ChemInform Abstract: The First General, Efficient and Highly Enantioselective Reduction of Quinoxalines and Quinoxalinones

They function as potent inhibitors of glycoproteins; including DC-SIGN, which facilitates the spread of viruses such as HIV, Hepatitis C, or Ebola; or CETP, which in its inhibited state counteracts atherosclerosis. Furthermore, they have been reported to open calcium channels; or serve as highly selective antagonists for diverse receptors, for example Kinin B1, which is associated with inflammation and pain in septicemia. An example of a promising dihydroquinoxalinone is GW420867X, a non-nucleoside HIV-1 reverse transcriptase inhibitor, which is currently in clinical trials. Furthermore, due to the similarity in their structure, tetrahydroquinoxalines are used as models for tetrahydrofolic acids (coenzyme F) and their derivatives, for example, leucovorine. The latter serves as a “rescue agent” in chemotherapy together with methotrexate. Even though it is only the natural diastereomer of leucovorine that acts as a competitive inhibitor, and the possibility that long-term use of the unnatural diasteromer may be toxic, leucovorine is still generally used as a racemate due to the lack of alternative synthetic methods. Despite the great importance of the tetahydroquinoxalines and dihydroquinoxalinones there are only very few enantioselective synthetic routes. To date efficient synthetic methods include catalytic reactions or solid-phase synthesis. However, they generally require multiple reaction steps and the introduction of a chiral amino alcohol or a corresponding amino acid. With particular emphasis on economic and ecologically valuable processes, asymmetric hydrogenation represents a highly efficient and atom-economic approach. General, catalytic, enantioselective hydrogenations of quinoxalines and quinoxalinones are not known, yet they represent the simplest method for synthesizing optically active tetrahydroquinoxalines and dihydroquinoxalinones. To date only the catalytic enantioselective reduction of 2-methylchinoxaline has been described. However, for instance in the case of DC-SIGN, as is often the case with tetrahydroquinoxalinones, the ones with aromatic substituents in the 2position are more biologically active. Therefore, we decided to examine a general, catalytic, enantioselective reduction of both quinoxalines and quinoxalinones. In particular, we wanted to concentrate on arylsubstituted derivatives, as these have been shown to be especially biologically active. As our initial work towards a metal-catalyzed, asymmetric reduction did not deliver the desired results with regard to high reactivity and selectivity, we decided to also examine metal-free transfer hydrogenations. 16] Here, the initial experiments showed that various Bronsted acids such as diphenylphosphate are able to catalyze the transfer hydrogenation of quinoxaline 1a to the corresponding 2-phenyl-tetrahydroquinoxaline 3a in the presence of the Hantzsch dihydropyridine 2a as a hydride source. Further, it was shown that the concentration of the solvent is a determining reaction parameter, especially with regard to the reactivity: The reactivity continuously increases with increasing solvent concentration. The following studies concentrated on the development of the first asymmetric variant in which the chiral phosphoric [a] Prof. Dr. M. Rueping, Dr. F. Tato, F. R. Schoepke Institute of Organic Chemisty, RWTH Aachen Landoltweg 1, 52074 Aachen (Germany) Fax: (+49)241-809-2127 E-mail : magnus.rueping@rwth-aachen.de Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200902907.