alkylation. The enolonium equivalents can be accessed either by hypervalent iodine reagents, activation/oxidation of amides, or the oxidation of alkynes. Under umpolung conditions, highly basic conditions required for classical enolate chemistry can be avoided, and they can couple with unmodified nucleophiles such as heteroatom donors and electron-rich arenes.

Gold-Catalyzed Asymmetric Thioallylation of Propiolates via Charge-Induced Thio-Claisen Rearrangement.

A gold(I)-catalyzed enantioselective thioallylation of propiolates with allyl sulfides is described. The key mechanistic element is a sulfonium-induced Claisen rearrangement which helps minimize the allyl dissociation and render higher enantioselectivity. This protocol features remarkable scope of the allyl moiety, allowing enantiocontrolled synthesis of all-carbon quaternary centers, and exhibits exceptional functional group compatibility with many Lewis bases and π-bonds. This intermolecular variant of Claisen rearrangement forges both C-S and C-C bonds concomitantly, providing efficient access to interesting optically active organosulfur compounds which can be transformed further through the vinyl sulfide as a functional handle. The rate of the reaction was zeroth order with respect to allyl sulfides, which suggested a reversible inhibition, providing a resting state for the catalyst. The Hammett plot displayed a correlation with σp values, suggesting a turnover-limiting sigmatropic rearrangement where decreased electron-density on sulfur accelerated the rearrangement.

Aminooxygenation of Ynamides with N-Hydroxybenzotriazoles: Synthesis of α-Benzotriazolyl Carbonyl Compounds.

Addition of N-hydroxybenzotriazoles to ynamides causes spontaneous rearrangement, resulting in α-benzotriazolyl imides. The transformation proceeded at rt in the absence of any catalyst but could be efficiently catalyzed by Zn(OTf)2. Crossover experiments confirmed that the rearrangement is an intramolecular process, most likely via a concerted mechanism. However, heating the mixture above 110 °C resulted in isomerization of N2 into N1 product, via heterolytic C-N bond dissociation. This tandem addition-rearrangement sequence provides an efficient and atom-economical synthetic route for the synthesis of α-benzotriazolyl carbonyl compounds.

Total Synthesis of (±)-Clivonine via Diels-Alder Reactions of 3,5-Dibromo-2-pyrone.

New synthetic routes to (±)-clivonine were devised starting with the Diels-Alder cycloadditions of 3,5-dibromo-2-pyrone with styrene pinacol boronate dienophiles. In the first-generation synthesis, the pivotal perhydroindoline system including the C5-hydroxyl group was constructed via a reaction sequence involving the Eschenmoser-Claisen rearrangement and regio/stereoselective epoxide opening reaction. In the second-generation synthesis, a radical-mediated cyclization approach was employed for the rapid assembly of the pyrrolidine ring. In this route, the C5-hydroxyl group provided by the dienophile in a stereochemically defined form was preserved throughout the synthesis.

Metal-Free Iodine-Catalyzed Oxidation of Ynamides and Diaryl Acetylenes into 1,2-Diketo Compounds.

Metal-free oxidation of ynamides is described, employing pyridine- N-oxides as oxidants under molecular iodine catalysis. In stark contrast to Brønsted acid catalysis, iodophilic activation of ynamides diverts the reaction manifold into a dioxygenation pathway. This oxidation is very rapid at room temperature with only 2.5 mol % I2. Furthermore, this protocol could be extended to nonactivated alkynes, such as diarylacetylenes, to deliver various benzil derivatives.

Asymmetric Synthesis of Dihydropyranones via Gold(I)-Catalyzed Intermolecular [4+2] Annulation of Propiolates and Alkenes.

Intermolecular asymmetric gold catalysis involving alkyne activation presents a significant challenge due to its distinct mechanistic mode from other metals. Herein, we report a highly enantioselective synthesis of α,ß-unsaturated δ-lactones from [4+2] annulation of propiolates and alkenes in upto 95 % ee. Notably, for the desired chiral recognition, the choice of 1,1,2,2-tetrachloroethane as solvent was found to be crucial. Furthermore, an anionic surfactant (sodium dodecyl sulfate) improved the product selectivity in the divergence of the cyclopropyl gold carbene intermediate.

