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An efficient stereoselective syntheses of a series of functionalized optically active γ-aryl-γ-butyrolactones is achieved by enzymatic asymmetric reduction of the corresponding sterically demanding γ-keto esters employing wild-type and recombinant alcohol dehydrogenases. The best stereoselectivities for the reduction via hydrogen transfer was obtained with two short chain dehydrogenases (SDRs) of complementary stereospecificity from Aromatoleum aromaticum, namely the Prelog-specific NADH-dependent (S)-1-phenylethanol dehydrogenase [(S)-PED] and the anti-Prelog-specific (R)-1-(4-hydroxyphenyl)-ethanol dehydrogenase [(R)-HPED], respectively.Biotransformations catalyzed by both enzymes, followed by TFA-catalyzed cyclization of the resulting γ-hydroxy esters, furnished the respective (S)- and (R)-configured products with exquisite optical purity (up to >99% ee). The synthetic value was demonstrated on preparative scale for the asymmetric bioreduction of the model compound, methyl 4-oxo-4-phenylbutanoate, affording optically pure (S)-γ-phenyl-γ-butyrolactone (>99% ee) in 67–74% isolated yield at 89–95% conversion depending on the applied scale. (Figure presented.).

A direct approach to γ-keto esters through cascade alkyne-aldehyde reductive C?C coupling of propargyl esters and aromatic aldehydes under transition-metal-free (TM-free) fashion was developed. Compared with multistep processes, this procedure provides a

Photoredox-catalyzed isomerization of γ-carbonyl-substituted allylic alcohols to their corresponding carbonyl compounds was achieved for the first time by C?H bond activation. This catalytic redox-neutral process resulted in the synthesis of 1,4-dicarbonyl compounds. Notably, allylic alcohols bearing tetrasubstituted olefins can also be transformed into their corresponding carbonyl compounds. Density functional theory calculations show that the carbonyl group at the γ-position of allylic alcohols are beneficial to the formation of their corresponding allylic alcohol radicals with high vertical electron affinity, which contributes to the completion of the photoredox catalytic cycle.

A single-step gateway synthesis of glochidine and its congeners that possess the rare uncommon tetrahydroimidazo[1,5-c]pyrrolo[1,2-a]pyrimidine core was developed employing histamine and readily available γ-ketoesters. Key features of the developed reaction involve tandem three C–N bonds formation and concomitant annulation of two rings in one pot to access this unique and complex tricyclic structure. Exploration of the unknown bioactivity of these compounds revealed that they elicit antiproliferative activity comparable to the anticancer drug imatinib against 6 cancer cell lines.

The synthesis of novel, highly functionalized, C 2 -symmetric sulfur-based catalysts is developed and their catalytic applications are explored in asymmetric bromo-, iodo- and seleno-functionalizations of alkenoic acids. This protocol provides

We report the first electrochemical strategy to synthesize functionalized naphthalene derivatives through [4+2] annulation—rearrangement–aromatization from styrenes under mild conditions. The electrolysis does not require metals, oxidants and high valence substrates, indicating the atom and step-economy ideals. The dehydrodimer produced through [4+2] cycloaddition of 4-methoxy α-methyl styrene is isolated and proved to be the key intermediate for the following oxydehydrogenation to form carbon cation, which undergoes rearrangement–aromatization to afford the final products. This reaction represents a powerful access to construct multi-substituted naphthalene blocks in a single step.

A one-pot two-step enzymatic strategy has been designed for the production of optically active γ- and δ-lactams in aqueous medium under mild conditions. The approach is based on the biotransamination of ethyl or methyl keto esters bearing different alkyl or aryl substitution patterns at α-position to the ketone functionality. In this manner, the keto esters were transformed into the corresponding amino esters with excellent conversions, which underwent spontaneous cyclisation in the reaction medium without addition of external reagents. Depending on the transaminase selectivity, both lactam enantiomers can be obtained, so initial enzyme screenings were performed using commercially available and made in house enzymes. Reaction conditions were optimised focusing on the substrate concentration, temperature and ratio of amine donor vs acceptor. Thus, ten γ- and δ-lactams were obtained in good to high isolated yields (70–90%) and excellent selectivities (94–99%) after one or two days at 30 or 45 °C. (Figure presented.).

Allylic and acrylic substrates may be efficiently transformed by a sequential bichromatic photochemical process into derivatives of levulinates or butenolides with high selectivity when phenanthrene is used as a regulator. Thus, UV-A photoinduced cross-metathesis (CM) couples the acrylic and allylic counterparts and subsequent UV-C irradiation initiates E-Z isomerization of the carbon-carbon double bond, followed by one of two competing processes; namely, cyclization by transesterification or a 1,5-H shift and tautomerization. Quantum chemical calculations demonstrate that intermediates are strongly blue-shifted for the cyclization while red-shifted for the 1,5-H shift reaction. Hence, delaying the double bond migration by employing UV-C absorbing phenanthrene, results in a selective novel divergent all-photochemical pathway for the synthesis of fundamental structural motifs of ubiquitous natural products.

