Insights into Endo/Exo Stereopreference in Diels-Alder Cycloadditions of Chitin-Derived Furans

Chitin represents an abundant source of nitrogenous polysaccharides, making it a suitable feedstock for organonitrogen platform chemicals. In particular, furanic compounds, such as 3-acetamido-5-acetylfuran (3A5AF), can be readily obtained. Furans can be further functionalized using a Diels-Alder (DA) cycloaddition with a variety of dienophiles. Herein, we report on the DA of 3A5AF, dihydroxyethyl acetamidofuran (Di-HAF), and several derivatives, with maleimide dienophiles. The formation of exo and endo isomers was monitored in detail, and reactivity trends were established experimentally. Kinetic modeling allowed us to establish a reaction network that included a hydration side reaction involving specifically the exo isomer which affects the overall endo/exo ratio of the reaction. Carbonyl and alkyl hydroxyl substituents on the furans changed the DA rate significantly and shifted the selectivity from the exo to the endo product. Density functional theory (DFT) calculations revealed that the presence of a hydroxyl group leads to a thermodynamically favored endo isomer, evidenced by a decreased ΔG_endo. Stronger hydrogen bonding interactions and van der Waals interaction in HMFA-involved TS are responsible for its lower ΔG^⧧ values as evidenced by noncovalent interaction analysis, probably promoting the cycloaddition rate in the HMFA case. The activation strain model revealed that a faster cycloaddition rate can be attributed to lower interaction and distortion energies in the HMFA case. Additionally, it is the orbital interactions and electrostatic attractions that favor the endo addition in the HMFA case, while easier structural distortion possibly causes the exo selectivity for 3A5AF. These findings aid the development of synthetic strategies for complex chiral skeletons containing compounds based on chitin-derived building blocks.