Stereoselektive reduktive Dimerisierung von α-Cyan-β-(4-pyridyl)acrylsäurederivaten

Stereoselective Reductive Dimerisation of α-Cyano-β-(4-pyridyl)acrylic Acid Derivatives Catalytic hydrogenation of the α-substituted β-(4-pyridyl)acrylonitriles 3 and 4 (see Scheme 3) yields via stereoselective reductive dimerization the substituted cyclo-pentene derivatives 7 and 8 (see Scheme 4 and 5) instead of the expected dihydro-products 5 and 6 . The mechanism of this reaction is discussed. The structure and relative configuration of 10 have been established by X-ray single crystal analysis.     

An enantioselective synthesis of β2-amino acid derivatives

Enantioselective hydrogenation of a series of (E)-α-substituted β-amidoacrylates using Rh(I)-catalysts with chiral phosphine ligands (BPE, DuPHOS) gives β²-amino acid derivatives with enantioselectivities of up to 67%. A β^2,3-amino acid derivative was also synthesised with similar enantioselectivity (⩽65%) from the corresponding prochiral enamide.     

Synthesis of chiral β2-amino acids by asymmetric hydrogenation

The synthesis of chiral β²-amino acids by homogeneous asymmetric hydrogenation is discussed. Prochiral β-aryl- or β-hetaryl-α-N-benzyl/N-acetyl/N-Boc substituted α-aminomethylacrylates used as substrates were prepared by a Baylis–Hillman reaction, followed by acylation and amination. For the asymmetric hydrogenation, a large variety of chiral, preferentially rhodium catalysts bearing commercially available phosphorus ligands were tested. Conversions and enantioselectivities were dependent on the reaction conditions and varied strongly between the substrates used. A chiral N-α-phenylethyl group supports the stereoface discriminating ability of the chiral catalysts and thus a matching pair effect could be realized. In strong contrast, a chiral ester group has almost no effect in this respect. In some cases the use of the corresponding substrate acid was better in comparison to the use of its ester. After optimization of the hydrogenation conditions (chiral catalyst, H₂-pressure, temperature, solvent), full conversions and products with up to 99% ee were achieved.     

Dynamic kinetic resolution of α-chloro β-keto esters and phosphonates: hemisynthesis of Taxotere® through Ru-DIFLUORPHOS asymmetric hydrogenation

The dynamic kinetic resolution (DKR) of racemic α-chloro β-ketoesters and α-chloro β-ketophosphonates through ruthenium-mediated asymmetric hydrogenation is reported. The corresponding α-chloro β-hydroxyesters and α-chloro β-hydroxyphosphonates were obtained in good to high enantio- and diastereomeric excesses using, in particular, the atropisomeric ligand DIFLUORPHOS. This methodology allowed an efficient preparation of the anti phenylisoserine side chain of Taxotere® which has been used for the hemisynthesis of the cancer therapeutic agent itself. In addition, ¹³C NMR in chiral oriented solvents was used to investigate the DKR effect.     

Copper-Catalyzed Enantioselective Formation of C−CF3 Centers from β-CF3-Substituted Acrylates and Acrylonitriles

The catalytic asymmetric synthesis of β-trifluoromethylated esters or nitriles is reported. The use of an in situ formed chiral Cu−H complex allowed the enantioselective reduction of β-trifluoromethylated acrylates or acrylonitriles. The reaction proceeds smoothly affording the corresponding enantioenriched products in good to excellent yields and outstanding enantioselectivities (up to 98 % ee). The mechanism of the reaction was studied, and a plausible reaction pathway was suggested accordingly. Finally, the versatility of the products was highlighted through functional group manipulations.     

Asymmetric Synthesis of Unnatural Amino Acids and Tamsulosin Chiral Intermediate

An efficient and enantioselective hydrogenation of N-acetylamino phenyl acrylic acids was successfully developed by using ruthenium catalyst. This methodology is important in the field of pharmaceuticals and provides a new process for the preparation of unnatural amino acids and tamsulosin chiral intermediate.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource: Full experimental and spectral details.]     

Enantioselective synthesis of (R)-incrustoporin,an antibiotic isolated from Incrustoporia carneola

Highly enantiomerically enriched (R)-incrustoporin was enantioselectively synthesized in 43.6% overall yield starting from 4-iodotoluene. The key steps of the synthesis included the asymmetric hydrogenation of 1-(p-tolyl)-1-pentyn-3-one catalyzed by a non-racemic Ru(II) complex and the Pd-catalyzed cyclocarbonylation of so-obtained highly enantiomerically enriched 1-(p-tolyl)-1-pentyn-3-ol. This Pd-catalyzed reaction, whose stereochemical outcome was previously unknown, proceeded with retention of configuration and 2.5% or less racemization. The enantiomeric purities of (R)-1-(p-tolyl)-1-pentyn-3-ol and (R)-incrustoporin were evaluated by HPLC analysis on a Chiralcel OJ column as well as by performing the ¹H NMR spectra of these compounds in a D₂O solution which was saturated with α- or β-cyclodextrin, respectively.     

