13 アルテミシジンの合成研究(口頭発表の部)

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Altemicidin (1) was the first 6-azaindene monoterpene alkaloid isolated as a metabolite of microorganisms by Takeuchi and coworkers in 1989. In addition to its potent acaricidal activity, Altemicidin has been shown to strongly inhibit the growth of tumor cells. The first total synthesis of Altemicidin was achieved by A. S. Kende et al in 1995. The unique β-hydroxyl α-disubstituted-α-amino acid structure was an attractive feature of this molecule and prompted synthetic studies in our laboratories. Our synthetic strategy was based on the idea that key intermediate 2, with Altemicidin's azabicyclo[4.3.0.]skelton, could be constructed from amide 4 via lactam 3 by the ring expansion. In turn amide 4 could be synthesized from β-ketoester 5 wherein the tetrasubstituted carbon and the neighboring secondary alcohol could be stereoselectively installed early on in the synthesis(Scheme 1). The synthesis initiated from the treatment of α-diazo-β-ketoester 6 with rhodium acetate to afforded bicyclo[3.3.0] β-ketoester 7 in excellent yield(Scheme 2). The bicyclo[3.3.0] framework provided excellent stereochemistry for the hydroxymethylation and carbonyl reduction to furnish diol 8. Amide 9 was quickly obtained after hydroxy group protections and an ester to amide transformation. Amide 9 was converted into lactam 11 by oxidative cleavage of double bond and subsequent hemiaminal reduction. Then the activation of lactam by nosyl group and opening of lactam followed by cyclization gave cyclic enamide 13. Cyclic enamide 13 which has Altemicidin's azabicyclo[4.3.0]skelton was successfully synthesized in 13 steps from bicyclic β-ketoester 7. After the introduction of the formyl group by Vilsmeier type reaction and the removal of nosyl group, the methylation smoothly occurred(Scheme 3). Deprotections followed by Curtius rearrangement gave oxazolidinone 16. Alcohol 17, oxazolidinone opening product, was obtained from the Boc imide under hydrolysis conditions. Like this, we succeeded in the introduction of the nitrogen into the tetrasubstituted carbon and formylation after the construction of the basic skelton. Final transformations toward the natural product are currently under investigation. Importantly, the synthesis of optically active Altemicidin has also been examined. In our laboratories, it was found out that the combination of chiral rhodium catalyst and chiral auxiliary derived from lactic acid gives high diastereoselectivity for C-H insertion reactions(Scheme 4). Applying this method to α-diazo β-ketoester 6, the C-H insertion reaction proceeded to give β-ketoester 21 with good diastereoselectivity. The determination of the absolute configulation and the application to total syntesis of Altemicidin is now under investigation.
天然有機化合物討論会の論文
2005-09-15

13 アルテミシジンの合成研究(口頭発表の部)

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