Lecture1: 123.702

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General introduction to the course followed by a basic introduction to asymmetric or stereoselective Synthesis. Then starting the course proper by looking at substrate control.

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Lecture1: 123.702

  1. 1. STEREOSELECTIVE AND TOTAL SYNTHESIS 123.702 gareth j rowlands
  2. 2. why do we need Total Synthesis? AcO O OH AcO BzHN O Ph O H OH OH AcO O taxol OBz ©Wsiegmund@wikimedia commons
  3. 3. do we need why Asymmetric Synthesis? O H N O O N O H ©Trois Têtes (TT)@Flickr
  4. 4. pure synthesis of enantiomers important Me Me NMe2 Me2N O Ph O Ph O Et O novrad cough-suppr Et essant darvon painkiller
  5. 5. course outline 6 asymmetric synthesis lectures 6 total synthesis lectures ©natashalcd@Flickr
  6. 6. course no tes
  7. 7. recommended books
  8. 8. ume 7 | Number 2009 9| Number 16 | 2009 www.rs c.org/obc s 2053–2224 ril 20 09 | Page 16 | 28 Ap Number ications Volume Commun Chemical 7 | Num ber 9 | 7 May 2009 | Pa ges 1737 co mm –1988 .org/chem www.rsc 5/2009 ChemCo D7903 · ASCAF7 · 351 (5) · 661–804 (2009) · ISSN 1615-4150 · No. 5, March 2009 m m journals Showca sing rese laborato arch from ry, Southe Professo rn Metho r Brent Su . dist Unive nic acid bl merlin’s rsity, USA ers ock copo lym As feature Chemical www.rsc.org Communication /chemcomm s d in: Number 16 | 28 April 2009 | Pages 2053–2224 sive boro ly-respon erent Title: Trip to three di e sensitive re ts that ar lymers we er segmen ock copo ng polym onsive bl aining By includi triply-resp acid cont hizo phrenic”, a boronic stimuli, “sc tion with forming bo th ARTICLE Kita 09)16;1-0 polymeriza FEATURE Yasuyuki a new TION et al. Dohi and as 1359-7345(20 ISSN 1359-7345 COMMUNICA Seiji Shinkai Toshifumi reagents Fujita, control the Hypervalent iodine sts Norifumi system can to organocataly pable of An organogel al course of anthracene entrance . RAFT co stereochemic zation photodimeri obtained lymers ca bly being block copo self-assem e Cambre monom er led to with the tion of th Jennifer N. d reverse micelles, r concentra shish Roy, See Deba Sumerlin, Chem. Co mmun., , and suga micelles an rature, pH d Brent S. the tempe an by 2009, 2106. COMMUN governed Jennifer ICATION onment. FEATURE ARTICLE suyuki Kita ;1-0 R. local envir ICATION Dohi and Ya s as a new 1359-7345 (2009)16 Fluoresce Hiscock et al. ISSN 135 9-7345 et al. COMMUN jita, Seiji Shinkai rol the Toshifumi t iodine reagent Pages 20 nt carbaz Fu nt len receptor olylurea Norifumi gel system can co racene Hyperva catalysts s to organo m an th ion An organo ical course of an entrance mcom .org/che stereochem zation www.rsc eri photodim 53–2224 207890 Charit y Number Registered 1477-052 0(2009)7 :9;1-6 Review: Transition Metal-Catalysed, Direct and ASC 5-Year Impact Factor 2007 Site-Selective N1-, C2- or C3-Arylation 5.193 of the Indole Nucleus: The Cutting Edge that Stays Sharp! 20 Years of Improvements Lionel Joucla, Laurent Djakovitch
