Towards the Perfect Marriage Between Theory and Experiments in Drug Discovery and Synthesis : Insights into Structure Determination of Complex Natural Products and Mechanistic Understandings of Lactam Synthesis Public Deposited


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  • In this report, three studies are presented that aid in the development of drug discovery and their synthesis. In each, the importance of the marriage between computations and experiments is highlighted. Continued efforts in this vein are essential for future efforts towards improving human health. The first case study investigated the effectiveness of computational tools in determining relative configurations of complex molecules, using natural products mandelalides and coibamide A, towards a generalized recipe for the scientific community at large. Ultimately, continuing efforts in this vein will accelerate and strengthen relative structure elucidation of complex molecules, such as natural products. Molecular mechanics conformational search, quantum mechanical nuclear magnetic resonance (NMR) chemical shift predictions, and DP4 analyses led to the revision of relative configurations of mandelalides A-D and coibamide A, reaffirming recent reports from total syntheses. All chiral centers in the northern hemisphere of mandelalides A-D are inverted with respect to the originally proposed structures, in agreement with recent total syntheses of mandelalide A by Ye, Fürstner & Carter. In the case of coibamide A, it was found that the computed and experimental ¹H and ¹³C NMR spectra of Fang & Su's revised structure, in which both the macrocycle [MeAla¹¹] and the side chain [HIV²] residues are inverted from L to D, was consistent with the spectra of the authentic natural product. In the second study, Shaw and coworkers reported the synthesis of 2- piperidinones in a single step from imines and 2-cyano glutaric anhydrides. The reaction provides the products in good diastereoselectivity and generates a quaternary stereogenic center. Substitutions on the anhydride skeleton are well tolerated to provide 2-piperidinones with three stereogenic centers from a single transformation. The pertinent transition structures have been computed using quantum mechanics, and we reveal the key interactions controlling the stereochemical outcome of the reaction. In the final study, the mechanism of a four-component reaction (4CR) involving aldehydes, maleic anhydrides, thiols and primary amines to form trisubstituted gamma lactams is presented. Computations reveal that the 4CR reaction proceeds by a base-catalyzed thiol-anhydride pathway, followed by an in situ acid-catalyzed formation of an imine and an anhydride. Finally, a stepwise Mannich-acylation mechanism leads to γ-lactam. The rate determining step (RDS) involves loss of water to form the imine, crucial for the Mannich-acylation process. The RDS is verified by agreement between experimental and computed natural abundance kinetic isotope effects (KIEs). Computations also show that the resting state is a complex of the amide/acid isomer and the in situ acid as shown earlier by the Shaw group. The in situ acid is essential to catalysis for this entire process. These discoveries could shed light on the understanding of the mechanisms for other related multicomponent reactions such as the Biginelli and Ugi reactions.
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