4.促进有机化学发展 e NMR/MIS Techniques BTX-E ined BTX-B after 12 years'work,in Brevetoxin BTX-A 于2？年5月日在中国科学上海有机化学研究所法行学术告
1 111 4. 促进有机化学发展 NMR/MS Techniques The architecturally complex molecules provide the driving force for the development of new synthetic strategies/new reactions. Nicolaou Group total synthesized BTX 112 -B after 12 years’ work, in 1995 BTX-B 短裸甲藻毒素 O O O O O O O O O O O H3C O HO CH3 CH3 H3C H3C H3C H3C H H H H H H H H H H H H H H H O H 有机全合成大师-K. C. Nicolaou 113 114 O O O O HO H Me H H H H Me H O O O O Me H H H Me H H H H O O O H H Me OHC Brevetoxin BTX-A 115 •Nicolaou Group total synthesized BTX A after 10 years’ work, in 1998 116 Nicolaou教授于2009年3月26日在中国科学院上海有机化学研究所进行学术报告
西加毒素(Ciguatoxin) 平间正博 20700-7m7 Developing New Methodology for Total Synthesis Total Synthesis of PTX eoR入T入 金1 士林流ru心 Total Synthesis of Tetrodotoxin symmetric Total in20
2 117 J. Org. Chem. 2005, 70, 7007-7027 118 Hirama M. Science 2001, 294: 1904. 平间正博 PNAS, 2004,101, 12013–12018. 西加毒素(Ciguatoxin) After a twelve-year struggle, the total synthesis of ciguatoxin CTX3C has been achieved. 119 Shi epoxidation 80% 20% O BuO O t- O BuO O t- O O O O BF3 1. BF3 Et2O 2. H2O O O O O O O H H H H OH ... Scheme 1. Lewis acid promoted epoxide-opening cascade to give fused polyoxepane systems. （1） 硒诱导的关环反应 （2） 基于硫代糖苷的糖化反应， （3） 环醚化反应 （4） 基于IBX- 和DMP的氧化反 应 和环化反应 （5）大环成环反应 （6）金属催化和无机催化的不 对称环化反应等等都是具 有代表性的工作 (7) Yamaguchi macrolactonization (8) Grubbs’s ring-closing metathesis (RCM) Developing New Methodology for Total Synthesis Minoru Isobe. Nat. Prod. Rep., 2010, 27, 1204-1226. 120 Armstrong R. W. Kishi et al. J. Am. Chem. Soc. 1989, 111: 7530. Totalsynthesis “珠穆朗玛峰的攀登” 64 C* & 7db 21 P-PhD and Dr. Students spend more than 8 years 岸 义人教授1937-，歧阜人，名大毕业，哈佛 教授载入美国化学会过去75最伟大的化学研究 Total Synthesis of PTX O OH OH OH HO O OH OH O HO OH OH OH OH O OH HO OH OH OH OH O O O OH NH2 HO OH O O O OH OH OH HO OH OH HO OH HN O NH OH O OH OH OH OH OH HO OH OH OH OH OH OH OH 121 Total Synthesis of Tetrodotoxin Yoshito Kishi Racemic Total synthesis in 1972 Asymmetric Total in 2003 N H N O O OH H NH HO OH HO OH H OH + 1 4 4a 8 10 11 6 122 Prof. Yoshito Kishi 岸 义人 Emeritus Department of Chemistry and Chemical Biology Harvard University Robert Woodward博士生 岸义人 N H N OO OH H NH HO OH HO OH H OH + 1 4 4a 8 10 11 6 1977 Ph.D Harvard University (Prof. Y. Kishi) Prof. Pharmaceutical Sciences University of Tokyo
(-)-Palau'amine Phil S.Baran H 卤代有机化合物 moan c McENain Seminar 上世纪70年代海弹天然产物的研究对象主要是店类化 20 机物从海洋生 物中不断地被发现， 改变了以往人们认为 代有机化合物在 中很少存在甚至认为安代有机化合 桑之逃叫 ,符别是离子诱导作用产生的分子环化或 配 Marin Biomedical Sciences--The Future 海洋天然产物研究的对象 Monoterpenoids and Quinone in Alga Green Algae:Relatively few comp Brown Algae:Diterpenoids steroids 之世 7 3
