抄録
Prorocentin, isolated from dinoflagellate Prorocentrum lima by Lu et al., exhibits inhibitory activity against some human cancer cell lines [IC_<50>: 16.7μg/mL (DLD-1); 83.67μg/mL (RPM17951)] and possesses an unique polyether structure, characterized by a [6,6]-spirocyclic acetal fused with an oxane ring (BCD-ring), an epoxide (A-ring), a five membered ether (E-ring) and a side chain including a conjugated triene group. Although the absolute configuration of prorocentin has not yet been determined, its biological and structural features make it an attractive synthetic target. Thus,a project toward the total synthesis of prorocentin aiming at determination of the absolute stereochemistry has been commenced. The partial relative structure of prorocentin was proposed by Lu et al. from their intensive NMR experiments, and a possible stereostructure was also shown as 1 in their report. Therefore, we first performed the total symthesis of 1. First, the C8-C20 segment (6) was synthesized from alkyne 7 and 8 via a process including Pd-catalyzed 6-endo cyclization. Aldehyde 6 was then connected with the C21-C35 segment(5), and the resulting alcohol was transformed to 27. The intramolecular double conjugate addition reaction of 27 produced the CD-ring spiroacetal (28), which was transformed to E-iodoalkene 4. The Suzuki-Miyaura coupling of 4 with dienylborane 3 followed by the removal of TBS groups and the concomitant epoxide fromation completed the total synthesis of 1. However, the ^1H and ^<13>C NMR spectra of 1 disagreed with those of natural prorocentin. Since the large deviations of chemical shifts between them were observed in the B-ring, we conferred with Lu on the deviations and deduced structure 2, having a hydroxy group at C17 of the B-ring, as a plausible structure of prorocentin. Thus, we next achieved the total synthesis of 2. The synthetic process was almost similar to that of 1, except the preparation of the B-ring (36), which was carried out by a process involving the aldol reaction of ketone 37 and 38. Finally, compound 2 showed the same spectral properties as natural prorocentin, except the opposite sign of optical rotation, thereby concluding that natural prorocentin is the enantiomer of 2.
