An efficient and simple methodology was developed for the synthesis of oxazolidinones, oxazolidinthiones, imidazolidinthiones, and imidazolidinones from the corresponding propargylic starting materials using Pd(OAc)(2) and n-Bu4NOAc as catalysts in DCE at room temperature.

Highly selective protocols for the carbocyclization/arylation of allenynes using arylboronic acids are reported. Arylated vinylallenes are obtained with the use of BF3 center dot Et2O as an additive, whereas addition of water leads to arylated trienes. These conditions provide the respective products with excellent selectivities (generally > 97:3) for a range of boronic acids and different allenynes. It has been revealed that water plays a crucial role for the product distribution.

A water-soluble rhodium complex formed from commercially available [Rh(COD)(CH3CN)(2)]BF4 and 1,3,5-triaza-7-phosphaadamantane (PTA) catalyzes the isomerization of both codeine and morphine into hydrocodone and hydromorphone with very high efficiency. The reaction is performed in water, allowing isolation of the final products by simple filtration, which results in very high isolated yields. The reactions can be easily scaled up to 100 g.

Combining the advantages of homogeneous and heterogeneous catalysis is possible by heterogenization of homogeneous transition metal complexes based on a grafting/anchoring technique. Wilkinson’s catalyst ((RhCl(PPh₃)₃) immobilized on common silica showed high activity and selectivity in transfer hydrogenation reactions of different carbonyl compounds in isopropanol. Reactions conducted at reflux in isopropanol afforded the corresponding carbinols in high yields in short reaction times. The heterogeneous feature of the catalyst allows easy recovery and efficient reuse in the same reaction up to 5 times without loss of catalytic activity.

Dynamic kinetic asymmetric transformation (DYKAT) of a series of 1,4-diols is carried out with Candida antarctica lipase B (CALB), Pseudomonas cepacia lipase II (PS-C II), and a ruthenium catalyst. A β-chloro-substituted 1,4-diol is successfully transformed into an optically pure 1,4-diacetate, which is a highly useful synthetic intermediate. The usefulness of the optically pure 1,4-diacetates is demonstrated by the synthesis of enantiopure 2,5-disubstituted pyrrolidines.

Suzuki-Miyaura cross-coupling reactions of heteroaromatics catalyzed by palladium supported in the cavities of amino-functionalized siliceous mesocellular foam are presented. The nanopalladium catalyst effectively couples not only heteroaryl halides with boronic acids but also heteroaryl halides with boronate esters, potassium trifluoroborates, MIDA boronates, and triolborates, producing a wide range of heterobiaryls in good to excellent yields. Furthermore, the heterogeneous palladium nanocatalyst can easily be removed from the reaction mixture by filtration and recycled several times with minimal loss in activity. This catalyst provides an alternative, environmentally friendly, low-leaching process for the preparation of heterobiaryls.

Dimeric palladium bromide complexes bearing monodentate N-heterocyclic carbene ligands have been identified as efficient catalysts for the chemoselective racemization of axially chiral allenyl alcohols. In combination with porcine pancreatic lipase as biocatalyst, a dynamic kinetic resolution has been developed, giving access to optically active allenes in good yield and high enantiomeric purity (

A general combined purification and immobilization method to facilitate biocatalytic process development is presented. The support material, EziG (TM), is based on controlled porosity glass (CPG) or polymer-coated versions thereof (HybCPG) and binds protein affinity tags. Biocatalytic reactions in aqueous and organic media with seven enzymes of biocatalytic interest are shown.

A variant of Candida antarctica lipase A (CalA) was developed for the hydrolysis of α-substituted p-nitrophenyl esters by directed evolution. The E values of this variant for 7 different esters was 45−276, which is a large improvement compared to 2−20 for the wild type. The broad substrate scope of this enzyme variant is of synthetic use, and hydrolysis of the tested substrates proceeded with an enantiomeric excess between 95−99%. A 30-fold increase in activity was also observed for most substrates. The developed enzyme variant shows (R)-selectivity, which is reversed compared to the wild type that is (S)-selective for most substrates.

A variant of Candida antarctica lipase A (CalA) was developed for the hydrolysis of α-substituted p-nitrophenyl esters by directed evolution. The E values of this variant for 7 different esters was 45−276, which is a large improvement compared to 2−20 for the wild type. The broad substrate scope of this enzyme variant is of synthetic use, and hydrolysis of the tested substrates proceeded with an enantiomeric excess between 95−99%. A 30-fold increase in activity was also observed for most substrates. The developed enzyme variant shows (R)-selectivity, which is reversed compared to the wild type that is (S)-selective for most substrates.