3 123 (-)-Palau’amine Kinnel, R. B.; Gehrken, H.-P.; Scheuer, P. J. J. Am. Chem. Soc. 1993, 115, 3376-3377. Thomas Lindel, et al. Study on the absolute configuration of (-)-palau’amine. Tetrahedron Lett. 2010, 51, 6353-6355. Total Synthesis of Palau'amine, Angew. Chem. Int. Ed. 2010, 49, 1095-1098. Phil S. Baran Barab, P. S. Angew. Chem. Int. Ed. 2010, 49, 1095-1098. J. Org. Chem., 2010, 75, 4657-4673. N N HN NH HN NH NH2 NH2 H H Cl O OH H2N H 124 2013年MacArthur天才奖揭晓，Scripps研究所的Phil S. Baran成为24 位获奖者之一，获得62.5万美元奖金。36岁的有机化学家Phil S. Baran最 近合成了巨大戟醇，将37-45的全合成路线缩减为14步，天才般的构思不 只是科学，更是艺术。2012年巨大戟醇甲基丁烯酸酯（商品名Picato）被 FDA批准用于治疗日光性角化病（全球有2.5亿患者），成为目前首个也是 唯一针对该适应症的药物，另外针对基底细胞癌的II期临床试验也已经完 成。2008年晋升为Full Prof.，年仅31岁。 Phil S. Phil S. Baran Ingenol 巨大戟醇 OH HO HO O O O H 125 126 卤代有机化合物 • 上世纪70年代海洋天然产物的研究对象主要是萜类化 合物，包括卤代的单萜、倍半萜、二萜、二倍半萜以及一 些卤代的C15-乙酸原类化合物，大量含卤素原子的萜类有 机物从海洋生物中不断地被发现，改变了以往人们认为卤 代有机化合物在天然界中很少存在甚至认为卤代有机化合 物均有毒的不正确看法。 • 卤离子，特别是溴离子诱导作用产生的分子环化或重 排过程称为海洋卤化过程 Marin Biomedical Sciences--The Future 127 海洋天然产物研究的对象 1.海藻 Algae：Reported 32 Structural Types More Than 170 Diterpenoids. Green Algae: Relatively few comp. Brown Algae: Diterpenoids & steroids Red Algae: Terpenoids:Mono-,Sesqui-,di-, Triterpenoid & Steroids dominated, especially halogenated monoterpene. Br OH H H H OH OH D Itomanol ictyol Cl Br B Cl r Cl Halomon Maryssa G. A. Mann, 128 et al: J. Nat. Prod., 2007, 70 (4), 596 -599. Catherine E. Sansom, et al. J. Nat. Prod. 2007, 70 : 2042-2044. Monoterpenoids and Quinone in Algae CH3 Br Br CH3 CHO 1 CH3 Cl CH3 CHO 2 Cl South African marine red alga Brown Alga Perithalia capillaris
Monoterpenoids in Red Algae Sesquiterpenoids in Red Algae 主买来源于凹顶LT 有 活性 which was C1s聚乙酰类代谢物 2.海绵Sponge C,聚乙联类新生物是红藻的一大类代谢产物，广泛存在 海纳动物门又称多孔动物门，为原始多细胞动物。没有 于凹顶藻属的多种红藻中，通常以魅状或环氧形式存在。 口，清化道，每言系绕。多孔，含一或多个内腔。 s mill 2.海绵Sponge 海绵化学结构类型 三 C Aplysinopsin Petrosia ficifom 4
4 129 Cl Br B Cl r Cl Halomon Cl Cl Br Cl Cl Br Cl Cl Cl Br Halogenated monoterpene is very popular in red algae. Especially Cl and Br often occur in monoterpenoids of red algae. Halomon, which was isolated from Portieria hornemannii, was regonized as an anti-cancer lead by NCI. Monoterpenoids Monoterpenoids in Red Algae in Red Algae 130 Sesquiterpenoids in Red Algae • 主要来源于凹顶藻属Laurencia OAc 1 HO Br CHBr2 OH 2 1 来源于澳大利亚Laurencia rigida,具有抗附着活性。 2 来源于未确定的Laurencia sp, 对乳腺癌和克隆癌有显著的活性。 J. Nat. Prod. 2001, 64, 690-791. 131 C15聚乙酰类代谢物 C15聚乙酰类衍生物是红藻的一大类代谢产物，广泛存在 于凹顶藻属的多种红藻中，通常以链状或环氧形式存在。 1 来源于土耳其海域红藻，具12元环醚结构。 2 来源于希腊海域红藻，具很强的杀蚂蚁活性。 Phytochemistry 2002, 59, 111-116 1 2 O O Cl Br Br H H O Br Cl AcO Cl 1 2 3 4 5 7 6 8 9 10 11 12 13 14 15 1 2 3 4 5 7 6 8 9 10 11 12 13 14 15 132 海绵动物门又称多孔动物门，为原始多细胞动物。没有 口，消化道，器官系统。多孔，含一或多个内腔。 2. 海 绵 Sponge Sponges are most primitive of the multicelled animals that have existed for 700–800 million years. 