Kosho Makino

<p> Macrocyclic bisbibenzyls are natural products that occur mainly in liverworts and feature two bibenzyl structures double-linked by ether bonds and/or biaryl bond. It is known that macrocyclic bisbibenzyl compounds exhibit a variety of biological activities, and thus their intriguing structures and biological activities have made them attractive synthetic targets. We have continued synthetic studies on macrocyclic bisbibenzyl compounds by an independent strategy using Pd-catalyzed macrocyclization. In this symposium, we report the synthesis of riccardin C (1), asterelin A (2), and cavicularin (3). </p><p> A boronic ester 18 was prepared from commercially available compounds 11 and 12 over 9 steps, and the intramolecular Suzuki-Miyaura reaction of 18 was examined for macrocyclization of 18. As a result, macrocyclic 19was obtained in 48% yield by using 10 mol % Pd<sub>2</sub>(dba)<sub>3</sub>, 20 mol % SPhos, 3 eq Na<sub>2</sub>CO<sub>3</sub>, and then 19 was treated with BBr<sub>3</sub> in CH<sub>2</sub>Cl<sub>2</sub>to give rise to riccardin C (1). Next, we focused on the synthesis of asterelin A (2) and cavicularin (3). The dibenzofuran of 2 would be formed through an intramolecular oxidative coupling of riccardin derivative 4. Oxidative coupling using VOCl<sub>3</sub>as an oxidant<sub> </sub>formed the dibenzofuran in 58% yield to accomplish the synthesis of 2 followed by demethylation. On the other hand, construction of dihydrophenanthrene moiety in 3 was examined by applying Pd-catalyzed Ar-Ar coupling to iodinated compound 5. We were pleased to find suitable reaction conditions such as 20 mol % Pd(OAc)<sub>2</sub>, 20 mol % n-Bu<sub>3</sub>P and Ag<sub>2</sub>CO<sub>3</sub>in DMF, giving rise to dihydrophenanthrene 27in 50% yield. Finally, treatment of 27 with BBr<sub>3</sub> completed the synthesis of 3. Furthermore, control of biaryl chirality in 3could be made possible by using chiral bidentate ligands for this Pd-catalyzed Ar-Ar coupling reaction.</p>