Bifunctional catalysis by natural cinchona alkaloids: a mechanism explained.
The use of bifunctional chiral catalysts, which are able to simultaneously bind and activate two reacting partners, currently represents an efficient and reliable strategy for the stereoselective preparation of valuable chiral compounds. Cinchona alkaloids such as quinine and quinidine, simple organic molecules generously provided by Nature, were the first compounds to be proposed to operate through a cooperative catalysis. To date, a full mechanistic characterization of the dual catalysis mode of cinchona alkaloids has proven a challenging objective, due to the transient, non-covalent nature of the involved catalyst-substrate interactions. Here, we propose a mechanistic rationale on how natural cinchona alkaloids act as efficient bifunctional catalysts by using a broad range of computational methods, including classical molecular dynamics, a mixed quantum mechanical/molecular mechanics (QM/MM) approach, and correlated ab-initio calculations. We also unravel the origin of enantio- and diastereoselectivity, which is due to a specific network of hydrogen bonds that stabilize the transition state of the rate-determining step. The results are validated by experimental evidence.
Cucinotta
Clotilde S
CS
Computational Science, Department of Chemistry and Applied Biosciences, ETH Zurich c/o USI-Campus, Via Giuseppe Buffi 13, 6900 Lugano (Switzerland), Fax: (+41) 58-666-4817.
Kosa
Monica
M
Computational Science, Department of Chemistry and Applied Biosciences, ETH Zurich c/o USI-Campus, Via Giuseppe Buffi 13, 6900 Lugano (Switzerland), Fax: (+41) 58-666-4817.
Melchiorre
Paolo
P
Dipartimento di Chimica Organica "A. Mangini", Alma Mater Studiorum-Università di Bologna, Viale Risorgimento, 4, 40136 Bologna (Italy).
Cavalli
Andrea
A
Dipartimento di Scienze Farmaceutiche, Alma Mater Studiorum-Università di Bologna, Via Belmeloro 6, 40126 Bologna (Italy), Unit of Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, 16163 Genova (Italy).
Gervasio
Francesco L
FL
Computational Science, Department of Chemistry and Applied Biosciences, ETH Zurich c/o USI-Campus, Via Giuseppe Buffi 13, 6900 Lugano (Switzerland), Computational Biophysics Group, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre c/Melchor Fdez. Almagro 3, 28029 Madrid (Spain).
D002384:Catalysis; D002930:Cinchona Alkaloids / Q000737:chemistry / Q000378:metabolism*; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D013237:Stereoisomerism
D002930:Cinchona Alkaloids