Theoretical Studies On The Stereoselectivities In The Enantioselective Reductions Of Prochiral Ketones Catalyzed By Oxazaborolidines

Semiempirical method AM1 and density functional theory (B3LYP/6-31G*) were used to study six enantioselective reductions of four prochiral ketones catalyzed by five 1,3,2-oxazaborolines. The stereoselectivities of the reductions were analyzed with the differences between the activation energies forming R and S enantiomers in the stereo-controlling step. The optical activities of the final products were computed with the enthalpies and entropies of the (R) and (S)- transition states in the step. The results are in well consistent with the experimental values.First, the enantioselectivive reductions of phenyl ethyl ketones and p-chlorophenyl ethyl ketones catalyzed by two (R)-1,3,2-oxazaborolidines and two (S)-1,3,2-oxazaborolidines, respectively, were studied with AM 1 method. The reaction heat of each step and the activation energy of the stereo-controlling step were obtained. It was found that step I and III in the CBS mechanism are exothermic, while step II and IV are endothermic, and the reaction heat of step IV is much higher than that of step II. The predicted chiralities and optical activities of the fina products are in agreement with the experimental results. The (R)-1,3,2-oxazaborodine with (CH3)3C(CH2)5 group at position 4 is a better catalyst than the one with (CH3)3C(CH2)2 group at position 4. The PhO derivative of (S)-l,3,2-oxazaborodine as the catalyst can ir.crease the stereoselectivity of thereduction.Secondly, DFT (B3LYP/6-31G*) method was applied to study the enantioselective reduction of 3-morpholin-4-yl-l-propane catalyzed by (5)-4-beneyl-5, 5- dipheynl -1, 3,2-oxazaborodine. The optimized structures of all the molecular species, involved in the reaction, were obtained. The catalyst-alkoxyborane adduct formed in step III exhibits aB-O-B-N tetra-atomic ring. Reaction coordination ejaculations show that BHa can react with aminoketone spontaneously, which theoretically explains the experimental fact that 2mol BHa was needed in the reaction.Finally, AMI method was used to study the stereoselectivities of the reductions of a-and p-amnioketones catalyzed by (S)-4-benzyl-5,5-iiphenyl-l,3,2-oxazaborolidine. The optimized structures of R and S configurations and their thermodynamics data such as enthalpies and entropies of the transition states in the stereo-controlling step have been obtained from the reaction coordinate calculations. The calculated optical activities (e.e. values) of the final products in the enantioselective reductions are in good agreement with the experimental results. The p-amnioketone gives better stereoselectivities than its a-analog, because the difference of entropies of (R) and (5)- transition states in thestereo-controlling step in the reduction of p-amnioketone is much higher than that in the reduction of its a-analog.