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KE-4.4120 Organic Synthesis 1. Introduction

KE-4.4120 Organic Synthesis 1. Introduction. Prof. Ari Koskinen Laboratory of Organic Chemistry C318. Organic Synthesis. Lectures : Mon 10-12 Ke4 ; Wed 10-12 Ke4 Total ca . 48 hrs TA: Essi Karppanen Course outline , lectures and other handouts in Noppa

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KE-4.4120 Organic Synthesis 1. Introduction

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  1. KE-4.4120 Organic Synthesis1. Introduction Prof. Ari Koskinen Laboratory of Organic Chemistry C318

  2. Organic Synthesis • Lectures: Mon10-12 Ke4; Wed 10-12 Ke4 • Total ca. 48 hrs • TA: Essi Karppanen • Course outline, lectures and otherhandouts in Noppa • Course requirements and grading: • Learning diary (40%) • Litessay (period 1): evaluation of twosyntheses (20%) • Seminarpresentation (period 2): syntheticanalysis (30%) • Self-assessment (10%) • Lectures

  3. Futureeducation • Dominatedbysynthesis • Integrate: • Biology • Intramolecular interactions • Structure – property • Topology – DMPKT • Overview of: • Cellbiology, • Biophysics, • Biophysicalanalyticalmethods, • Bioinformatics • Etc…

  4. Can I make all conceivable molecules? • Only C,H,N,O • Avg mol wt of permeable drug molecule ca 500; max 750 • Avogadro’s number 6.1023 • Only one molecule each 10200 molecules • Total mass: 10173tonnes • Weight of the Earth: 6.1021tonnes! • Weight of the Universe: ca 1053tonnes!!! David Weininger Ari Koskinen Laboratory of Organic Chemistry

  5. Ingredients for synthesis

  6. Matter available on Earth

  7. … as theremaybemoreElementsthenfive, orsix; so the Elements of onebodymaybeDifferentfromthose of another; whenceitwouldfollow, thatfrom the Resolution of De-compoundbody, theremayresultMixts of an altogether new kind, by the Coalition of Elementsthatneverperhapsconven’dbefore. Robert Boyle, The SkepticalChymist, 1661

  8. Chemistryis… … The art of SeparatingBodies into theirsimplestconstituentparts, of unitingthosepartsagain and reproducing the originalCompound, and alsobydifferentmixtures and Variousmethods of CombiningBodies to produce new Substanceswhichexistnot in nature. John Hadley, Introduction to Chemistry, Fourth Cambridge BP1702 Chemistryprofessor 1756-1764.

  9. Heinrich Friedrich Delius • 8 July 1720 Wernigerode - 22 October1791 Erlangen • StudiedmedicineattheUniversitiesofHalleandBerlin. • Finishedstudieswithpromotion in 1743. • Became a memberofLeopoldina(Deutsche Akademie der Naturforscher) in 1746. • In 1749 took a jobatthe University ofErlangen. Againsttheoppositionbycolleagues he initiated "Chemie" as an individual academicdiscipline. by Johann EberhardIhle (1727-1814)

  10. Wöhler Berlin 22nd February 1828 Dear Professor, While I certainly hope that my letter of 12 January and the postscript of 2 February have arrived, and I live daily, or better hourly, in the eager hope of receiving your reply, still I will not wait for it but rather write already again, because I cannot, so to say, hold my chemical water and must tell you that I can make urea without the help of a kidney or even an animal, neither man nor dog. Ammonium cyanate is urea. J. C. Poggendorff'sAnnalen der Physik und Chemie1828, 88, 253-256.

  11. The birthof synthesis 19th Century: The Century of Aromatics • In his 1845 publication, Kolbe used the word “synthesis” for the first time • to describe the process of assembling a chemical compound from other substances Kolbe, H. Ann. Chem. Pharm.1845, 54, 145.

