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Lectures 2014 Selective Organic Synthesis KD 2390 (9 hp) Christina Moberg The advent of organic chemistry shaped the world • Biology is dependent on organic synthesis • Organic synthesis is the foundation for biotechnology, nanotechnology, pharmaceutical industry, and material industry About the course: • Disposition: lectures, exercises, lab, workshop • Course book: Clayden, Greeves and Warren Organic Chemistry, Oxford University Press, 2012 (ISBN 978-0-19-927029-3) [or Clayden, Greeves, Warren and Wothers: Organic Chemistry, Oxford University Press, 2001 (ISBN 0 19 850346 6)] and distributed material • Examination: oral exam, lab work (lab and workshop compulsory) After the course the student should be able to:" " • Describe basic stereochemical concepts • Describe principles for stereoselective synthesis, in particular for enantioselective synthesis • Explain the stereochemistry observed in chemical reactions • Suggest methods for stereoselective synthesis of simple organic compounds containing stereogenic elements • Identify suitable reagents for stereoselective transformations • Use retrosynthetic analysis for the construction of synthetic routes for simple organic compounds • Prepare organic compounds using advanced synthetic methodology Contents • Fundamental stereochemical concepts • Synthetic strategy and principles for stereoselective, in particular enantioselective, chemical transformations • Transition metal catalysis • Applications of frontier orbital theory • Retrosynthetic analysis • Advanced organic synthesis Marcellin Pierre Eugène Berthelot (1827 - 1907) " "La Chimie crée ses objets" “This is an important point: neither biology nor chemistry would be served best by a development in which all organic chemists would simply become biological such that, as a consequence, research at the core of organic chemistry and, therefore, progress in understanding the reactivity of organic molecules, would dry out. Progress at its core in understanding and reasoning in not only essential for organic chemistry itself, but for life sciences as a whole. Life science needs Organic Chemistry that remains strong.” Axel Eschenmoser (2008) “Without the possibility of synthesis on the molecular level, efforts in reconstructing or engineering life are certainly bound to fail” P. Schwille, Angewandte Editorial 2013 Why are new molecules synthesized? Verify structure Curiosity Challenge Understand properties Function Paclitaxel (Taxol) O O H2N NH2 “I can no longer, so to CH3COOH speak, hold my NH Cl + Ag N=C=O CCl4 + CS2 4 chemical water and Camphor must tell you that I Komppa1903 Urea can make urea Wöhler 1828 without needing Acetic acid a kidney, whether Kolbe 1847 first organic of man or dog; the compound ammonium salt of first C-C bond cyanic acid is urea.” O H N OMe H H O N Progesterone OH Djerassi 1951 O H Tropinone N Robinson 1917 Quinine …it is in the course of attack of the Woodward & most difficult problems, without Doering 1944 consideration of applications, that new fundamental knowledge is most certainly generated. OH O H NH2 Cedrol H O Stork 1955 -O C N S O 2 CN NH2 NH N N NH + O N OAC 2 3 O Co O CO2H H N N H2N O Cephalosporin O Woodward 1966 O NH2 N NH N HO Vitamin B12 O H Eschenmoser & O O P O Woodward 1973 O OH O OH OH Erythronolide O OH Corey 1978 O OH OH H N 2 O O O OH OH OH HO OH OH OH CH3 HO OH OH OH OH OH OH HO OH O O CH3 OH OH O OH OH HO N N H H OH OH OH OH HO O H3C HO OH OH O CH3 OH O H3C HO CH OH OH 3 O OH OH OH OH HO OH OH Palytoxin Kishi 1994 Vancomycin Nicolau 1998 Därför säger nu Herren så: “Härav skall du förnimma att jag är Herren: Brevetoxin B se, med staven som jag håller i min hand vill jag slå på vattnet i Nilfloden, och då skall det förvandlas till blod. Och fiskarna i floden skola dö, och floden skall bliva stinkande, så att egyptierna skola vämjas vid att dricka vatten ifrån floden.” 2:a Mosebok 7:17-18 Maitotoxin Isolated 1971 from ciguateric fish (svart kirurgfisk) LD50: 50 ng/kg - 1 mg can kill 1 million mice 98 stereogenic centers 11 rings 26 stereogenic centers Structure determination - O NH You need to know which 2 O O CN NH2 N N molecule to synthesize NH2 Co O H N N H2N O O O NH2 N NH HO N O H Vitamin B12 O Dorothy Crowfoot Hodgkin 1956 O P O O OH Nicolau 2006 Epothilone A (anticancer) R O S N OH O O OH O Discodormelide HO O O OH O NH2 OH O OH first isolated in 1990 from the Caribbean marine sponge Discodermia dissoluta! Erythromycin (antibiotic) Malaria Malaria kills two children every minute OMe N OH H N Strategy Retrosynthesis S HO N O O OH O epothilone C and methodology: chemoselectivity regioselectivity stereoselectivity yield Chirality - Asymmetric synthesis A compound which is not identical to its mirror image is chiral A chiral compound is not identical to its mirror image A compound which is identical to its mirror image is not chiral A compound which is not chiral is identical to its mirror image S-(-)-limonene R-(+)-limonene HO OH N N H3C O O CH3 Muskarin ”Lorsqu’il se forme un corps dissymmétrique dans une réaction ou l’on n’a mis en présence les uns des autres que des corps symmetriques, il y aura formation dans la meme proportions des deux isomères de symétrie inverse… Il n’en est pas nécessairement de meme composés dissymétriques formés en présence de corps actifs euxmemes ou traversés de la lumière polarisée circulairement…” J.