93(P-50) 橋頭位に窒素原子をもつ多環状天然物の簡易合成(ポスター発表の部)

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Since tacamomine (1), originally isolated from Tabernaemontana eglandulosa, is structurally related to eburnamonine (2), an activating drug for cerebral circulation, synthetic study of analogs would be attractive. Mappicine ketone (3) (=nothapodytine) has recently isolated from Nothapodytes foetida of which ethanol extract exhibits significant cytotoxity in the human KB cell line. In addition, 3 possesses potent activity against the herpes viruses HSV-1 and HSV-2 and human cytomegalovirus (HCMV). Quite recently, luotonin A (6), cytotoxic pyrroloquinazolinoquinoline alkaloid, was isolated from Peganum nigellastrum. All of above natural products (1, 3 and 6) contain a bridgehead nitrogen which might play a role in their biological activities. As a result of their biological properties, they have attracted considerable attention as targets for total synthesis. Herein we report concise syntheses of the alkaloids (1, 3 and 6). We planned to synthesize the basic skeleton (10) of tacamonine (1) by means of intramolecular double Michael reaction of the unsaturated amide ester (9). Intramolecular double Michael reaction was performed by treatment of 9 with TBSOTf-Et_3N. After the construction of the tetracyclic ring system, 10 was reduced with BH_3・THF to give rise to the amine (12). Compound 12 had already been transformed into tacamonine (1). In order to construct mappicine ketone framework in a single step, we designed novel intramolecular hetero Diels-Alder reaction of the 1-azadienyne (15). Intramolecular hetero Diels-Alder reaction of 14 was carried out in the presence of ZnCl_2-TMSCl-Et_3N to provide the tetracyclic compound 16 in good yield. This methodology was applied to the synthesis of mappicine ketone (3). Intramolecular hetero Diels-alder reaction of 19 led to the cycloadduct 20, which was treated with aqueous hydrogen bromide to furnish the ester in a single step. As it turned out, the electron withdrawing substituent group did not have a bad influence on the cycloaddition; on the contrary, it promoted the autoxidation of the corresponding cycloadduct. Finally, the product was subjected to transesterification reaction to afford 21, which had already converted to mappicine ketone (3). To demonstrate the flexibility of our protocol, we envisioned a novel one-pot generation of quinazolinone ring system by using cyano group as a Diels-Alder dienophile. Since luotonin A (6) possesses quinazolinone ring system as its partial structure, 6 was adopted as our present target molecule. As expected, heating of 24 with ZnCl_2-TMSCl-Et_3N gave luotonin A (6). As described above, we have developed concise synthetic methodologies for the construction of polycyclic natural products having a bridgehead nitrogen.
天然有機化合物討論会の論文
2001-09-01

93(P-50) 橋頭位に窒素原子をもつ多環状天然物の簡易合成(ポスター発表の部)

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