Significance: Wöhler was the first to make an organic substance from an inorganic substance. - PDF

ö Wöhler, 1928 K + C + 4 Cl + 4 C 2 2 Friedrich Wöhler Annalen der Physik und Chemie 1828, 88, Significance: Wöhler was the first to make an organic substance from an inorganic substance. This

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ö Wöhler, 1928 K + C + 4 Cl + 4 C 2 2 Friedrich Wöhler Annalen der Physik und Chemie 1828, 88, Significance: Wöhler was the first to make an organic substance from an inorganic substance. This was the beginning of the end of the theory of vitalism: the idea that organic and inorganic materials differed essentially by the presence of the vital force present only in organic material. To his mentor Berzelius: I can make urea without thereby needing to have kidneys, or anyhow, an animal, be it human or dog Friedrich Wöhler, Polytechnic School in Berlin Polytechnic School at Kassel University of Göttingen Support for vitalism remained until 1845, when Kolbe synthesized acetic acid from carbon disulfide Ph Br Br Δ α acrose Ph 2 2 Ph aq. Cl C 2 C 2 α acrosazone α acrosone an osazone (osazone test for reducing sugars) Zn/Ac C 2 C 2 D-Mannonic acid Br 2 then resolve via strychnine salts C C 2 DL-Mannose 3 C 2 DL-Mannitol a-g 3 + C 2 DL-Fructose quinoline C 2 a-g C Established stereochemical relationship between mannose and glucose (part of Fischer proof) C 2 D-Gluconic acid 3 + C 2 D-Glucose work mechanisms from acrosazone on Emil Fischer, University of Munich ( ) University of Erlangen ( ) University of Würzburg ( ) University of Berlin ( ) Fischer, E. Ber. 1890, 23, 799. also see: The total synthesis of natural products, Volume 1 By John ApSimon emiterpenes consist of a single isoprene unit. Isoprene itself is considered the only hemiterpene, but oxygen-containing derivatives such as prenol and isovaleric acid are hemiterpenoids. Monoterpenes consist of two isoprene units and have the molecular formula C1016. Examples of monoterpenes are: geraniol, limonene and terpineol. Sesquiterpenes consist of three isoprene units and have the molecular formula C1524. Examples of sesquiterpenes are: farnesenes, farnesol. (The sesqui- prefix means one and a half.) Diterpenes are composed for four isoprene units and have the molecular formula C2032. They derive from geranylgeranyl pyrophosphate. Examples of diterpenes are cafestol, kahweol, cembrene and taxadiene (precursor of taxol). Diterpenes also form the basis for biologically important compounds such as retinol, retinal, and phytol. They are known to be antimicrobial and antiinflammatory. Sesterterpenes, terpenes having 25 carbons and five isoprene units, are rare relative to the other sizes. (The sester- prefix means half to three, i.e. two and a half.) Examples of sesterterpenes are geranylfarnesol. Triterpenes consist of six isoprene units and have the molecular formula C3048. The linear triterpene squalene, the major constituent of shark liver oil, is derived from the reductive coupling of two molecules of farnesyl pyrophosphate. Squalene is then processed biosynthetically to generate either lanosterol or cycloartenol, the structural precursors to all the steroids. farnesyl pyrophosphate Tetraterpenes contain eight isoprene units and have the molecular formula C4064. Biologically important tetraterpenes include the acyclic lycopene, the monocyclic gamma-carotene, and the bicyclic alpha- and beta-carotenes. Polyterpenes consist of long chains of many isoprene units. atural rubber consists of polyisoprene in which the double bonds are cis. Some plants produce a polyisoprene with trans double bonds, known as gutta-percha. a C I Et 2 C C C 2 Et aq. Cl 2 C 2 C C 2 Ac 2 heat C 2 fuming Br C 2 1) MgI 2) aq. Cl C 2 Et Et + C 2 William enry Perkin J. Chem. Soc., Trans., 1904, 85, Br C 2 Et C 2 Et MgI KS 4 + α-terpineol limonene ote: use of symmetry Sir William enry Perkin vs began study at age of 15 under August Wilhelm von ofmann at Royal College of Chemistry in London (attempted study on synthesis of quinine) made