Pericyclic reactions are important class of chemical reaction because they occur stereospecifically often with a high degree of regio-, stereoselectivity, and atom economy. This dissertation summarizes our efforts – using chemical computations – to better understand how these reactions occur in both biological and abiological settings.
This dissertation is divided into two portions; the first of which describes quantum mechanical studies of biosynthetic and enzyme-catalyzed cycloadditions. Chapter 1, 2, and 3 detail studies of these enzymatic processes. Using state-of-the-art density functional theory, we have determined whether these reactions are feasible biosynthetic transformations, elucidated the mechanistic subtleties of these reactions, and proposed how enzymes may catalyze such transformations.
Chapter 1 describes a computational study of a strained biosynthetic transannular 1,3-dipolar cycloaddition. Computations reveal that substrate preorganization overrides distortion in the transitions, resulting in a reaction is feasible. Efforts to account for the influence of water – through solvent-solute hydrogen-bonding interactions – were modeled using “mircosolvated” reactant and transition states: We conclude that the reaction remains feasible in aqueous media. Strategic hydrogen bonding, according to theory, can accelerate the reaction by 2000-fold.
Chapter 2 summarizes a computational investigation of the Diels-Alder reaction involved in the biosynthesis of spinosyn A. We find that the mechanism of this transannular cycloaddition is “ambimodal”, proceeding through a “bis-pericyclic” transition structure that leads directly two products, the observed Diels-Alder adduct and an unstable [6+4] adduct. This [6+4] adduct can readily and irreversibly rearrange into the Diels-Alder adduct via a Cope rearrangement. Simulations of the reaction mechanism determine that the nonenzymatic cycloaddition occurs predominantly via a mechanism that involves the intermediacy of the [6+4] adduct.
Chapter 3 discusses an ongoing collaboration with the Tang laboratory at UCLA and involves an effort to understand the intramolecular Diels-Alder reaction involved in the biosynthesis of cholesterol-reducing agent, lovastatin. We have modeled the reaction of a related cycloaddition performed experimentally, and computations recapitulate the selectivity observed experimentally for this nonenzymatic process. The stereochemical outcome of the enzymatic reaction diverges from the outcome of its synthetic analogue. Computation of the reactive conformer of the model substrate suggests that substrate preorganization could accelerate the intramolecular Diels-Alder reaction by approximately a 1000-fold.
Theoretical studies of stereoselective electrocyclic reactions are described in Chapters 4, 5, 6, 7, and 8. These reactions have been examined by experimentally by chemists in the laboratory and, subsequently, have been modeled using quantum mechanical computations. From this computational work, we have determined the stereoselectivity of several synthetically relevant electrocyclic reactions, the effect of substituents of the reactivity of the electrocyclization precursors.
In Chapter 4, we summarize our work with Dr. Gregg Barcan and Prof. Ohyun Kwon to elucidate the origins of 1,6-stereoinduction of a triene electrocyclization employed in their total synthesis of reserpine. We determine that conformational transmission of the stereochemical information found at a distal stereocenter is “transmitted” to the forming stereogenic center via A1,3 strain. Allylic strain destabilizes the disfavored mode of ring closure. According to both theory and experiment, stereoselectivity is shown to be sensitive to the size of the substituent involved in the A1,3 strain.
Chapter 5 outlines a computational investigation of the 8π-6π electrocyclization cascades of substituted tetraenes, such species are common intermediates in the biosyntheses of many natural products containing bicyclo[4.2.0]-octadiene ring systems. These cascades reaction occur spontaneously in a growing number of natural products. Here we determined the influence terminal substitution on the reactivities, thermodynamics, and stereoselectivities of these reactions. Terminal substituents destabilize the tetraene precursor and the resulting 8π electrocyclization product. Strain relief drives and promotes the subsequent 6π electrocyclization. Where possible, the diastereoselectivity of this cascade is controlled by a steric effect that destabilizes the endo mode of electrocyclic ring closure.
Chapter 6 reviews a density functional theory study of a series of torquoselective triene and Nazarov electrocyclizations of bridged bicyclic substrates. We find that the torquoselectivities of highly exo selective ring closures are controlled by action of torsional effect that acts in concert with either steric attraction or repulsion. In one case, a Nazarov cyclization, a through space orbital interaction overrides this exo selectivity.