Despite efforts over the past three decades, efficient synthesis of 4,5,6,7,8-pentasubstituted coumarins, particularly those bearing a geranyl group at the sterically hindered C-6 position, remains a significant challenge. In this study, we describe the first total syntheses of 4,5,6,7,8-pentasubstituted geranylated coumarins, Kayeassamin A (1) and Mammeasin A (2), achieved via a strategically designed synthetic route. Specifically, a key boronic ester intermediate (21) was obtained through water-promoted Miyaura borylation, followed by Suzuki-Miyaura cross-coupling of 20 with 21 and subsequent intramolecular lactonization, which facilitated the efficient construction of the 8-acyl-substituted 4,5,7,8-tetrasubstituted coumarin core (29). Furthermore, a Lewis acid-mediated 1,3-rearrangement of the 7-O-geranyl derivative 44, prepared from 29, enabled the migration of the geranyl group from the C-7 oxygen to the sterically congested C-6 position, establishing a key transformation for the total syntheses of compounds 1 and 2. This study provides a practical and versatile synthetic strategy for accessing sterically congested geranylated coumarins.
Takashima et al. (Thu,) studied this question.