Rhodium(I)/Chiral Diene Complexes Catalyzed Asymmetric Desymmetrization of Alkynyl-Tethered 2,5-Cyclohexadienones Through an Arylative Cyclization Cascade.

Cis-hydrobenzofurans, cis-hydroindoles, and cis-hydrindanes, privileged structural motifs found in numerous biologically active natural and synthetic compounds, are efficiently prepared by a Rh(I)-catalyzed cascade syn-arylation/1,4-addition protocol. This approach starts with the regioselective syn-arylation of the alkyne tethered to 2,5-hexadienone moieties, using a chiral Rh(I) catalyst generated in situ from a chiral bicyclo[2.2.1]hepatadiene ligand L4f. By forging two new carbon-carbon bonds and introducing two chiral centers, the resulting alkenylrhodium species undergoes desymmetrization via an intramolecular 1,4-addition reaction, delivering annulated products with high yields and enantioselectivities.

Progress in recent development of stereoselective synthesis of ß2-amino acid derivatives from ß-nitroacrylate derivatives.

The synthesis and properties of ß-amino acids have drawn considerable attention owing to their ubiquitous presence in naturally occurring products of biological importance. While ß3-amino acids can be readily prepared from α-amino acids via one-carbon homologation, the synthesis of ß2-amino acids generally requires multistep efforts. This review focuses on the recent advances in the synthesis of ß2-amino acids and their derivatives from substituted ß-nitropropionate analogues obtained from the stereoselective transformation of ß-nitroacrylates.

Access to ß2-Amino Acids via Enantioselective 1,4-Arylation of ß-Nitroacrylates Catalyzed by Chiral Rhodium Catalysts.

The highly enantioselective conjugate addition of a variety of arylboronic acids to ß-nitroacrylates is reported to provide optically active α-aryl ß-nitropropionates in up to 70% yields and >99.5% ee's, which are useful building blocks for preparing chiral ß2-amino acids. The applicability of this transformation is demonstrated by converting 3aa into the ß2-amino acid 5 and transforming 3ap to ß-amino ester 7 via reduction and reductive N-alkylation. The latter compound is a precursor for preparing ent-ipatasertib.

Synthesis of Quaternary-Carbon-Containing ß2,2 -Amino Acids by the RhI -Catalyzed Enantioselective Arylation of α-Substituted ß-Nitroacrylates.

An enantioselective RhI -catalyzed conjugate addition reaction of α-substituted ß-nitroacrylates with various arylboronic acids by using chiral RhI diene catalysts is described for the first time. The addition reaction proceeds under mild conditions in a range of common organic solvents and additives, and it affords the corresponding quaternary-carbon-containing α,α-disubstituted ß-nitropropionate products in up to 63 % yield and 99 % ee. Reaction of either (E)- or (Z)-ß-nitroacrylates provided the same enantiomer of the product, and a range of esters and aryl groups were tolerated. To demonstrate the utility of the method, ethyl (R)-1,1-methyl-1-phenyl-3-nitropropionate, prepared herein, was converted to the non-proteinogenic ß2,2 -amino acid, (R)-2-(aminomethyl)-2-phenylpropanoic acid, and to the ß2,2 -lactam, (R)-3-methyl-3-phenylazetidin-2-one. In addition, a tripeptide, which comprised l-phenylalanine, l-alanine, and ß2,2 -amino acid 7, was also synthesized.

Design and Synthesis of Chiral Diene Ligands for RhI -Catalyzed Enantioselective Arylation of N-DPP-protected Aldimines: Synthesis of the Antifungal Agent Bifonazole.

Herein we describe the design and synthesis of a novel family of bifunctional, chiral bicyclo[2.2.1]heptadiene ligands bearing aryl and secondary amido groups, and demonstrate their usefulness in the RhI -catalyzed enantioselective addition reaction of arylboronic acids to N-diphenylphosphinyl (N-DPP)-protected aldimines. Unlike the analogous RhI -catalysts comprising diene ligands substituted with aryl and carboxylic ester groups, or only with aryl groups, the addition reaction proceeded with high stereoselectivity. The protocol tolerated a range of N-DPP-aldimines and arylboronic acids, producing the desired optically active N-DPP-protected amines with yields between 31-99 % and with ee values up to 91-99 %. The synthetic utility of the method was demonstrated by the conversion of N-DPP-protected amine 3 ae into the antifungal agent, bifonazole (13).

