降龙蜓醚Ambro,: Ambergris:the grey gold from sperm whal Sperm whale·抹香 15万英 天然产物一生活中无处不在 Spider Venom 7) - -竖 Gibberellic Acid赤霉素 Synthetic Vs Natural 1938 as a m
1 O H 降龙蜒醚 Ambrox Sperm whale - 抹香鲸 天然龙涎香的国际市场，完全由香水大国法国控制，每 Kg 的收购价在 1~4.5 万法郎之间，香料公司加工后的售价 为每 Kg 6~10 万法郎。据商业资料显示，世界龙涎香交易 最盛时每年在 600 Kg。 Ambrox 11.5万英镑 Ambergris: the grey gold from sperm whale OH Ambrein O Ambrox O O O2 龙涎精 降龙蜒醚 抗菌 O O O Periplanone B 白 蚁 Sexual excitant 蟑 螂 H H OH HO Trinervitane 天然产物—生活中无处不在 O O OMe H N O Me OMe OH OMe MeO OH Me Me Me Pederin Spider Venom 黑寡妇 Black Widow O H N O N H N H N H N H O NH2 N H NH2 OH NH HO NH2 Argiopin 巴西漫游蜘蛛 Gibberellic Acid 赤霉素 1926年日本黑泽英一发现，当水稻感染了赤霉素后，病株往往比正常 植株高50%以上，而且结实率大大降低，因而称之为“恶苗病”。1938年日 本薮田贞治郎和住木谕介从赤霉菌培养基的滤液中分离出这种活性物质， 并鉴定了它的化学结构。命名为赤霉酸。1956年 C.A.韦斯特和 B.O.菲尼分 别证明在高等植物中普遍存在着一些类似赤霉酸的物质。到1983年已分离 和鉴定出60多种。一般分为自由态及结合态两类，统称赤霉素，分别被命 名为GA1，GA2等。 其化学结构属于贝壳杉烯型二萜类酸类化合物 HO COOH O OH O H H Kenji Mori 森 谦治 Gibberellins are phytohormones and discovered by Yabuta and Sumiki in 1938 as a metabolite of the fungus Gibberella fujikuroi. In 1968, just after completion of the synthesis starting from o-xylene, a famous microbiologist Arima said to Dr. Mori: ‘‘Congratulations, Dr. Mori! You finally synthesized the gibberellins. It’s great. But it took 9 years of your life. Don’t forget that the fungus Gibberella fujikuroi will make them within a couple of days.’’ 9 years Kenji Mori. Bioactive Natural Products and Chirality. Chirality 2011, 23, 449-462. Synthetic Vs Natural
秋水仙素与无籽西瓜 油菜素内酯Brassinolide 上为第大，A所广生长清节 8 的物生长进。可使多种作 ·[活性]抑制铜胞的生长。抑制细胞有丝分。 Digitoxigenin:One of the Most Molecules that Changed the World Ingested Drugs in Medicine 重要小 re the enlv in 鸦片（吗啡）彻底改变了两个帝国 药物改变了世界Prde KeyDea What if Fleming had
2 秋水仙素与无籽西瓜 O N H H3CO H3CO H3CO CH3 O OCH3 木原 均 Hitoshi Kihara 秋水仙碱 Colchicine u ［来源］百合科植物秋水仙Colchicum autumnale、老鸦 瓣Tulipa edulis、 丽江山慈菇Iphigenia indica鳞茎等。 u ［活性］抑制癌细胞的生长。抑制细胞有丝分裂。 油菜素内酯 Brassinolide Brassinolide 油菜素内酯是从油菜花粉中分得的植物生长促进剂，可使多种作物 增产，目前已在国内进行大田试验。 1. 促进细胞伸长和分裂 2. 促进光合作用 3. 提高抗逆性 格罗夫(Grove)等(1979)用227 kg油菜花粉提取得到10 mg的高活性结晶物BR1. 国际上誉为第六激素，属新型广谱植物生长调节剂 芸苔素内酯 O OH H HO HO OH H H O HO H 天丰素 Nature 1979, 281, 216-217. Digitoxigenin is a cardenolide isolated from Digitalis purpurrea and Digitalis lanata (Foxglove). These cardiac glycosides are the only inotropic drugs suitable for chronic treatment of congestive heart failure. Inhibit HT-1080 cell line growth, and show cytotoxic activities agaisnt breast and lung cancer cell lines. Digitoxigenin: One of the Most Ingested Drugs in Medicine O OH H O O Digitoxin R=H Digoxin R=OH H H O HO O O O OH O OH HO R HO OH H O O Digitoxigenin H H 洋地黄毒苷和地高辛 洋地黄毒苷元 大自然是位神奇的化学家，合成了许许多多形形色色结构复杂的天 然产物，它们在人类医学发展史上扮演了非常重要角色，曾诞生了许多 影响人类历史进程和命运的重要小分子，aspirin, morphine, quinine, steroidal contraceptives, digoxin, penicillin, streptomycin, cyclosporin, taxol, vinblastine, ginkgolides, artemisinin and lavastatin and so on，这些 分子说明了天然产物具有巨大的历史作用和未来发展潜力。在现代药物 研究中，每一次具有轰动效应的药物的出现一般都伴随着一种新类型天 然产物的发现，同时也推动了有机化学和生命科学的发展。 Molecules that Changed the World O O OH O O OH HO HO HO HO OH OHC NH NH2 HN HN H2N NH NHMe O O O O H CH3 H CH3 O H H3C Artemisinin C C O NH N S H H H COOH H H O O O O HO O Lovastatin Penicillin Streptomycin 鸦片(吗啡)彻底改变了两个帝国 Disease: the greatest enemy? What if Fleming had not discovered penicillin? President Kennedy's Death A poison arrow-assisted homicide? saxitoxin 石房蛤毒素 N N H N N H NH2 H2N O H OH OH H H + + 1 6 8 H H2N O 11 药物改变了世界
