The natural product colletoic acid has been identified as an inhibitor of the enzyme 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1), which participates in the biological conversion of cortisone to cortisol. A distinctive structural feature of colletoic acid is its all-carbon spirocenter. However, the spirocenter provides a substantial synthetic challenge to the drug design of derivatives of colletoic acid to regulate cellular cortisol levels. One of our laboratories [Ling, Griffith, Mitachi, and Rivas, Org. Lett. 2013, 15, 5790–5793] has employed Pd-mediated intramolecular Heck catalysis to synthesize a spirocenter-containing colletoic acid scaffold. In the current work, Density Functional Theory is compared to newly synthesized colletoic acid derivatives in order to provide a deeper understanding of stereoselectivity and electronic effects of tuning substituents and/or protecting groups, and to propose atom-level mechanisms for the overall intramolecular Heck catalysis. Unfortunately, the Heck reaction substrate has astounding conformational complexity, with tens to hundreds of conformers Boltzmann-accessible at room temperature, depending on the structure of three modifiable substituents on the colletoic acid scaffold. Does the reaction coordinate of the lowest energy Heck substrate connect with the lowest energy conformer of the catalytic product? Probing answers to this question leads to even more fascinating questions about the role of brute force and targeted sampling techniques in elucidating complicated, multistep catalytic mechanisms with computational chemistry. Our results will lead to a theoretical “scaffold” that can be used for in silico optimization of stereoselectivity and the design of promising colletoic acid derivatives.

Is an exhaustive conformational search necessary for proposing catalytic mechanisms? An investigation of intramolecular Heck catalysis in the formation of colletoic acid derivatives

253rd National Meeting (2017)

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