Cationic Iridium-Catalyzed Decarboxylation of Aromatic Carboxylic Acids.

Practical synthetic applications of catalytic decarboxylation in producing useful molecules are limited. We report herein the cationic Ir-catalyzed decarboxylations of various electron-rich and -poor aromatic carboxylic acids to produce hydrocarbons in good yield (up to >99%). Additionally, this reaction is applicable in decarboxylative hydroarylation of bicyclic alkenes and decarboxylative fluorination, indicating the potential utility of this catalytic decarboxylation in synthetic chemistry.

Organocatalytic Synthesis of Chiral Halogenated Compounds.

This account summarizes our recent efforts in the enantioselective organocatalytic synthesis of chiral halogenated compounds. The enantioselective α-halogenation of aldehydes, decarboxylative chlorination of ß-keto acids, and enantioselective C-C bond formation at the trifluoromethylated prochiral carbon to yield the corresponding organohalides with chlorinated, fluorinated, or trifluoromethylated chiral stereogenic centers are discussed. We applied common organocatalysts, such as Jørgensen-Hayashi catalyst and cinchona alkaloid-derivatived catalyst, and developed novel chiral amine catalysts for these reactions. This account also discusses stereospecific derivatizations of the resulting chiral halogenated compounds via nucleophilic substitution. Thus, we synthesized many novel chiral compounds that have not been reported, even as racemates.

Enantioselective decarboxylative protonation and deuteration of ß-ketocarboxylic acids.

Enantioselective decarboxylative protonation of tetralone-derived ß-ketocarboxylic acids was achieved with up to 89% enantiomeric excess (ee)-in the presence of a chiral primary amine catalyst. Furthermore, this method was applied to enantioselective deuteration to afford the corresponding α-deuterioketones with up to 88% ee.

Decarboxylative trifluoromethylthiolation of pyridylacetates.

Decarboxylative trifluoromethylthiolation of lithium pyridylacetates was achieved using N-(trifluoromethylthio)benzenesulfonimide as the electrophilic trifluoromethylthiolation reagent. The reaction afforded the corresponding trifluoromethyl thioethers in good yield. Furthermore, the preparation of lithium pyridylacetates by saponification of the corresponding methyl esters and subsequent decarboxylative trifluoromethylthiolation were performed in a one-pot fashion.

Asymmetric Synthesis of Tertiary α -Hydroxyketones by Enantioselective Decarboxylative Chlorination and Subsequent Nucleophilic Substitution.

Chiral tertiary α-hydroxyketones were synthesized with high enantiopurity by asymmetric decarboxylative chlorination and subsequent nucleophilic substitution. We recently reported the asymmetric decarboxylative chlorination of ß-ketocarboxylic acids in the presence of a chiral primary amine catalyst to obtain α-chloroketones with high enantiopurity. Here, we found that nucleophilic substitution of the resulting α-chloroketones with tetrabutylammonium hydroxide yielded the corresponding α-hydroxyketones without loss of enantiopurity. The reaction proceeded smoothly even at a tertiary carbon. The proposed method would be useful for the preparation of chiral tertiary alcohols.

Amine-Catalyzed Decarboxylative Aldol Reaction of ß-Ketocarboxylic Acids with Trifluoropyruvates.

Decarboxylative aldol reaction of aliphatic carboxylic acids is a useful method for C-C bond formation because carboxylic acids are an easily available class of compounds. In this study, we found that the decarboxylative aldol reaction of tertiary ß-ketocarboxylic acids and trifluoropyruvates proceeded smoothly to yield the corresponding aldol products in high yields and with high diastereoselectivity in the presence of a tertiary amine catalyst. In this reaction, we efficiently constructed a quaternary carbon center and an adjacent trifluoromethylated carbon center. This protocol was also extended to an enantioselective reaction with a chiral amine catalyst, and the desired product was obtained with up to 73% enantioselectivity.

Decarboxylative Fluorination of 2-Pyridylacetates.

Syntheses of substituted pyridines and fluorinated compounds, which are often pharmaceutical targets, are important objectives in organic chemistry. Herein, we found that decarboxylative fluorination of lithium 2-pyridylacetates occur under catalyst-free conditions. The phenomenon can be applied to one-pot transformation of substituted methyl 2-pyridylacetate to 2-(fluoroalkyl)pyridine by decarboxylative fluorination of the intermediate lithium 2-pyridylacetate. This method was also applied to the syntheses of 2-(difluoroalkyl)pyridines.

Regio- and Enantioselective Intramolecular Amide Carbene Insertion into Primary C-H Bonds Using Ru(II)-Pheox Catalyst.

