br Experimental section br Acknowledgment S B

Experimental section
Acknowledgment S.B.T. is grateful to the Deutsche Forschungsgemeinschaft (DFG), the Wilhelm Sander-Stiftung and Interdisciplinary Center for Molecular Materials (ICMM) for generous research support. M.M. greatly acknowledges the experimental support and the scientific contribution in developing strategies of antiviral drug design by Dr. Corina Hutterer (Inst. Virol., Univ. Erlangen-Nuremberg); financial support was provided by the Wilhelm Sander-Stiftung (2011.085.1 and 2011.085.2) and Deutsche Forschungsgemeinschaft (MA 1289/7-1). We also thank Mr. Bhasem Gharib (University of Erlangen-Nuremberg, Germany) for the supply with ferrocene monocarboxylic GNE-7915 and ferrocene dicarboxylic acid.
Introduction Artemisinin (1, Fig. 1) and its derivatives are well-known for their remarkable antimalaria activity, and they are the worldwide standard therapy against Plasmodium falciparum malaria [1]. Besides antimalaria activity, artemisinin has been shown to possess various pharmacological actions, such as anti-cancer, anti-fungal, and anti-inflammatory [2]. Artemisinin was first isolated from Artemisia annua, a plant used in Chinese traditional medicine. Apart from isolation from plants, artemisinin can also be produced in large scale using genetically engineered yeast [3]. Artemether (2, Fig. 1) is a methyl ether derivative of artemisinin and possesses higher antimalaria activity. Artemisinin is a sesquiterpene δ-lactone with a special peroxide group, which is regarded to be responsible for kinds of biological activities. Because of the particularly of the peroxide group, chemical structures of artemisinin and its derivatives still attracted great interest from chemists and medicinal chemists. Chiroptical properties including electronic circular dichroism (ECD) and optical rotational dispersion (ORD) utilize different effects of chiral compounds on the left- and right-handed polarized light to study stereochemical characteristics. They are thought as an efficient alternative way to X-ray crystallization in the field of stereochemistry, but the interpretation of Cotton effects often hindered its wide application in the past. As shown in Fig. 1, there are several chiral centers in chemical structures of 1 and 2. It should be emphasized that chiroptical properties played a great role on the primary absolute configuration establishment of 1. In the first report on the structure and reaction of 1, it was stated that its chemical formula and relative configuration was identified by X-ray diffraction. Meanwhile, its absolute configuration was firstly deduced by comparison of ORD curve of 1 in chloroform with a trans-lactone from arteannuin B and using empirical lactone rule [4]. Then, the assignment was further verified by anomalous dispersion of Cu-radiation by oxygen atoms and total synthesis [5], [6]. In 1982, Professor Liang reported ECD spectra of several artemisinin derivatives and proposed the maximum at 260nm might be caused by overlay of ECD bands from δ-lactone and peroxide groups [7]. Nearly ten years later, they studied the correlation between the absolute configuration and Cotton effect of organic peroxide using CH3OOCH3 as a model molecule [8]. Nowadays, with the rapid development of time-dependent density functional theory (TDDFT) and computer technology, chiroptical properties including ECD and ORD spectra of small molecules could be calculated theoretically with high accuracy and reliability [9], [10], [11]. This provides the feasibility to revisit chiroptical properties of 1 and 2 and the correlation with their stereochemical characteristics. However, up to our knowledge, no report was found to discuss theoretically ECD and ORD spectra of 1 and its derivatives as a full molecule. Thus, as a part of our continuous effort to investigate chiroptical properties of natural products and chiral drugs, we studied chiroptical properties of compounds 1 and 2 using modern quantum-chemical calculation via TDDFT methodology. Herein, we will provide our results and discuss the ECD behavior of the peroxide bridge.