Rh(I)-Catalyzed 1,4-Conjugate Addition of Alkenylboronic Acids to a Cyclopentenone Useful for the Synthesis of Prostaglandins.

An efficient and trans-diastereoselective Rh(I)-catalyzed 1,4-conjugate addition reaction of alkenylboronic acids and a homochiral (R)-4-silyloxycyclopentenone useful for the synthesis of derivatives of prostaglandins E and F is described for the first time. The reaction functions under mild conditions and is particularly rapid (≤6 h) under low power (50 W) microwave irradiation at 30 °C in MeOH in the presence of a catalytic amount of KOH. Under these conditions, 3 mol % of [RhCl(COD)]2 is typically required to produce high yields. The method also functions without microwave irradiation at 3 °C in the presence of a stoichiometric amount of KOH. Under these conditions, only 1.5 mol % of [RhCl(COD)]2 is needed, but the reaction is considerably slower. The method accepts a range of aryl- and alkyl-substituted alkenylboronic acids, and its utility has been demonstrated by the synthesis of PGF2α (dinoprost) and tafluprost.

Direct synthesis of chiral 3-arylsuccinimides by rhodium-catalyzed enantioselective conjugate addition of arylboronic acids to maleimides.

Chiral rhodium catalysts comprising 2,5-diaryl- substituted bicyclo[2.2.1]diene ligands L1-L10 were utilized in the enantioselective 1,4-addition reaction of arylboronic acids to N-substituted maleimides. In the presence of 2.5 mol % of Rh(I) /L2, enantioenriched conjugate addition adducts were isolated in 72-99 % yields with 86-98 % ee. This protocol offers a convenient method to access a variety of 3-arylsuccinimides in a highly enantioselective manner. Maleimides with readily cleavable N-protecting groups were tolerated enabling the synthesis of useful synthetic intermediates. Pyrrolidine 4, a biologically active compound, and pyrrolidine 5, an ent-precursor to an HSD-1 inhibitor, were synthesized to demonstrate the utility of this method.

ß-Selective C-Arylation of Diisobutylaluminum Hydride Modified 1,6-Anhydroglucose: Synthesis of Canagliflozin without Recourse to Conventional Protecting Groups.

The ß-selective phenylation of benzyl and boronate protected 1,6-anhydroglucose and the direct phenylation of unprotected 1,6-anhydroglucose (10), pretreated with i-Bu2AlH, i-Bu3Al, Et3Al, Me3Al, or n-octyl3Al, with triphenylalane or aryl(chloro)alanes is reported. The utility of the unprotected version of the method is demonstrated by the synthesis of the SGLT2 inhibitor, canagliflozin (1a), from commercially available 10 in one C-C bond-forming step. This approach circumvents the need for conventional protecting groups, and therefore no formal protection and deprotection steps are required.

ß-selective C-arylation of silyl protected 1,6-anhydroglucose with arylalanes: the synthesis of SGLT2 inhibitors.

The stereoselective arylation of hydroxy protected 1,6-anhydro-ß-d-glucose with arylalanes to provide ß-C-arylglucosides is reported. Modification of triarylalanes, Ar3Al, with strong Brønsted acids (HX) or AlCl3 produced more reactive arylating agents, Ar2AlX, while the incorporation of alkyl dummy ligands into the arylating agents was also viable. Me3Al and i-Bu2AlH were found useful in the in situ blocking of the C3-hydroxyl group of 2,4-di-O-TBDPS protected 1,6-anhydroglucose. The utility of the method was demonstrated by the synthesis of the SGLT2 inhibitor, canagliflozin.

Enantioselective and rapid Rh-catalyzed arylation of N-tosyl- and N-nosylaldimines in methanol.

Enantiomerically enriched tosyl-protected diarylmethylamines were rapidly prepared by the asymmetric addition of arylboronic acids to N-tosylaldimines under mild conditions in the presence of a catalyst prepared in situ from Rh(I) and a chiral diene ligand. This methodology offers access to diarylmethylamines in good yields with excellent chiral purity at room temperature using MeOH as a solvent and NEt3 as a base. Its synthetic utility was demonstrated by the preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (14), an antagonist of the N-methyl-d-aspartate (NMDA) receptor.

