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Enzyme-catalyzed dynamic kinetic resolution was applied to the one-pot regio- and enantioselective synthesis of 2,5-disubstituted tetrazole hemiaminal esters, among which 72% of the products were obtained in excellent enantiopurities (99% ee s). Tunable stereoselectivity was achieved by using different types of enzymes during the synthesis of a key intermediate for a clinic drug candidate. Successful preparation of tetrazole ester prodrugs and high catalyst recyclability further demonstrated the potential practical application of this protocol.

Metabolic changes often occur long before pathologies manifest and treatment becomes challenging. As key elements of energy metabolism, α-ketocarboxylic acids (α-KCA) are particularly interesting, e.g., as the upregulation of pyruvate to lactate conversion is a hallmark of cancer (Warburg effect). Magnetic resonance imaging with hyperpolarized metabolites has enabled imaging of this effect non-invasively and in vivo, allowing the early detection of cancerous tissue and its treatment. Hyperpolarization by means of dynamic nuclear polarization, however, is complex, slow, and expensive, while available precursors often limit parahydrogen-based alternatives. Here, we report the synthesis for novel 13 C, deuterated ketocarboxylic acids, and a much-improved synthesis of 1- 13 C-vinyl pruvate-d6, arguably the most promising tracer for hyperpolarizing pyruvate using parahydrogen-induced hyperpolarization by side arm hydrogenation. The new synthesis is scalable and provides a high yield of 52%. We elucidated the mechanism of our Pd-catalyzed trans-vinylation reaction. Hydrogenation with parahydrogen allowed us to monitor the addition, which was found to depend on the electron demand of the vinyl ester. Electron-poor α-keto vinyl esters react slower than "normal" alkyl vinyl esters. This synthesis of 13 C, deuterated α-ketocarboxylic acids opens up an entirely new class of biomolecules for fast and cost-efficient hyperpolarization with parahydrogen and their use for metabolic imaging.

Borate esters have been applied widely as coupling partners in organic synthesis. However, the direct utilization of borate acceptors in O -glycosylation with glycal donors remains underexplored. Herein, we describe a novel O -glycosylation resulting in the formation of 2,3-unsaturated O -glycosides and 2-deoxy O -glycosides mediated by palladium and copper catalysis, respectively. This O -glycosylation method tolerated a broad scope of trialkyl/triaryl borates and various glycals with exclusive stereoselectivities in high yields. All the desired aliphatic/aromatic O -glycosides and 2-deoxy O -glycosides were generated successfully, without the hemiacetal byproducts and O→C rearrangement because of the nature of borate esters. The utility of this strategy was demonstrated by functionalizing the 2,3-unsaturated glycoside products to form saturated β- O -glycosides, 2,3-deoxy O -glycosides, and 2,3-epoxy O -glycosides.

α-Branched amines are key motifs that exist in a plethora of natural products and pharmaceuticals. Herein we disclose the first convergent synthesis of α-branched amines bearing β-carbonyl in isoindolinones by employing unactivated tertiary amides and unactivated alkyl esters as benign electrophile sources. The reaction proceeds by the direct aroylation of a C( sp )-H carbon adjacent to the nitrogen atom in core isoindolinones. Several amides and esters were screened to choose the potential acyl source for the substrate scope. The reaction is carried out with a repertoire of substrates under mild conditions and shows high functional group compatibility. Remarkably the reaction is amenable to organometallic ferrocenyl ester and indole methyl esters bearing an acidic NH moiety. Strikingly no trace of amidation product 3 is observed. In particular α-branched amines bearing β-carbonyl synthesized from indole methyl esters are considered important targets, as both motifs are prevalent in many drugs. This protocol is scalable, and products obtained from indole methyl esters show strong solid-state emission properties which are complementary with DFT calculations.8 is observed. In particular α-branched amines bearing β-carbonyl synthesized from indole methyl esters are considered important targets, as both motifs are prevalent in many drugs. This protocol is scalable, and products obtained from indole methyl esters show strong solid-state emission properties which are complementary with DFT calculations.