mauveine at age 18 over easter break launched the synthetic dye industry (never mind quinine...) CC 3 atropine anticholinergic drug cocaine Ph tropinone Ph used for opthamology, recuscitation, organophosphate poisoning Tropane alkaloids occur in plants of the families Erythroxylaceae (including coca) and Solanaceae from Wikipedia First synthesis by Willstätter in 1901: arduous, 0.75% yield Robert Robinson, 1917: classic retrosynthetic analysis and biomimetic synthesis... and biomimetic synthesis Institutions University of Sydney University of Liverpool British Dyestuffs Corporation University of Manchester University College, London University of xford Alma mater University of Manchester Birch, Arthur J., 'Investigating a Scientific Legend: the Tropinone Synthesis of Sir Robert Robinson, FRS', otes and Records of the Royal Society of London, vol. 47, 1993, pp Total synthesis C C 2 C 2 - C 2 - Ca ++ 2 C C 2 Cl -C 2 Cl Robinson J. Chem. Soc. 1917, 762. chanism: Double Mannich (go through entire mechanism yourself) + C 2 C 2 C 2 + C 2 C 2 C 2 C 2 C 2 African Calabar Bean Potent reversible inhibitor of acetyl and butylcholinesterases Clinical treatment of glaucoma (reduces intraocular pressure) Alzheimer s disease Pyrrolindinoindoline Polonovski and itzberg, Bull. Soc. Chim. 1916, 19, 33. Figure from A. Audt, J. Chem. Educ. 2008, 85, 1524. K Cl + Br Br SnCl 2 Cl a Br C 2 Et C 2 Et Et 2 C Et 2 C SCl 2 2 a, then Cl 3 Cl SCl 2 SnCl 2 + Et Et 2 2 S 4 Et + Robinson was unable to resolve eserethole, and therefore to confirm structure vs atural Product Et Et Et + 2 Described in 11 papers from , most recent is: King, F. E.; Robinson, R. J. Chem. Soc. 1935, Robinson's d,l-eserethole d,l-noreserethole Classical resolu1on of 8 eserethole from atalee Smith, JC BA. DePauw University, I, 1920 Fisk University, T MS. arvard University, 1923 oward University, (D.C.) 1929 PhD University of Vienna, 1931 (Rockefeller FoundaSon Fellowship) 1931 Rosenwald Research Fellow Depauw University (Dean W. M. Blanchard) 1935 Total Synthesis of PhysosSgmine CollaboraSon with Josef Pikl 1936 Director of Research for soya products, Glidden, Chicago Large scale, cost effecsve producson of synthesc progesterone and hydrocorssone. Foam fire exsnguishers WWII 1953 Julian Laboratories Sold for $2M in 1961 138 patents, 160 publicasons before his death in 1975 from Audt, J. Chem. Educ. 2008, 85, 1524. Audt, J. Chem. Educ. 2008, 85, 1524. Kobayashi says, in the sentence following the one quoted just above, that eserethole-b is unlikely to have been formed from noreserethole, 17, in which the indoline nitrogen bears a methyl group, although the English researchers, as mentioned above, did observe its formation. Audt, J. Chem. Educ. 2008, 85, 1524. Audt, J. Chem. Educ. 2008, 85, 1524. Malaria is a female-mosquito-borne infectious disease caused by a eukaryotic protist of the genus Plasmodium. It is widespread in tropical and subtropical regions, including parts of the Americas (22 countries), Asia, and Africa. After a period of between two weeks and several months (occasionally years) spent in the liver, the malaria parasites start to multiply within red blood cells, causing symptoms that include fever, and headache. In severe cases the disease worsens leading to hallucinations, coma, and death. -from Wikipedia The life cycle of malaria parasites in the human body. A mosquito infects a person by taking a blood meal. First, sporozoites enter the bloodstream, and migrate to the liver. They infect liver cells (hepatocytes), where they multiply into merozoites, rupture the liver cells, and escape back into the bloodstream. Then, the merozoites infect red blood cells, where they develop into ring forms, trophozoites and schizonts which in turn produce further merozoites. Sexual forms (gametocytes) are also produced, which, if taken up by a mosquito, will infect the insect and continue the life cycle. References to the unique periodic fevers of malaria are found throughout recorded history, beginning in 2700 BC in China Malaria was the most