Structure of Ti1−yVyHx alloys studied by X-ray diffraction and by 1H and 51V NMR

The structure of the TiVH system is studied by X-ray diffraction and ¹H and ⁵¹V NMR measurements. It is shown that the solid solution of TiV is separated into a few phases by hydrogenation. They are α-TiVH, β-TiVH, γ-TiVH, and γ-TiH phases, which are assumed to have their origins either in TiH_x or in VH_x. The concentration of each phase can be estimated by NMR, which is dependent on the composition of the system. The phase separation caused by hydrogenation is due to the large stability of the γ-TiH phase.     

Synthesis of 1,2- and 1,4-amino alcohols from 1,3-dienes via oxazines. Rearrangements of 1,4-amino alcohol derivatives to oxazolines

Conjugated dienes were converted to 1,2-oxazines by reaction with an acyl nitroso dienophile. The oxazines were reduced to 1,4-N-acetylamino alcohols, which were rearranged to the corresponding oxazolines upon treatment with methanesulfonyl chloride or anhydride. The oxazolines yielded 1,2-N-acetylamino alcohols upon hydrolysis. Thus either 1,4- or 1,2-N-acetylamino alcohols are available from 1,3-dienes via this methodology. Experimental and spectral data are provided for all new compounds.     

N-Benzyl-norephedrine derivatives as new,efficient ligands for ruthenium-catalyzed asymmetric transfer hydrogenation of functionalized ketones

Significant catalytic activities (up to 600 h⁻¹ at 20°C) and enantiomeric excesses ranging from 56 to 89% for the asymmetric transfer hydrogenation of β-ketoesters, methoxyacetone and 2-acetylpyridine to the corresponding alcohols are achieved in the presence of catalytic combinations of [RuCl₂(η⁶-arene)]₂ and N-substituted derivatives of (1S,2R)-norephedrine such as N-benzyl-norephedrine and N-(4-biphenyl)methyl-norephedrine.     

Endo-selective Diels-Alder reaction of methacrylonitrile: application to the synthesis of Georgywood

Diels-Alder reactions of alkyl-substituted dienes with acrylonitriles give good yields and endo-selectivities if catalyzed by (organo)aluminum, (organo)boron or gallium halides. The activity of these group IIIa Lewis acids in this reaction correlates with the coordination strength of their nitrile complexes, which deactivate Lewis acids sufficiently, so that the subsequently added diene partner undergoes the Diels-Alder reaction without serious side-reactions. Boron trichloride is the most effective catalyst for this purpose. This method gives the best endo/exo-ratios reported so far for these components and was applied in the selective synthesis of the olfactory vector of Georgywood^®.     

Enantioselective hydrogenation of (Z)- and (E)-β-arylenamides catalyzed by rhodium complexes of monodentate chiral spiro phosphorous ligands: a new access to chiral β-arylisopropylamines

A highly enantioselective rhodium-catalyzed hydrogenation of both (Z)- and (E)-β-arylenamides was developed by using monodentate chiral spiro phosphite and phosphine ligands, respectively. The hydrogenation reaction provides an efficient access to optically active β-arylisopropylamines, important building blocks for the synthesis of biologically active compounds.     

Inclusion complexes of rosmarinic acid and cyclodextrins: stoichiometry,association constants,and antioxidant potential

The interaction between β-cyclodextrin (β-CD) and the polyphenol rosmarinic acid (RA) is here reported by ¹H NMR titration experiments. The formation of an aqueous soluble inclusion complex is confirmed and valuable information regarding mode of penetration of guest into β-CD, stoichiometry, and stability of the complex is obtained. The analysis by the continuous variation method shows the undoubted formation of 1:1 β-CD/RA complex. Additionally, the estimated apparent association constants reveal the importance of the asymmetry of the RA in the complexation; the incorporation of the catechol moiety closer to the carboxylic group is more favorable (K?=?2,028 M^?1) than from the other end of the RA molecule (K?=?1,184 M^?1). Finally, we have also investigated the antioxidant activity and storage stability of the β-CD/RA complexed system; the presence of β-CD was found to produce a remarkable enhancement on the antioxidant activity.     