A simple method for the iodination of unsaturated sugars to form sugar vinyl iodides was developed under oxidant-free conditions using NaH/DMF/iodine as a reagent system at ambient temperature. 2-Iodoglycals bearing ester, ether, silicon, and acetonide protection were synthesized in good to excellent yield. 3-Vinyl iodides derived from 1,2:5,6-diacetonide glucofuranose were transformed to C-3 enofuranose and bicyclic 3,4-pyran-fused furanose via Pd-catalyzed C-3 carbonylation and intramolecular Heck reaction, respectively, as the key step.

A concise and efficient synthesis of fully substituted cyclobutane derivatives from 1,4-diyn-3-ols and anhydrides was developed. Mechanistic studies indicated that a tandem esterification, isomerization to give allenyl ester, and homointermolecular [2+2] cycloaddition might be involved. The features of this protocol are its operational practicality, mild reaction conditions, and high regio- and stereoselectivity, and it is a readily accessible gram-scale synthesis.

Deuterated organic molecules have immense value in the pharmaceutical industry. Here, we present a synthetic strategy for direct trideuteromethylation of sulfenate ions derived in situ from β-sulfinyl esters in the presence of a base utilizing inexpensive and abundant CD 3 OTs as the electrophilic trideuteromethylating agent. This protocol provides straightforward access to an array of trideuteromethyl sulfoxides in yields of 75-92% with a high degree of deuteration. The ensuing trideuteromethyl sulfoxide can be readily modified into trideuteromethyl sulfone and sulfoximine.

An efficient strategy for visible-light-promoted decarboxylative alkylation of vinylcyclopropanes with alkyl N -(acyloxy)phthalimide esters through the dual C-C bond and single N-O bond cleavage, employing triphenylphosphine and lithium iodide as the photoredox system to synthesize 2-alkylated 3,4-dihydronaphthalenes, has been established. This alkylation/cyclization involves a radical process and undergoes a sequence of N -(acyloxy)phthalimide ester single-electron reduction, N-O bond cleavage, decarboxylative, alkyl radical addition, C-C bond cleavage, and intramolecular cyclization. Moreover, using the photocatalyst Na 2 -Eosin Y instead of triphenylphosphine and lithium iodide, the vinyl transfer products are acquired when vinylcyclobutanes or vinylcyclopentanes are utilized as alkyl radical receptors.

Herein, a reaction in which the benzyl C-H bonds of alkylarenes are directly esterified by carboxylic acids to produce benzyl esters in high yields is reported. This reaction is catalyzed by Pd nanoparticles (NPs) on N -doped carbon (CN) composites based on a carbonizing Al-MIL-101(NH 2 ) material, and no oxidants or hydrogen acceptors are required. Use of o -alkylbenzoic acids as substrates leads to phthalides, whereas with carboxylic acids and alkylarenes as the feedstock, the reaction produces the benzyl esters. These reactions that use readily available alkylarenes instead of benzyl halides or benzyl alcohols as raw materials for one-step synthesis of benzyl esters without oxidants are inherently atom- and step-efficient. The CN composites and the CN-supported Pd NP catalysts were prepared and are well characterized. The proposed mechanism involves dehydrogenation of both the carboxylic groups and the benzylic groups and the transformation of benzylic C-H bond into the C-O bond via hydrogen abstraction from the benzylic group through an organopalladium intermediate. The kinetic isotope effect ( k H / k D = 2.77) indicated that C(sp 3 )-H bond cleavage of the alkane aromatics is the rate-determining step.

A visible-light-induced three-component reaction of 2-aryl indoles/benzimidazoles, Hantzsch esters, and sodium pyrosulfite through a radical cascade cyclization process with the insertion of sulfur dioxide is described. It provides a novel and powerful way for the synthesis of alkylsulfonated isoquinolinones. Hantzsch esters and Na 2 S 2 O 5 are employed as alkyl radical precursors and SO 2 surrogate, respectively. This transformation exhibits good functional group tolerance and substrate applicability under mild conditions.

