title: Organocatalytic asymmetric direct phosphonylation of alpha,beta-unsaturated aldehydes: mechanism, scope, and application in synthesis.
abstract: The first direct organocatalytic enantioselective phosphonylation of alpha,beta-unsaturated aldehydes with phosphite, in combination with a Brønsted acid and a nucleophile, is presented. Mechanistic investigations have revealed that the first step in the catalytic process, after the formation of the iminium intermediate, is the addition of phosphite to the beta-carbon atom, leading to the phosphonium ion-enamine intermediate. The rate-determining step for the reaction is the transformation of P(III) to P(V), which occurs via a nucleophilic SN2-type dealkylation, and a screening of various nucleophiles shows that soft nucleophiles in combination with a Brønsted acid improve the reaction rate and enantioselectivity. The reaction conditions developed show that the use of 2-[bis(3,5-bistrifluoromethylphenyl)trimethylsilanoxymethyl]pyrrolidine as the catalyst and tri-iso-propyl phosphite as the phosphonylation reagent, in the presence of stoichiometric amount of benzoic acid and sodium iodide, gave the beta-phosphonylation of aromatic and aliphatic alpha,beta-unsaturated aldehydes in good yields and enantioselectivities. The products formed by this new reaction have been used for the synthesis of a number of biologically important compounds, such as optically active hydroxyl phosphonate esters, phosphonic acids, and especially glutamic acid and fosmidomycin precursors, of which the two latter are showing important properties for the treatment of central nervous system diseases and as anti-malarial compounds, respectively. DFT calculations have been applied to explain the approach of the phosphite to the reactive carbon atom in the iminium intermediate in order to account for the observed absolute enantioselectivity in the reaction.
authors.affiliation: Danish National Research Foundation, Center for Catalysis, Department of Chemistry, Aarhus University, DK-8000, Aarhus C, Denmark.
authors.forename: Eddy
authors.initials: E
authors.lastname: Maerten
authors.forename: Silvia
authors.initials: S
authors.lastname: Cabrera
authors.forename: Anne
authors.initials: A
authors.lastname: Kjaersgaard
authors.forename: Karl Anker
authors.initials: KA
authors.lastname: Jørgensen
mesh_terms: D000447:Aldehydes / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D063065:Organophosphonates / Q000737:chemistry*; D017905:Phosphites / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D000447:Aldehydes; D063065:Organophosphonates; D017905:Phosphites