Brønsted Acid Catalyzed Oxygenative Bimolecular Friedel-Crafts-type Coupling of Ynamides.

A non-metal approach for accessing α-oxo carbene surrogates for a C-C bond-forming bimolecular coupling between ynamides and nucleophilic arenes was developed. This acid-catalyzed coupling features mild temperature, which is critical for the required temporal chemoselectivity among nucleophiles. The scope of nucleophiles includes indoles, pyrroles, anilines, phenols and silyl enolethers. Furthermore, a direct test of SN 2' mechanism has been provided by employing chiral N,N'-dioxides which also enlightens the nature of the intermediates in related metal-catalyzed processes.

Catalytic access to α-oxo gold carbenes by N-O bond oxidants.

Metal carbenes are highly versatile species that mediate various transformations. Recent advances in gold catalysis have allowed catalytic access to α-oxo metal carbenes from the alkyne functionality. Compared with traditional methods that rely upon metal-catalyzed decomposition of diazo precursors, the generation of this synthon occurs in an environmentally more appealing fashion by gold-catalyzed alkyne oxygenation. Hydroxylamine derivatives are typically prepared from hydroxylamine salts that are cheap and can be handled without special precaution. In reactions with an alkyne activated by gold, relatively stable nitrones and related reagents undergo efficient O-atom transfer to form putative α-oxo gold carbenes. The highly reactive nature of these species could be utilized in a variety of cascade transformations. Herein, recent synthetic methods based on this reactivity as well as the currently available mechanistic and structural studies through computational and experimental methods have been discussed. A variety of tandem reactions performed by our laboratory and others have demonstrated the synthetic utility of catalytically generated α-oxo gold carbenes and enabled access to various heterocycles. For example, a reaction between nitrones and alkynes led to azomethine ylides for the [3 + 2] dipolar cycloaddition. Alternatively, α-oxo gold carbenes can be transformed into enolate equivalents through a 1,2-pinacol shift. The addition of hydroxylamine derivatives across triple bonds led to oxoamination, providing α-aminocarbonyl compounds or regioselective Fisher indole-type synthesis. N-O bond cleaving redox chemistry paved the way for intermolecular redox processes, most notably by use of pyridine-N-oxide derivatives with expanding synthetic applications. In closing, other metal-based oxygenations using N-O bond oxidants will be highlighted. One particularly interesting aspect is the process leading to metal vinylidene complexes. Trapping of this intermediate resulted in opposite regioselectivity from gold catalysis in alkyne oxygenation and led to ketene intermediates for use in subsequent cascade transformations.

Gold-catalyzed carbene transfer reactions.

In homogeneous gold catalysis, generations and reactions of metal carbenes have been one of the most rapidly developing areas because of their diverse reactivity under mild conditions. This review covers recent advances in the gold-catalyzed oxygen atom transfer and carbene transfer reactions to alkynes. Atom transfer to an alkyne enables alkynes to function as metal carbene synthons. Many such reactions fulfill redox neutrality starting from safe and easily handled precursors.

Polymorphisms in PDE4D are associated with a risk of COPD in non-emphysematous Koreans.

Despite extensive effort, only a few chronic obstructive pulmonary disease (COPD)-associated genes have been suggested, indicating that there must be additional risk-associated loci. Here we aimed to identify additional COPD-associated SNPs and to explore the potential relationship between COPD subgroups and the SNPs in the Korean population. We performed a genome-wide association study (GWAS) with 990 Korean individuals; 102 COPD cases and 544 controls for GWAS using Affymetrix SNP array 5.0, and 173 COPD cases and 171 controls for replication. After validating the candidate single nucleotide polymorphisms (SNP), we performed subgroup analysis by disease phenotype. Through GWAS, we identified a novel SNP in the phosphodiesterase-4D (PDE4D) gene [rs16878037 (C>T), p = 1.66 ◊ 10(-6)] that was significantly associated with COPD. This signal in PDE4D was successfully replicated in the independent set (p = 0.041). When we combined the discovery and replication data, the association signal became more significant (p = 5.69 ◊ 10(-7)). In the COPD subgroup analysis, the T allele of rs16878037 was significantly more frequent in COPD patients without severe diffusion capacity impairment (mild mixed and obstruction-dominant group) than in patients with severe impairment (severe mixed and emphysema-dominant groups). This result supports that PDE4D polymorphisms might be involved in the susceptibility to COPD especially in non-emphysematous individuals and that they could also affect the responsiveness of the PDE4 inhibitor treatment.

