24 (-)-Conophyllineの全合成(口頭発表の部)

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(-)-Conophylline (1), a bisindole alkaloid constituted of highly oxygenated vincadifformine-tabersonine moieties, was isolated from Tabernaemontana divaricata in 1992. It was shown to possess a potent inhibitory activity of ras function. The interesting biological activities coupled with the unique structural features have attracted our attention as a synthetic target. Herein, we report a convergent total synthesis of (-)-conophylline (1) utilizing a regio- and stereoselective coupling of the upper unit 5 and the lower unit 4 as a key reaction. The synthesis of the lower unit 4 is shown in Schemes 2-5. The Key indole intermediate 13 was synthesized through our tin-mediated indole formation from isocyanide 11, which was readily prepared from a commercially available benzoate 7 in a 11-step sequence including monoprotection of phenolic hydroxyl groups, nitration, Wittig reaction, and conversion to isocyanide. The 2-stannylindole, obtained by the radical cyclization was converted to 2-iodoindole 12 by immediate treatment with iodine and reduction of the ester group. Finally, installation of the methyl acrylate moiety and manipulation of protective groups provided the key indole unit 13. The alcohol 13 thus obtained was coupled with 14 by Mitsunobu reaction to give the desired protected secondary amine 15. The crucial construction of aspidosperma skelton was executed by sequential reactions including deprotection of Boc group, cleavage of DNs, and cyclization under heating to furnish compound 18. Dehydration of 18 gave tabersonine derivative 19, which was then converted to the lower unit 4 by protection of nitrogen with Troc group followed by stereoselective epoxidation according to Szantay's procedure. On the other hand, the upper unit 5 was readily synthesized from 21, which was a key intermediate in our (-)-vindoline synthesis, according to the above synthetic route to 4. With both the upper and the lower units in hand, we next focused on the coupling of these units by Polonovski-Potier reaction. We found that upon treatment of the N-oxide 23 with TFAA, generation of iminium salt 24 and subsequent nucleophilic addition of the upper unit 5 occurred regio- and stereoselectively to give the desired coupling compound 25 as a single isomer. The characteristic dihydrobenzofuran moiety was constructed efficiently via the cleavage of the allyl group followed by intramolecular 5-exo ring closing reaction. Finally, the mesyl and Troc groups were removed with LDA to complete a total synthesis of (-)-conophylline (1). In the same manner, we have completed a total synthesis of (-)-conophyllidine (2) as well. As an alternative route to access the key intermediate 21, we have developed a 9-step sequence starting from natural (-)-vindoline (29) in 27% overall yield. We believe that these synthetic pathways should be amenable to the synthesis of a wide variety of conophylline analogs.
天然有機化合物討論会の論文
2007-08-24

24 (-)-Conophyllineの全合成(口頭発表の部)

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