Rationalizing the Stereoselectivity of Osmium Tetroxide Asymmetric Dihydroxylations with Transition State Modeling Using Quantum Mechanics-Guided Molecular Mechanics

Abstract

A new transition state force field has been developed for the AD reaction, purely from quantum mechanical reference data. A new methodology was used for converting quantum mechanical normal modes into a form suitable for parametrization. The force field has been thoroughly validated by comparison to structural and energetic data, and by prediction of experimental enantioselectivities. Excellent agreement was observed, frequently within a few percent of the experimental enantioselectivity. The interactions responsible for enantioselectivity have been identified and compared to the Sharpless and Corey models.

Phenyl versus Ethyl Transfer in the Addition of Organozinc Reagents to Aldehydes: A Theoretical Study

“…[20] A full computational analysis of the selectivity should include both the aromatic aldehyde and ligand 1 in the calculation. However, such an analysis at the DFT level is still beyond our computational resources.…”

“…However, such an analysis at the DFT level is still beyond our computational resources. We plan to address the selectivity issue further by Q2MM [20,21] or QM/MM [14c-e] calculations. With regard to the selectivity, we know from experimental studies that for most aldehydes, the ee values obtained with only Ph 2 Zn and ligand 1 is lower than when the Ph 2 Zn/Et 2 Zn mixture is employed.…”

Development of a Q2MM Force Field for the Silver(I)‐Catalyzed Hydroamination of Alkynes

“…Transition state force fields derived by the Q2MM method have been successful in rationalizing and predicting the experimentally observed stereoselectivities for a number of reactions. [8] Many biologically important compounds contain nitrogen heterocycles. [9] The synthesis of these heterocycles is therefore of particular interest.…”

Asymmetric Dihydroxylation of 2‐Substituted 1‐Vinylferrocenes: The First Non‐Enzymatic Kinetic Resolution of Planar‐Chiral Ferrocenes

“…Theoretical calculations on the AD of styrene and of stilbene show that in the TS the phenyl and the alkene moieties present a coplanar geometry. [11] We reasoned that a similar coplanarity requirement should be operative in the AD of vinylferrocenes. If this is the case, the presence of a bulky substituent adjacent to the vinyl group would strongly destabilize one of the two limiting planar conformations of the molecule, so that for a given enantiomer of a 2-substituted 1-vinylferrocene one face of the olefin would be much more reactive than the other (see Figure 1).…”

“…[11,21] c) Apart from its interest on a mechanistic level, the process may be of preparative value, since it allows the direct access, from relatively inexpensive starting materials, to new planar-and central-chiral ferrocene derivatives, with high degrees of stereochemical control. Finally, the present findings pave the way to the discovery of other non-enzymatic catalytic kinetic resolutions of planar-chiral ferrocenes, an issue that is being currently addressed in our laboratory.…”