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

在本项目中，一些具有独特环结构的化合物，如金刚烷、富勒烯和方酸，经过适当的官能化处理，已被证明是包括一些天然产物在内的生物活性分子的分子设计的有用的新型合成嵌段。研究成果概述如下：(1)官能化碳环和杂多环合成方法的发展：由4-苯基或-甲氧基羰基共轭稳定的同质3-烯已被证明是有用的新型构筑单元。N-(2-取代苯基)亚胺基膦已成功地应用于生物活性天然产物的全合成，如Vascinone和Benzomalvin A等，N-(2-杂芳基)亚胺基膦杂环已被开发为合成蝶烷酮及其类似物的有用构块。通过3，4-二氢异喹啉N-氧化物…的[3+2]环加成反应，开发了合成5，6-二氢吡咯并[2，1-a]异喹啉的新途径通过环加成反应设计含杂环的[60]富勒烯：C60已被证明具有足够的活性，即使1，3-二烯具有电子吸引基团，也可以得到官能化的富勒环己烯。通过与杂二烯、杂环喹二甲烷和杂环的[2+4]环加成反应，设计并合成了含杂环的富勒烯。并通过[2+3]与硝酸硅酯、硝基丙烷和β-二酮类化合物的环加成反应。作为这些杂环的独特行为之一，呋喃和恶唑连接的富勒烯很容易被氧化。(3)方酸作为C4合成子的新潜力：我们开发了一种新的方酸官能化方法，通过Lewis酸催化不饱和有机硅烷通过1，2-和/或1，4-模式的亲电加成反应。这样得到的衍生物可以转化为官能化的双环[3.2.0]-庚烷和呋喃酮，并已用于合成三环化合物，如三喹环骨架和(E)-巴西达林。我们发现了一种新的通过0-自由基诱导开环的扩环反应，然后通过一种新的5-内基引发的环化反应来提供亚烷基呋喃酮类化合物，并将其用于合成抗生素(Z)-多戊酸酯。(4)新型含氟合成嵌段的开发：通过与二氟二氯烯的自由基加成，然后进行溶剂分解，开发了一种合成α，α-二氟亚甲基烷羧酸和-酯的通用方法。从三氟甲酸甲酯开始，通过自由基环化和/或亚胺环合反应合成了稠氮杂环，包括桥头位置带有CF3基团的生物碱。由三氟乙酸酯合成的β-三氟甲基乙烯基磺酰基化合物已被证明是用于区域、立体和对映体选择性合成三氟甲基化有机化合物的新的合成嵌段。较少

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