48(P05) ドリマン型セスキテルペノイド,ニオペタールEの全合成(ポスター発表の部)

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Six novel drimane sesquiterpenoids, mniopetals A-F, were isolated from the fermentation broth of Mniopetalum sp. 87256 and their relative configurations were determined by Steglich and co-workers in 1994. These natural products inhibit RNA directed DNA polymerases (reverse transcriptases ) of some RNA viruses, such as human immunodeficiency virus (HIV)-1. The structural characteristics of mniopetals are (1) a tricyclic framework including a trans-fused octahydronaphthalene skeleton, (2) five or six contiguous stereogenic centers, one of which is quaternary, and (3) a variety of oxygenated functionalities containing a γ-hydroxy-γ-lactone moiety. To establish their unsettled absolute stereochemistries, we have been engaged in enantiospecific synthetic studies of mniopetal E and mniopetal F, the former is prototype of mniopetals A-D, and the hydroxy group at C-2 in mniopetal E lacks in the latter. We have accomplished the first total synthesis of mniopetal E in natural enantiomeric form. We disclose the details of our total synthesis. The known triol 13 and diol 14, prepared from D-mannitol with high stereoselectivity using the Sharpless asymmetric epoxidation, were selected as the starting compounds. The construction of the gem-dimethyl group was achieved by a Wittig reaction followed by the α-methylation. The diene and dienophile moieties were introduced by inter- and intramolecular Horner-Emmons reaction eventually leading to trienes (22, 24, 26, 27 and 29). The intramolecular Diels-Alder reactions of these substrates were carried out under thermal conditions, and all reactions proceeded in endo mode to afford two trans-fused octahydronaphthalene skeletons stereoselectively. As anticipated, the desired 30-A and 31-A (for the synthesis of mniopetal E) were obtained as major products. However, the reverse π-facial selectivity was observed in the cases of the trienes 26, 27, 29 (for the synthesis of mniopetal F). These stereochemical outcomes were explainable by secondary orbital interaction and 1,3-diaxial repulsion generable in each transition state. The transformation of the cycloadduct 31-A into mniopetal E was achieved as follows. The 1,3-dithiolane part was converted to a dimethyl acetal providing 35. After oxidation of the γ-lactone ring, reduction of the resulting γ-hydroxy-γ-lactone 36 with DIBAL-H provided dialdehyde hydrate 37. Treatment of 37 with 1N HCl solution gave a tetracyclic compound 38, and the resulting hemiacetal moiety was oxidized with DMSO in acetic anhydride. Finally, lactone 39 was treated with 6N HCl solution to hydrolyze all the protecting groups accompanied by a double bond migration to provide (-)-mniopetal E (5). The ^1H NMR spectrum of the synthetic 5 was well matched with that reported for natural 5. Also, the optical rotation of the synthetic 5 led the conclusion that the absolute stereochemistry of the natural 5 is that as depicted.
天然有機化合物討論会の論文
1999-09-01

48(P05) ドリマン型セスキテルペノイド,ニオペタールEの全合成(ポスター発表の部)

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