Isotopic assessment of soil N2O emission from a sub-tropical agricultural soil under varying N-inputs.

Nitrogen fertilizers result in high crop productivity but also enhance the emission of N2O, an environmentally harmful greenhouse gas. Only approximately a half of the applied nitrogen is utilized by crops and the rest is either vaporized, leached, or lost as NO, N2O and N2 via soil microbial activity. Thus, improving the nitrogen use efficiency of cropping systems has become a global concern. Factors such as types and rates of fertilizer application, soil texture, moisture level, pH, and microbial activity/diversity play important roles in N2O production. Here, we report the results of N2O production from a set of chamber experiments on an acidic sandy-loam agricultural soil under varying levels of an inorganic N-fertilizer, urea. Stable isotope technique was employed to determine the effect of increasing N-fertilizer levels on N2O emissions and identify the microbial processes involved in fertilizer N-transformation that give rise to N2O. We monitored the isotopic changes in both substrate (ammonium and nitrate) and the product N2O during the entire course of the incubation experiments. Peak N2O emissions of 122 ± 98 µg N2O-N m-2 h-1, 338 ± 49 µg N2O-N m-2 h-1 and 739 ± 296 µg N2O-N m-2 h-1 were observed for urea application rate of 40, 80, and 120 µg N g-1. The duration of emissions also increased with urea levels. The concentration and isotopic compositions of the substrates and product showed time-bound variation. Combining the observations of isotopic effects in δ15N, δ18O, and 15N site preference, we inferred co-occurrence of several microbial N2O production pathways with nitrification and/or fungal denitrification as the dominant processes responsible for N2O emissions. Besides this, dominant signatures of bacterial denitrification were observed in a second N2O emission pulse in intermediate urea-N levels. Signature of N2O consumption by reduction could be traced during declining emissions in treatment with high urea level.

Forrest Classification for Bleeding Peptic Ulcer: A New Look at the Old Endoscopic Classification.

The management of peptic ulcer bleeding is clinically challenging. For decades, the Forrest classification has been used for risk stratification for nonvariceal ulcer bleeding. The perception and interpretation of the Forrest classification vary among different endoscopists. The relationship between the bleeder and ulcer images and the different stages of the Forrest classification has not been studied yet. Endoscopic still images of 276 patients with peptic ulcer bleeding for the past 3 years were retrieved and reviewed. The intra-rater agreement and inter-rater agreement were compared. The obtained endoscopic images were manually drawn to delineate the extent of the ulcer and bleeding area. The areas of the region of interest were compared between the different stages of the Forrest classification. A total of 276 images were first classified by two experienced tutor endoscopists. The images were reviewed by six other endoscopists. A good intra-rater correlation was observed (0.92-0.98). A good inter-rater correlation was observed among the different levels of experience (0.639-0.859). The correlation was higher among tutor and junior endoscopists than among experienced endoscopists. Low-risk Forrest IIC and III lesions show distinct patterns compared to high-risk Forrest I, IIA, or IIB lesions. We found good agreement of the Forrest classification among different endoscopists in a single institution. This is the first study to quantitively analyze the obtained and explain the distinct patterns of bleeding ulcers from endoscopy images.

Enantioselective Synthesis of 1-Aryl Tetrahydroisoquinolines by the Rhodium-Catalyzed Reaction of 3,4-Dihydroisoquinolinium Tetraarylborates.

The 1-aryl tetrahydroisoquinolines (1-aryl THIQs) are omnipresent in biologically active molecules. Here we report on the direct asymmetric synthesis of these valuable compounds via the reaction of 3,4-dihydroisoquinolinium tetraarylborates. The dual roles of anionic tetraarylborates, which function as both prenucleophiles and stabilizers of 3,4-dihydroisoquinolinium cations, enable this rhodium(I)-catalyzed protocol to convergently provide enantioenriched 1-aryl THIQs in good yields (≤95%) with ≤97% ee, as demonstrated by the formal synthesis of (-)-solifenacin and the facile synthesis of (-)-Cryptostyline I.

Current Status and Future Perspective of Artificial Intelligence in the Management of Peptic Ulcer Bleeding: A Review of Recent Literature.