Chiral cyclopropanols are highly desirable building blocks for medicinal chemistry, but the stereoselective synthesis of these molecules remains challenging. Here, a novel strategy is reported for the diastereo- and enantioselective synthesis of cyclopropanol derivatives via the biocatalytic asymmetric cyclopropanation of vinyl esters with ethyl diazoacetate (EDA). A dehaloperoxidase enzyme from Amphitrite ornata was repurposed to catalyze this challenging cyclopropanation reaction, and its activity and stereoselectivity were optimized via protein engineering. Using this system, a broad range of electron-deficient vinyl esters were efficiently converted to the desired cyclopropanation products with up to 99.5:0.5 diastereomeric and enantiomeric ratios. In addition, the engineered dehaloperoxidase-based biocatalyst is able to catalyze a variety of other abiological carbene transfer reactions, including N-H/S-H carbene insertion with EDA as well as cyclopropanation with diazoacetonitrile, thus adding to the multifunctionality of this enzyme and defining it as a valuable new scaffold for the development of novel carbene transferases.

A 2'-deoxycytidin- N 4-yl radical (dC·), a strong oxidant that also abstracts hydrogen atoms from carbon-hydrogen bonds, is produced in a variety of DNA damaging processes. We describe here the independent generation of dC· from oxime esters under UV-irradiation or single electron transfer conditions. Support for this σ-type iminyl radical generation is provided by product studies carried out under aerobic and anaerobic conditions, as well as electron spin resonance (ESR) characterization of dC· in a homogeneous glassy solution at low temperature. Density functional theory (DFT) calculations also support fragmentation of the corresponding radical anions of oxime esters 2d and 2e to dC· and subsequent hydrogen atom abstraction from organic solvents. The corresponding 2'-deoxynucleotide triphosphate (dNTP) of isopropyl oxime ester 2c ( 5 ) is incorporated opposite 2'-deoxyadenosine and 2'-deoxyguanosine by a DNA polymerase with approximately equal efficiency. Photolysis experiments of DNA containing 2c support dC· generation and indicate that the radical produces tandem lesions when flanked on the 5'-side by 5'-d(GGT). These experiments suggest that oxime esters are reliable sources of nitrogen radicals in nucleic acids that will be useful mechanistic tools and possibly radiosensitizing agents when incorporated in DNA.

An enzyme-catalyzed dynamic kinetic resolution strategy was applied for the asymmetric synthesis of phthalidyl esters in high yields (up to 95%) and enantiomeric purities (up to 99% ee ) through a direct one-pot procedure. Preparation of phthalidyl ester prodrugs and a scale-up reaction demonstrated the potential of this method for practical applications.

A regioselective alkoxycarbonylation of imidazoheterocycles using carbazates as ester group sources in DMSO was developed, in which an inexpensive FeCl2·4H2O was used as the catalyst and (NH4)2S2O8 was the oxidant. The reaction proceeded smoothly under an air atmosphere to give the 3-alkoxycarbonylated products in moderate to good yields. [ABSTRACT FROM AUTHOR]

Silver-mediated annulation of 2-iodo enol esters leading to 4- and 3,4-substituted isocoumarins was accomplished selectively at room temperature. Coupling of 2-iodo benzoic acids with enolates that were produced in situ from the simple esters was also performed to produce isocoumarins under analogous reaction conditions. Owing to the mildness of the current protocol, 4-acyl 3-substituted isocoumarins were efficiently produced without any deacylation. [ABSTRACT FROM AUTHOR]

A valuable analog of the K+-ionophore valinomycin (1), bearing a pentafluorophenyl ester moiety, has been obtained by selective reaction between the tertiary hydroxyl moiety of analog 2 (available from valinomycin hydroxylation) and the isocyanate group of pentafluorophenyl N-carbonyl glycinate (3) catalyzed by bis(N,N-dimethylformamide)dichlorodioxomolybdenum(VI). LC-HRMS studies show that analog 4 undergoes easy derivatization under mild conditions by reaction with OH- and NH2-containing compounds. Mitochondrial depolarization assays suggest that 4 acts as a K+-ionophore, provided that the glycine carboxyl group is appropriately masked. [ABSTRACT FROM AUTHOR]

A copper-mediated radiobromination of (hetero)aryl boronic pinacol esters is described. Cyclotron-produced [ 76/77 Br]bromide was isolated using an anion exchange cartridge, wherein the pre-equilibration and elution solutions played a critical role in downstream deboro-bromination. The bromination tolerates a broad range of functional groups, labeling molecules with ranging electronic and steric effects. Bologically active radiopharmaceuticals were synthesized, including two radiobrominated inhibitors of poly ADP ribose polymerase, a clinically relevant chemotherapeutic target for ovarian, breast, and prostate cancers.

