title: Nonclassical CH-π supramolecular interactions in artemisinic acid favor a single conformation, yielding high diastereoselectivity in the reduction with diazene.
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.
authors.affiliation: Institut Charles Gerhardt, CNRS 5253, Université Montpellier 2 , cc 1501, place E. Bataillon, F-34095 Montpellier, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Castro
authors.forename: Robin
authors.initials: R
authors.lastname: Chaudret
authors.forename: Gino
authors.initials: G
authors.lastname: Ricci
authors.forename: Michael
authors.initials: M
authors.lastname: Kurz
authors.forename: Philippe
authors.initials: P
authors.lastname: Ochsenbein
authors.forename: Gerhard
authors.initials: G
authors.lastname: Kretzschmar
authors.forename: Volker
authors.initials: V
authors.lastname: Kraft
authors.forename: Kai
authors.initials: K
authors.lastname: Rossen
authors.forename: Odile
authors.initials: O
authors.lastname: Eisenstein
mesh_terms: D037621:Artemisinins / Q000737:chemistry*; D006860:Hydrogen Bonding; D007094:Imides / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D010100:Oxygen / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D037621:Artemisinins; D007094:Imides; C047721:artemisic acid; C038867:diazene; D010100:Oxygen