Protein kinase B (PknB) is an essential serine/threonine protein kinase required for Mycobacterium tuberculosis (M. tb) cell division and cell-wall biosynthesis. A high throughput screen using PknB identified a (E)-4-oxo-crotonic acid inhibitor, named YH-8, which was used as a scaffold for SAR investigations. A significant improvement in enzyme affinity was achieved. The results indicated that the α,β-unsaturated ketone scaffold and “trans-” configuration are essential for the activity against PknB. And compounds with an aryl group, especially with electron-withdrawing substituents on benzene ring, exhibited four fold potency than that of YH-8.

Cyclic ethers have been effectively synthesized via the intramolecular cyclization of diols using trimethyl phosphate and NaH. The present cyclization could proceed at room temperature to produce 5-7 membered cyclic ethers in good to excellent yields. Substrates possessing a chiral secondary hydroxy group were transformed into the corresponding chiral cyclic ethers along with the retention of their stereochemistries.

This work concerns the Mg(OMe)2 promoted allylic isomerization of γ-hydroxy-α,β-alkenoic esters with TMEDA as an additive. The isomerization proceeded under mild conditions and afforded γ-keto esters in high yield (up to 96%) within 2 h. Both (Z)- and (E)-γ-hydroxy-α,β-alkenoic esters were tolerated under the reaction conditions. This transformation involves the in situ formation of a dienolate intermediate from the easily accessible γ-hydroxy-α,β-alkenoic ester. The in situ generated dienolate can react with benzaldehyde and undergo a practical, useful tandem allylic isomerization-Aldol reaction to afford more functionalized compounds.

Emerging work on organocatalytic enantioselective halocyclizations naturally draws on conditions where both new bonds must be formed under delicate control, the reaction regime where the concerted nature of the AdE3 mechanism is of greatest importance. Without assistance, many simple alkene substrates react slowly or not at all with conventional halenium donors under synthetically relevant reaction conditions. As demonstrated earlier by Shilov, Cambie, Williams, Fahey, and others, alkenes can undergo a concerted AdE3-type reaction via nucleophile participation, which sets the configuration of the newly created stereocenters at both ends in one step. Herein, we explore the modulation of alkene reactivity and halocyclization rates by nucleophile proximity and basicity, through detailed analyses of starting material spectroscopy, addition stereopreferences, isotope effects, and nucleophile-alkene interactions, all obtained in a context directly relevant to synthesis reaction conditions. The findings build on the prior work by highlighting the reactivity spectrum of halocyclizations from stepwise to concerted, and suggest strategies for design of new reactions. Alkene reactivity is seen to span the range from the often overgeneralized "sophomore textbook" image of stepwise electrophilic attack on the alkene and subsequent nucleophilic bond formation, to the nucleophile-assisted alkene activation (NAAA) cases where electron donation from the nucleophilic addition partner activates the alkene for electrophilic attack. By highlighting the factors that control reactivity across this range, this study suggests opportunities to explain and control stereo-, regio-, and organocatalytic chemistry in this important class of alkene additions.

The present invention relates to compound of Formula (I) containing carbon-carbon linker, a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a prodrug, a polymorph, N -oxide, S-oxide, or a carboxylic aci

The concept of the remote activation of reactivity was first applied in asymmetric organocatalysis. An isatin 3-phenylimine derivative acts as a donor in the thiourea catalyzed asymmetric addition to unsaturated 1,4-ketoesters, affording aza-Michael adducts in high enantiomeric purity and yield.

Under standard conditions the cross metathesis of allyl alcohols and methyl acrylate is accompanied by the formation of ketones, resulting from uncontrolled and undesired double bond isomerization. By conducting the CM in the presence of phenol, the catalyst loading and the reaction time required for quantiative conversion can be reduced, and isomerization can be suppressed. On the other hand, consecutive isomerization can be deliberately promoted by evaporating excess methyl acrylate after completing cross metathesis and by adding a base or silane as chemical triggers.

"Chemical Equation Presented" Rhodium(lI)-catalyzed reactions of vinyldiazoacetates with dihydronaphthalenes were systematically studied. These substrates underwent cyclopropanantion and/or the combined C-H activation/ Cope rearrangement in good overall y

Gold(I) and (III) salts have been found to be highly effective at the catalysis of ether formation from alcohols. Intramolecular ether formation of a 1,5-diol was also achieved, with a stereoselectivity that indicates that an SN1 mechanism predominates. In an attempt to form a seven-membered ring, a stable 14-membered dimer product was also formed. Attempts to control the diastereoselectivity of the reaction using a chiral anionic counterion did not give products with a high de.