On the basis of DFT computations and experimental results, we show that the presence of the ester group in the backbone of organic substrates can influence the mechanism of metal-catalyzed carbocyclization reactions. The non-innocent role of the ester functionality in lowering the activation barrier of the key step of the gallium- and indium-catalyzed cycloisomerization of 1,6-enynes is revealed. In the case of the gallium-catalyzed hydroarylation of arenynes, the esters in the tether can deprotonate the Wheland intermediate, thus avoiding more energetically demanding [1,3]- or [1,2]/[1,2]-H shifts. As for the gallium-catalyzed Friedel-Crafts alkylation, an unusual concerted SEAr mechanism involving the esters has been calculated. Lastly, computations evidence that the ester group of methyl propiolates enables a divergent mechanism in the platinum-catalyzed intramolecular hydroarylation. [ABSTRACT FROM AUTHOR]

syn-Diastereoselective conjugate addition of 1-pyrroline esters to nitroalkenes in good yields with an excellent enantioselectivity by using CuOAc/Me-FcPHOX catalyst in the presence of pyridine. In contrast, AgOAc/tBu-ThioClickFerrophos catalyzed the anti diastereoselective conjugate addition with a high enantioselectivity without additional base. Thus, the preparation of chiral 1-pyrroline derivatives bearing diverse stereochemistry could be achieved. The diastereoselective reduction of the imine group in the conjugate adduct could afford the 2,5-cis-proline ester derivative. [ABSTRACT FROM AUTHOR]

Pyrrolidine-2-carboxylate esters substituted in the 3-, 4- or 5-positions were converted to their N′-aryl urea derivatives. Deprotonation at the 2-position to form a potassium enolate led to migration of the N′-aryl substituent to the 2 position of the pyrrolidine ring, followed by cyclization of the resulting urea to give bicyclic α-aryl hydantoin derivatives of substituted prolines. Depending on the substitution pattern of the starting material, high diastereoselectivity was observed in the aryl migration, allowing formation of the products in enantiomerically enriched form, despite the intermediacy of a planar enolate. The hydrolysis of the bicyclic hydantoins under basic conditions gave a range of enantiopure and enantioenriched quaternary α-aryl proline derivatives. [ABSTRACT FROM AUTHOR]

Allylation and benzylation of phenylazocarboxylic tert-butyl esters have been achieved under Barbier-type reaction conditions and in very short reactions times using the corresponding allyl and benzyl bromides or iodides in combination with zinc powder. Whereas all reactions occurred exclusively at the β-nitrogen atom of the azocarboxylic esters, the linkage of allyl units was shown to depend on the substitution pattern at the double bond of the allyl halide. The hydrazines obtained are useful precursors for indoles and indazoles. [ABSTRACT FROM AUTHOR]

The Diels-Alder dimer of cyclopentadiene carboxylate, Thiele's acid has conformational properties that make it attractive as a molecular scaffold for applications in supramolecular and biological chemistry. However, a lack of known reaction methodology for derivatives of Thiele's acid (or the corresponding esters) has hampered its utilization in these fields. We describe an improved preparation of Thiele's esters and survey the chemistry of these versatile intermediates. As part of this effort, we also describe the synthesis of a suite of Thiele's acid (or ester) analogues spanning a broad range of cleft angles. [ABSTRACT FROM AUTHOR]

We report a diastereoselective addition reaction of fluoroacetate and α-alkylated fluoroacetate to N-tert-butylsulfinyl imines. This method provides a concise route to α-fluoro-β-amino acids containing fluorinated quaternary stereogenic carbon centers with very good yields and high diastereoselectivities. This protocol has the benefit of using abundant and readily accessible starting materials and is operationally simple. Additionally, the stereochemical outcome of the present reaction was different from that of the previously known addition of comparable nonfluorinated, brominated, and chlorinated enolates to N-sulfinyl imines, suggesting that an open transition state (rather than a closed one) is involved in the current fluoroalkylation reaction. [ABSTRACT FROM AUTHOR]