  12. August Wilhelm von Hofmann • 8 April 1818 – 5 May 1892. • Studied with Justus von Liebig: studied coal-tar and established the nature of aniline, a base in naphtha. • First director of Royal College of Chemistry (London). • Isolated sorbic acid from rowanberries oil. • Introduced molecular models (carbon black, hydrogen white, nitrogen blue, oxygen red, chlorine green, sulfur yellow). • William Perkin was Hofmann’s student when he discovered mauveine (aniline purple) in 1856.

  13. Synthetic quinine?

  14. Perkin: Mauve - Dye Industry

  15. Carbochemical Industry BASF (BadischeAnilin und Soda Fabrik) 1865 AGFA (Aktien-GesellschaftfürAnilinFabrikation) 1867; Paul Mendelssohn Bartholdy Operational transformations of FG’s Associative or analogue based planning Late 19th Century: Aromatic Compounds

  16. Paul Mendelssohn Bartholdy • 1841 – 1880 • Second son of Felix Mendelssohn-Bartholdy • Studied at Heidelberg (contemporary of Robert Bunsen). • After graduating in 1863 went to Berlin to study with Wilhelm Hoffmann. • Co-founder of Aktien-GesellschaftfürAnilinFabrikation in 1873 with Alexander Martius (student of Justus von Liebig) (became AGFA in 1898).

  17. Jacobus van’t Hoff • 30 August 1852 – 1 March 1911 • 1874 (with LeBel): Tetrahedral carbon atom • Kolbe simply dismissed van’t Hoff’s tetrahedral carbon atom! • Received the first Nobel prize in chemistry in 1901 “in recognition of the extraordinary services he has rendered by the discovery of the laws of chemical dynamics and osmotic pressure in solutions”

  18. Tetrahedral carbon atom: Organic chemistry becomes 3 Dimensional Pre-WW II: Planning

  19. Camphor: Berthelot • Pierre EugèneMarcellinBerthelot • 25 October 1827 – 18 March1907 • Contributed to disproving the concept of vitalism. • ” I do not want chemistry to degenerate into a religion; I do not want the chemist to believe in the existence of atoms as the Christian believes in the existence of Christ in the communion wafer.” • Berichte1908, 41, 4855. Berthelot, M. Comptes rendus, 1852, 35, 136–138. Comptes rendus, 1858, 47, 266–xxx.

  20. Camphor: Komppa Komppa, G. Ber. 1903, 36, 4332.

  21. Berthelot’s • camphor investigations provide another interesting episode: when he made artificial camphor out of terebenthin (l-pinene), he obtained l-terecamphene (l-camphene). However, when artificial camphene was prepared from australene (d-pinene), the product was d-austracamphene (d-camphene). • The l-form of pinene occurs in the ’old world’, and the existence of d-form in the ’new world’ provides a case of interesting geopolitical chemistry.

  22. Commercial production • In 1908, Komppa initiated a factory ‘Finnish Chemical Company’, later Finnish Chemicals, which produced some 200 kg of synthetic camphor! • In 1906, Schering Co starts producing synthetic camphor from turpentine oil; production reached 800 tons pa. • Schering-Plough 1971 • Merck 2009

  23. The logic, the tactics, the art ”There is excitement, adventure, and challenge and therecanbegreatart in organicsynthesis.” ”Chemicalsynthesisalwayshassomeelement of planning in it. But, the planningshouldneverbetoorigid. Because, in fact, the specificobjectwhich the syntheticchemistuses as the excuse of hisactivity is often of notspecialimportance in the general sense; rather, the importantthingsarethosethat he finds out in the course of attempting to reachhisobjective.” R.B. Woodward (1917-1979) "La Chimiecrée son objet." – "Chemistry creates its object. This creative capability, resembling that of art itself, distinguishes it essentially from the natural and historical sciences.” (1860) Marcellin Berthelot (1827-1907)

  24. In this kind of experimental research in the field of organic chemistry – the presentiment, that is ‘the chemical sensation’, has a very great importance. … On the other hand, we have to admit that this kind of work, where, together with purely scientific and sharply logical contemplation, imagination has been given an important position, yields inner satisfaction that best can be compared to what an artist feels about his work, when this work also bears great practical importance. Komppa – Inauguration of HUT 1908 Gustaf Komppa 1st Professor of Organic Chemistry at HUT Ari Koskinen Laboratory of Organic Chemistry