Nature Is A Great Architecture Nature,An Excellent Synthetic Chemist 天然产物极大地丰言了化学结构库 醉衫举袋海 金 裤南 逐 Mi0 x刺尾金海素比河原零家盟00告 Taxol（紫杉醇®一最后一道防线） 红豆杉Yew tree::A Tree of Life Worldwide Race For TaxolSynthesis Total Synthesis of Taxol 1971-Presen 尝端定器满 器演止器一 尘÷器时 6：63期-6 208年akahachi离桥用了48步收率L0W70%
3 Nature Is A Great Architecture Nature Is A Great Architecture N OH O CH3 OH O Ph O HO H3C O O H3C O H3C O H3C O CH3 Aconitine O O O O O CH3 H3C H3C Qinghaosu O O O O HO O O HO O HO H OH H H N H N OO OH H NH HO OH HO OH H OH OH OH OAc AcO H HO O H MeO2C O O O O OH O H AcO O O H OH CO2Me OH N N O O H H H H H N N OH OH H H CH3 Ajmaline N O H3CO OH CH3 Ryanodine H3C CH3 O O O NH HO HO HO OH HO HO CH3 CH3 OCH3 O H H H Echinopine B N O O N N OH OH O H3C Morphine O O H O OAc HO H Maoecrystal Z O O O O O CO2CH3 O Khayasin Ginkgolide C Metaphanine O OH Azadiractin H N CH3 H3C O NH2 Huperzine A N H N O O H3C Gelsemine OH OH OH Vinigrol Tetrodotoxin Strychnine Zoanthamine N O O O O O CH3 H3C CH3 CH3 CH3 CH3 H H H H CH3 H H3C CH3 HO O H O CH3 H O O O H OH O H CH3 O O H3C O O OH H N O Ph H H H Taxol Taxane 天然产物极大地丰富了化学结构库 Nature, An Excellent Synthetic Chemist Nature, An Excellent Synthetic Chemist Maitotoxin 刺尾鱼毒素 比河豚毒素强200倍 O O O O O O O O O O O O O OH O O O OH O O O O HO OH O OH S O O ONa HO OH OH OH OH OH O S O ONa HO OH O H H H H H H H HO H H H H H H H H OH OHH H H H H H OH H OH HO OH H H OH H H OH OH H H HO H H H H H O O O O O O O OH H H H H H H H H H HO H A B C D E F G H I J K L M N P Q R S T U V Y X W 51 52 O O O O O HO OH H H H H H H O Z A' B' D C' ' F E' ' Taxol® (紫杉醇® —最后一道防线) 红豆杉: 希望之树 CH3 H H3C CH3 HO O H O CH3 H O O O H OH O H 20 5 CH3 O O H3C O O HO H N O 1 15 13 H H H 10 Nature 1979, 277: 665-667 红豆杉 Yew tree: Yew tree: A Tree of Life A Tree of Life Ross Longley and Steven Schmid for pharmacology Taxol is not as taxing Thank Goodness! Worldwide Race For Worldwide Race For Taxol® Synthesis Synthesis Nature, 1994, 367: 630-634. K. C. Nicolaou R. A. Holton Total Synthesis of Taxol® 广藿香醇 黏酸 维兰德-米舍尔酮 蒎烯 合成构素 L-丝氨酸 O OH O Nicolaou (1994) 39 steps Wender (1997) 37 steps Me Holton (1994) 39 steps Kuwajima (1998) 60 steps O Danishefsky (1995) 49 steps Mukaiyama (1998) 60 steps O Me Me Me Me HO COOH H Me O O 4.3% 0.041% 0.63% 0.63% 0.17% 0.014% NH2 1971-Present 2008年Takahashi (高桥)用了48步收率0.0070% +16
Nature,An Excellent Synthetic Chemist C0+H,0 4
4 Nature, An Excellent Synthetic Chemist 紫杉醇 Taxol Me Me HO Me AcO OBz H Me OAc OH O O O OH Ph NH O O 红豆杉 Yew Ұ750 Ұ1300 Nat. Prod. Chem. Nat. Prod. Chem. hu CO2 + H2O $ $ $ $ $ $ $ $ Blockbuster Drug: 10 billion $ in 2000