Asymmetric transfer hydrogenation of C=N and C=O bonds

Introduction

The pharmacological effect of chiral compounds is very often caused by only one enantiomer, while the other one can have a different, or even no effect.
For that reason, direct methods of obtaining optically pure chiral compounds are highly demanded nowadays. Conventional organic reaactions almost always lead to a racemic mixture (Figure 1a), but asymmetric (or enantioselective) reactions can give products of high optical purity (Figure 1b).
 

Figure 1: Schemes of (a) a conventional reaction yielding a racemic mixture and (b) asymmetric reaction. In the case of standard hydrogenation (a), the addition of hydrogen to the double bond (here C=C) occurs evenly at boths sides of the molecule, but in asymmetric hydrogenation (b), the addition is done preferrentially at one side of the molecule (the product is a mixture of enantiomers in a ratio up to 99:1).

There are many different asymmetric reactions. Our group focuses on the asymmetric transfer hydrogenation (ATH) of prochiral imines and ketones. The reaction is catalyzed by Noyori's RuII complexes1,2 that facilitate the addition of hydrogen preferrentially from one side of the molecule (Figure 1b), making the reaction asymmetric. The source of hydrogen can be isopropanol or a HCOOH/Et3N mixture and the reaction is done at room temperature (Figure 2). Therefore, there is no need for an autoclave and the hydrogenation is easy to handle.
Most of our work is done with cyclic imines - dihydroisoquinolines (Figure 2). The products of ATH tetrahydroisoquinolines (chiral amines) are the building block of many naturally occurring alkaloids3 and active pharmaceutical ingredients (most notably muscle relaxants: Mivacurium, Atracurium, Doxacurium, Cisatracurium).
 

Figure 2: Asymmetric transfer hydrogenation of dihydroisoquinoline (DHIQ) to tetrahydroisoquinoline (THIQ) catalyzed by a chiral Ru catalyst.

Research activities and interests

Reaction mechanism studies

The ATH proceeds via two (diastereomeric) transition states, out of which one leads the the (R)-product and one to the (S-product).As the energy of these transition states is different, they are formed with different probability, i.e. one of them is formed more often. Therefore, higher difference of energies gives higher enantioselectivity.
These diastereometric transition states can be explored by means of molecular modelling. The calculated structures display the transition states at the very moment of hydrogen transfer from ruthenium to the double bond of the substrate. Using these models, it is possible to discuss the steric and electronic properties of the substrate and catalyst.
Interestingly, the mechanism is different for ketones and imines. For ketones, a six-membered cyclic transition state is expected, while imines are protonated and only one hydrogen atom is transferred (Figure 3). These hypotheses were supported by our results from molecular modelling2,4. In the next stage, we studied the differences in the ATH of cyclic and acyclic imines. If was found that acyclic N-acetophenone benzylimine undergoes interconversion between two isomers and its flexibility complicates the analysis of transition states5. As a result, a product with opposite configuration is formed during ATH than in the case of cyclic substrates.

 


Figure 3: Model transition states of ATH of acetophenone (ketone) and DHIQ (imine).
(a) the ketone is hydrogenated via a six-membered transition state, (b) the imine is protonated and one hydrogen is transferred. The model depicts a calculated transition state of the ATH of a protonated imine.

The developed know-how is applied in the studies of further mechanistic aspects, which also employ NMR spectroscopy in collaboration with Institue of Microbiology, Adacemy of Sciences of the Czech Republic. Jiří Václavík and Petr Šot are currently involved in the mechanistic studies.

 

Catalyst immobilization

Standard ATH falls into the area of homogeneous catalysis and is inherently connected with the issue of difficult separation of the catalyst from the reaction mixture. The presence of heavy metals in the products of ATH is not acceptable for its usage e.g. in pharmaceutical industry and moreover, the catalysts used are considerably expensive. For that reason, it is highly desirable to immobilize2 these homogeneous complexes onto a solid support, which would allow facile separation of the catalyst after reaction and its recycling.
Our aim is to immobilize the Ru catalysts on solid supports such as mesoporous silicates6 or polymers. This topic is currently being solved by Beáta Vilhanová.

 

Influence of various parameters on the reaction performance

It has been found out that the reaction performance is affected by a number of alterable parameters which are very often interconnected. Searching for the optimal reaction conditions is therefore rather difficult: if one set of parameters works for a certain substrate-catalyst combination, it does not have to be the case of another combination. The most important influential parameters are displayed in Figure 4.
 

Figure 4: Scheme of the most significant influential parameters.

Our target is to systematically map the influence of individual parameters and their combinations on the course of ATH. For the monitoring of hydrogenation, we developed efficient in situ7 methods. Some results have already been published8 and Jan Pecháček is currently working on this topic.

 

References

1. Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. Asymmetric transfer hydrogenation of imines. J. Am. Chem. Soc. 1996, 118, 4916-4917.
2.  Václavík, J.; Kačer, P.; Kuzma, M.; Červený, L. Opportunities Offered by Chiral η6-Arene/N-Arylsulfonyl-diamine-RuII Catalysts in the Asymmetric Transfer Hydrogenation of Ketones and Imines. Molecules 2011, 16 (7), 5460-5495.
DOI: 10.3390/molecules16075460
3. Bentley, K. W. β-Phenylethylamines and the isoquinoline alkaloids. Nat. Prod. Rep. 1992, 9, 365-391.
4.  Václavík, J.; Kuzma, M.; Přech, J.; Kačer, P. Asymmetric Transfer Hydrogenation of Imines and Ketones Using Chiral RuIICl(η6-p-cymene)[(S,S)-N-TsDPEN] as a Catalyst: A Computational Study. Organometallics 2011, 30 (18), 4822–4829.
DOI: 10.1021/om200263d
5. Šot, P.; Kuzma, M.; Václavík, J.; Pecháček, J.; Přech, J.; Januščák, J.; Kačer, P. Asymmetric Transfer Hydrogenation of Acetophenone N-Benzylimine using [RuIICl(S,S)-N-(TsDPEN)η6-(p-cymene)]: A DFT Study. Organometallics 2012, 31 (17), 6496–6499.
DOI: 10.1021/om300413n
6. Šiklová, H.; Leitmannová, E.; Kačer, P.; Červený, L. Immobilization of Ru-TsDPEN catalyst on functionalized MCM-41. React. Kinet. Catal. Lett. 2007, 92, 129-136.
DOI: 10.1007/s11144-007-5140-2
7. Václavík, J.; Pecháček, J.; Přech, J.; Kuzma, M.; Kačer, P.; Červený, L. In situ Monitoring of Asymmetric Transfer Hydrogenation of Imines Using NMR Spectroscopy. Chem. Listy 2012, 106, 206-210.
article online
8. Gulamhussen, A. M.; Kačer, P.; Přech, J.; Kuzma, M.; Červený, L. Highly efficient preparation of R-1-methyl-tetrahydroisoquinoline using chiral Ru(II)-catalyst. React. Kin. Catal. Lett. 2009, 97 (2), 335-340.
DOI: 10.1007/s11144-009-0036-y