SYNTHESIS

1. SYNTHESIS Make me a molecule “Chemists makemolecules… they study the properties of these molecules; they analyze, they form theories as to why molecules are stable, why they have the shapes and colors they do; they study mechanisms, trying to find out how molecules react.” “At heart of their science is the molecule that is made.” ― Roald Hoffmann―

2. In the beginning synthesis was unnecessary. Chemistry was founded upon the study of those materials which were available from natural sources. Many of the materials we use today are made by chemical synthesis.

3. Organic Chemistry Organic Compounds Most of the new compounds made today are organic, that is, they are composed largely of carbon. This element has a unique ability to form strong chemical bonds between not only carbon atoms but also many other elements. The chemistry of life is largely a result of the incredible versatility of carbon and is, of course, why carbon chemistry is calledorganic chemistry. unstable stable and versatile

4. Product e.g. paint and pigment vitamin synthetic fiber pesticide plastic explosive pharmaceutical

5. Organic Synthesis: • Carbon-Carbon Bond Formation • Functional Group Interconversion enantiomers Efficiency and selectivity are important characteristics that have to be taken into account. Efficiency:yields, number of steps Selectivity:chemoselectivity, regioselectivity, stereoselectivity

6. 분자식입체이성질체(Stereoisomers) cis-1,2-dichloroethylene (bp: 60 oC) trans-1,2-dichloroethylene (bp: 48 oC) cis trans (+)-2-iodobutane (bp: 119 oC) (-)-2-iodobutane (bp: 119 oC) Chiral compounds “Enantiomer”

7. Conformations of Ethane conformation: the different arrangements of atoms that result from rotation about a single bond conformers: a specific conformation (conformational isomer); same connections of atoms Eclipsed conformation Staggered conformation

8. Conformational Mobility of Cyclohexane Hax Heq Heq Hax - Energy barrier of interconversion; 45 kJ/mol (10.8 kcal/mol) (20 kcal/mol available at 25 ℃) - Hax and Heq are indistinguishable

9. Twist-Boat Cyclohexane

10. Chirality • If an object has a plane of symmetry it is the same as its mirror image. • The lack of a plane of symmetry is called “handedness”, chirality Chiral: [Greek; cheir (hand) + al] Crystals, molecules, or three-dimensional objects that are not superimposable with their mirror images are said to be chiral. (cf.achiral) Chiral ObjectsAchiral Objects baseball glove pencil golf club tennis racket Chiral object (molecule) A is different object (molecule) from its mirror image object (molecule) A’.

11. Chiral Molecules and Achiral Molecules Enantiomers and the Tetrahedral Carbon Mirror Images identical (superimposable) achiral identical (superimposable) achiral enantiomers (nonsuperimposable) chiral

12. Chirality Centers • A point in a molecule where four different groups (or atoms) are attached to carbon is called a chirality center(asymmetric center or stereogenic center). • Note thatchirality is a property of the entire molecule, whereas a chirality center is a structural feature within the molecule that causes chirality. *

13. Pasteur’s Discovery of Enantiomers • Louis Pasteur discovered that sodium ammonium salts of tartaric acid crystallize into right handed and left handed forms– such an event is rare. Resolution of enantiomers Louis Pasteur Chemist 1822-1895 “Chance favors only prepared mind. -Louis Pasteur

14. Optical Activity • Light restricted to pass through a plane is plane-polarized. • Solutions of chiral compounds rotate plane-polarized light andthe molecules are said to be optically active.

15. Chiral Compounds (-)-2-iodobutane (bp: 119 oC) (+)-2-iodobutane (bp: 119 oC) [ ]D = +15.9 [ ]D = -15.9 Enatiomers Optical isomers They are optically active.

18. MAKING COMPLEX MOLECULES Fischer achieved the first synthesis of the first truly complicated organic molecules, the sugar molecule D-glucose in 1890. Hermann Emil Fischer Germany (1852-1919) D-Glucsoe The Nobel Prize in Chemistry 1902 Fischer’s work on the total synthesis of D-glucose is regarded as the catalyst for the development of synthetic organic chemistry in the 20th century.

19. Willstatter’s synthesis of tropine Sir Robert Robinson United Kingdom (1886-1975) The Nobel Prize in Chemistry 1947 Robinson’s synthesis of tropinone in 1917 The Robinson’s synthesis of tropinone was hailed as revolutionary. This was to look at the target molecule and try to imagine how the molecule could be constructed from simpler chemical units.