The combination of Et2Zn and RhCl(PPh3)3 led to the facile generation of a rhodium-hydride complex (Rh-H) that catalyzed the 1,4-reduction of α,β-unsaturated esters. The resulting rhodium enolate performed as a Reformatsky-type reagent and reacted with various imines to give syn-β-lactams in good to excellent yields with high diastereoselectivity. [ABSTRACT FROM AUTHOR]

In search for better mimics of the glutathione peroxidase enzymes, pyridoxine-like diselenides 6 and 11, carrying a 6-bromo substituent, were prepared. Reaction of 2,6-dibromo-3-pyridinol 5 with sodium diselenide provided 6 via aromatic nucleophilic substitution of the 2-bromo substituent. LiAlH4 caused reduction of all four ester groups and returned 11 after acidic workup. The X-ray structure of 6 showed that the dipyridyl diselenide moiety was kept in an almost planar, transoid conformation. According to NBO-analysis, this was due to weak intramolecular Se⋯O (1.1 kcal/mol) and Se⋯N-interactions (2.5 kcal/mol). That the 6-bromo substituent increased the positive charge on selenium was confirmed by NPA-analysis and seen in calculated and observed 77Se NMR-shifts. Diselenide 6 showed a more than 3-fold higher reactivity than the corresponding des-bromo compound 3a and ebselen when evaluated in the coupled reductase assay. Experiments followed for longer time (2 h) confirmed that diselenide 6 is a better GPx-catalyst than 11. On the basis of 77Se-NMR experiments, a catalytic mechanism for diselenide 6 was proposed involving selenol, selenosulfide and seleninic acid intermediates. At low concentration (10 µM) where it showed only minimal toxicity, it could scavenge ROS produced by MNC- and PMNC-cells more efficiently than Trolox. [ABSTRACT FROM AUTHOR]

The reactivity of enol esters toward [hydroxy(tosyloxy)iodo]benzene (HTIB) was assessed. These substrates were found to be rapidly converted in high yields to their corresponding α-tosyloxy ketones. This transformation demonstrates that these substrates can act as ketone surrogates. The scope of the method was investigated and aromatic, aliphatic, and cyclic enol esters were found to be suitable substrates for the reaction. The relative reactivity of a model substrate toward HTIB and m-CPBA was investigated, and it was found that the reaction could be performed under catalytic conditions. [ABSTRACT FROM AUTHOR]

α-Chlorocarbanions generated via base-induced vicarious nucleophilic substitution reaction of alkyl dichloroacetates with nitroarenes react with Michael acceptors to give esters of cyclopropane carboxylic acids substituted with p-nitroaromatic rings. [ABSTRACT FROM AUTHOR]

The β-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. [ABSTRACT FROM AUTHOR]

The reductive coupling of aliphatic esters with benzophenones by Zn-TiCl4 in THF gave two- and four-electron reduced products, diaryl(hydroxy)methyl ketones, and diarylmethyl ketones selectively by controlling the reaction conditions. In the reaction of aromatic esters with benzophenones, diarylmethyl ketones were obtained as the sole products. N-(Alkoxycarbonyl)-(S)-α-amino acid methyl esters gave optically active diphenylmethyl ketones by reduction with benzophenone. The obtained diphenylmethyl ketones were transformed to 4,5-cis-disubstituted oxazolidin-2-ones stereoselectively. [ABSTRACT FROM AUTHOR]

Treatment of benzylamines with esters at an elevated temperature are expected to give amides. However, in the presence of TBAI/TBHP, esters possessing a methylene carbon α-to oxygen with benzylamines provide bis-esters rather than the expected amides. Benzylamines under oxidative conditions generate less nucleophilic carboxylates, which couples at the sp3 C-H bonds of esters and cyclic ethers to give bis-acyl ketals and α-acyloxy ethers, respectively. [ABSTRACT FROM AUTHOR]