In nature, lipases (EC 3.1.1.3) catalyze the hydrolysis of triglycerides to form glycerol and fatty acids. Under the appropriate conditions, the reaction is reversible, and so biotechnological applications commonly make use of their capacity for esterification as well as for hydrolysis of a wide variety of compounds. In the present paper, we report the X-ray structure of lipase A from Candida antarctica, solved by single isomorphous replacement with anomalous scattering, and refined to 2.2-Å resolution. The structure is the first from a novel family of lipases. Contrary to previous predictions, the fold includes a well-defined lid as well as a classic α/β hydrolase domain. The catalytic triad is identified as Ser184, Asp334 and His366, which follow the sequential order considered to be characteristic of lipases; the serine lies within a typical nucleophilic elbow. Computer docking studies, as well as comparisons to related structures, place the carboxylate group of a fatty acid product near the serine nucleophile, with the long lipid tail closely following the path through the lid that is marked by a fortuitously bound molecule of polyethylene glycol. For an ester substrate to bind in an equivalent fashion, loop movements near Phe431 will be required, suggesting the primary focus of the conformational changes required for interfacial activation. Such movements will provide virtually unlimited access to solvent for the alcohol moiety of an ester substrate. The structure thus provides a basis for understanding the enzyme's preference for acyl moieties with long, straight tails, and for its highly promiscuous acceptance of widely different alcohol and amine moieties. An unconventional oxyanion hole is observed in the present structure, although the situation may change during interfacial activation

With the aim of extending the usefulness of an existing biomimetic catalytic system, cobalt porphyrin catalytic units with thiol linkers were heterogenized via chemical grafting to silicon wafers and utilized for the catalytic oxidation of hydroquinone to p-benzoquinone. Atomic force microscopy (AFM) and X-ray photoelectron spectroscopy (XPS) were used to analyze the morphology and composition of the heterogeneous catalyst. The results of the catalytic oxidation of hydroquinone obtained with porphyrins grafted on silicon were compared with those obtained earlier with the same catalyst in homogeneous phase and immobilized on gold. It was found that the catalysis could run over 400 h, without showing any sign of deactivation. The measured catalytic activity is at least 10 times higher than that measured under homogeneous conditions, but also 10 times lower than that observed with the catalytic unit immobilized on gold. The reasons of this discrepancy are discussed in term of substrate influence and overlayer organization. The silicon-immobilized catalyst has potential as an advanced functional material with applications in oxidative heterogeneous catalysis of organic reactions, as it combines long-term relatively high activity with low cost.

An efficient kinetic resolution of racemic gamma-hydroxy amides 1 was performed via Pseudomas cepacia lipase (PS-C)-catalyzed transesterification. The enzyme PS-C tolerates both variation in the chain length and different functionalities giving good to high enantioselectivity (E values of up to > 250). The combination of enzymatic kinetic resolution with a ruthenium-catalyzed racemization led to a dynamic kinetic resolution. The use of 2,4-dimethyl-3-pentanol as a hydrogen source to suppress ketone formation in the dynamic kinetic resolution yields the corresponding acetates in good yield and good to high enantioselectivity (ee's up to 98%). The synthetic utility of this procedure was illustrated by the practical synthesis of the versatile intermediate gamma-lactone (R)-5-methyltetrahydrofuran-2-one.

An efficient desymmetrization of cis-1,3-cyclohexanediol to (1S,3R)-3-(acetoxy)-1-cyclohexanol ((R,S)-2a) was performed via Candida antarctica lipase B (CALB)-catalyzed transesterification, in high yield (up to 93%) and excellent enantioselectivity (ee's up to >99.5%). (R,R)-Diacetate ((R,R)-3a) was obtained in a DYKAT process at room temperature from (1S,3R)-3-acetoxy-1-cyclohexanol ((R,S)-2a), in a high trans/cis ratio (91:9) and in excellent enantioselectivity of >99%. Metal- and enzyme-catalyzed dynamic transformation of cis/trans-1,3-cyclohexanediol using PS-C gave a high diastereoselectivity for cis-diacetate (cis/trans = 97:3). The (1R,3S)-3-acetoxy-1-cyclohexanol (ent-(R,S)-2a) was obtained from cis-diacetate by CALB-catalyzed hydrolysis in an excellent yield (97%) and selectivity (>99% ee). By deuterium labeling it was shown that intramolecular acyl migration does not occur in the transformation of cis-monoacetate to the cis-diacetate.