-A. LeBel 1874 E OH HO N N O CH3 H3C O t OCH3 H3C CH3 N S N HN OCH3 OCH3 H3C CH3 OCH3 H C CH O 3 3 N S N O N S N HN OCH3 HN OCH3 O O H2N NH2 OH Aspargine HO O H H O H2N NH2 bitter taste sweet taste Cl OH 1-Chloro-2,3- HO Cl HO H propanediol H OH poison pharmaceutical O O N O Thalidomide O N NH HN O O O O teratogenic CO H CO H HS 2 HS 2 Penicillamine NH2 NH2 Pharmaceutical against artrite poison In 2006, 80% of small-molecule drugs approved by FDA were chiral and 75% were single enantiomers. The field of asymmetric synthesis is expanding rapidly. Cl O Cl O O CN O Cl O N H S-Metolachlor herbicide Largest asymmetric metal-catalyzed process in the world (via hydrogenation of the imine using an Ir catalyst) Classification of isomers Stereoisomers Constitutional Isomers Enantiomers Diastereomers Stereogenic center Interchange of two ligands at a stereogenic center leads to a stereoisomer. H H * * Cl F Br Br Cl F For the tetrahedral carbon atom the interchange leads to an enantiomer F F This is not necessarily the case F * Cl F * Cl for molecules with other Cl F geometries F Cl A stereogenic center may or may not be chiral, but all chiral centers are stereogenic. Diastereomers HO HO CHO CHO H OH H Me H HO H Me Et Me H OH H OH N N Et H OH H OH Me H OH H OH CH2OH CH2OH Chiral? NH2 Me Me N H2N Me NH2 Me Me Me H MeO Me H Me OMe Chiral (or stereogenic) elements H H • Chiral (stereogenic) F F Cl Cl Br Br center NO 2 NO O N NO2 2 2 O2N NO2 HO2C S • Chiral (stereogenic) O2N CO2H HO2C CO2H O2N axis CO2H HO2C CO2H CO2H Me (H2C)4 Me • Chiral (stereogentic) OH HO O O plane Br Exercise Racemic 2-(1-hydroxyethyl)pyridine reacts with OH POCl3 to yield a phosphoric ester, OP(OR)3. 1 Describe the methyl part of the H NMR spectrum N O of the product mixture, assuming a statiscial ratio OH P RO OR of isomers RO N Exercise Draw all stereoisomers of the anhydride 1. Which isomers are chiral? Are there any symmetry elements? The optical rotation of two of the isomers approaches zero after standing at room temperature. Which are these isomers? Explain the phenomenon. O O O 1 AB-spectrum http://micro.magnet.fsu.edu/electromag/java/nmr/abspectrum/ Karplus’ equation J. Chem. Phys. 1959, 30, 11 J. Am. Chem. Soc. 1963, 85, 2870 How to get chiral enantioenriched molecules? • The chiral pool • Separation of enantiomers • Kinetic resolution (dynamic kinetic resolution) • Stereoselective synthesis ”Life depends on chiral recognition, because living systems interact with enantiomers in decisively different manners” (R Noyori) Paul Walden The Chiral Pool - Kirala poolen (R)-Hydroxy- Isobutyric acid (S)-Malic acid (äppelsyra-E296) Inhibits leukocyte adhesion to endothelial cells Cyclamenol A (2001) OH COOH HOOC OH OH COOH HOOC OH Asymmetric synthesis: De novo synthesis of a chiral substance from an achiral precursor such that one enantiomer predominates over the other. Molecules which contain at least one chiral element: lack of agreement; use Stereoselective synthesis Enantioselective synthesis Diastereoselkective synthesis Methods for stereoselective (asymmetric) synthesis –Diastereoselective reaction with chiral substrate –Use of chiral auxiliary –Use of chiral reagent –Asymmetric catalysis •Chiral metal catalyst Catalysis has a key role to •Enzymatic catalysis play in the development of Green Chemistry - not only •Catalytic antibodies for replacement of old •Organocatalysis stoichiometric reactions, but also for the development of new reactions. Chiral induction in catalytic reactions O Enantiotopic faces Ph Ph Ph X Enantiotopic groups X (-)-Menthol 20 000 ton/year N N OH 98% ee 100% ee TOF = 50 000 Enzymatic hydrolysis CO2CH3 pig liver CO2H 1. BH3 O esterase 2. H+ CO2CH3 CO2CH3 O Examples of additions to enantiotopic faces O HO H R1 H H2 H2 R1 R1 R2 R1 R2 cat "M" R2 cat "M" R2 hydrogenation hydrogenation O 1 Ph SiH Ph2HSiO H R ROOH O 2 2 R1 1 2 R1 R2 R R cat "M" R2 cat "M" R2 hydrosilylation epoxidation R1 O XCN NC OX ox HO OH R1 1 2 1 2 R R cat "M" R R R2 cat "M" R2 hydrocyanation dihydroxylation OH O O O- + 1 1 R R 2 R R2 aldol condensation Catalytic cycle Catalytic hydrogenation E Naproxen t H3C CH2 H H CH3 COOH COOH COOH H3C H3C H3C O O O Bonding in transition metal complexes Octahedral complex
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