DOI: 10.1002/chem.200902907 The First General, Efficient and Highly Enantioselective Reduction of Quinoxalines and Quinoxalinones Magnus Rueping,* Francisco Tato, and Fenja. R. Schoepke [a] Tetrahydroquinoxalines and dihydroquinoxalinones pos- sess important biological and pharmacological properties. [1] By 1947 various tetrahydroquinoxalines had already been synthesized to examine their antimalarial activity. [2] Since then interest in the tetrahydroquinoxalines and dihydroqui- noxalinones has significantly increased. They function as potent inhibitors of glycoproteins; in- cluding DC-SIGN, [3] which facilitates the spread of viruses such as HIV, Hepatitis C, or Ebola; or CETP, which in its inhibited state counteracts atherosclerosis. [4] Furthermore, they have been reported to open calcium channels; [5] or serve as highly selective antagonists for diverse receptors, for example Kinin B 1 , which is associated with inflammation and pain in septicemia. [6] An example of a promising dihy- droquinoxalinone is GW420867X, a non-nucleoside HIV-1 reverse transcriptase inhibitor, which is currently in clinical trials. [7] Furthermore, due to the similarity in their structure, tetrahydroquinoxalines are used as models for tetrahydrofol- ic acids (coenzyme F) and their derivatives, for example, leucovorine. [8] The latter serves as a “rescue agent” in che- motherapy 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 alterna- tive synthetic methods. Despite the great importance of the tetahydroquinoxalines and dihydroquinoxalinones there are only very few enantioselective synthetic routes. To date effi- cient synthetic methods include catalytic reactions [9] or solid-phase synthesis. [10] However, they generally require multiple reaction steps and the introduction of a chiral amino alcohol or a corresponding amino acid. [11] With par- ticular emphasis on economic and ecologically valuable pro- cesses, asymmetric hydrogenation represents a highly effi- cient and atom-economic approach. [12] General, catalytic, enantioselective hydrogenations of qui- noxalines and quinoxalinones are not known, yet they repre- sent the simplest method for synthesizing optically active tetrahydroquinoxalines and dihydroquinoxalinones. To date only the catalytic enantioselective reduction of 2-methylchi- noxaline has been described. [13, 14] However, for instance in the case of DC-SIGN, as is often the case with tetrahydro- quinoxalinones, the ones with aromatic substituents in the 2- position are more biologically active. Therefore, we decided to examine a general, catalytic, enantioselective reduction of both quinoxalines and quinox- alinones. In particular, we wanted to concentrate on aryl- substituted derivatives, as these have been shown to be es- pecially 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 hydrogena- tions. [15, 16] Here, the initial experiments showed that various Brønsted acids such as diphenylphosphate are able to cata- lyze the transfer hydrogenation of quinoxaline 1a to the cor- responding 2-phenyl-tetrahydroquinoxaline 3a in the pres- ence 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 increas- es 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. # 2010 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim Chem. Eur. J. 2010, 16, 2688 – 2691 2688