49(P07) ムスカリンM_2サブタイプレセプターアンタゴニスト(+)-ヒンバシンの全合成(ポスター発表の部)

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(+)-Himbacine (1), which is a piperidine alkaloid isolated from the bark of Galbuliminza Bacrata, bears a charactaristic structural feature in which the tricyclic part, consisting of cis-fused γ-lactone and trans-fused decaline moieties, is connected with trans-disubstituted piperidine via an (E)-double bond. It is reported that 1 behaves as a potent antagonist of the muscarinic receptor of M_2 subtype with 20-fold selectivity toward the M_1 receptor. Thus, blockage of the presynaptic muscarinic receptor of M_2 subtype leads to an elevation of the synaptic levels of acetylcholine, possibly offsetting some of the losses in the cholinergic system that occurs in Alzheimer' s disease. The two total syntheses of 1 have hitherto been achieved by employing an intramolecular Diels-Alder reaction as the key step. In order to disclose novel aspects of the structure-activity relationships of 1 and, moreover, to explore the promising congeners of 1 which may show more improved M_2 subtype selectivity, an efficient synthetic route to 1 was sought which is more convergent and flexible than those reported. Aiming to make the synthesis of variety analogues of himbacine possible, our synthetic route to 1 was designed by employing the intermolecular Diels-Alder reaction of the tetrahydroisobenzofuran 5 with the chiral butenolide 6 as the key step. It is generally accepted that an intermolecular Diels-Alder reaction is more convergent and flexible than an intramolecular one, especially for the synthesis of complex natural products. After experimentation, we found that the expected intermolecular Diels-Alder reaction of 5 with 6 takes place in ether containing LiClO_4 (5M solution), giving rise to 4 as the sole isolable product. It appeared evident that, probably due to steric and electronic reasons, the intermolecular Diels-Alder reaction proceeds in a highly stereoselective and diastereoselective manner, exclusively producing the exo-adduct. Hydrogenation of the double bond in 4 was afforded the saturated compound 7. This was subjected to base-induced β-elimination of the oxygen bridge followed by double bond isomerization, affording the unsaturated alcohol 9 as the sole product. Stereoselective catalytic reduction of 9 over PtO_2 smoothly gave the saturated tricyclic alcohol 10a. Thus, stereoselective construction of the decahydronaphtho[2,3-c]furan system involved in 1 was readily furnished in 4 steps from the Diels-Alder exo-cycloadduct 4. After the lactone carbonyl group in 10a was protected, the hydroxy group in the acetal 11 was oxidized. Methylenation and sequential hydroboration and oxidation of 13 gave rise to the β-methyl alcohol 14a stereoselectively, which carried all of the desired chiral centers in the tricyclic part of 1. Next, according to the known protpcol, 14a was transformed to the sulfone 2. Following the reported procedure, 2 was finally converted to 1 in 5 steps. Physical and spectral properties of the synthetic sample of 1 were found to be identical to those reported. Following the same sequence, preparation of the enantiomer of 1 (ent-1) was accomplished starting with (-)-6. In summary, we have developed a novel synthetic route to (+)-himbacine (1), a potent antagonist of the muscarinic receptor of M_2 subtype, by employing an intermolecular Diels-Alder reaction of 5 with 6 as the key step. The explored synthetic scheme which is anticipated to be highly convergent and flexible, may be applicable to the synthesis of various structural types of the novel congeners of 1.
天然有機化合物討論会の論文
1999-09-01

49(P07) ムスカリンM_2サブタイプレセプターアンタゴニスト(+)-ヒンバシンの全合成(ポスター発表の部)

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