Rapid access to molecular complexity from bioderived 5-HMF derivatives via cascade cycloadditions

Abstract

For the first time, the transformation of biobased 5-HMF derivatives succeeded in a 2 × [4 + 2] cascade cycloaddition reaction, leading to a drastic (3–5-fold) increase in molecular complexity as a result of one synthetic step. A new approach to the use of plant biomass in organic synthesis using a cascade Diels–Alder reaction of 5-HMF dimer derivatives with alkynes has been developed. This reaction proceeds under thermodynamic control, diastereoselectively and regioselectively, providing rapid access to compounds of high molecular complexity with the same synthetic availability as previously obtained regular cycloadducts. As a concept illustration, under conditions of kinetic control, cycloadditions of two molecules of dienophiles are realized, and the resulting products, when heated, rearrange into thermodynamically more favorable cascade products. Reaction pathways were studied in detail using quantum chemical calculations to reveal major factors influencing the selectivity of the process. Discovery of a new sustainability pathway should be noted – to date, oligomeric derivatives are considered a waste of 5-HMF degradation, while the present study highlights them as a valuable material for the synthesis of nonplanar scaffolds.