A highly chemoselective synthesis of β-ketophosphonates from pentafluorophenyl esters and lithiated methyl α-(trimethylsilyl)methylphosphonate has been developed. This mild lithiated phosphonate reagent allows the synthesis of functionalized β-ketophosphonates in the presence of unactivated esters with high yields. This method has been compared with the standard lithiated methylphosphonate reagent. [ABSTRACT FROM AUTHOR]

A highly efficient nonenzymatic kinetic resolution of a series of structurally diverse racemic α-methylene-β-hydroxy esters utilizing the acyl transfer catalyst An-PIQ and propionic anhydride is reported. This procedure provides recovered alcohols with extremely high ee's (up to >99%) in reasonable conversions and excellent selectivity factors (S up to 108). Several synthetically important substrates were resolved in gram-scale reactions, and highly optically pure α-methylene-β-hydroxy esters were obtained with excellent S values and good yields. [ABSTRACT FROM AUTHOR]

One of the most recent developments in asymmetric catalysis is to employ two or more catalysts under one-pot reaction conditions. This article presents some interesting mechanistic insights on a cooperative dual-catalytic protocol relying on the catalytic ability of dirhodium carbenoid (derived from rhodium(II) tetracarboxylate and a diazo compound) and a chiral spirophosphoric acid ((R)-SPA) in an asymmetric N-H insertion reaction. We have employed DFT(M06 and B3LYP) computational methods to identify the stereocontrolling transition states wherein a chiral (R)-SPA protonates a dirhodium-bound enol intermediate. A true cooperative action elicited by both catalysts has been noted in the enantioselective protonation. More importantly, whether the second axial ligand on the remote rhodium atom could influence the energetic features of the reaction has been probed for the first time. In all steps (such as nitrogen extrusion, addition of amine to the dirhodium carbenoid, and the enol formation), except that in the stereocontrolling event, no major effect of axial ligation has been noticed. However, the presence of the axial ligand helps in stabilizing the protonation transition state and reduces the activation barrier for protonation, suggesting a vital role in stereoselectivity. The predicted sense of stereoselectivities is in good agreement with the experimental results. [ABSTRACT FROM AUTHOR]

A base-promoted domino reaction of 2-acyl-1-chlorocyclopropaneformic esters with amines is described. In the presence of inorganic bases like Cs2CO3 or Mg(OEt)2, the reaction proceeded smoothly in acetonitrile to afford 2-pyrone derivatives in modest to excellent yields (up to 97%). This reaction provides a straightforward and transition metal-free protocol to efficiently construct 2-pyrone skeleton. A possible mechanistic process involving 1,2-elimination of hydrogen chloride, aza-Michael addition, ring-opening, and intramolecular lactonization was suggested to rationalize the formation of the target 2-pyrone derivatives. [ABSTRACT FROM AUTHOR]

The kinetic resolution of hydroxy tert-butyl esters through a Brønsted acid catalyzed lactonization is described. The resulting enantioenriched molecules have cyclic backbones and/or multiple stereocenters. DFT calculations explore how small changes in substrate structure can have a large impact on the selectivity of the process. [ABSTRACT FROM AUTHOR]

In continuation of our previous study on the intramolecular reductive coupling of simple homoallylic esters promoted by allylSmBr/HMPA/H2O, which afforded a facile synthesis of 2-(2-hydroxyalkyl)cyclopropanols, here we report the reductive cascade cyclization of but-3-enyl but-3-enoates mediated by allylSmBr/HMPA/CuCl2⋅2H2O, in which the two C=C bonds were successively coupled to allow the construction of the structurally interesting bridged bicyclic tertiary alcohols. Thus, the 2-(2-hydroxyethyl)bicyclo[2.1.1]hexan-1-ols were prepared in moderate to good yields with excellent diastereoselectivity. [ABSTRACT FROM AUTHOR]

An enantioselective carbonyl-ene reaction of glyoxylate esters with 1,1-disubstituted alkenes catalyzed by chiral cationic dirhodium(II,III) carboxamidates is described. The paddlewheel dirhodium(II,III) carboxamidates having one open coordination site at each rhodium smoothly catalyze the carbonyl-ene reaction to afford homoallylic alcohol products in good isolated yields with high enantioselectivities. [ABSTRACT FROM AUTHOR]

