Theoretical Characterization of an Intermediate for the [3 + 2] Cycloaddition Mechanism in the Bis(dihydroxy- quinidine)-3,6-Pyridazine‚Osmium Tetroxide-Catalyzed Dihydroxylation of Styrene Gregori Ujaque, † Feliu Maseras,* ,‡ and Agustı ´ Lledo ´s † Laboratoire de Structure et Dynamique des Syste ` mes Mole ´ culaires et Solides, U.M.R. 5636, Universite ´ de Montpellier II, 34095 Montpellier CEDEX 5, France, and Unitat de Quı ´mica Fı ´sica, Departament de Quı ´mica, Edifici C.n, Universitat Auto ` noma de Barcelona, 08193 Bellaterra, Catalonia, Spain Received July 23, 1997 The osmium-catalyzed asymmetric dihydroxylation of olefins constitutes one of the most successful exam- ples of application of transition metal complexes to the practical synthesis of biologically important com- pounds. 1,2 A lot of experimental studies have been devoted to the understanding of the mechanism of this reaction. 3-10 In particular, there has been a lot of controversy on the precise mechanism of the key step where the stereoselectivity of the reaction is decided, namely the formation of the cyclic ether. Different pathways have been postulated, but all of them seem to be summarized in two major proposals: (i) a concerted [3 + 2] cycloaddition of two oxygens to the olefin bond 3-5 and (ii) a stepwise mechanism starting with a [2 + 2] addition of the olefin to an Os-O bond and going through an osmaoxoethane intermediate. 1,6,8 Theoretical work has been also devoted to this topic. Early extended Hu ¨ ckel studies predicted a [3 + 2] mechanism, 11 while the [2 + 2] mechanism found support in the theoretical study of epoxydation processes. 12 The definitive clarification of the reaction mechanism was however not possible because of the need for electron correlation in the location of transition states, with results based in RHF-optimized geometries being incon- clusive. 13 The recent application of non-local DFT meth- ods to the model system OsO 4 (NH 3 ) + C 2 H 4 has provided a substantial boost to the [3 + 2] proposal, with similar results by us 14 and two other groups 15,16 indicating a difference in energy barriers as large as 53.8 kcal/mol between the two mechanisms. These theoretical studies have however failed to locate any intermediate in the reaction, an intermediate that is required by the experi- mental evidence emerging from the independent experi- ments indicating the existence of an inversion point in the Eyring plot 9 and a Michaelis-Menten kinetics. 10 The nature of such an intermediate remains unknown, having been postulated from experiments to be either the [2 + 2] osmaoxoethane 1,9 or a weak olefin-Os(VIII) π-d complex. 5,10 This paper presents the application of the hybrid method IMOMM 17 to this problem. This method, mixing quantum mechanics (QM) and molecular mechanics (MM) descriptions for different parts of the same system, has already been proved successful in a number of examples, 18-20 including a case with complexes related to the process under study. 20 The use of an MM descrip- tion for part of the system is the only option allowing the introduction in the calculation of the large NR 3 ligand, which is indeed the key factor deciding the stereoselectivity of the reaction. Pure MM studies previ- ously carried out on these systems 21 had the serious limitation of relying on MM parameters for osmium, not necessarily well fitted to this reaction. IMOMM(BECKE3LYP:MM3) calculations are carried out on the (DHQD) 2 PYDZ‚OsO 4 [(DHQD) 2 PYDZ ) bis- (dihydroxyquinidine)-3,6-pyridazine] + CH 2 dCHPh sys- tem. This system is chosen because, despite its relative simplicity, it provides a high experimental enantioselec- tivity for the R product and because there are a lot of experimental data available as a result of the extensive work by Corey, Noe, and their coworkers. 4,10 These available data are used to choose the conformation of the reactant, as well as the disposition of the phenyl sub- stituent in the attacking styrene. Full geometry optimizations succeed in locating four different stationary points: the separated reactants (1), the intermediate (2), the transition state (3), and the osmium(VI) glycolate product (4). The transition state 3 has a negative eigenvalue of -0.070 au in the ap- proximate Hessian, with the corresponding eigenvector having large components in the O-C distances. The connection of 2 and 4 through 3 is further proved by downhill geometry optimizations with small step size from 3. 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Chem. 1997, 62, 7892-7894 S0022-3263(97)01345-5 CCC: $14.00 © 1997 American Chemical Society