We have established a method for the highly regio- and enantioselective functionalization of tert-butyl groups via intramolecular amide carbene insertion into C-H bonds, yielding γ-lactams with 91% ee in up to 99% yield. This reaction uses a ruthenium(II) phenyl oxazoline (Ru(II)-Pheox) complex. The catalytic intramolecular carbene transfer reaction to the primary C-H bond proceeds rapidly and selectively compared to that with secondary C-H, benzylic secondary C-H, tert-C-H, or sp2C-H bonds in the presence of 1 mol % Ru(II)-Pheox catalyst. This is the first example of a catalytic carbenoid insertion into an unactivated tert-butyl group with enantiocontrol at the carbenoid carbon.

Computational chemical analysis of Ru(II)-Pheox-catalyzed highly enantioselective intramolecular cyclopropanation reactions.

Computational chemical analysis of Ru(II)-Pheox-catalyzed highly enantioselective intramolecular cyclopropanation reactions was performed using density functional theory (DFT). In this study, cyclopropane ring-fused γ-lactones, which are 5.8 kcal/mol more stable than the corresponding minor enantiomer, are obtained as the major product. The results of the calculations suggest that the enantioselectivity of the Ru(II)-Pheox-catalyzed intramolecular cyclopropanation reaction is affected by the energy differences between the starting structures 5l and 5i. The reaction pathway was found to be a stepwise mechanism that proceeds through the formation of a metallacyclobutane intermediate. This is the first example of a computational chemical analysis of enantioselective control in an intramolecular carbene-transfer reaction using C1 -symmetric catalysts.

Direct Catalytic Asymmetric Cyclopropylphosphonation Reactions of N,N-Dialkyl Groups of Aniline Derivatives by Ru(II)-Pheox Complex.

Novel catalysis involving phosphonomethylation of N-methylaniline and asymmetric cyclopropylphosphonation reactions of N,N-diethylaniline derivatives with diazomethylphosphonates are reported. Optically active cyclopropylphosphonate derivatives were directly synthesized from diazomethylphosphonates and N,N-diethylaniline derivatives catalyzed by a Ru(II)-Pheox complex in one step in good yields and high diastereoselectivities (up to trans/ cis = > 99:1<) and enantioselectivities (up to 99% ee). D-labeling mechanistic studies of phosphonomethylation and cyclopropylphosphonation suggested that an enamine or iminium intermediate was generated in the reaction process.

Highly enantioselective synthesis of trifluoromethyl cyclopropanes by using Ru(ii)-Pheox catalysts.

An asymmetric synthesis of various trifluoromethyl cyclopropanes from olefins, such as vinyl ferrocene, vinyl ethers, vinyl amines, vinyl carbamates and dienes, was achieved by using Ru(ii)-Pheox catalysts. This catalytic system can function at a low catalyst loading (3 mol%) compared with those reported previously, and the desired cyclopropane products are obtained in high yields with excellent diastereoselectivity (up to >99 : 1) and enantioselectivity (up to 97% ee).

Compared effects of calcium and sodium polystyrene sulfonate on mineral and bone metabolism and volume overload in pre-dialysis patients with hyperkalemia.

BACKGROUND: Hyperkalemia is prevalent in end-stage renal disease patients, being involved in life-threatening arrhythmias. Although polystyrene sulfonate (PS) is commonly used for the treatment of hyperkalemia, direct comparison of effects between calcium and sodium PS (CPS and SPS) on mineral and bone metabolism has not yet been studied. METHODS: In a randomized and crossover design, 20 pre-dialysis patients with hyperkalemia (>5 mmol/l) received either oral CPS or SPS therapy for 4 weeks. RESULTS: After 4-week treatments, there was no significant difference of changes in serum potassium (K) from the baseline (ΔK) between the two groups. However, SPS significantly decreased serum calcium (Ca) and magnesium (Mg) and increased intact parathyroid hormone (iPTH) values, whereas CPS reduced iPTH. ΔiPTH was inversely correlated with ΔCa and ΔMg (r = -0.53 and r = -0.50, respectively). Furthermore, sodium (Na) and atrial natriuretic peptide (ANP) levels were significantly elevated in patients with SPS, but not with CPS, whereas ΔNa and ΔANP were significantly correlated with each other in all the patients. We also found that ΔNa and Δ(Na to chloride ratio) were positively correlated with ΔHCO3-. In artificial colon fluid, CPS increased Ca and decreased Na. Furthermore, SPS greatly reduced K, Mg, and NH3. CONCLUSION: Compared with SPS, CPS may be safer for the treatment of hyperkalemia in pre-dialysis patients, because it did not induce hyperparathyroidism or volume overload.

Ligand Exchange Reaction on a Ru(II)-Pheox Complex as a Mechanistic Study of Catalytic Reactions.

