Developement of Novel Synthetic Blocks with Unique Structure and Their Application to Molecular Design of Bioactive Molecules

具有独特结构的新型合成嵌段的开发及其在生物活性分子分子设计中的应用

• 批准号: 07555285
• 负责人: EGUCHI Shoji
• 金额: $ 9.73万
• 依托单位: NAGOYA UNIVERSITY,GRADUATE SCHOOL OF ENGINEERING
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07555285/
• 关键词: radicalcyclization; [60] fullerene; pteridine; squaric acid; bridgehead olefin; nitrone; iminophosphorane; trifluoromethyl compounds; アルキニルシラン; 不斉合成; ホモアダマンテン; トリフルオロメチルアミノアルコール; ラジカル環拡大反応; 複素環縮合フラーレン; 酸化的[2+3]環化付加; トリフルオロメチル含窒素複素環

In this project, some selected compounds with unique ring structures such as adamantane, fullerene, and squaric acid after appropriate functionalization have been shown to be useful novel synthetic blocks for molecular design of bioactive molecules including some natural products. The outline of he research results are summarized below :(1) Developement of synthetic methods of functionalized carbo- and heteropolycycles : Homoadmant 3-enes conjugatively stabilized by 4-phenyl or -methoxycarbonyl group have been shown to be useful as novel building blocks. N-(2-Substituted phenyl) iminophosphosranes have been applied successfully to total synthesis of bioactive natural products such as Vascinone and Benzomalvin A etc. N-(2-Heteroaryl) iminophosphoranes have been developed as useful building blocks for synthesis of pteridinones and their analogues. New efficient routes to 5,6-dihydropyrrolo [2,1-a] isoquinolines have been developed via [3+2] cycloaddition of 3,4-dihydroisoquinoline N-oxid … More es with alkynes and allenes, followed by rearrangements.(2) Molecular design of heterocycle-containing [60] fullerenes by cycloaddition : C60 has been shown to be reactive enough even with 1,3-dienes having elecvtron-withdrawing groups to afford functionalyzed fullerocyclohexenes. Heterocycle-containing fullerenes have desinged and synthesized via [2+4] cycloaddition with various hetero dienes, heterocyclic quinodimethanes, and heterocycles. and via [2+3] cycloadditions with silylnitoronate, nitroalaknes, and beta-dicarbonyl compounds. Furan and oxazole-linked fullerenes have been oxygenated readily by self-sensitized photooxygenation as one of unique behaviors of these heterocycles.(3) New potentials of squaric acid as C4 synthon : We have developed a new method for functionalization of squaric acid by the Lewis acid catalyzed elecrophilic addition to unsaturated organosilanes via 1,2-and/or 1,4-modes. Thus obtained derivatives could be converted to functionalyzed bicyclo [3.2.0]-heptanes and furanones, which have been utilized to synthesize tricyles such as triquinane skeletons and (E)-Basidalin. We have found a new ring exapansion via 0-radical-induced ring opening, followed by a novel 5-endo trig cyclization to provide alkylidenefuranones which were utilized to synthesis of antibiotic (Z)-Multicolanate.(4) Developement of novel fluorine-containing synthetic blocks : A general synthetic method for alpha, alpha-difluoromethylenealkane carboxylic acid and -ester has been developed via radical addition to difluorodichloroalkenes, followed by solvolysis. Starting from trifluoromethylaceate, synthestic routes to fused nitrogen heterocycles including alkaloids carrying a CF_3 group on the bridgehead position have been developed via radical-and/or iminium cyclizations. beta-Trifluoromethylvinylsulfonyl compounds prepared from trifluoroacetate have been shown to be new synthetic blocks useful for regio-, stereo-, and enantioselective synthesis of trifluoromethylated organic compounds. Less