  9. 9. lecture one terminology and substrate control
  10. 10. chiral object ©DrStarbuck @ Flickr non-superposable
  11. 11. chiral object non-superposable
  12. 12. chiral compounds O O HS OH HO SH H NH2 H2N H non-superposable
  13. 13. chiral compounds O O HS OH HO SH H NH2 H2N H enantiomers
  14. 14. achiral object sup erposable
  15. 15. achiral compounds H OH sup erposable
  16. 16. achiral compounds H OH Me Me plane of symmetry
  17. 17. O CH3 HO H NH2 naming: see1 23.202
  18. 18. O 3 2 CH3 HO H NH2 4 1 groups CH3 NH2 H CO2H 1st atom C N H C naming: 2nd atom H, H, H O, O, O priorities priority 3 1 4 2
  19. 19. O O 3 3 HO 2 CH3 ≡ H3C 2 OH H NH2 H2N H 4 1 1 4 naming: lowest priority points away
  20. 20. 3 2 2 3 1 1 S R anticlockwise clockwise right naming:
  21. 21. 3 2 O 3 H3C CO2H 2 H3C OH 1 H2N H 4 NH2 1 S S naming: finally... (S)-2-aminopropanoic acid
  22. 22. O S t-Bu N N H Ph N N Ru non-carbon-based N N chiral compounds N O P Me OMe same principals
  23. 23. other forms axia of chirality l O O O O O O O O ©MonkeyBoy69@flickr
  24. 24. other forms axia of chirality l PPh2 PPh2 Ph2P Ph2P ©mugley@flickr
  25. 25. other forms helic of chirality al P [8]helicene M [8]helicene
  26. 26. other forms of chirality Ph Ph Fe PPh2 Ph2P Fe planar
  27. 27. compounds with 2 stereocentres or more OH OH NH2 NH2 enantiomers
  28. 28. compounds with 2 stereocentres or more OH OH NH2 NH2 OH OH NH2 NH2 diastereoisomers
  29. 29. compounds with 2 stereocentres or more OH OH NH2 NH2 enantiomers
  30. 30. 2 stereocentres OH OH NH2 NH2 OH OH NH2 NH2 4 compounds
  31. 31. 3 stereocentres OH OH OH OH CHO CHO CHO CHO HO HO HO HO OH OH OH OH OH OH OH OH OH OH OH OH CHO CHO CHO CHO HO HO HO HO OH OH OH OH OH OH OH OH 8 compounds
  32. 32. n stereocentres 2n compounds
  33. 33. this is a ! generalisation!
  34. 34. 2 stereocentres OH OH HO2C HO2C CO2H CO2H OH OH OH OH HO2C HO2C CO2H CO2H OH OH 3 compounds
  35. 35. 2 stereocentres OH OH HO2C HO2C CO2H CO2H OH OH OH OH HO2C HO2C CO2H CO2H OH OH 3 diastereoisomers compounds
  36. 36. 2 stereocentres OH OH HO2C HO2C CO2H CO2H OH OH OH OH HO2C HO2C CO2H CO2H OH OH 3 enantiomers compounds
  37. 37. 2 stereocentres OH OH HO2C HO2C CO2H CO2H OH OH OH OH HO2C HO2C CO2H CO2H meso OH OH 3 identical compounds
  38. 38. meso compounds OH HO OH HO2C CO2H ≡ HO2C CO2H OH
  39. 39. meso compounds HO OH HO2C CO2H achiral of plane symmetry
  40. 40. enantiomers NH2 NH2 NH2 H2N have identical properties mp = 41-45°C mp = 40-43°C
  41. 41. diast ereoisomers NH2 NH2 NH2 NH2 have different properties mp = 41-45°C bp = 221°C
  42. 42. difference between dia stereoisomers key toasymmetric synthesis
