Abstract
The high diastereoselectivity of the hydrogenation of artemisinate by diazene to form dihydroartemisinate (diastereoselective ratio, dr, 97:3) necessary for efficient production of artemisin has been rationalized by state-of-the-art DFT calculations and identification of the noncovalent interactions by coupled ELF/NCI analysis. Remarkably, a single conformer of artemisinate is responsible for the high diastereoselectivity of the reaction. NMR studies confirm the preference for a single conformation that is found to be identical to that predicted by the calculations. The calculations and ELF/NCI analyses show that the hydrogenation of the exocyclic activated C═C double bond has a low energy barrier and that the lowest transition state and the preferred conformation of free artemisinate develop the same network of weak noncovalent interactions between the electron donor groups (oxygen and exocyclic C═C double bond) and CH bonds of the cis-decalene group of the artemisinate, which rationalize the high diastereoselectivity unusual for a strongly exothermic reaction.
Supporting Information
Additional information for the NMR study of 1ate. Full list of authors for ref 43. Rotational barrier of 1ate. Additional energy information associated with Tables 1 and 2. Full size and additional ELF/NCI figures with technical and cutoff information. ELF analysis for 1ate and the transition states corresponding to entries 1 and 6 in Table 1. List of coordinates of all optimized structures. This material is available free of charge via the Internet at http://pubs.acs.org.
