Summarized in this article are the syntheses of heterocyclic natural products by means of Rh-catalyzed C-H insertion reaction of diazoester. During the course of our total synthesis of (−)-ephedradine A (1) by application of Ns-strategy, we found that the Rh₂(S-DOSP)₄ mediated C-H insertion reaction was enabled to simplify the synthetic process and decided to use it for the natural product synthesis. In the synthesis of serotobenine (4), the C-H insertion precursor was efficiently synthesized by the Leimgruber-Batcho protocol and a regioselective Claisen rearrangement. The racemic nature of serotobenine (4) is suggested by the presence of p-quinonemethide intermediate 6. Enantioselective synthesis of SB-203207 (25a) was accomplished by desymmetric C-H insertion reaction of 33 for construction of a bicyclo[3.3.0] framework, stereoselective construction of sequential stereocenters of 37, novel conversion from an aldehyde to a carboxylic acid, and nitrile hydrolysis. Stereoselective synthesis of MFPA (54) was accomplished by intermolecular C-H insertion and the asymmetric center at the benzylic position of 58 permitted efficient incorporation of the three sequential stereochemistries on the pyrrolidine ring of 68. Synthesis of aperidine (70) was featured by the cis-selective construction of a dihydrobenzofuran ring of 82 utilizing by Hashimoto’s catalyst and preparation of diazoamide of 81 by Raines’ protocol.

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Serotobenine (1) was isolated from the seed of safflower by Sato and co-worker in 1985 and the structurally-related compound decursivine (3) was isolated by Fong et al. in 2002 Both of these compounds 1 and 3 are characterized by the fused polycyclic ring systems including indole, dihydrobenzofuran and 8-membered lactam rings. Although biosynthesis of both compounds would be similar, 1 existed as a racemic form and 3 was composed of an optically active form. The difference of stereochemistry also prompted us to investigate the synthetic study of these compounds. Herein, we report the total synthesis of optically active serotobenine (1). Recently we found that an intramolecular C-H insertion reaction by the combination of Davies Rh catalyse and the chiral auxiliary provided an optically active trans-2,3-dihydro-3-benzofuran derivatives efficiently. We envisioned that this method would be applicable for the synthesis of the optically active dihydrobenzofuran ring of 1. The indole derivative 9, readily synthesized by Leimgruber-Batcho's protocol was converted to 4-allylindole derivative 10 by regioselective Claisen rearrangement (Scheme 4). As shown in Scheme 5, conversion to the diazoester 15 from 10 was achieved by diazotransfer reaction. Upon treatment of 15 with achiral rhodium catalyst Rh_2(OAc)_4, the C-H insertion reaction was proceeded smoothly to afforded dihydrobenzofuran 16 in high diastereoselectivity. After the transformation to the activated ester 18, construction of 8-membered lactam ring was accomplished by after reduction of azide group. Finally, deprotection of Ts group and Bn group was carried out in stepwise manner and total synthesis of (-)-serotobenine (1) has been accomplished. We are currently investigating the stereochemical behavior of 1, according to our racemization hypothesis, as shown in Scheme I.

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【目的】ハーブサプリメント（HS）の安全・安心な利用の原点は，安全性・有効性の科学的根拠に基づく利用である。これに資するため，日本で人気の高いHS素材を調べ，その安全性・有効性の評価について日米間で比較・検討し，日本での利用状況，また情報源やその提供の問題点を探り，論考する。
【方法】売上高上位20素材を年次別（2009年・1999年），国別（日米）にリストアップし，冊子体Natural Medicines Comprehensive Databaseの2010版（NMCD）による安全性・有効性の評価を点数化し，解析・検討した。
【結果】同国間で人気のある素材は10年間を経ても大きな変化はなかった。日米で重複する素材は5～7品目あった。NMCD未収載品は，日本では両年3素材，米国では1999年に1素材あった。安全性評点には年次別・国別間に有意差はなかった。有効性評点は日米間の差が大きく，両年とも米国の評点が高く，日本のリストにはNMCDにより情報不足と評価されている素材が多かった。また，日米で重複のない素材は，重複する素材よりも全ての評点が有意に低かった。
【結論】日本で人気の高いHS素材は，NMCDの評価によると米国よりも有効性の科学的根拠が低い。日本特有の素材はNMCDによる評価を受けていない素材が多く，日本では，適正な情報提供によらずにHS素材が利用されている可能性が示唆された。日本の現状に即したデータベース構築，アドバイザリースタッフ養成等を含め，レギュラトリーサイエンスの観点からの取組みが必要と考える。

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