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A new [Ru(II)( η 6 - p -cymene)(1 R ,2 R )- N -((1 S ,2 S )-borneol-10-sulfonyl)-1,2-diphenylethylenediamine] catalyst for the asymmetric transfer hydrogenation of both 1-alkyl and 1-aryl dihydroisoquinolines has been isolated. For the first time in this type of reaction, the catalyst employs an N-alkylsulfonyl group instead of N-arylsulfonyl.

The asymmetric transfer hydrogenation of five dihydroisoquinolines (DHIQs) was studied by NMR spectroscopy. The DHIQs differed by substitution with methoxy groups, which had a significant effect upon the reaction performance in terms of reaction rate and enantioselectivity. The differences are most probably related to the basicity of DHIQs.

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(η 6 - p -cymene)((1 S ,2 S )- 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.

A method for the analysis of the optical purity of a series of chiral substituted tetrahydroisoquinolines (THIQs) was developed. The method is based on pre-column derivatization of the analytes with the derivatization reagent (–)-(1R)-menthyl chloroformate. The derivatization reaction selectively gives diastereomeric carbamates that are resolvable on an achiral non-polar GC column. The developed technique covers variously substituted THIQs, which differ significantly in volatility, steric and electronic properties. In all cases, the resolution factors (R) exceeded the value of 1.5. The method represents a robust way of analysis of mixtures of THIQs, which are often present in various matrixes such as body fluids, tissues and reaction mixtures.

A chiral precursor of Mivacurium chloride, (R)-5′-methoxylaudanosine, was prepared using two different methods. The chiral resolution of racemic 5′-methoxylaudanosine, typically used in industry, was carried out in parallel with a procedure consisting of asymmetric transfer hydrogenation (ATH) and reductive methylation. A novel one-pot synthetic step was developed for the synthesis of racemic 5′-methoxylaudanosine. In both routes, the enantioselectivity was high but further purification was necessary to reach the level of a pharmaceutical standard. The individual synthetic steps reported herein can also be used for the synthesis of analogous bistetrahydroisoquinoline-based skeletal muscle relaxants.

Asymmetric transfer hydrogenation of the acyclic imine acetophenone N-benzylimine was studied by means of computational chemistry. Calculated transition states offer an explanation of why this proc...

Asymmetric hydrogenation ranks to the most intensively researched way of preparation of enantiomerically pure compounds which are demanded e.g. in pharmaceutical industry, cosmetics or agriculture. In the field of asymmetric transfer hydrogenations (ATH) of C=N and C=O double bonds Noyori’s ruthenium (II) complexes represent significant breakthrough. This catalytic system consists of three integral parts - chiral monotosylated diamine ligand – i.e. N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (TsDPEN), η6-coordinated aromatic molecule (e.g. benzene or p-cymene) and halogen counteranion (usually chloride). General formula of the catalyst can be written as [RuCl(η6-arene)(N-arylsulfonylDPEN)]. Aforementioned fragments/ligands offer countless number of possibilities for structural modifications – e.g. elongation of carbonaceous spacer between phenyl rings within 1,2-diphenylethylendiamino fragment, alkylation of amino group, usage of diversely substituted η6-aromatic molecule, employment of different aryls within arylsulfonyl fragment etc. Systematic evaluation of these modifications has multilateral benefits because it not only helps to clarify mechanistic phenomena but also contributes to the deeper understanding of relationship between structure and catalytic activity. With sufficiently big and rich data base it should be possible to tailor catalyst’s properties specifically for given substrate (or class of substrates) and reaction conditions (solubility, stability, etc.). Our research is focused primarily on comprehension of role of the η6-aromatic molecule during asymmetric transfer hydrogenation of imines. This ligand plays very important mechanistic role because its structure (respectively interaction with the substrate) allows asymmetric course of the reaction. Arene ligand can in certain cases form stabilizing CH/π interaction between aromatic part of substrate and therefore lower energy of transition state. This led us to the hypothesis that alteration of its structure could strongly affect enantioselectivity and reaction rate. This hypothesis has been brought up and discussed but only in case of ATH of C=O bonds, which dramatically differs from hydrogenation of C=N bonds. Usually only simply alkyl-substituted arene molecules are used as aromatic ligands. In our study we have prepared and compared four catalysts with different aromatic ligands (benzene, p-cymene, mesitylene, 1,2,3,4,5,6-hexamethylbenzene) according to their performance (reaction rate, enantioselectivity) during hydrogenation of variously substituted 3,4-dihydroisoquinolines and tried to interpret obtained results via means of computational chemistry.

Asymmetric transfer hydrogenation (ATH) of cyclic imines using [RuCl(η(6)-p-cymene)TsDPEN] (TsDPEN = N-tosyl-1,2-diphenylethylenediamine) was tested with various aliphatic (secondary, tertiary) and aromatic amines employed in the HCOOH-base hydrogen donor mixture. Significant differences in reaction rates and stereoselectivity were observed, which pointed to the fact that the role of the base in the overall mechanism could be more significant than generally accepted. The hydrogenation mixture was studied by nuclear magnetic resonance (NMR), Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) and vibrational circular dichroism (VCD) with infrared spectroscopy. The results suggested that the protonated base formed an associate with the active ruthenium-hydride species, most probably via a hydrogen bond with the sulfonyl group of the complex. It is assumed that the steric and electronic differences among the bases were responsible for the results of the initial ATH experiments.