An efficient biomimetic aerobic oxidative dehydrogenative alkenylation of arenes with allyl esters is presented. The reaction proceeds under an ambient pressure of oxygen with relatively low catalyst loading of palladium acetate, employing catalytic amounts of electron-transfer mediators (ETMs). This study represents a new environmentally friendly method for the synthesis of cinnamyl derivatives.

An efficient ligand-promoted biomimetic aerobic oxidative dehydrogenative cross-coupling between arenes and nonbiased olefins is presented. Acridine as a ligand was found to significantly enhance the rate, the yield, and the scope of the reaction under ambient oxygen pressure, providing a variety of alkenylarenes via an environmentally friendly procedure.

The synthesis of 3-aryl-2-cyclohexenones is a topic of current interest as they are not only privileged structures in bioactive molecules, but they are also relevant feedstocks for the synthesis of substituted phenols or anilines, which are ubiquitous structural elements both in drug design and medicinal chemistry. A simple and sustainable one-pot aerobic double dehydrogenative reaction under mild conditions for the introduction of arenes in the -position of cyclic ketones has been developed. Starting from the corresponding saturated ketone, this reaction sequence proceeds under relatively low Pd catalyst loading and involves catalytic amounts of electron-transfer mediators (ETMs) under ambient oxygen pressure.

A catalyst consisting of palladium nanoparticles supported on amino-functionalized siliceous mesocellular foam (Pd-AmP-MCF) was used in chemoenzymatic dynamic kinetic resolution (DKR) to convert primary amines to amides in high yields and excellent ee's. The efficiency of the nanocatalyst at temperatures below 70 degrees C enables reaction conditions that are more suitable for enzymes. In the present study, this is exemplified by subjecting 1-phenylethylamine (1a) and analogous benzylic amines to DKR reactions using two commercially available lipases, Novozyme-435 (Candida antartica Lipase B) and Amano Lipase PS-C1 (lipase from Burkholderia cepacia) as biocatalysts. The latter enzyme has not previously been used in the DKR of amines because of its low stability at temperatures over 60 degrees C. The viability of the heterogeneous Pd-AmP-MCF was further demonstrated in a recycling study, which shows that the catalyst can be reused up to five times.

Allenes undergo racemization in the presence of catalytic amounts of Pd(OAc)₂/LiBr under mild conditions; the reaction proceeds via a bromopalladation–debromopalladation sequence and tolerates various functional groups.

Cyclization of -amino allenes in the presence of N-bromosuccinimide afforded pyrrolines in good yields. The products were obtained with high enantiomeric excesses when optically active allenes were used as substrates. The synthesis of a 2,5-dehydroprolinol derivative is also presented.

An enantioselective synthesis of (R)-bufuralol via a ruthenium- and enzyme-catalyzed dynamic kinetic resolution (DKR) has been achieved. The synthesis starts from readily available 2-ethylphenol and provides (R)-bufuralol in high ee and a good overall yield of 31%.

The major limitation in the synthetic application of two-component Baeyer-Villiger monooxygenases was addressed by identifying the 28-kDa flavin-reductase Fre from Escherichia coli as a suitable supplier of reduced FMN for these enzymes. Coexpression of Fre with either 2,5- or 3,6-diketocamphane monooxygenase from Pseudomonas putida NCIMB 10007 significantly enhanced the conversion of camphor and norcamphor serving as representative ketones. With purified enzymes, full conversion was achieved, while only slight amounts of product were formed in the absence of this flavin reductase. Fusion of the genes of Fre and DKCMOs into single open reading frame constructs resulted in unstable proteins exhibiting flavin reducing, but poor oxygenating activity, which led to overall decreased conversion of camphor.