With the decreasing incidence of peptic ulcer bleeding (PUB) over the past two decades, the clinician experience of managing patients with PUB has also declined, especially for young endoscopists. A patient with PUB management requires collaborative care involving the emergency department, gastroenterologist, radiologist, and surgeon, from initial assessment to hospital discharge. The application of artificial intelligence (AI) methods has remarkably improved people's lives. In particular, AI systems have shown great potential in many areas of gastroenterology to increase human performance. Colonoscopy polyp detection or diagnosis by an AI system was recently introduced for commercial use to improve endoscopist performance. Although PUB is a longstanding health problem, these newly introduced AI technologies may soon impact endoscopists' clinical practice by improving the quality of care for these patients. To update the current status of AI application in PUB, we reviewed recent relevant literature and provided future perspectives that are required to integrate such AI tools into real-world practice.

Enantioselective Rhodium-Catalyzed Allylation of Aliphatic Imines: Synthesis of Chiral C-Aliphatic Homoallylic Amines.

Reported herein is a method for the efficient syntheses of optically active 1-alkyl homoallylic amines in yields up to 95%, 13.5:1 dr, and 98% ee under mild, aqueous reaction conditions, via the Rh-catalyzed asymmetric allylation of aliphatic aldimines. This method provides a streamlined synthetic platform for the preparation of indolizidine and piperidine alkaloids, thus demonstrating its usefulness.

Asymmetric Synthesis of Functionalized Phenylalanine Derivatives via Rh-Catalyzed Conjugate Addition and Enantioselective Protonation Cascade.

The asymmetric conjugate addition of arylboronic acids to N-phthalimidodehydroalanine 1i catalyzed by Rh(I)/L1a enables the facile preparation of chiral functionalized phenylalanines. The reaction proceeds by a conjugate addition and enantioselective protonation cascade, affording a rhodium enolate that undergoes re-face protonation. The reaction tolerates various arylboronic acids and can be used in the gram-scale synthesis of (S)-phenylalanine hydrochloride, demonstrating the reaction scope and the synthetic feasibility of the process.

Asymmetric Synthesis of ß-Aryl ß-Imido Sulfones Using Rhodium Catalysts with Chiral Diene Ligands: Synthesis of Apremilast.

A chiral rhodium(I)-diene catalyst enabled the one-step synthesis of ß-aryl ß-imido sulfones under mild reaction conditions. By selection of the chiral diene ligand L1a or L2, each enantiomer of the chiral ß-aryl ß-imido sulfone target can be accessed with high stereoselectivity. Demonstration of the scope of the reaction, which includes the synthesis of an N-protected chiral ß-amino ß-phenyl sulfone, culminated with the efficient synthesis of the heteroatom-rich active pharmaceutical ingredient apremilast.

Asymmetric addition of dimethylzinc to alpha-ketoesters catalyzed by (-)-MITH.

This investigation describes the catalytic asymmetric addition of dimethylzinc to alpha-ketoesters in the presence of (-)-MITH ( 5) and triethyl borate as an additive to give the corresponding chiral alpha-hydroxy esters with good yields and high enantioselectivities.

Rh-Catalyzed Enantioselective Allylation of N-Tosyl- and N-Nosylaldimines: Total Synthesis of (-)-Crispine A.

The unprecedented development of asymmetric Rh-catalyzed 1,2-allylation of N-Ts- and N-Ns-aldimines is achieved. This protocol utilizes potassium allyltrifluoroborates and various aldimines to generate enantioenriched homoallylic amines in the presence of 3.0 mol % of Rh(I)/L1b catalyst with up to 90% yield, 98% ee (R = H), and 10:1 diastereoselectivity (R = Me or Ph), yielding the same major diastereomer when using potassium (E)- and (Z)-crotyltrifluoroborate. Its synthetic utility is also illustrated in the total synthesis of (-)-crispine A.

Rhodium/chiral diene complexes in the catalytic asymmetric arylation of ß-pyrazol-1-yl acrylates.

The asymmetric conjugate addition of arylboronic acids to substituted and unsubstituted ß-pyrazol-1-yl (E)-tert-butyl acrylates 4 catalyzed by 5 mol % of the Rh(I)/diene 2a catalyst provided the corresponding addition products in 44-98% yield and 91->99.5% ee. The method was applied to the formal synthesis of (3S)-3-aryl-3-(pyrazol-1-yl)propanoic acid 1b with agonistic activity toward the human GPR40 G-protein coupled receptor.