Abstract
Isodehydrothyrsiferol, one of the possible structures of which was shown as 1, was isolated from the red alga Laurencia viridis by Norte et al. in 1996 (Scheme 1). The plane structure of isodehydrothyrsiferol and the relative configuration of the D-ring were determined by the NMR analysis. The stereostructure of the A,B,C-ring system was elucidated by comparing the NMR data with those of dehydrothyrsiferol (2), isolated from the red alga Laurencia pinnatifida by Martin et al. in 1984. However, the stereochemical relationship between the A,B,C- and the D-ring systems due to the intervening methylene chain and the absolute configuration have never been determined. Both of isodehydrothyrsiferol and 2 exhibit cytotoxic activity with IC_<50> = 0.01 μg/mL against murine leukemia P388. To determine the entire stereostructure of isodehydrothyrsiferol, we embarked on the total synthesis. We planned convergent strategy that united the common B,C-ring system 4 with the D-ring 5 or 6 by Suzuki-Miyaura cross coupling (Scheme 1). The common B,C-ring system 4 was constructed from the known epoxy alcohol 10^4 through two 6-exo oxacyclizations of appropriate epoxy alcohols (Scheme 2). After hydroborating D-ring 22, prepared as shown in Schemes 3 and 4, with an excess of 9-BBN, Suzuki-Miyaura cross coupling with triflate 4 in the presence of LiCl and Ph_3As^<12> afforded a coupling product 23 in 66% yield (Scheme 4). Removal of protective groups and subsequent 6-endo bromoetherification gave target molecule 1, ^1H and ^<13>C NMR spectra of which were inconsistent with those of natural isodehydrothyrsiferol. Another possible diastereomer 25 was synthesized from ent-22. ^1H and ^<13>C NMR spectra of synthetic 25 was identical to those of natural isodehydrothyrsiferol except for a sign of the optical rotation. Thus, it was found that the entire stereostructure of natural (+)-isodehydrothyrsiferol is shown as ent-25 including the absolute configuration. We have also achieved the total synthesis of dehydrothyrsiferol (2) and 15(28)-anhydrothyrsiferyl diacetate (3).
