Total Synthesis of a Dimeric Thymol Derivative Isolated from Arnica sachalinensis

Abstract

The total synthesis of a dimeric thymol derivative (thymarnicol) isolated from Arnica sachalinensis was accomplished in 6 steps. A key biomimetic Diels–Alder dimerization was found to occur at ambient temperature and the final oxidative cyclization occurs when the substrate is exposed to air and visible light. These results indicate that this natural product is likely the result of spontaneous (non‐enzyme‐mediated) reactivity.

Total Synthesis and Prediction of Ulodione Natural Products Guided by DFT Calculations**

“…There are two [ π 4 s + π 2 s ] transition states that can lead to the formation of each cyclohexene adduct A – D (Scheme 3a; TS label indicates which structures could form, i.e., TS X/Y could lead to structures X and Y ). For example, cyclohexene A (i.e., (±)‐ulodione A) could form through a C 2 ‐symmetric bis‐pericyclic TS ( TS A ) or through a bifurcating ambimodal TS ( TS A/G ) [8c, 13] . The calculated barriers were found to be significantly lower for transition states involving the α‐alkene as the dienophile, to give cyclohexenes A and B , compared to when the β‐alkene acts as the dienophile, to give cyclohexenes C and D (Scheme 3a).…”