133 Petrosia ficiformis Petrosia ficiformis u Sponges are taxonomically grouped into 4 classes, 21 orders and 107 genuses with over approximately 15,000 species (ca 5000 occurred in our country). Sponge is about 1/15 of marine biomass. 2. 海 绵 Sponge 134 海绵化学结构类型 • 长链多烯，炔，醚，酰胺（多烯酮类）Polyketide • 吲哚生物碱类: Anticancer, Antivirus, Antibacterial • 大环内酯 • 甾体化合物 • 萜类化合物 • 肽化合物 O H2N OH Pachastrissamine O O OH O N H N N O NH Aplysinopsin Sponges are the rich source of novel secondary metabolites with diversities of biological activities Sesquiterpenoids Diterpenoids Sesterterpenoids Triterpenoids (few) Structural Diversity
An illustration of the chemical diversity Triterpene of sponge-derived molecules 气人 Sipholenol A 海绵化学结构类型 8 。A paCa设 人 and it 装水 aear Meroditerpene Ceramide鞘苷 selated from a marin evaluation showed that the meroditerpenes olated p2 dF人C,3e,43
5 135 An illustration of the chemical diversity of sponge-derived molecules H O O O H O Stellettin A (from South China Sea Jaspis Sp.) 异臭椿类三萜（Isomalabaricane triterpene）具 有很强的抗肿瘤及抗病毒等生理活性. 邓松之. 海洋臭椿类三萜的研究进展. 中国海洋药物，2004，23（1）：37-41. 三 萜 136 Triterpene Triterpene Four isomalabaricane triterpenoids were isolated from an extract of the sponge Rhabdastrella globostellata that was active in an assay measuring stabilization of the binding of DNA with DNA polymerase-b. This is the first report of natural products with the ability to promote stabilization of the DNA-polymerase covalent binary complex. J. Nat. Prod., 69 (3), 373 -376, 2006. H AcO O H O H HO O H HO O OH OH HO 137 Triterpenoids were isolated from the Red Sea sponge Callyspongia (=Siphonochalina) siphonella. Sipholane triterpenoids were evaluated for their cytotoxicity and effect on reversing P-glycoprotein-mediated MDR to colchicine. Sipholenol A was found to be the most potent, and it increased the sensitivity of resistant KB-C2 cells by 16 times toward colchicine (秋水 仙碱). This is the first report related to reversal of cancer chemotherapy resistance using these triterpenoids. J. Nat. Prod., 2007, 70 , 928 -931. Sipholenol Sipholenol A 138 海绵化学结构类型 Xestospongin C (Xestospongia sp. ) macrocyclic bis-oxaquinolizidine Jaspamide (Hemiastrella minor) macrocyclic lactam/lactone Alkaloids Peptide 139 A new meroditerpene, (+)-isojaspic acid has been isolated from a marine sponge Cacospongia. Bioactivity evaluation showed that the meroditerpenes isolated significantly inhibited Staphylococcus epidermidis. J. Nat. Prod., 70 (4), 628 -631, 2007 Meroditerpene 140 Ceramide Ceramide 鞘苷 Ectyoceramide is the first hexofuranosylceramide from the sponge Ectoplasia ferox. V. Costantino, et al. Eur. J. Org. Chem., 2003, 1433
Sesterterpenoid 甾体化合物Steroid 食数经清5 sponge Cacospongis sealaris. Halogenated Helianane Derivatives (+)-discodermolide 贤品 ted de abalin-sabiliring v Points for Attention 海与生物长进化形成密切的共 生关系 占海纳本体干置的0%，因此。许多从海绵中获海的天然 产物可能是与其共生的徽生物的次生代诸产物。 ae 1