  25. Chemistry must be practical Strongly curiosity driven Industriallyapplicable Robustness Scaleuporscale out Useful and meaningful Generality of reactions; Target diversity Economies: atom, step and complexity Methodology The state of the art of organic synthesis is defined by the complexity of the targets attacked Science is about making the impossible possible Komppa heritage (1908)

  26. Professors of Chemistry and Organic Chemistry Since 1848 to 2003 Saelan, Anders 1848 - 1874 Wahlfors, Henrik 1874 - 1898 Komppa, Gustaf 1899 - 1937 Palmén, Oscar 1941 - 1952 Nyman, Gustaf 1954 - 1972 Gripenberg, Jarl 1972 - 1977 Lounasmaa, Mauri 1979 - 1998 Koskinen, Ari 1999 – present

  27. History Logic Perception Innovation Perseverance Synthesis Art

  28. SYNTHESIS • Preparation of COMPLEX target structures using INNOVATIVE chemical transformations • Typical applications: • total synthesis of natural products • development of new synthetic methodology

  29. Trends in Synthetic Methodology PERIOD TREND OBJECTIVE/OUTPUT 1950-1960 Classical synthesis of natural products Target conquest Mechanisms, Spectroscopy Hardware 1970-1980 Multistep, strategy and transformation based synthesis Stereo/enantiocontrol Synthetic methods Software R.B. Woodward Nobel 1965 for his outstanding achievements in the art of organic synthesis 1990- Designed molecules Selectivity, Recognition Function, Intelligence Content E.J. Corey Nobel 1990 for his development of the theory and methodology of organic synthesis

  30. Roles of Organic Synthesis

  31. Importance of Synthesis • Total synthesis of Natural Products • Industrially important compounds • Compounds of theoretical interest • Structure proof • Development of new synthetic methodology • Other areas of science and technology

  32. Natural Products

  33. Industrially Important Compounds Monomers and polymers Adhesives and coating agents Dyes Flavorings and scents Pharmaceutical products Cosmetics Insecticides Pesticides Herbicides

  34. Compounds of Theoretical Interest

  35. Structure Proof

  36. Development of new synthetic methodology Chemoselective transformations Diastereocontrolled reactions Enantioselective reactions Multi-step transformations (organometallic catalysis) Two-directional synthesis Solid phase organic synthesis Combinatorial synthesis

  37. Other Areas of Science Materials sciences Investigation of biological mechanisms Blood substitutes (perfluorocarbons) Organic (semi)conductors Dyes Energy storage Cooling liquids for photovoltaic cells ....

  38. UNDERLYING CHALLENGE Synthesis vs. preparation SYNTHETIC CHEMISTRY BASIS: • Transformations • Synthesis design • Mechanisms Problem? • TARGET (TGT) • stereochemistry • carbon skeleton • heteroatom content • biological activity • mechanistic problem

  39. Description of complexity Oftensimilarity! Druginvention Language: SMILES (Weininger) MOLECULAR COMPLEXITY Molecular size Element content Functional group content Stereocenter content Cyclic connectivity Chemical reactivity Structural instability

  40. 1940’s-1950’s: Planning

  41. WWII - 1960’s: Sophistication Increases Detailed mechanisms Conformational analysis Spectroscopy Chromatography New selective reagents

  42. Erythromycin is... • ‘so hopelessly difficult that its conquest cannot be conceived within the foreseeable future’ (Woodward, 1956)

  43. Targetsprior to 1980

  44. Targets 1980’s and 1990’s

  45. Supercarbonmolecules

  46. ComplexityEvolution

  47. Poorsteps (yieldor %ee!) quicklydestroyefficiency

  48. Tetrahydrocannabinol R. Adams J. Am. Chem. Soc.1940, 62, 2402-2405.

  49. Tetrahydrocannabinol B.M. Trost Org. Lett.2007, 9, 861-863.

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