Computational Investigation and Prediction of Mechanisms and Stereocontrol in Complex Organic Reactions

Graduation date: 2016Complex organic transformations, such as the addition of pyrrole to ketene using planar chiral organocatalyst (*PPY), the four-component anhydride- Manniach reactions, and the site-selective desymmetrization of meso-1,2-diol, are remarkable synthetic reactions that provide high yield and high selectivity. However, the exact mechanism and origins of stereocontrol for theses synthetic organic reactions have so far remained elusive. For the conformational chirality, the rule to predict the chirality of the diarylether heptanoid (DAEH) natural products has not been developed. Therefore, the theme of this dissertation is to investigate atomistic and energetic details of complex organic reactions by using quantum mechanic calculations in order to understand the fundamental mechanisms and origins of stereocontrol.\ud Ultimately, the atomistic features and energetic details 1) allow for better understanding the key stabilizing interactions of ketene-*PPY enolate complex for the related reaction; 2) the development of a predictive rules that enable identification of conformational chirality DAEH natural products; 3) the design of a new reaction to access complex molecular architectures for in anhydride- Mannich reactions (AMR); and 4) the future catalyst design & expansion of the site-selective functionalization of 1,3-diols, diamines and aminoalcohol.\ud \ud Computational study of planar-chiral 4-(pyrrolidino) pyridine (PPY*) catalysis is reported. A chiral-acid resting state and a chiral-base rate- determining step are operative in the enantioselective coupling of ketenes and pyrroles. The catalyst controls the enantioselectivity via a combination of stereoelectronic effects and CH···O interactions. The former differentiates the E/Z-catalyst enolates in the transition states while the latter control the facial selectivity of the protonation.\ud \ud DAEH natural products often do not contain a stereocenter but can manifest conformational chirality. The complete structural and energetic details related to the stereoisomerizations of four such key DAEHs are reported. Computations reveal that the local symmetry of ring B and the stereochemistry of vinylogous acid/ester determine the chiral properties. A general way to predict the existence of conformational chirality in any arbitrary DAEHs that do not contain a stereocenter is also reported.\ud \ud Formal cycloaddition between cyanosuccinic anhydrides and various imines lead to efficient diastereoselective synthesis of γ-lactams. Computational elucidation of the mechanism and the origins of stereocontrol in this entire series of reactions are reported. Computations revealed that the transformation proceeds through a stepwise Mannich- acylation. The computed free energy barriers and selectivity are in agreement with experiments. The diastereocontrol arises from a combination of hydrogen bonding & CH···O electrostatic stabilizations in the Mannich and transannular steric repulsion in the acylation step. This new mechanistic picture applies to the related reactions of homophthalic anhydrides with imines and presents new vistas for the design of a new reaction to access complex molecular architectures.\ud \ud The detail study of the mechanism and the origins of stereocontrol of site- selective desymmetrization of meso-1,2-diols are reported. The computations reveal that PMP·HCl salt is a free energy driving force for this reaction. The mechanistic pathways of this transformation can be described by the relationship between the alcohol and the i-Pr of the catalyst. The syn-bound pathway is when a substrate alcohol bounds syn to i-Pr of the catalyst (vise versa for anti). We have discovered that the resting state is a syn-bound complex; where as, the rate- and stereo- determining steps involve the anti-bound substrate-binding complex. The selectivity in substrate-binding step stems from the stabilizing hydrogen-bonding interaction between the imidazole and free alcohol. The selectivity in silylation is governed by a combination of gearing effect of the liker i- Pr and the facial approach of electrophile.\ud \ud A detailed study of the mechanism and the origins of stereocontrol for the dichlorination of (Z)-allylic alcohol derivative are reported in this dissertation. Computations reveal that the reaction involves a chlorine π-complex rather than a free chloronium ion. We hypothesize that a dynamic mechanism is operative. The stereocontrol of this reaction are determined by non-classical hydrogen bonding which controls the trajectory of the chloride anion on a free energy reaction surface