  43. 43. how do we measure purity? ©brittanyculver@flickr
  44. 44. = NH2 NH2 NH2 NH2 H2N NH2 80% 20% 60%ee enantiomeric excess (ee)
  45. 45. = 4:1 NH2 NH2 NH2 H2N 80% 20% enantiomeric ratio (er)
  46. 46. NH2 NH2 NH2 NH2 80% 20% diastereoisomeric excess 60% de diastereoisomeric ratio 4 : 1 dr
  47. 47. how do we measure ee? ©brittanyculver@flickr
  48. 48. left and right handed gloves arei d entical
  49. 49. tilyou un add a hand
  50. 50. chem istry thesam e need ©David Reeves from Flickr diastereoisomers
  51. 51. chem istry thesam R S e R R R R S R S need.. diastereoisomers
  52. 52. covalent derivatisation O Ph O H OH DCC, F3C OMe F3C OMe DMAP iPr Ph CO2H O Ph O H F3C OMe iPr Mosher’s acid 73JACS512, 73JOC2143 & 91JACS4092
  53. 53. OTol HO2C OH CO2H OH O O OTol OTol O2C NH NH2 CO2H OTol S diastereoisomer is insoluble NaOH OH O ionic (salt) NH derivatisation (–)-propranolol β-blocker
  54. 54. temporary interactions O O O Si O Si O H O O O Si N Si O Me Si O Si NO2 O Me O O NO2 silica chiral amine chiral ©Pere Tubert Juhé@flickr ch romatography
  55. 55. asymmetric ©Tony the Misfit@flickr synthesis
  56. 56. O O H H n-C4H9 O O canadensolide3 2, 971 006, 6 ©simpologist@flickr Tetrahderon, 2
  57. 57. substrate O O H H control n-C4H9 O O OH O n-C4H9 OMe OBn O OSiMe3 TiCl4 100% n-C4H9 H OH O OMe 77% OBn n-C4H9 OMe OBn 0% 100% de
  58. 58. ©SarahWynne@flickr
  59. 59. C ram helation Cln ontrol Ti BnO O n-C4H9 Me3SiO H H MeO
  60. 60. Bürghi-Dunitz angle OR R Nu RR Nu Nu repulsion R R C O C O R R π π*
  61. 61. C ram helation ontrol M O O Nu OH L M Z L R R R Z S S L Z S Nu
  62. 62. C ram helation ontrol M O O Nu OH L M Z L R R R Z S S L Z S Nu L Z Z O O OH L Nu OH Nu Z S Nu S L S L Z S R R R R
  63. 63. Me HO O OH O MeO Me HO Me HO OH OH Me Me O Me OMe preswinholide 7 , 943 51 Tetra hderon, 1995, ©Ed Bierman@flickr this isn’t the right sponge!
  64. 64. substrate control Me t-Bu O H Me t-Bu Si t-Bu O O O Me t-Bu Si Me O OH Me O TiCl4 Me Me 94% Me O 95% de Me OMe OMe Me3Si Me
  65. 65. why
  66. 66. Felkin-Ahn model O M S O L L Nu M H Nu H S Nu
  67. 67. Felkin-Ahn H OH model Ph Et O Me H EtMgBr 25% Ph H HO H Me H Ph Et Me H 75% (50% de)
  68. 68. Felkin-Ahn model O Ph O Ph H ≡ Me H Me H H draw first... Newman projection
  69. 69. Felkin-Ahn model Ph O Ph O OH Me O H Ph Ph Me H Me H H Me HH H rotate group large perpendicular
  70. 70. Felkin-Ahn model Me O Me OH Ph Ph HH Et H Et H HO H Me OH Ph Et ≡ Et Ph Me H H H
  71. 71. notthe whole O story Ph SMe Zn(BH4)2 LiEt3BH H OH HO H iPr iPr Ph Ph SMe SMe
  72. 72. chelation control Zn MeS O iPr H3B H H Ph
  73. 73. no chelation O iPr MeS Ph H H BEt3 electronegative element perpendicular carbonyl
  74. 74. sterics electronics ©Capt Kodak@flickr
  75. 75. substrate control O n-C4H9 H OH O TiCl4 n-C4H9 OBn OMe OSiMe3 OBn OMe

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