Lecture1 123713A
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Introduction to asymmetric synthesis and total synthesis
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Lecture1 123713A
- 1. gareth j rowlands AND TOTAL SYNTHESIS 123.713 A/B STEREOSELECTIVE 1
- 2. why do we needTotal Synthesis? ©Wsiegmund@wikimedia commons O AcO H OH OBz OH O O OH Ph BzHN AcO O AcO taxol 2
- 3. ©ALTO CONTRASTE . Edgar AVG --BUSY--@flickr AcHN O H2N CO2Et Tamiflu® oseltamivir 3
- 5. © Armed Forces Pest Management Board@flickr N N Cl N NH O2N Imidacloprid (Advantage®) EUR 597 million 5
- 7. light-driven molecular motor Me(ax) Me(ax) (3R,3'R)-(P,P)-trans stable Me(eq) Me(eq) (3R,3'R)-(M,M)-trans unstable (3R,3'R)-(M,M)-cis unstable Me(eq) Me(eq) (3R,3'R)-(P,P)-cis stable Me(ax) Me(ax) ≥ 280 nm ≥ 380 nm ≥ 280 nm ≥ 380 nm 20°C60°C direction of rotation Feringa, Acc. Chem. Res. 2001, 34, 504 7
- 8. nanomotor to move objects rotor controls direction anchor Feringa et al., Nature 2006, 440, 163 8
- 9. nanomotor to move objects Feringa et al., Nature 2006, 440, 163 x8 real time 9
- 10. nanomotor to move objects Feringa et al., Nature 2006, 440, 163 x8 real time 9
- 11. O AcO H OH OBz OH O O OH Ph BzHN AcO O AcO taxol Me(ax) Me(ax) AcHN O H2N CO2Et what property do all these molecules share ? 10
- 12. chiralchiral 11
- 13. course structure Lecture 1: introduction Lecture 1: problems Lecture 2: catalysis Lecture 2: problems Lecture 3: retrosynthesis Lecture 3: examples Lecture 4: synthesis Lecture 4: assignment 12
- 15. Number16|2009 ChemComm Pages2053–2224 FEATURE ARTICLE Toshifumi Dohi and Yasuyuki Kita Hypervalent iodine reagents as a new entrance to organocatalystsISSN 1359-7345 COMMUNICATION Norifumi Fujita, Seiji Shinkai et al. An organogel system can control the stereochemical course of anthracene photodimerization 1359-7345(2009)16;1-0 www.rsc.org/chemcomm Number 16 | 28 April 2009 | Pages 2053–2224 Chemical Communications As featured in: See Debashish Roy, Jennifer N. Cambre and Brent S. Sumerlin, Chem. Commun., 2009, 2106. www.rsc.org/chemcomm Registered Charity Number 207890 By including polymer segments that are sensitive to three different stimuli,“schizophrenic”, triply-responsive block copolymers were obtained. RAFT copolymerization with a boronic acid containing monomer led to block copolymers capable of forming both micelles and reverse micelles, with the self-assembly being governed by the temperature, pH, and sugar concentration of the local environment. Title: Triply-responsive boronic acid block copolymers Showcasing research from Professor Brent Sumerlin’s laboratory, Southern Methodist University, USA. FEATURE ARTICLE Toshifumi Dohi and Yasuyuki Kita Hypervalent iodine reagents as a new entrance to organocataly stsISSN 1359-7345 COMMUNICA TION Norifumi Fujita, Seiji Shinkai et al. An organogel system can control the stereochemic al course of anthracene photodimeri zation 1359-7345(20 09)16;1-0 www.rsc.org /chemcomm Number 