important health hazard encountered by U.S. troops in the South Pacific during World War II, where about 500,000 men were infected. Sixty thousand American soldiers died of malaria during the orth African and South Pacific campaigns. Europeans brought malaria to the new world in 1500ʻs. The Peruvians would mix the ground bark of trees with sweetened water to offset the bark's bitter taste, thus producing tonic water. Spanish Jesuit Missionaries in Peru first learned of the healing power of a tree bark in I 1640, the Countess of Chinchon-- consort to the Spanish Viceroy of Peru-- was saved from death by administration of a native tonic made from the bark of a tree know as quina-quina (later cinchonia bark) by local people. Afterwards, tonic bark soon became widespread in popularity in Europe. Initially resisted in England due to the association with the papacy (bark at that time were known as Cardinalʼs powder or Popeʼs powder. liver Cromwell, the Puritan who overthrew King Charles I in the 17th century English Civil War, preferred to treat his fevers with mercury and bloodletting, rather than take a Jesuit powder (he died) from Wikipedia and Molecules that Changed the World by icolaou In Africa a child dies every 45 seconds of Malaria, the disease accounts for 20% of all childhood deaths. quinine quinidine cinchonidine cinchonine 1820: Quinine was isolated and named in 1820 by French researchers Pierre Joseph Pelletier and Joseph Bienaimé Caventou. The name was derived from the original Quechua (Inca) word for the cinchona tree bark, quina or quina-quina , which roughly means bark of bark or holy bark . (from wikipedia) 1853 Pasteur: acid catalyzed rearrangement of quinine to quinotoxine 2 S 4 quinotoxine 22 1856: Perkin and offman's 'mathematical' approach 2 + []? - 2 C quinine C unsuccessful experiments led to the aniline dye industry = image from ver a 40-year period, Paul Rabe and his students published over 40 papers on the structure, chemical and physical properties, and synthesis of quinine and other cinchona alkaloids. Rabe: Universities of Jena, Prague and amburg 1908: proposed the correct structure of quinine 1918: Rabe and Karl Kindler synthesize quinine from quinotoxine 1935: Rabe forced by the azis into early retirement from his position as Director of the Institute in amburg. This was retaliation because Rabe had removed a notice from the notice board notifying of a boycott against Jewish students at his Institute. Rabe continues to conduct experiments with limited resources 1939: 21 years after their preliminary communication, Rabe and Kindler published a brief publication (1939) with experimental details, Rabe and Kindler report the isolation of additional quantities of quinine from the preserved twodecades-old reaction residues from the aluminum powder reduction of quininone from: J. I. Seeman, Angew. Chem. Int. Ed. 2007, 46, from: J. I. Seeman, Angew. Chem. Int. Ed. 2007, 46, William von Eggers Doering (b. 1917) undergraduate and graduate student at arvard, receiving the Ph.D. in 1943 Columbia in , Yale , arvard 1968-present Robert Burns Woodward BS (MIT) 1936 Ph.D. (MIT) : postdoc at Illinois : arvard 1965: obel Prize 26 retrosynthesis Rabe Prelog/Rabe Et quinine quinotoxine ethyl quininate Et ester of homomeroquinene 2 Ac + Et- Ac 3 + Et Pomeranz-Fritsch reaction Et 2 Et quant. Et Et 2 S 4 64% 62% C 2 64% a 220 C Ac + Ac 20% (crystalline) 1) Rai 2 (3000 psi) 2) Cr 3 Ac 1) Pt 2 2 2) Ac 2 pyr 95% Ac aet, Et Et C 2 Et Et 1) Pt 2 2 Ac 2) I K 2 C Et I Ag K homomeroquinene (purified by as urea formed with C) 1) Et, Cl aet Et2 C homomeroquinene 2) K 2 C 3 PhCCl Bz C 2 Et Bz 6 Cl Rabe 1918 quinine quinotoxine Malaria was the most important health hazard encountered by U.S. troops in the South Pacific during World War II, where about 500,000 men were infected. Sixty thousand American soldiers died of malaria during the orth African and South Pacific campaigns. During the war, the U.S. had been cut off from the Dutch East Indies, its major sources of cinchona bark from: