Substituent Control of Peri- and Regioselectivity in Enantioselective Aminocatalyzed Cycloadditions of Tropone Derivatives

Abstract

Troponoids exhibit unique reactivity in Diels–Alder and higher-order cycloadditions, since they can partake as 2π-, 4π-, 6π-, and 8π-components, affording various peri- and regioisomers depending on both the reaction conditions and, importantly, their substitution pattern. Herein, we identify 2-cyanotropone as a promising lead substrate and demonstrate an aminocatalytic, dienamine-mediated, enantioselective [4 + 2] cycloaddition with α,β-unsaturated aldehydes providing the corresponding cycloadducts in good yields, high enantioselectivity, and moderate-to-high diastereocontrol as separable isomers. One of the cycloadducts undergoes an intramolecular aldol-type cyclization upon treatment with a reductant, generating an octahydro-2,6-methanonaphthalen-9-one scaffold. The mechanistic details of this substituent-controlled reaction were investigated by DFT studies to (i) identify a suitable troponoid substrate to unlock the anticipated reactivity; (ii) shed light on the observed regio-, diastereo-, and periselectivity; and (iii) understand the difference in enantiocontrol obtained using an aminocatalyst capable of hydrogen-bonding with the troponoid substrate to induce facial selectivity versus an aminocatalyst relying on steric bulk to achieve facial discrimination.