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Novel Metal Amido-Complexes for the Efficient Asymmetric Hydrogenation of Imines

By Kathrin Kutlescha (3.12.2010)

One of the most fascinating phenomena in nature and science is the (homo)chirality of the world. The observation that our two hands and feet are similar but not identical, thus not being superimposable onto their mirror image, marks our first contact with macroscopic chirality [1].Chirality is not only observed on a macroscopic scale (Figure 1), e.g. for objects bearing a rotation axis such as screws, propellers or snail shells, it can additionally be found on the molecular level. Molecules, which consist at least of one asymmetric substituted (Carbon)-atom, are chiral. They appear as stereoisomers that differ in the orientation of the stereogenic center(s).

The molecules that make up life, namely RNA, DNA, amino acids, proteins and sugars, are all chiral. In living organisms they only occur in one enantiomeric form - right handed B-DNA, left handed Z-DNA, l-amino acids and d-sugars (Fig. 1). This tremendous biological selectivity is called homochirality. 

Figure 1: Chirality on macroscopic (snail Euhadra and flower of Romanesco) and molecular level.[Bildunterschrift / Subline]: Figure 1: Chirality on macroscopic (snail Euhadra and flower of Romanesco) and molecular level.

Thus, many biological processes, for instance enzyme catalysis, signal transduction or molecular recognition, are inherently dissymmetric. Enzymes and receptor sites are capable of differential binding, thereby distinguishing the enatiomers. The biological responses, which are generated upon binding, differ for each enantiomer [2]. The undesired enantiomer can be inactive (metabolic waste) or have an unwanted, even toxic effect [3], [4]. Therefore, certain chiral active pharmaceutical ingredients should be employed as enantiopure compound (Table 1).

Table 1: Different biological activities of drug enantiomers [3], [4].[Bildunterschrift / Subline]: Table 1: Different biological activities of drug enantiomers [3], [4].

Due to the fact that about 80% of the pharmaceuticals in the product pipeline are chiral and furthermore that the FDA (Food and Drug Administration) is improving the regulations for the launch of chiral pharmaceutical ingredients, there is an increasing demand for optically active intermediates such as amines, alcohols or acids [5], [6]. This ‘chiral switch’ in the pharmaceutical industry has boosted the field of asymmetric catalytic technologies, because these provide excellent access to those substances. Since mainly chiral transition metal complexes are applied for asymmetric chemocatalytic reactions, great efforts have been made to develop novel chiral ligand-systems for asymmetric catalysis.

Chiral amino acids and amino alcohols, which are easily accessible from the chiral pool, represent ideal building blocks for the synthesis of chiral imidazopyridazine-substituted amines. Based on previous results regarding the synthesis of chiral imidazo[1,5-b]pyridazine-substituted amino alcohols, which are suitable for the stabilization of transition metal amido-complexes [7], a novel optically active amido-ligand system was developed (Fig. 2). The hydroxyl function of the imidazo[1,5-b]pyridazine-substituted amino alcohols was selectively deprotonated with nBuLi and subsequently one equiv. of a chlorophosphine or chlorophosphite was added, thereby giving rise to novel amines in high yield and purity.

Figure 2: Synthesis of novel amines.[Bildunterschrift / Subline]: Figure 2: Synthesis of novel amines.

The chiral amines were utilized for the stabilization of group 9 metal complexes via alcohol elimination reaction with 0.5 eq. of [M(cod)Cl]2 (M= Ir, Rh; cod = 1,5-cyclooctadiene). The resulting amido-complexes were applied to the asymmetric hydrogenation of imines (Fig. 3).

Figure 3: Asymmetric hydrogenation of various N-aryl imines.[Bildunterschrift / Subline]: Figure 3: Asymmetric hydrogenation of various N-aryl imines.

Since promising initial selectivities and activities were obtained for rhodium amido-complexes, these were chosen for the optimization of the reaction. Thus, first the ideal reaction conditions by means of reaction temperature, pressure and the added base were determined. Next a ligand screening was conducted to find the best combination of amino alcohol (R2) and P-substituent (R5). Therein, the combination of leucinol (iBu) and -PiPr2 provided the best selectivity and activity in the asymmetric hydrogenation of N-aryl imines.

The amido-complexes represent a novel class of efficient and easily accessible catalysts for the asymmetric hydrogenation. Due to the modular ligand design, broad substitution patterns can be realized. This allows for fine-tuning of the catalyst towards the substrate. The remarkably high selectivity and efficiency combined with the novel structural motif opens up new prospects for the enantioselective hydrogenation of imines.


[1] G. H. Wagnière, On Chirality and the Universal Asymmetry – Reflection on Image and Mirror Image, Wiley-VCH, Weinheim, 2007, p. 3-5

[2] G. Beck, Synlett 2002, 6, 837-850.

[3] H.-J. Federsel, Ch. i. u. Z. 2007, 27, 78-87.

[4] J. Knabe, Ph. i. u. Z. 1995, 6, 324-330.

[5] M. Breuer, K. Ditrich, T. Habicher, B. Hauer, M. Keßeler, R. Stürmer, Th. Zelinski, Angew. Chem. Int. Ed. 2004, 43, 788-824.

[6] N. B. Johnson, I. C. Lennon, P. H. Moran, J. A. Ramsden, Acc. Chem. Res. 2007, 40, 1291-1299.

[7] R. Kempe, T. Irrgang, D. Friedrich, WO/061663 A1 PCT Int. Appl. 49 pp. 2008.

Kathrin Kutlescha
Kathrin Kutlescha
*1983, Suhl

  • 8/2009-11/2010
  • Elitenetzwerk Bayern, International Graduate Programme NanoCat
  • 2/2007-10/2010
  • Universität Bayreuth, Chair of Inorganic Chemistry II (Prof. Dr. Rhett Kempe), PhD-thesis: ‘Novel Metal Amido-Complexes – Syntheses, Reactivity and Asymmetric Catalysis’
  • 10/2006-5/2008
  • Advanced Training “Certified project manager in business chemistry - German Chemical Society”; final paper on the evaluation of merger success regarding the merger of Ribopharma AG and Alnylam Pharmaceuticals.
  • 6/2006-12/2006
  • Universität Bayreuth, Chair of Inorganic Chemistry II (Prof. Dr. Rhett Kempe), Diploma thesis: “Amido-Komplex-Katalysatoren später Übergangsmetalle”
  • 10/2002-12/2006
  • Universität Bayreuth, Studies of biochemistry (Diploma)

  • K. Kutlescha, T. Irrgang, R. Kempe, New J. Chem. 2010, 34, 1954-1960.
  • R. Kempe, T. Irrgang, K. Kutlescha, 210ak01.DE (Patent Application)
  • K. Kutlescha, T. Irrgang, R. Kempe; Adv. Synth. Catal., accepted.