J. I. Seeman, Angew. Chem. Int. Ed. 2007, 46, : Gilbert Stork characterized the impression of the achievement of the synthesis of quinine by Woodward and Doering as a widely believed myth. Stork concluded that the claim by Woodward and Doering is a myth because they had synthesized only homomeroquinene and d-quinotoxine; no synthetic quinine had been made in Cambridge. In fact, Rabe and Kindler never published the experimental details of their conversion of d-quinotoxine into quinine. Gilbert Stork Born in Brussels, Belgium, 1921 University of Florida, B.S. 1942; University of Wisconsin Madison, PhD 1945 with Samuel M. McElvain 1946 arvard University: Instructor 1948 Assistant Professor 1953 Columbia University from: J. I. Seeman, Angew. Chem. Int. Ed. 2007, 46, from: J. I. Seeman, Angew. Chem. Int. Ed. 2007, 46, from: J. I. Seeman, Angew. Chem. Int. Ed. 2007, 46, In the very last phase of the Rabe pathway, one has to reduce a ketone, quininone and quinidinone, to alcohol.... We tried to repeat it but we were not successful to obtain quinine in a yield that one can consider successful. ne obtained a mixture: quinine was one of the components but not in substantial amount that in my point of view we could call a practical yield. Milan Uskokovic from: J. I. Seeman, Angew. Chem. Int. Ed. 2007, 46, from: J. I. Seeman, Angew. Chem. Int. Ed. 2007, 46, from: J. I. Seeman, Angew. Chem. Int. Ed. 2007, 46, ur validation of the formal total synthesis of quinine as originally reported by Woodward and Doering in 1944[1] should serve to remove the blemish asserted[6,7] on the reputations of Rabe and Kindler as well as those of Woodward and Doering. poisonous chemical compound secreted by many species of blister beetle, and most notably by the Spanish fly, Lytta vesicatoria (a beetle). The beetle contains up to 5% cantharidin Cantharidin was first isolated in 1810 by Pierre Robiquet, LD50 is around 0.5 mg/kg, with a dose of as little as 10 milligrams being potentially fatal Various preparations of desiccated Spanish flies have been used as some of the worldʼs oldest alleged aphrodisiacs, with a reputation dating back to the early western mediterranean classical civilizations: In Roman times, Livia, the scheming wife of Augustus Caesar, slipped it into food hoping to inspire her guests to some indiscretion with which she could later blackmail them. enry IV ( ) is known to have consumed Spanish fly at the risk of his health. It was slipped into the food of Louis XIV to secure the king's lust for Madame de Montespan. In the 18th century, cantharides became fashionable, known as pastilles Richelieu in France. -wikipedia Maquis had invited either a small select number, or a large one, of guests who were either local innocents or local libertines (or both), and with the intention of inciting them all to a friendly sexual frenzy he fed them either aniseed comfits or chocolate pastilles (or both) laced with Spanish Fly and/or other more genuine aphrodisiacs. Madame de Montespan The planned fun backfired in the worst possible way for both the guests (who became seriously compromised and/or seriously ill) and the Maquis who was arrested and charged with poisoning. hep:// of- bon- bons.html Von Bruchhausen, F; Bersch,. W. Arch. Pharm. 1928, 266, 697 from Gas phase reactions in organic synthesis By Yannick Vallée the first planned stereospecific synthesis oxidize reduce C 2 C 2 C 2 C 2 C 2 C 2 C 2 C 2 C 2 C 2 C 2 C 2 1) 2 /Pd 2) C 2 C 2 1) LA C 2 C 2 2) MsCl 3) KSEt Rai EtS EtS s 4 EtS EtS 1) I 4 2)! PhLi Ph 1) 27 C 13 CCl 2)! 3 ; 2 2 Ph 42 strychnine isolated by Pierre Joseph Pelletier and Joseph Bienamé Caventou in 1818 from the Saint Ignatius bean of the Strychnos ignatii tree, named by Jesuit missionaries who named the plant medicinally. Indigenous to the Philippines Decades of experimentation, particularly by Robinson (250 papers!) and ermann Leuchs led to structure elucidation by Robinson in The Strychnine tree (Strychnos nux-vomica L.) also known as ux vomica, Poison ut, Semen strychnos and Quaker Buttonswith, is native to India, southeast Asia It is a major source of the highly poisonous alkaloids strychnine and brucine, derived from the seeds inside the tree's round, green to orange fruit. The seeds contain approximately 1.5% strychnine, and the dried blossoms contain 1.023%.