Rationalization of Enantioselectivities in Dialkylzinc Additions to Benzaldehyde Catalyzed by Fenchone Derivatives

Abstract

Three (-)-fenchyl alcohol derivatives, ¿(1R,2R,4S)-exo-(2-Ar)-1,3, 3-trimethylbicyclo[2.2.1] heptan-2-ol, Ar = o-anisyl (2), 2-N-methylimidazolyl (3), 2-N,N-dimethylbenzylamine (4)¿ were synthesized, characterized by X-ray analyses, and employed as precatalysts in diethyl zinc additions to benzaldehyde. Directions and relative degrees of enantioselectivities are rationalized by QM/MM ONIOM computations of mu-O transition structure models. Enantioselectivities arise from repulsive interactions between "transferring" or "passive" alkyl groups at the zinc centers and the substituents at donor groups or the bicyclo[2.2.1]heptane moieties. These results enable predictions for ligand-tuning to improve catalyst efficiency of fenchone-based ligands in dialkylzinc additions to aldehydes.

Increasing Enantioselectivities and Reactivities by Stereochemical Tuning: Fenchone-Based Catalysts in Dialkylzinc Additions to Benzaldehyde

“…[6,11] With chelating fenchyl alcohols, variations of coordination donor functions (e.g., OMe, CH 2 NMe 2 , Scheme 2) are easily accessible; [12] this enables tuning of the stereochemical outcome of enantioselective diethylzinc additions. [13] Substituents (X, e.g., SiMe 3 ) in ortho positions of the aryl moieties (Scheme 2) should even further influence reactivities and enantioselectivities of the catalysts. [14] Scheme 2.…”

“…Table 1. X-ray crystal structural data of chelating fenchyl alcohols 1 [13] and 3 (see Scheme 2); distances in Å , angles in°H [a] Average values of four independent molecules of 1. Table 2.…”

“…Table 2. X-ray crystal structural data of fenchyl alcohols 2 [13] and 4 (see Scheme 2); distances in Å , angles in°H A comparison of the X-ray crystal structures of 2 (X ϭ H) and 4 (X ϭ SiMe 3 , Scheme 2, Figure 2) shows a small decrease of the C4-C5-C6 angle (126°in 2, 121°in 4) and a slight increase of the C6-C5-C8 angle (116°in 2 and 118°i n 4) upon trimethylsilyl substitution ( Table 2). The O2-C3-C4-C5 segment is less coplanar in 4 (49°) than in 2 (43°).…”

“…[13] Scheme 3. Synthesis and monomer-dimer equilibrium of methylzinc chelate complexes meric species and hence influences the reactivity.…”

A Priori Theoretical Prediction of Selectivity in Asymmetric Catalysis: Design of Chiral Catalysts by Using Quantum Molecular Interaction Fields

“…Since the initial pioneering theoretical analyses (MP2/6-31G*/Zn//RHF/3-21G/Zn [12] and B3LYP/6-31G*/Zn//RHF/3-21G/Zn [13] ) by Yamakawa and Noyori of the asymmetric alkylation of aldehydes, many groups have used various types of transition state calculations employing parameterized force fields (Q2MM [3c] ), semiempirical approaches (AM1, [3a] PM3 [18] ), mixed methods (RHF/LanL2DZ:UFF, [19] RHF/ LanL2DZ:MM3 [20] ), DFT, [21] and post-HF methods (MP2 [3b] ) to understand or design selective chiral catalysts. Notably, the complexity of the system, the number of relevant structures, and the presence of the zinc atom require considerable computational resources for full ab initio or DFT calculations.…”