Lecture3 123713B
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The document discusses various methodologies and strategies involved in total synthesis and retrosynthesis in organic chemistry, highlighting the importance of functional group identification, pattern recognition, and disconnection strategies. It provides specific examples and reaction schemes for various compounds, illustrating techniques such as aldol reactions, Diels-Alder reactions, and more. Additionally, the document emphasizes the need for simplification and convergent synthesis approaches in the design of synthetic pathways.
Lecture3 123713B
- 1. LECTURE THREE total synthesis ©Michael Budde@flickr 1
- 3. ? PPh3I O O OH HO OH Cl OH OH OH O O OHO AcO HO O O O O O HO OMe how total synthesis do we design a 3
- 5. R1 R2 ? how alkene do we make an 5
- 6. R1 R2 R1 R2 R1 R2 O R1 IPh3P R2 O R1 O R2 Wittig alkene metathesis reduction McMurry targets new 6
- 12. representations 0. draw multiple N N H H N N N N H H H H N N H H N N H H 12
- 13. 1. identify functional groups N OO O O cocaine N OO O O ester N OO O O ester N OO O O tertiary amine N OO O O N OO O O pyrrolidine piperidine 13
- 16. O O N H O OH H N O O O OH HH bistramide A peptide coupling O O O HH OH H2N OTBS OTIPS O H2N O O OTBS 4. convergent 16
- 17. N O O Cl OH H H NO H H OH OH Cl HO (+)-halichlorine Angew. Chem. Int. Ed. Engl. 1999, 38, 3542 lactone formation C–X C–X 5. disconnections 17
- 18. C–X 5. disconnections EtO2C O NH3•H2PO4 NHAc C–X EtO2C NH3•H2PO4 NHAc Tamiflu Angew. Chem. Int. Ed. Engl. 2009, 38, 1070 aziridine opening 18
- 19. C–C next to functional group 6. disconnections O O OH O H bipinnatin J Org. Lett. 2006, 8, 345 C–C O O O O Br nucleophilic addition Nozaki-Hiyama-Kishi 19
- 20. C–C next to functional group 6. disconnections O OH OH H H O halicholactone J. Org. Chem. 1997, 62, 6638 C–C nucleophilic addition Nozaki-Hiyama-Kishi OH I O O H H CHO 20
- 21. C–C next to functional group 6. disconnections N N N H N H OH manzamine A J. Am. Chem. Soc. 2012, 134, 17482 C–C N N H OH OTf Bu3Sn N N H Pd-cross coupling 21
- 22. N N H OH OTf N N H OH OTf precursor manzamine A J. Am. Chem. Soc. 2012, 134, 17482 RCM C=C C=C 7. disconnections 22
- 23. O TIPSO O O OH MeO2C O TIPSO O OH MeO2C O O P(O)(OMe)2 C=C precursor to palmerolide A J. Am. Chem. Soc. 2007, 129, 6386 Horner-Wadsworth-Emmons C=C 7. disconnections 23
- 24. group interconversions 8. functional TBSO O ON O O O precursor to penarolide sulfate A1 Eur. J. Org. Chem. 2008, 6213 FGI N O O O O O OTBS C–C Sonogashira TBSO O ON O O O I simplification 24
- 25. N O O HO O O O C7H15 hapalosin Tetrahedron Lett. 1996, 37, 6557 C7H15 OTBS CO2H C7H15 OH O ON O Bn O ON O Bn O C7H15 FGI C–C Evans aldol group interconversions 8. functional control 25
- 26. recognition 9. pattern H O H H H NH OH OH hirsutellone B J. Org. Chem. 2013, 78, 9584 ≡ H O H H H NH OH OH O O Diels-Alder H O H H H NH O O OP H O H NH O OP O 26
- 27. 9. pattern R OH OH R2 R O OH R2 R O O R2 FGI C–C aldol recognition OHO O O O O HO OH OH O rutamycin B ≡ OHO O O O O HO OH OH O 6 obvious aldol disconnections 27
- 28. ©Christian Puff Angew. Chem. Int. Ed., 1996, 35, 904 (–)-stenine N O H H H H O H 28
- 29. N O H H H H O H N O H H H H O H 6-membered ring 6 contiguous stereocentres 29
- 31. normally poor choice early C–C disconnection 2 x C–C N O H H H H O H N O H H H H O H enolate alkylation alkylation 31
- 32. N O H H H H O H 2 x C–N NH2 CHO O H H H H O H I reductive amination alkylation C–X disconnection simple 32
- 33. NH2 CHO O H H H H O H I C–O NH2 CHO HO H H H O H I ≡ (CH2)4I NH2 CHO CO2H Diels-Alder 4 of the 7 stereocentres of stenine iodolactonisation C–X disconnection simple 33
- 36. N O H H H H O H O I(CH2)4 O N O Ph O intramolecular DA solution + auxiliary 36
- 37. S S THPO Cl (CH2)4OPMB i. BuLi, then R–Cl ii. H+ 68% OH (CH2)4OPMB SS synthesis umpolung 37
- 38. OH (CH2)4OPMB SS ON OO (EtO)2(O)P i. Parikh-Doering oxidation ii. LiCl, Et3N, imide 77% PMBO(CH2)4 SS N O O O Ph synthesis activated DMSO (Swern) 38
- 39. synthesis intramolecular Diels-Alder (IMDA) PMBO(CH2)4 SS N O O O Ph S S PMBO(CH2)4 H H O O N O Ph Me2AlCl 85% 39
- 41. S S PMBO(CH2)4 H H O O N O Ph H H R N O Al O O H H S S Ph H H determining stereochemistry 41
- 42. S S PMBO(CH2)4 H H O O N O Ph i. AgNO3, NCS ii. LiSEt iii. Et3SiH, Pd/C iv. NaClO2, NaH2PO4 53% PMBO(CH2)4 H H O OH O synthesis removal auxiliary 42
- 44. synthesis PMBO(CH2)4 H H N H C O OMe O i. TMSCl, Et3N, 50°C ii. mCPBA iii. H5IO6 then I2, NaHCO3 50% N CO2Me O H I H H O H (CH2)4OPMB OH 44
- 48. N CO2Me O H H O H (CH2)4OPMB OH I i. H+, CH(OMe)3, MeOH ii. CH2=CHCH2SnBu3, AIBN iii. LDA, MeI 53% N CO2Me O H H O H (CH2)4OPMB OMe synthesis alkylation (twice) 48
- 50. N CO2Me O H H O H (CH2)4OPMB OMe i. Et3SiH, BF3•OEt2 ii. OsO4, NaIO4 iii. HSCH2CH2SH 50% N O H H O H S S OH CO2Me synthesis 50
- 51. synthesis N O H H O H S S OH CO2Me i. Raney Ni ii. MsCl, Et3N iii. NaI 73% N O H H O H I CO2Me 51