[1] owever, the tree's bark also contains brucine and other poisonous compounds. from wikipedia and Molecules that changed the world by icolaou 43 Strychnine acts as a blocker or antagonist at the inhibitory or strychnine-sensitive glycine receptor (GlyR), a ligand-gated chloride channel in the spinal cord and the brain Strychnine causes muscular convulsions and eventually death through asphyxia or sheer exhaustion. -wikipedia Irwin and Rippe's intensive care medicine By Richard S. Irwin, James M. Rippe, 2008 LD50 = 1-2 mg/kg orally in humans otable strychnine poisonings Strychnine poisoning (in contaminated wine) is one of the theories concerning the death of Alexander the Great. Strychnine was used in several of the murders committed by serial killer Thomas eill Cream, who poisoned prostitutes on the streets of London. Famous Delta Blues legend Robert Johnson's whiskey bottle was laced with strychnine, resulting in pneumonia. A childhood friend of Vincent Van Gogh, Margot Begemann, attempted suicide by ingestion of strychnine. Belle Gunness of La Porte, Indiana, also known as Lady Bluebeard, reportedly used strychnine to murder her victims at the turn of the last century.[6] annes irtzberger, Mayor of Spitz in Lower Austria was reported to have been poisoned by elmut sberger, a local wine producer.[7] Jane Stanford, co founder of Stanford University may have died from strychnine poisoning.[8] skar Dirlewanger, the notorious WWII leader of the SS-Sturmbrigade Dirlewanger, a penal battalion composed of German criminals, was known to have murdered several Jewish girls in the Lublin Ghetto in Poland by having them stripped naked and injected with strychnine. This was done for the entertainment of himself and his officers who watched their fatal convulsions while relaxing. [ citation needed ] A woman in San Diego, California was a victim of strychnine poisoning in 1990 at the hands of her husband, who had dialed 911 but hung up the telephone without leaving his name or address. Persistence on the part of the dispatcher and the rescue workers allowed them to locate and extract the victim, but she eventually died in the hospital.[9] Fictional strychnine poisonings Mrs. Emily Inglethorp in Agatha Christie's The Mysterious Affair at Styles Inmates in the popular TV series The Wire were given heroin doses laced with strychnine. orman Bates' mother and her lover were killed with strychnine in Alfred itchcock's Psycho. The sheriff comments: Ugly way to die. Chief Constable Riddle's daughter, Emily was killed with an accidentally lethal case of strychnine-laced cocaine in Peter Robinson's Cold Is The Grave . erb in Die Softly by Christopher Pike. In Cape Fear Max Cady poisons Sam Bowden's dog with strychnine. Rio Takeuchi in the manga Spiral: Suiri no Kizuna threatens main character, Ayumu arumi in a game to test his luck using strychnine poisoning. In All Things Wise and Wonderful , James erriot, the main character and local veterinarian, deals with several victims of strychnine poisoning when a dog-killer attacks the neighborhood dogs. The murder in the Monk episode Mr. Monk and the Secret Santa is carried out through a bottle of port poisoned with strychnine. The Joker makes a cameo appearance in the Elseworld graphic novel Gotham by Gaslight as a serial killer who tries to kill himself with strychnine, leaving him with a permanent grin. text from wikipedia; photo from smithsonian R. B. Woodward, M. P. Cava, W. D. llis, A. unger,. U. Daeniker, K. Schenker Tetrahedron, 1963, 19, Pages Communication: J. Am. Chem. Soc. 1954, 76, 4749 strychnine isostrychnine [] 48 I II I, ac LA TsCl pyridine stereochemistry unconfirmed V ab 4 unlikely [] single diastereomer single diastereomer
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