Enzyme- and ruthenium-catalyzed dynamic kinetic asymmetric transformation (DYKAT) of bicyclic diols to their diacetates was highly enantio- and diastereoselective to give the corresponding diacetates in high yield with high enantioselectivity (99.9 % ee). The enantiomerically pure diols are accessible by simple hydrolysis (NaOH, MeOH), but an alternative enzyme-catalyzed ester cleavage was also used to give the trans-diol (R,R)-1 b in extremely high diastereomeric purity (trans/cis=99.9:0.1, >99.9 % ee). It was demonstrated that the diols can be selectively oxidized to the ketoalcohols in a ruthenium-catalyzed Oppenauer-type reaction. A formal enantioselective synthesis of sertraline from a simple racemic cis/trans diol 1 b was demonstrated.

Dynamic kinetic asymmetric transformation (DYKAT) of a series of 1,5-diols has been performed in the presence of Candida antarctica lipase B (CALB), Pseudomonas cepacia lipase H (PS-C II), and ruthenium catalyst 4. The resulting optically pure 1,5-diacetates are useful synthetic intermediates, which was demonstrated by the syntheses of both an enantiopure 2,6-disubstituted piperidine and an enantiopure 3,5-disubstituted morpholine.

Epimerization of a non-anomeric stereogenic center in carbohydrates is an important transformation in the synthesis of natural products. In this study an epimerization procedure of the allylic alcohols of glycals by cyclopentadienylruthenium catalyst 1 is presented. The epimerization of 4,6-O-benzylidene-D-glucal 4 in toluene is rapid, and an equlibrium with its D-allal epimer 5 is established within 5min at room temperature. Exchange rates for allal and glucal formation were determined by 1D H-1 EXSY NMR experiments to be 0.055s(-1) and 0.075s(-1), respectively. For 4-O-benzyl-L-rhamnal 8 the epimerization was less rapid and four days of epimerization was required to achieve equilibration of the epimers at room temperature. The epimerization methodology was subsequently combined with acylating enzymes in a dynamic kinetic asymmetric transformation (DYKAT), giving stereoselective acylation to the desired stereoisomers 12, 13, and 15. The net effect of this process is an inversion of a stereogenic center on the glycal, and yields ranging from 71% to 83% of the epimer were obtained.

A simple and efficient method to prepare synthetically useful 2-arylindoles is presented, using a heterogeneous Pd catalyst and diaryliodonium salts in water under mild conditions. A remarkably low leaching of metal catalyst was observed under the applied conditions. The developed protocol is highly C-2 selective and tolerates structural variations both in the indole and in the diaryliodonium salt. Arylations of both NH indoles and N-protected indoles with ortho-substituted, electron-rich, electron-deficient, or halogenated diaryliodonium salts were achieved to give the desired products in high to excellent isolated yields within 6 to 15 h at room temperature or 40 °C.

Cycloisomerization of various gamma-acetylenic acids to their corresponding gamma-alkylidene lactones by the use of a heterogeneous Pd(II) catalyst supported on amino-functionalized siliceous mesocellular foam is described. Substrates containing terminal as well as internal alkynes were cyclized in high to excellent yields within 2-24 h under mild reaction conditions. The protocol exhibited high regio- and stereoselectivity, favoring the exo-dig product with high Z selectivity. Moreover, the catalyst displayed excellent stability under the employed reaction conditions, as demonstrated by its good recyclability and low leaching.

Dynamic kinetic resolution of allylic alcohols to allylic acetates followed by copper-catalyzed allylic substitution gave alkenes in high yields and high optical purity. Subsequent oxidative C-C double bond cleavage afforded pharmaceutically important alpha-methyl substituted carboxylic acids in high ee.

Two possible pathways of inner-sphere racemization of sec-alcohols by using the [RuCl(CO)(2)(eta(5)-pentaphenylcyclopentadienyl)] catalyst (1) have been thoroughly investigated by means of density function calculations. To be able to racemize alcohols, catalyst 1 needs to have a free coordination site on the metal. This can be achieved either by a eta(5)-->eta(3) ring slippage or by dissociation of a carbon monoxide (CO) ligand. The eta(5)-->eta(3) ring-slip pathway was found to have a high potential energy barrier, 42 kcal mol(-1), which can be explained by steric congestion in the transition state. On the other hand, CO dissociation to give a 16-electron complex has a barrier of only 22.6 kcal mol(-1). We have computationally discovered a mechanism involving CO participation that does not require eta(5)-->eta(3) ring slippage. The key features of this mechanism are 1) CO-assisted exchange of chloride for alkoxide, 2) alcohol-alkoxide exchange, and 3) generation of an active 16-electron complex through CO dissociation with subsequent beta-hydride elimination as the racemization step. We have found a low-energy pathway for reaction of 1 with potassium tert-butoxide and a pathway for fast alkoxide exchange with interaction between the incoming/leaving alcohol and one of the two CO ligands. We predict that dissociation of a Ru-bound CO ligand does not occur in these exchange reactions. Dissociation of one of the two Ru-bound CO ligands has been found necessary only at a later stage of the reaction. Though this barrier is still quite high, our results indicate that it is not necessary to cross the CO dissociation barrier for the racemization of each new alcohol. Thus, the dissociation of a CO ligand is interpreted as a rate-limiting reaction step in order to create a catalytically active 16-electron complex.