Ab initio calculations are reported for the reaction of methyl boronic ester with organolithium reagents with α-leaving groups. The best calculations rely on density functional theory prediction of structures and coupled-cluster theory calculation of accurate potential energies. The results provide strong confirmation of the feasibility of a two-step mechanism with rapid initial formation of a boron-ate complex followed by slower migration of methyl from boron to carbon with loss of the leaving group. The calculated free energy of activation is consistent with observed kinetic behavior, and the calculations provide a framework for exploring substituent and other effects on reactivity. Obtaining reasonable agreement with experiment in this way is not trivial and requires careful treatment of level of theory (density functional theory calculations tend to yield inaccurate results), of conformational complexity, especially for the ate complexes, and of the nature of the microscopic model of reactants and solvent. The methodological challenges and possible pitfalls, many of which are relevant more broadly to computational modeling of organic reaction mechanisms, are discussed in detail. [ABSTRACT FROM AUTHOR]

A catalytic protocol for synthesis of thioesters from aryl, vinyl, and benzyl bromides as well as benzyl chlorides was developed using only stoichiometric amounts of carbon monoxide, produced from a solid CO precursor inside a two-chamber system. As a catalytic system, the combination of bis(benzonitrile) palladium(II) chloride and Xantphos furnished the highest yields of the desired compounds, along with the weak base, NaOAc, in anisole at 120 °C. The choice of catalytic system as well as solvent turned out to be important in order to ensure a high chemoselectivity in the reaction. Both electron-rich and electron-deficient aryl bromides worked well in this reaction. Addition of 1 equiv of sodium iodide to the reaction improved the chemoselectivity with the electron-deficient aryl bromides. The thiol scope included both aryl and alkyl thiols, including 2-mercaptobenzophenones, whereby a thiocarbonylation followed by a subsequent McMurry coupling yielded differently substituted benzothiophenes. It was demonstrated that the methodology could be applied for 13C introduction into the thiophene ring. [ABSTRACT FROM AUTHOR]

A direct metal-free α-hydroxylation of α-unsubstituted β-oxoesters and β-oxoamides was developed using m-chloroperbenzoic acid as the oxidant. This transformation enabled straightforward metal-free access to important α-hydroxy-β-dicarbonyl moieties under mild reaction conditions. Furthermore, the hydroxylated products were readily converted into vicinal tricarbonyl compounds, which are useful synthetic precursors of numerous biological targets. [ABSTRACT FROM AUTHOR]

Regioselective ring opening of cyclic sulfamidates was achieved by means of nucleophilic polyfluorinated alkoxides to access achiral and chiral β- and γ-OR F amines and α-amino esters. Subsequent transformations provide free amines ready for incorporation into bioactive substances through amide bond formation or nucleophilic aromatic substitution.

A P(NMe2)3-mediated reductive cyclopropanation reaction of α-keto esters or amides with isatin-derived alkenes has been developed, providing efficient and diastereoselective synthesis of highly functionalized spirocyclopropyl oxindoles bearing two all-carbon quaternary centers. This reaction also represents a complementary and nonmetal-involving protocol for the challenging cyclopropanation of electron-deficient alkenes. [ABSTRACT FROM AUTHOR]

The eco-friendly preparation of 5- and 5,5-disubstituted hydantoins from various amino ester hydrochlorides and potassium cyanate in a planetary ball-mill is described. The one-pot/two-step protocol consisted in the formation of ureido ester intermediates, followed by a base-catalyzed cyclization to hydantoins. This easy-handling mechanochemical methodology was applied to a large variety of α- and β-amino esters, in smooth conditions, leading to hydantoins in good yields and with no need of purification steps. As an example, the methodology was applied to the "green" synthesis of the antiepileptic drug Phenytoin, with no use of any harmful organic solvent. [ABSTRACT FROM AUTHOR]