Asymmetric transfer hydrogenations of β-N-substituted enamino esters with ammonia borane

Optically active β-amino acids and their derivatives are very useful building blocks in synthetic and medicinal chemistry. The catalytic asymmetric reduction of β-enamino esters is one of the most efficient approaches for their synthesis. Ammonia borane with low molecular weight, high hydrogen capacity, and good stability, is an ideal hydrogen source for the transfer hydrogenation. However, only a few successful examples have been reported for the asymmetric reduction with ammonia borane. In this work, an asymmetric metal-free transfer hydrogenation of β-N-substituted enamino esters with ammoinia borane was successfully realized by using a frustrated Lewis pair of Piers’ borane and (S)-tert-butylsulfinamide as a chiral catalyst. A variety of β-amino acid derivatives were obtained in 51–90% yields with up to 91% ee.     

Complexation studies of pioglitazone hydrochloride and β-cyclodextrin: NMR (1H, ROESY) spectroscopic study in solution

Pioglitazone hydrochloride (PIO) is an agonist of the peroxisome proliferator-activated receptor γ (PPARγ), used to treat diabetes. ¹H-NMR spectroscopic analysis of varying ratios of β-cyclodextrin (β-CyD) and PIO in D₂O confirmed the formation of β-CyD–PIO inclusion complex in aqueous solution. The 1:1 stoichiometry of β-CyD–PIO inclusion complex was determined by Scott’s plot method and binding constant (K _a ) was calculated to be 155 M^?1. 2D ROESY experiments confirmed that the phenyl ring of PIO act as a guest and deeply penetrate in β-CyD cavity from wider as well as narrower rim side and form two 1:1 stable inclusion complexes. Some of the PIO protons exhibited splitting, in the presence of β-CyD, indicating chiral differentiation of PIO by β-CyD.     

Rhodium N-heterocyclic carbene complexes: Synthesis,structure, NMR studies and catalytic activity

The solid state structure, phosphine dissociation rates and catalytic activity of several Rh-N-heterocyclic carbene complexes were studied. Catalytic activity for the hydrogenation of β-methylstyrene was improved by up to two orders of magnitude upon the addition of copper chloride. The catalyst with the highest inherent activity was found to be [Rh(IMes)(P-p-FC₆H₄)₃], although the p-methoxy derivative benefited the most from the addition of CuCl, giving turnover numbers of over 400 h⁻¹.     

Asymmetric transfer hydrogenation of imines catalyzed by a Noyori-type Ru(II) complex—a parametric study

We present, to the best of our knowledge, the first parametric study of the asymmetric transfer hydrogenation of imines catalyzed by a Noyori-type catalytic complex based on ruthenium. A model imine for this study was 1-methyl-3,4-dihydroisoquinoline, and a well-known complex RuCl(η⁶-p-cymene)((1S,2S)-N-p-toluenesulfonyl-1,2-diphenylethylenediamine) was chosen as the model catalyst. The reactions were performed in the presence of a formic acid–triethylamine mixture as the source of hydrogen.The parameters examined include general parameters, for example, concentration, temperature, and substrate-to-catalyst molar ratio, as well as parameters specific to this particular reaction, such as the amount of the hydrogenation mixture used, the ratio of its components, or the inhibitive effect of carbon dioxide. During this study, several unexpected parameters worth further investigation have emerged.     

Catalytic Hydrocyanation of Activated Terminal Alkynes

A universal, practical and scalable organocatalytic hydrocyanation manifold to provide β-substituted acrylonitriles bearing an electron-withdrawing functionality has been implemented. The catalytic manifold operates under the reactivity generation principle “a good nucleophile generates a strong base”, and it uses 1,4-diazabicyclo[2.2.2]octane (DABCO) as the catalyst, activated terminal alkynes as substrates and acetone cyanohydrin as the cyanide source. The acrylonitriles obtained as E,Z mixtures are straightforwardly resolved by simple flash chromatography delivering the pure isomers in preparative amounts.     

Synthesis of (R)-tembamide and (R)-aegeline via asymmetric transfer hydrogenation in water

The synthesis of (R)-tembamide and (R)-aegeline via asymmetric transfer hydrogenation involving enantioenriched monosulfonamide–RhCp¹ complex in aqueous sodium formate as hydride donor is described.     

Statistical design analysis of isophorone electrocatalytic hydrogenation: the use of cyclodextrins as inverse phase transfer catalysts

Fundamentals and applications of a 2³ factorial design were performed for assessing the influence of the cyclodextrin (CyD) type, concentration and encapsulation time on the electrocatalytic hydrogenation (ECH) of isophorone. Electrolysis were carried out using nickel as electrocatalyst and sacrificial anode. A discussion of model validation is presented. The analysis of the results showed that the most significant factors to the conversion rate were the CyD type and concentration, with 3 mmol dm^?3 of βCyD giving the best results. The isophorone C=C hydrogenation yield, in the presence of βCyD, was 28 % higher than in its absence, and it is comparable to those obtained by other well-established ECH procedures in terms of hydrogenation yield, selectivity and current efficiency.