Au(I)-catalyzed intramolecular oxidative cyclopropanation of 1,6-enynes derived from propiolamides with diphenyl sulfoxide.

We have developed gold(I)-catalyzed oxidative cyclopropanation of 1,6-enynes derived from propiolamides employing diphenyl sulfoxide as an oxidant. 1,6-Enynes having a terminal alkyne and a propiolamide tether efficiently transformed into cyclopropane carboxaldehyde derivatives.

Gold-catalyzed intermolecular coupling of sulfonylacetylene with allyl ethers: [3,3]- and [1,3]-rearrangements.

Gold-catalyzed intermolecular couplings of sulfonylacetylenes with allyl ethers are reported. A cooperative polarization of alkynes both by a gold catalyst and a sulfonyl substituent resulted in an efficient intermolecular tandem carboalkoxylation. Reactions of linear allyl ethers are consistent with the [3,3]-sigmatropic rearrangement mechanism, while those of branched allyl ethers provided [3,3]- and [1,3]-rearrangement products through the formation of a tight ion-dipole pair.

Enantioselective Sulfonium-Claisen Rearrangement with Cinnamyl Thioethers.

Sulfonium-Claisen rearrangement leveraged by the gold-catalyzed formation of allyl sulfonium intermediates has enabled an exceptional level of regio- and enantiocontrol for the synthesis of skipped 1,4-dienes. However, the application of cinnamyl thioether derivatives to the sulfonium-Claisen rearrangement has been unsuccessful so far due to the extensive dissociation of the cinnamyl cation. By fine-tuning bisphosphine ligands, we were able to engage cinnamyl thioethers in the [3,3]-sigmatropic rearrangement, delivering the desired 1,4-dienes in a highly enantioselective manner and in good yields. The resulting products could be transformed into optically active 2-chromanones and 4H-chromenes having a vinyl moiety.

Chiral Recognition and Resolution of Phosphoric Acids Using Octahedral Cobalt Complexes.

Determining the chirality of phosphoric acids can be a challenging task. In this study, we present a novel approach for the chiral recognition of phosphates using cationic octahedral cobalt complexes. By utilizing 31P NMR spectroscopy, we are able to accurately measure the enantiopurities of chiral phosphoric acids after forming ion pairs with the cobalt complexes. We have successfully applied this method to a variety of chiral phosphoric acids derived from BINOL, H8-BINOL, SPINOL, VAPOL, and VANOL compounds, as well as ATP, and were able to efficiently resolve them in 31P{1H} NMR spectra. Furthermore, we were able to achieve an optical resolution of a phosphoric acid with an enantiomeric excess of greater than 99%.

Gold-catalyzed intermolecular reactions of propiolic acids with alkenes: [4 + 2] annulation and enyne cross metathesis.

A gold-catalyzed intermolecular reaction of propiolic acids with alkenes led to a [4 + 2] annulation or enyne cross metathesis. The [4 + 2] annulation proceeds with net cis-addition with respect to alkenes and provides an expedient route to α,ß-unsaturated δ-lactones, for which preliminary asymmetric reactions were also demonstrated. For 1,2-disubstituted alkenes, unprecedented enyne cross metathesis occurred to give 1,3-dienes in a completely stereospecific fashion. DFT calculations and experiments indicated that the cyclobutene derivatives are not viable intermediates and that the steric interactions during concerted σ-bond rearrangements are responsible for the observed unique stereospecificity.