A general study is undertaken to examine the scope of the reductive ring opening of aziridine-2-carboxylates with samarium diiodide. The competition between C-C and C-N bond cleavage is examined as a function of the nature of the N-substituent of the aziridine, the nature of the substituent in the 3-position of the aziridine, and whether the substituent in the 3-position is in a cis or trans relationship with the carboxylate in the 2-position. The desired C-N bond cleavage leads to β-amino esters that are the predominant products for most aziridines with an N-activating group. However, C-C cleavage products are observed with an aryl group in the 3-position; this can be particularly pronounced with cis-aziridines where a nearly equal mixture of the two is observed. Exclusive formation of the C-N cleavage product is observed for all aziridines with the strongly N-activating p-toluene sulfonate group. Similarly high selectivity is observed for the 2-trimethylsilylethyl sulfonate group (SES), which is easier to remove. The utility of these methods is illustrated in the synthesis of protected forms of (R)-β³-DOPA and l-DOPA from the same aziridine, the former by SmI2-mediated reductive opening at C-2 and the latter by palladium-mediated reductive opening at C-3. [ABSTRACT FROM AUTHOR]

A rhodium(II)-catalyzed denitrogenative coupling of N-sulfonyl-1,2,3-triazoles with ambiphilic β-enamino esters affords 2,5-dihydro-1H-imidazoles (3-imidazolines) with broad functional group tolerance. Mechanistic studies using a deuterium-labeled triazole suggest that the reaction proceeds in a cascade through the N-H insertion of an α-imino rhodium-carbene, followed by enamine-imine tautomerization and conjugate addition. Moreover, the reaction proceeds with high diastereoselectivity for α-substituted β-enamino esters (R³ = Me, Ph) to give a single diastereomer. [ABSTRACT FROM AUTHOR]

Cyclic seleninate esters function as mimetics of the antioxidant enzyme glutathione peroxidase and catalyze the reduction of hydrogen peroxide with a stoichiometric thiol. While a single electron-donating methoxy substituent para to the selenium atom enhances the catalytic activity, m-methoxy groups have little effect and o-methoxy substituents suppress activity. The effects of multiple methoxy groups are not cumulative. This behavior can be rationalized by opposing mesomeric and steric effects. Oxidation of the product disulfide via its thiolsulfinate was also observed. [ABSTRACT FROM AUTHOR]

A catalytic protocol for the base-mediated amidation of unactivated esters with amino alcohol derivatives is reported. Investigations into mechanistic aspects of the process indicate that the reaction involves an initial transesterification, followed by an intramolecular rearrangement. The reaction is highly general in nature and can be extended to include the synthesis of oxazolidinone systems through use of dimethyl carbonate. [ABSTRACT FROM AUTHOR]

The catalytic asymmetric synthesis of a series of tertiary α-aryl cyclopentanones and cyclohexanones has been accomplished via a Pd-catalyzed decarboxylative protonation of the corresponding α-aryl-β-keto allyl esters. Enantioselectivities of up to 92% ee and 74% ee were achieved for cyclopentanone and cyclohexanone substrates, respectively. The route described gives access to these important structural motifs in moderate to high levels of enantioselectivity. In particular, this is only the second direct approach for the preparation of tertiary α-aryl cyclopentanones. The synthetic approach allows for simple modification of the aryl group. Significantly, substrates containing sterically hindered aryl groups gave the highest levels of enantioselectivity, and these aryl groups were readily installed by a Pb-mediated arylation of a β-keto allyl ester. [ABSTRACT FROM AUTHOR]

4-Vinyl-substituted 1,3-dioxolan-2-ones are found to be good substrates for Ru-catalyzed allylic alkylations of chelated amino acid ester enolates. cis-1,3-Dioxolan-2-ones are more reactive than the corresponding trans-isomers. The attack occurs preferentially with regioretention at the position of the leaving group with perfect chirality transfer. Therefore, this protocol is a good complement to the Pd-catalyzed processes, which give only linear products with this type of substrate. [ABSTRACT FROM AUTHOR]

In situ derived acyclic and cyclic 1,2-diaza-1,3-dienes (DDs) were engaged in interceptive [4 + 1] annulation strategy with diazo esters (DEs). The catalytic activity of inexpensive copper(II) chloride allows the direct synthesis of mono-, bi-, and tricyclic 4,5-dihydropyrazole-5-carboxylic acid derivatives in a process that circumvents the use of an anhydrous and inert atmosphere. [ABSTRACT FROM AUTHOR]