26 海洋アルカロイドLepadin A、B、Cの全合成(口頭発表の部)

抄録

Lepadin A (1) isolated from the tunicate Clavelina lepadiformis represents the first example of a decahydroquinoline alkaloid from a marine natural source. Subsequently, the closely related compounds, lepadins B (2) and C (3), along with lepadin A have been found in the flatworm Prostheceraeus villatus and its tunicate prey C. lepadiformis. Both lepadins A (1) and B (2) have been shown to exhibit significant in vitro cytotoxicity against human cancer cell lines. We report here the first synthesis of (-)-lepadins A and C, as well as a new synthesis of (-)-lepadin B. The key feature involves the use of a stereoselective intramolecular hetero-Diels-Alder reaction of an N-acylnitroso compound and a Suzuki-type cross-coupling reaction for elaboration of the octadienyl side chain. Upon treatment of the chiral hydroxamic acid 15, prepared from enantiopure 2,4-O-benzylidene-2,4-dihydroxybutanal (8) as a C_3 chiral synthon, with Pr_4NIO_4 under the aqueous conditions, the in situ generated acylnitroso compound 16 was subjected to intramolecular Diels-Alder reaction to yield the trans-oxazinolactam 17 in a stereoselective manner. Subsequent hydroxylation at C-7 by Davis methodology and introduction of the methyl group were achieved by means of a tandem Grignard reaction-NaBH_3CN reduction in a highly stereocontrolled manner. The oxazine 20 thus obtained was converted to the common key intemediate 35 via transformations involving intramolecular aldol condensation of the keto aldehyde 26, epimerization at the C-5 stereocenter, hydroxyl-directed hydrogenation of the octahydroquinoline 32, and Takai olefination of the aldehyde 34. Subsequent elaboration of the octandienyl side chain was achieved by palladium-catalyzed Suzuki-type cross-coupling reaction between 35 and the alkenyldihydroxyborane to afford the coupling products 36 or 39, which was converted into (-)-lepadin A (1) and (-)-lepadin B (2), or (-)-lepadin C (3), respectively.