20. Sir Christopher Kelk Ingold (1893-1970)

21. In 1965 Professor R. B. Woodward was awarded the Nobel Prize for his contribution to ‘The Art of Organic Synthesis.’ The organic synthesis is like the game of chess. As the result of better understanding of the mechanistic principles of organic reactions, by the 1940s and 1950s the field of total synthesis really took off.

22. Robert Burns Woodward

23. Some of the Complex Molecules Made by Woodward “There is excitement, adventure, and challenge, and there can be great art in organic synthesis.” - Woodward Quinine (1944) anti-malarial drug Vitamin B12 (1973) Strychnine (1954) pesticide

24. Prostaglandins Corey, Elias James 1928–, American organic chemist and educator, b. Methuen, Mass., grad. Massachusetts Institute of Technology (B.S. 1948, Ph.D. 1951). In 1990, he was awarded the Nobel Prize in Chemistry. Some prostaglandins affect human blood pressure at concentrations as low as 0.1 microgram per kilogram of body weight. Substances that inhibit prostaglandin synthesis may be useful in controlling pain, asthma attacks, and anaphylactic shock and in reducing the clotting ability of blood.

25. Retrosynthetic Analysis by Corey “The organic chemist is more than a logician and strategist; he is an explorer strongly influenced to speculate, to imagine, and even to create.” - Corey

26. Chiral Compounds (-)-2-iodobutane (bp: 119 oC) (+)-2-iodobutane (bp: 119 oC) [ ]D = +15.9 [ ]D = -15.9 Enatiomers Optical isomers They are optically active. Separation of enantiomers: Resolutionor Optical resolution

27. To obtain one pure enantiomer, resolution is required. Only one enantiomer is obtained by asymmetric synthesis.

28. Asymmetric Synthesis Synthesis of One Enantiomer using a Chiral Auxiliary [ ] Chiral Auxiliary :

29. Asymmetric Synthesis Synthesis of an Enantiomer using a Chiral Reagent Hebert C. Brown (1912- ) The Nobel Prize in Chemistry 1979

31. Asymmetric Synthesis Synthesis of an Enantiomer using a Chiral Catalyst

32. Asymmetric Synthesis Synthesis of an Enantiomer using a Chiral Catalyst

33. The anticancer drug, Taxol Synthesis: K. C. Nicolaou at The Scripps Research Institute Robert Holton at Florida State University

34. Organometallic Chemistry Acid-Base Chemistry Carbon Species carbocation stable (neutral) carbene carbanion radical unstable species relatively stable complex

35. 1. Stabilize unstable organic compounds - strained, unstable - does not exist at normal temperatures and pressures - reacts with itself to form larger ring - stable - well-behaved and easily-manipulated - readily seperated - a convenient source of cyclobutadiene

36. 2. Change characters of organic compounds - surrounded by a cloud of negative electrons - prefer to interact withpositively-charged molecules - reacts with itself to form larger ring - Cr(CO)3 sucks away electrons from benzene - prefer to interact with negatively-chargedmolecules

37. • • • • Combinatorial Chemistry Combinatorial Library 4 개의 monomer Nn Combinations 44 = 256개 tetramer

38. Solid Phase Synthesis의 기본원리 resin + monomer shake wash resin cleavage wash

39. Split-Mix Process Mix-Split Couple 33= 27 tag each bead! Mix-Split Couple

40. Solid Phase Library In 1991s, Houghten & Lam: synthesis of a huge peptide library 20 amino acids Solid-phase synthesis 202 = 400 dipeptides DNA: fully automatic (solution) peptide 203 = 8000 tripeptides carbohydrate small molecule (drug-like) 204 = 160,000 tetrapeptides ln 1992, Jon Ellman: synthesis of non-peptide drug-like molecules by solid phase synthesis

41. Supramolecular Chemistry 초분자 화학 1. Molecular chemistry- Covalent bond 2. Supramolecular chemistry- Chemistry beyond molecules Assembly of molecules – Molecular recognition Non-covalent bonds: - electrostatic forces - hydrogen bonds - van der Waals interactions - dipole interactions - hydrophobic interactions, etc 1987 노벨화학상: 초분자화학 Charles Pedersen, Jean-Marie Lehn, and Donald J. Cram

42. The Binding between Drug and Bilogical Receptors through Non-Covalent Bonds physiological response ‘recognition’ Drug Molecule Biological Effects Biological Receptor Supramolecular ‘complex’

43. DNA Double Helix

45. Carcerand

46. Chemosensors Signals: - fluorescence - color - electric signal...