A divergent synthesis of various 3,5-dioxygenated piperidines with interesting pharmacological properties is described. A mixture of the achiral cis- and racemic trans-3,5-piperidine diol could be efficiently obtained from N-benzylglycinate in five steps by the use of chemoenzymatic methods. In the subsequent enzyme- and Ru-catalyzed reaction, the rac/meso diol mixture was efficiently transformed to the cis-(3R,5S)-diacetate with excellent diastereoselectivity and in high yield. Further transformations of the cis-diacetate selectively delivered the cis-piperidine diol and the cis-(3R,5S)-hydroxy acetate. Alternatively, the DYKAT could be stopped at the monoacetate stage to give the trans-(3R,5R)-hydroxy acetate.

Reaction of [2,3,4,5-Ph₄(η⁵-C₄COH)Ru(CO)₂H] (2) with different imines afforded ruthenium amine complexes at low temperatures. At higher temperatures in the presence of 2, the complexes decomposed to give [Ru₂(CO)₄(μ-H)(C₄Ph₄COHOCC₄Ph₄)] (1) and free amine. Electron-rich imines gave ruthenium amine complexes with 2 at a lower temperature than did electron-deficient imines. The negligible deuterium isotope effect (k_RuHOH/k_RuDOD = 1.05) observed in the reaction of 2 with N-phenyl[1-(4-methoxyphenyl)ethylidene]amine (12) shows that neither hydride (RuH) nor proton (OH) is transferred to the imine in the rate-determining step. In the dehydrogenation of N-phenyl-1-phenylethylamine (4) to the corresponding imine 8 by [2,3,4,5-Ph₄(η⁴-C₄CO)Ru(CO)₂] (A), the kinetic isotope effects observed support a stepwise hydrogen transfer where the isotope effect for C−H cleavage (k_CHNH/k_CDNH = 3.24) is equal to the combined (C−H, N−H) isotope effect (k_CHNH/k_CDND = 3.26). Hydrogenation of N-methyl(1-phenylethylidene)amine (14) by 2 in the presence of the external amine trap N-methyl-1-(4-methoxyphenyl)ethylamine (16) afforded 90−100% of complex [2,3,4,5-Ph₄(η⁴-C₄CO)]Ru(CO)₂NH(CH₃)(CHPhCH₃) (15), which is the complex between ruthenium and the amine newly generated from the imine. At −80 °C the reaction of hydride 2 with 4-BnNH-C₆H₉=NPh (18), with an internal amine trap, only afforded [2,3,4,5-Ph₄(η⁴-C₄CO)](CO)₂RuNH(Ph)(C₆H₁₀-4-NHBn) (19), where the ruthenium binds to the amine originating from the imine, showing that neither complex A nor the diamine is formed. Above −8 °C complex 19 rearranged to the thermodynamically more stable [Ph₄(η⁴-C₄CO)](CO)₂RuNH(Bn)(C₆H₁₀-4-NHPh) (20). These results are consistent with an inner sphere mechanism in which the substrate coordinates to ruthenium prior to hydrogen transfer and are difficult to explain with the outer sphere pathway previously proposed.

We herein report the first directed evolution of Candida antarctica lipase A (CalA), employing a combinatorial active-site saturation test (CAST). Wild-type CalA has a modest E-value of 5.1 in kinetic resolution of 4-nitrophenyl 2-methylheptanoate. Enzyme variants were expressed in Pichia pastoris by using the episomal vector pBGP1 which allowed efficient secretory expression of the lipase. Iterative rounds of CASTing yielded variants with good selectivity toward both the (S)- and the (R)-enantiomer. The best obtained enzyme variants had E-values of 52 (S) and 27 (R).