α-Carbonyl Radicals from N-Enoxybenzotriazoles: De Novo Synthesis of 9-Phenanthrols.

Visible-light-induced energy transfer to N-enoxybenzotriazoles in the presence of hydrogen atom donors or alcoholic solvents led to α-carbonyl radicals. The utility of the α-carbonyl radicals was demonstrated in intramolecular tandem cyclization and in the synthesis of 9-phenanthrols and their analogues. The mechanistic experiments suggested that quenching of the reactive benzotriazolyl radical by the alcohol was accompanied by the formation of an α-hydroxy radical that mediated hydrogen atom transfer or, itself, oxidized into aldehydes.

Octogenarian Survival After Neurosurgical Procedures To Treat Severe Head Trauma.

BACKGROUND: Falls are common for persons of advanced age and can result in severe traumatic brain injury (TBI). The purpose of the present study was to determine the survival benefit from aggressive operative intervention. METHODS: The trauma quality improvement program database from 2013 to 2016 was accessed for the present study. All patients aged 80-89 years who had sustained a severe TBI with a Glasgow coma scale (GCS) score of ≤8 and brain abbreviated injury scale score of ≥3 and had undergone operative intervention (craniotomy or craniectomy) were included in the present study. The patients were divided into 2 groups, those who had survived and those who had died, and the characteristics, injury severity score (ISS), types of intracranial hemorrhage, and comorbidities were compared. Multivariable logistic regression analysis was performed to determine the factors associated with survival. A receiving operating characteristic curve was created to test the model, and the area under the curve was calculated. RESULTS: Of the 1266 patients who had met the inclusion criteria for the present study, only 477 (37.68%) had survived. A lower ISS, higher GCS score, and no history of coagulopathy were factors indicating a greater chance of survival. Operative intervention for epidural hematoma, brain contusion, and subdural hematoma was associated with 3.5, 2.25, and 1.86 odds of survival, respectively. Procedure type (craniectomy vs. craniotomy) did not affect the outcome. The area under the curve was 0.723 (95% confidence interval, 0.694-0.752). CONCLUSIONS: The octogenarians who had undergone craniotomy or craniectomy for severe TBI after a fall had very high mortality. A lower ISS, higher GCS score, no history of coagulopathy and evacuation of subdural hematoma, epidural hematoma, or brain contusion indicated a greater probability of survival.

Ortho-selective C-H arylation of phenols with N-carboxyindoles under Brønsted acid- or Cu(i)-catalysis.

Control over chemo- and regioselectivity is a critical issue in the heterobiaryl synthesis via C-H oxidative coupling. To address this challenge, a strategy to invert the normal polarity of indoles in the heterobiaryl coupling was developed. With N-carboxyindoles as umpoled indoles, an exclusively ortho-selective coupling with phenols has been realized, employing a Brønsted acid- or Cu(i)-catalyst (as low as 0.01 mol%). A range of phenols and N-carboxyindoles coupled with exceptional efficiency and selectivity at ambient temperature and the substrates bearing redox-active aryl halides (-Br and -I) smoothly coupled in an orthogonal manner. Notably, preliminary examples of atropselective heterobiaryl coupling have been demonstrated, based on a chiral disulfonimide or a Cu(i)/chiral bisphosphine catalytic system. The reaction was proposed to occur through SN2' substitution or a Cu(i)-Cu(iii) cycle, with Brønsted acid or Cu(i) catalysts, respectively.

Energy Transfer Photocatalytic Radical Rearrangement in N-Indolyl Carbonates.

A new type of sp3-like N-centered radical has been generated by selective energy transfer catalysis. Upon photoexcitation, homolytic N-O bond cleavage of N-indolyl carbonate in the presence of an Ir complex produced N- and O-centered radicals. The high spin density at the C3 position of indole led to radical recombination with the O-centered radical, affording valuable 3-oxyindole derivatives without decarboxylation. Transformations of the desired products into various molecules were also demonstrated.