12 抗生物質ニオペタール類の全合成(口頭発表の部)

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Six novel drimane sesquiterpenoids, mniopetals A-F (1-6), 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 including an angular asymmetric quaternary carbon, and (3) a variety of oxygen functionalities such as a γ-hydroxy-γ-lactone ring (C ring). Thereby, to establish their unsettled absolute stereochemistries, we have been engaged in enantiospecific synthetic studies of mniopetal E and F, the former is the prototype of mniopetals A-D. In the latter, the hydroxy group at C-2 in mniopetals A-E is lacking. Recentry, we have accomplished the total syntheses of mniopetal E (5) and mniopetal F (6). The key reaction for our total synthesis of mniopetal E was the intramolecular Diels-Alder reaction of triene 21, which was prepared from known epoxide 15 as depicted in Sheme 3. Heating 21 in a toluene solution at 180℃ provided the desired 22 as the major product. This stereochemical outcome is explainable by secondary orbital interaction and 1,3-diaxial repulsion in their transition states as shown in Figure 2. The transformation of the cycloadduct 22 into mniopetal E was achieved in 6 steps via lactone 30 (Scheme 4). The ^1H NMR spectrum of the synthetic 5 was well matched with that of the reported data for natural 5. Netx, epoxide 15 was selected again as the starting material for the total synthesis of mniopetal F. From 15, the analogous reaction sequence used for mniopetal E synthesis afforded triene 33 (Scheme 5). The effect of hydroxy-protecting group at C-1 on stereoselectivity in the Diels-Alder reaction was investigated (Table 1). The reactions of silyl ethers 35-39 provided the desired cycloadducts A predominantly. The stereochemical outcome is explainable in consideration of the stereoelectronic effect of trialkylsilyloxy group, which overcomes the 1,3-diaxial repulsion as shown in TS-A (Figure 3). The total synthesis of mniopetal F was achieved from the dimethylisopropylsilyl ether 45 (Scheme 6). Deprotection of the silyl ether and acetal exchange enabled the separation of diastereomers 51 and 52. The total synthesis was achieved from 51 in the same way as described in Scheme 4. The spectral data of the synthetic 6 was also well matched with those of the reported data for natural 6. The optical rotations of the synthetic 5 and that of 6 led the conclusion that the absolute stereochemistries of these natural products are those as depicted.
2001-09-01

12 抗生物質ニオペタール類の全合成(口頭発表の部)

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