11 ネオビブサニン類の合成研究(口頭発表の部)

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Neobivsanins A (1) and B (2), novel tricyclic bistetrahydrofurans isolated from Viburnum awabuki, have been proved to enhance neurite-outgrowth of NGF-mediated PC12 cells by our group, and thus these are regarded as a seed compound to develop therapeutic agent for treatment of neurodegenerative disease such as Alzheimer disease. Therefore, we have launched synthetic study of neovibsanin A (1) and B (2), and its derivatives. Our synthetic plan is shown in Scheme 1. Tricyclic lactone 3 would be set up as the precursor of 1 and 2 or its derivatives and expected to be formed via succesive oxy-Michael addition and lactonization of 4. In order to construct three consecutive stereogenic centers of 4, the stereoselective alkylation and the regioselective intramolecular Diels-Alder reaction of tetraene 7 were envisaged. The intramolecular Diels-Alder reaction of 7, which was synthesized form geraniol in 3 steps, proceeded by heating to 200℃ in DMI for 3h to give lactone 6 in good yield. After conversion of lactone 6 into 11 via Baylis-Hillman reaction using triethylphosphine as a catalyst, alkylation of the resulted 11 with lithium ethyl propiolate afforded a mixture of 12a and 12b (1.3:1). By the treatment of reduced product of 12b with TBAF, successive oxy-Micael addition and lactoniaztion took place cleanly, giving rise to tricyclic lactone 15 in good yield. After deprotection of MOM group and TBS protection of the alcohol, the resulting 16 was treated with Tebbe reagent, and followed by a solvolysis of the enol ether with PPTS in methanol, leading acetal 17. TBS ether of 17 was removed with TBAF, and the resulting alcohol was oxidized with SO_3-pyridine, giving rise to unstable aldehyde 18 in 90% yield. Finally, a trapping lithium enolate prepared by treatment of 18 with KHMDS with 3,3-dimethylacryloyl chloride led to the complete syntheses of (±)-4, 5-bis-epi-neovibsanin A (19) and (±)-(8Z)-4, 5-bis-epi-neovibsanin A (20) in 90% yield (19/20 1:1). Furthermore, our synthetic procedure could be successfully applied to the preparation of a number of derivatives (31-39), and then the studies of structure activity relationships were carried out As results, it was revealed that 10μM of (±)-4, 5-bis-epi-neovibsanin A (19) promoted effectively neurite-outgrowth of NGF-mediated PC12 cells, comparable with neovibsanin B (2). Compounds 29-39 showed also activity, whereas lactone 29, bicyclic 31, and 37 and 38, which have longer side chains than propyl group at the acetal position, were found to be inactive.
2008-09-01

11 ネオビブサニン類の合成研究(口頭発表の部)

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