Stereoselective synthesis of (-)-centrolobine, an anti-Leishmania agent, was accomplished via an intramolecular Barbier-type reaction of iodo-ester with n- or t-butyllithium followed by Lewis acid-promoted Et3SiH reduction of the resulting hemi

A new protocol for the direct acylation of aryl bromides with aldehydes is established. It appears to involve palladium-amine cooperative catalysis, affording synthetically important alkyl aryl ketones in moderate to excellent yields in a straightforward manner, and broadening the scope of metal-catalyzed coupling reactions. Copyright

The invention provides novel imidazo[1,2-b]pyridazines of formula (I) and pharmaceutically acceptable salts, polymorphs, hydrates, tautomers, solvates and stereoisomers thereof. Compounds of formula (I) are useful for treating or preventing diseases assoc

The present invention relates to a novel process for the preparation of optically enriched substituted R(+)β-benzyl-γ-butyrolactones of the general formula 1, 1wherein, R1 and R2 independently represent the following groups, R1=R2=H, OH, —OCnH2n+1 (n=1 to 8), NH2, and/or CF3, R1 and R2 together represents —O(CH2)mO— where m=2 to 4.

Imidazolium-type room temperature ionic liquids (RTILs) have been used for the Stetter reaction, affording the desired 1,4-dicarbonyl compounds in good yields. Thiazolium salts and Et3N are efficient catalysts for this reaction performed in ionic liquid. The possibility to recycle and reuse the solvent has been demonstrated, although it was not possible to recycle the thiazolium catalyst. This method was used in the total synthesis of haloperidol.

β-Benzyl-γ-butyrolactones, important intermediates for the synthesis of butyrolactone lignans, have been synthesized by a new route involving preparation of α-β-unsaturated formyl esters. The formyl esters can easily be converted into the desired butyrolactones either through chemical transformations or by enzymatic methods.

The synthesis of 3,6-bis(triphenylphosphonium)cyclohexene peroxodisulfate and its application for the selective oxidation of benzylic alcohols is reported.

1,4-Dicarbonyl compounds can be prepared using a Rh(I) mediated hydroacylation reaction between (2-aminopicolyl)imines and acrylate esters followed by acid hydrolysis.

6-Aryl-2, 3, 4, 5-tetrahydro-3-pyridazinones (2c-22c) are obtained by dehydrocyclisation of various hydrazides formed by the reaction of appropriate methyl β-aroylpropionate and hydrazine hydrate in the presence of anhydrous sodium acetate. They show promising antiinflammatory activity during their evaluation by carrageenin induced paw edema test in rats.

Indole derivatives of formula (1) wherein the substituents are defined herein are disclosed. The compounds are useful in methods of antagonizing endothelin receptors, treating hypertension, treating renal failure and treating cerebrovascular disease. Pharmaceutical compositions are also disclosed.

Chemoselective cross-coupling reactions of monoesters of dicarboxylic acid chlorides with organocopper reagents derived from Grignard reagents, cuprous bromide, and lithium bromide, provide a simple and straightforward method for synthesizing a variety of ketoesters.

A full study of the use of phenyl selenoesters as precursors to acyl radicals and their subsequent participation in intermolecular and intramolecular alkene addition reactions is detailed.Primary alkyl-, vinyl-, and arylsubstituted acyl radicals generated by Bu3SnH treatment of the corresponding phenyl selenoesters participate cleanly in intermolecular addition reactions with alkenes bearing electron-withdrawing or radical-stabilizing substituents at rates that exceed those of the potentially competitive decarbonylation or reduction.Similarly, their intramolecular addition to activated or unactivated alkenes proceeds without significant competitive reduction or decarbonylation and at rates generally >/= 1 x 106 s-1 with some occuring at rates >/= 3 x 107 s-1.Consistent with their behavior in intermolecular addition reactions, the 5-exo-trig cyclizations of secondary and tertiary alkyl-substituted acyl radicals to an unactivated olefin acceptor may be accompanied by varying degrees of decarbonylation, even under low-temperature free-radical conditions.Studies are presented which suggest that the intramolecular additions of acyl radicals to alkenes under the conditions detailed herein may be regarded as irreversible, kinetically controlled processes which exhibit regioselectivity that is predictable based on well-established empirical rules set forth for the analogous free-radical cyclization reactions of alkyl radicals.

Lipases in anhydrous organic solvents catalyze the lactonization of esters of γ-hydroxy carboxylic acids with a high degree of stereospecifity.Under these conditions the lipases exhibit both enantioselectivity and prochiral selectivity.We exploited the enzymes' enantioselectivity for synthesis of chiral lactones from racemic γ-hydroxy esters and their prochiral stereospecifity, i.e. the ability to discriminate between enantiotopic groups of a prochiral molecule, for the enantioconvergent lactonization of symmetrical γ-hydroxy diesters.This approach was used to develop a convenient, high yielding, and stereoselective route to several optically active γ-substituted γ-butyrolactones.

The scope of the use of phenyl selenoesters as effective precursors to acyl radicals for use in intermolecular olefin addition reactions is detailed.