6 141 Sesterterpenoid Sesterterpenoid Astakolcatin is a sesterterpenoid with an unusual 8-membered lactone ring from the Mediterranean sponge Cacospongis scalaris. M. Tsoulatou, H. Siapi, C. Vagias and V. Roussis, J. Nat. Prod., 2003, 66, 444. 142 甾体化合物 Steroid • 海绵动物已被证明在所有生物体中含有最多样化的甾体 类化合物，一种海绵动物最多含74种。 Lensendeldia chondrodes HO OH O HO HO H H 9 11 19 Mar. Drugs 2005, 3, 84-111. 143 Two new halogenated derivatives (1 and 2) of helianane were isolated from the 2-propanol extract of the sponge Spirastrella hartmani. Compound 1 showed in vitro cytotoxicity against the human tumor cell lines A549, HT29, and MDA-MB-231. J. Nat. Prod., 68 (10), 1554 -1555, 2005 O R 1 R = Cl 2 R = Br Halogenated Halogenated Helianane Helianane Derivatives Derivatives 144 Tubulin-stabilizing agent isolated from a marine sponge (+)-discodermolide discodermolide Gunasekera, S. P.; Gunasekera, M.; Longley, R. E.; Schulte, G. K. J.Org. Chem. 1990, 55, 4912-4915 (correction: 1991, 56, 1346). J. Nat. Prod. 2001, 64, 171-174. 2002, 65, 1643-1648. Nerenberg, J. B.; Hung, D. T.; Somers, P. K.; Schreiber, S. L J. Am. Chem. Soc. 1993, 115, 12621. (Synthesis) O HO O HO OH O NH2 O 145 海绵与微生物长期进化形成密切的共生关系， 缺少某些微生物，会使海绵无法由受精卵发育成熟，而某 些微生物也无法脱离海绵而独立生存。海绵中的微生物可 占海绵本体干重的70%，因此，许多从海绵中获得的天然 产物可能是与其共生的微生物的次生代谢产物。 Points for Attention Figure 1. Distribution of marine natural products by phylum, 2001 146 Sponges are a rich source of new marine natural products, many of which are bioactive. Of all the new compounds reported by the end of 2001, 38 % were obtained from sponges
3.腔肠动物Coelenterates 腔肠动物一珊瑚Coral Prostaglandins 珊瑚Coral:6100(496-Steroid&Terpenoid Diterpenoids Sesquiterpenoids Sterols ● Coral reefs,often referred to as the Cembrane 西松烷型 “rainforest of the ocean”,are among the most ancient.complex.and faseinating life forms that still thrive Cembranolids 50-60 Anticancer 147 on Earth. Rainforest of the Ocean Eleutherobin Analogues 二萜苷 Isolated by Fenical from the Western Australian soft coral 巴布亚岛西部发荧光的珊瑚 Eleutherobia sp.,belongs to a small family of soft coral that are microtubule-stabilizing antimitotic agents-like Taxol. 150 7
7 147 3. 腔肠动物 Coelenterates Coelenterates 珊瑚 Coral : 6100 (496)-Steroid & Terpenoid Cembrane Cembranolids 50-60 Anticancer 西松烷型 O O O O H H 148 腔肠动物—珊瑚 Prostaglandins Diterpenoids Sesquiterpenoids Sterols Coral Coral reefs, often referred to as the “rainforest of the ocean”, are among the most ancient, complex, and fascinating life forms that still thrive on Earth. 149 巴布亚岛西部发荧光的珊瑚 Rainforest of the Ocean 150 Eleutherobin & Analogues & Analogues Isolated by Fenical from the Western Australian soft coral Eleutherobia sp., belongs to a small family of soft coral that are microtubule-stabilizing antimitotic agents-like Taxol. 二萜苷