16 | 28 April 2009 | Pages 2053–2224 Chemical Communications ume7|Number9|2009 www.rsc.org/obc Volume 7 | Number 9 | 7 May 2009 | Pages 1737–1988 COMMUNICATIONJennifer R. Hiscock et al.Fluorescent carbazolylurea anion receptors 1477-0520(2009)7:9;1-6 D7903 · ASCAF7 · 351 (5) · 661–804 (2009) · ISSN 1615-4150 · No. 5, March 2009 5/2009 ASC 5-Year Impact Factor 2007 5.193 The Cutting Edge that Stays Sharp! Review: Transition Metal-Catalysed, Direct and Site-Selective N1-, C2- or C3-Arylation of the Indole Nucleus: 20 Years of Improvements Lionel Joucla, Laurent Djakovitch journals 14
- 19. ©DrStarbuck @ Flickr chiral object non-superposable18
- 22. OH O HS NH2H HO O SH H2N H a 1:1 mixture of enantiomers racemate is called a 21
- 24. CH3 HO O H NH214 2 3 naming: priorities groups CH3 NH2 H CO2H 1st atom C N H C 2nd atom H, H, H O, O, O priority 3 1 4 2 23
- 25. naming: lowest priority points away CH3 HO O H NH2 H3C OH O HH2N ≡ 14 2 3 1 4 2 3 24
- 28. been taught is what you have O O O O O O O O ©MonkeyBoy69@flickr not entirely true chiral four different groups but does not have 27
- 30. chiralityof other forms helical P [8]helicene M [8]helicene 29
- 35. stereocentres3 compounds 8 HO CHO OH OH OH HO CHO OH OH OH HO CHO OH OH OH HO CHO OH OH OH HO CHO OH OH OH HO CHO OH OH OH HO CHO OH OH OH HO CHO OH OH OH 34
- 44. properties enantiomers identicalhave NH2 NH2 NH2 H2N mp = 41-45°C mp = 40-43°C 43
- 45. properties differenthave diastereoisomers NH2 NH2 mp = 41-45°C bp = 221°C NH2 NH2 44
- 47. ©brittanyculver@flickr how do we measure purity? 46
- 48. NH2 NH2 NH2 H2N NH2 NH2 = 80% 20% 60%ee enantiomeric excess (ee) 47
- 49. NH2 NH2 NH2 H2N = 80% 20% 4 : 1 enantiomeric ratio (er) 80 : 20 48
- 50. NH2 NH2 NH2 NH2 80% 20% diastereoisomeric excess 60% de diastereoisomeric ratio 4 : 1 dr diastereoisomeric ratio 80 : 20 dr 49
- 51. ©brittanyculver@flickr how do we measure ee? 50
- 54. samethe ©David Reeves from Flickr chemistry diastereoisomers need 53
- 55. samethe chemistry diastereoisomers need.. R S R R R SR R S 54
- 56. OH Ph CO2H DCC, DMAPOMeF3C iPr O H O Ph F3C OMe iPr O H O Ph F3C OMe covalent Mosher’s acid 73JACS512, 73JOC2143 & 91JACS4092 derivatisation 55
- 57. HO2C CO2H OTol OTol O2C CO2H OTol OTol S diastereoisomer is insoluble NaOH (–)-propranolol β-blocker O OH NH O OH NH2 O OH NH ionic (salt) derivatisation 56
- 58. ©Pere Tubert Juhé@flickr temporary interactions chiral chromatography Si N H O NO2 NO2 Si OSi Si O O O O OSi OSi O O O O O Me Me silica chiral amine 57
- 60. 7 = 97.5 2.5 95%: er ee δ𝚫G‡ = 8.3 kJ mol-1 at 0°C 59
- 61. one substituent CH3 CH3 H CH3 H 95% equatorial more stable by 8 kJmol–1 5% axial disfavoured 60
- 63. H3C H Ph O H Et ...although one conformation of a molecule is more stable than other possible conformations, this does not mean that the molecule is compelled to react a s i f i t w e r e i n t h i s conformation or that it is rigidly fixed in any way. “ ..” D.H.R. Barton, Experientia 1950, 6, 316 62