18 エンジイン化合物(ネオカルチノスタチン-クロモフォア、ダイネミシンA)の合成及びそのDNA切断活性(口頭発表の部)

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Neocarzinostatin chromophore (NCS-Chr., 1) and dynemicin A (2) are antitumor antibiotics that have unique structures and fascinating mode of action. These molecules inspire new strategy for the construction of the highly strained enediyne structures and novel design of the compounds to probe and mimic their chemical and biological actions. Here, we wish to report the syntheses of the NCS analogue 6 and the dynemicin analogue 27. In our synthetic plan, the key reaction for the synthesis of NCS analogue 6 is the transannular [2,3]-Wittig rearrangement of 12-membered cyclic ether 7. which allows the construction of highly strained 9-membered diyne 20. The stereoselectivity and reactivity of the Wittig reaction are predicted by MM2 transition structure model. Palladium catalyzed reaction of vinyl epoxide 11 is applied to the stereoselective introduction of the trans hydroxy groups on 5-membered ring which increase the solubility in water. The NCS analogue 6 with a phthalic acid triggering device is sufficiently stable at ambient temperature to allow it handling and shows strong DNA cleaving activity. Our strategy for the synthesis of the dynemicin analogue 27 consists of three key reactions; 1) intramolecular Diels-Alder reaction of 31 to construct the stereochemistries among C-2, C-4 and C-7, 2) cyclization of bromohydrin 30, 3) transannular [2,3]-Wittig reaction of the ether 29 to obtain the 10-membered enediyne skeleton. The stereoselectivity and reactivity of these three reactions are predicted based on molecular mechanics calculation and/or MM2 transition structure model.
天然有機化合物討論会の論文
1993-09-10

18 エンジイン化合物(ネオカルチノスタチン-クロモフォア、ダイネミシンA)の合成及びそのDNA切断活性(口頭発表の部)

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