A ligand exchange of one of the acetonitrile ligands of the (acetonitrile)4Ru(II)-phenyloxazoline complex (Ru(II)-Pheox) by pyridine was demonstrated, and the location of the exchange reaction was examined by density functional theory (DFT) calculations to study the mechanism of its catalytic asymmetric reactions. The acetonitrile was smoothly exchanged with a pyridine to afford the corresponding (pyridine)(acetonitrile)3Ru(II)-Pheox complex with a trans orientation (C-Ru-N(pyridine)) in a quantitative yield, and the complex was analyzed by single-crystal X-ray analysis. DFT calculations indicated that the most eliminable acetonitrile is the trans group, which is consistent with the X-ray analysis. The direction of the ligand exchange is thus determined on the basis of the energy gap of the ligand elimination instead of the stability of the metal complex. These results suggested that a reactant in a Ru-Pheox-catalyzed reaction should approach trans to the C-Ru bond to generate chirality on the Ru center.

Highly stereoselective spirocyclopropanation of various diazooxindoles with olefins catalyzed using Ru(ii)-complex.

Optically active spirocyclopropyloxindole derivatives were efficiently synthesized from diazooxindoles and olefins in the presence of a Ru(ii)-Pheox catalyst. Among a series of Ru(ii)-Pheox catalysts, Ru(ii)-Pheox 6e was determined to be the best catalyst for spirocyclopropanation reactions of diazooxindoles with various olefins in high yields (up to 98%) with high diastereoselectivities (up to trans:cis = >99:1<) and enantioselectivities (up to 99% ee). Furthermore, as the first catalytic asymmetric synthesis, anti-HIV active candidate 4a and a bioactive compound of AMPK modulator 4c were easily synthesized from the corresponding diazooxindoles 1i and 1b, respectively, in high yields with high enantioselectivities (4a: 82% yield, 95% ee, 4b: 99% yield, 93% ee).

Highly stereoselective cyclopropanation of various olefins with diazosulfones catalyzed by Ru(ii)-Pheox complexes.

A highly stereoselective cyclopropanation of various olefins with diazosulfones catalyzed by chiral Ru(ii)-Pheox complexes was developed to give chiral cyclopropyl sulfones in high yields (up to 99%) with excellent trans-selectivity and enantioselectivity (up to 98% ee).

Enantioselective decarboxylative chlorination of ß-ketocarboxylic acids.

Stereoselective halogenation is a highly useful organic transformation for multistep syntheses because the resulting chiral organohalides can serve as precursors for various medicinally relevant derivatives. Even though decarboxylative halogenation of aliphatic carboxylic acids is a useful and fundamental synthetic method for the preparation of a variety of organohalides, an enantioselective version of this reaction has not been reported. Here we report a highly enantioselective decarboxylative chlorination of ß-ketocarboxylic acids to obtain α-chloroketones under mild organocatalytic conditions. The present method is also applicable for the enantioselective synthesis of tertiary α-chloroketones. The conversions of the resulting α-chloroketones into α-aminoketones and α-thio-substituted ketones via SN2 reactions at the tertiary carbon centres are also demonstrated. These results constitute an efficient approach for the synthesis of chiral organohalides and are expected to enhance the availability of enantiomerically enriched chiral compounds with heteroatom-substituted chiral stereogenic centres.

Ru(ii)-Pheox-catalyzed Si-H insertion reaction: construction of enantioenriched carbon and silicon centers.

We established a highly enantioselective Si-H insertion reaction to construct chiral centers at the carbon and silicon atoms, using a Ru(ii)-pheox catalyst. The catalytic asymmetric Si-H insertion reaction of α-methyl-α-diazoesters proceeded smoothly with excellent stereoinduction at both the neighboring carbon and silicon atoms (up to 99% yield and 99% ee).

Highly stereoselective cyclopropanation of diazo Weinreb amides catalyzed by chiral Ru(ii)-Amm-Pheox complexes.

The first highly stereoselective cyclopropanation of diazo Weinreb amides with olefins was accomplished using chiral Ru(ii)-Amm-Pheox complex to give the corresponding chiral cyclopropyl Weinreb amides in high yields (up to 99%) with excellent diastereoselectivities (up to 99 : 1 dr) and enantioselectivities (up to 96% ee).

Enantioselective fluorination of α-branched aldehydes and subsequent conversion to α-hydroxyacetals via stereospecific C-F bond cleavage.

The highly enantioselective fluorination of α-branched aldehydes was achieved using newly developed chiral primary amine catalyst 1. Furthermore, the C-F bond cleavage of the resulting α-fluoroaldehydes proceeded smoothly under alcoholic alkaline conditions to yield the corresponding α-hydroxyacetals in a stereospecific manner. Accordingly, the one-pot conversion of α-branched aldehydes into α-hydroxyacetals was achieved for the first time in high enantioselectivity.

Williamson Ether Synthesis with Phenols at a Tertiary Stereogenic Carbon: Formal Enantioselective Phenoxylation of ß-Keto Esters.

The enantioselective formation of α-aryloxy-ß-keto esters is described for the first time. Lewis acid catalyzed enantioselective chlorination of ß-keto esters and subsequent SN 2 reactions with phenols yielded α-aryloxy-ß-keto esters with up to 96% ee. Favorskii rearrangement of α-chloro-ß-keto esters was also found to give 1,2-diesters with slightly reduced enantiopurity.