在本项目中，一些具有独特环状结构的化合物，如金刚烷、富勒烯和方酸，经过适当的功能化后，已被证明是有用的新型合成嵌段，用于生物活性分子的分子设计，包括一些天然产物。（1）功能化碳环和杂多环化合物合成方法的研究进展：由4-苯基或-甲氧羰基共轭稳定的同嵌段3-烯已被证明是有用的新型结构单元。N-（2-取代苯基）亚氨基膦已成功地应用于Vascinone和Benzomalvin A等生物活性天然产物的全合成，N-（2-杂芳基）亚氨基膦已被开发为合成蝶啶酮及其类似物的有用结构单元。通过3，4-二氢异喹啉N-氧化物的[3+2]环加成反应合成了5，6-二氢吡咯并[2，1-a]异喹啉 ...更多信息 与炔和联烯反应，然后重排。(2)含杂环[60]富勒烯的环加成分子设计：C60已被证明与具有吸电子基团的1，3-二烯具有足够的反应性，以提供官能化的富勒环己烯。含杂环富勒烯是通过与各种杂二烯、杂环醌二甲烷和杂环化合物的[2+4]环加成反应设计合成的。以及通过与甲硅烷基硝基硼酸酯、硝基烷烃和β-二羰基化合物的[2+3]环加成反应。自敏化光氧化反应是富勒烯类杂环化合物独特的氧化行为之一。(3)方酸作为C4合成子的新潜力：我们开发了一种通过刘易斯酸催化的不饱和有机硅烷通过1，2-和/或1，4-模式的亲电加成来官能化方酸的新方法。由此获得的衍生物可以转化为官能化的双环[3.2.0]-庚烷和呋喃酮，其已用于合成三环，如三喹烷骨架和（E）-黄芩苷。我们发现了一种新的开环反应，通过O-自由基诱导开环，然后通过一种新的5-内桥环化反应得到亚烷基呋喃酮，并将其用于抗生素（Z）-Multicolepine的合成。(4)新型含氟合成嵌段的开发：通过与二氟二氯烯烃的自由基加成，然后溶剂分解，开发了α，α-二氟亚甲基烷烃羧酸和酯的通用合成方法。以三氟乙酸甲酯为起始原料，通过自由基环化和亚胺环化反应，合成了包括桥头含CF_3的生物碱在内的稠氮杂环化合物。由三氟乙酸盐制备的β-三氟甲基乙烯基磺酰基化合物已被证明是用于三氟甲基化有机化合物的区域-、立体-和对映选择性合成的新合成嵌段。少

项目成果

Shoji Eguchi: "Synthesis of Heterocycle-Containing [60] Fulleren Derivatives. II. Recent Progress in [4+2]-and [3+2]-Cycloaddition Routes,Eguchi" Fullerene Sci. & Tech.5〔5〕. 977-987 (1997)

Shoji Eguchi：“含杂环的[60]富勒烯衍生物的合成。II。[4+2]-和[3+2]-环加成路线的最新进展，Eguchi”Fullerene Sci & Tech.5〔5〕。 -987 (1997)

M.Ohno, M.Ito, M.Umeda, R.Furuta, K.Kondo, S.Eguchi: "Conjugatively Stabilized Bridgehead Olefin : Formation and Reaction of Remarkably Stable Homoadamant-3-ene Substituted with Phenyl and Methoxycarbonyl Groups" J.Am.Chem.Soc.118 (30). 7075-7082 (1996)

M.Ohno、M.Ito、M.Umeda、R.Furuta、K.Kondo、S.Eguchi：“共轭稳定的桥头烯烃：被苯基和甲氧基羰基取代的非常稳定的 Homoadamant-3-ene 的形成和反应” J.

S.Eguchi, T.Suzuki, T.Okawa, Y.Matsshita, E.Yashima, Y.Okamotro: "Synthesis of Optically Active Vasicinone based on Intramolecular Aza-Witting Reaction and Asymmetric Oxidation" J.Org.Chem.61 (21). 7316-7319 (1996)

S.Eguchi、T.Suzuki、T.Okawa、Y.Matsshita、E.Yashima、Y.Okamotro：“基于分子内 Aza-Witting 反应和不对称氧化的光学活性 Vasicinone 的合成”J.Org.Chem.61 (21

Takashi Okano: "Synthesis of Indolizidine Derivatives Trifluoromethylated at Bridgehead Position via Acyliminium Intermediate Derived From Ring-Chain Tautomerism of 5,5,5-Trifluoro-4-oxopentanoyl Arylethylamide" Heterocycles. 44(1). 227-236 (1997)

Takashi Okano：“通过由 5,5,5-三氟-4-氧代戊酰基芳乙基酰胺的环链互变异构衍生的酰亚胺中间体合成在桥头位置三氟甲基化的吲哚里西啶衍生物”杂环。

Hiroyasu Tsuge: "Highly Diasteroselective Michael Addition to Optically Active Trifluoromethylated α、β-Unsaturated Sulfonamides Based on Their Hinge-Like Conformation" Tetrahedron. 53(3). 823-838 (1997)

Hiroyasu Tsuge：“基于铰链状构象的光学活性三氟甲基化 α,β-不饱和磺酰胺的高度非对映选择性迈克尔加成”四面体 53(3) (1997)。