1 / 53

Litterature Meeting

Litterature Meeting. Enantioselective Total Synthesis of Avrainvillamide and Stephacidins A and B. Aspergillus ochraceus. Aspergillus : A source of complexe prenylated indole alkaloids. - Isolation from Aspergillus ochraceus WC76466: 2002 – Bristol Myers Squibb

efuru
Download Presentation

Litterature Meeting

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Litterature Meeting Enantioselective Total Synthesis of Avrainvillamide and Stephacidins A and B Aspergillus ochraceus

  2. Aspergillus: A source of complexe prenylated indole alkaloids • - Isolation from Aspergillus ochraceus WC76466: 2002 – Bristol Myers Squibb • In vitro citotoxic activity (human tumor cell lines) • ⇒SPC B: 5-30 fold more active than SPC A (testosterone-dependent prostate LNCaP cell line: IC50=0.06 µM) 21 20 8 9 - Isolation from a fungal species found in an Indian clay sample (Sirsaganj, Uttar Pradesh, India) - Sources: 1/ Marine fungal strain Aspergillus: 2000 - Fenical and coworkers 2/ Fermentation broth of Aspergillus ochraceus: 2001 – Sugie and coworkers

  3. Biosynthesis of Stephacidin B: a lesson for the chemist * Birch and coworkers, J. Chem. Soc.Perkin I, 1974, 50. Sammes and coworkers Chem. Comm.,1970, 1103. . Reverse Prenylation Prenylation [O] 2 [O] 2 [O] Diels-Alder * 2 [O] [O] bicyclo[2.2.2]diazaoctane

  4. Presumed biosynthesis of Stephacidins A and B [O] [O] Intramolecular Diels-Alder Prenylation [O]

  5. Synthesis of Stephacidin A: formation of the bicyclo[2.2.2]diazaoctane nucleus Williams’ approaches NaH SN2’ Diels-Alder J. Am. Chem. Soc.1990, 112, 808. Acc. Chem. Res. 2003, 36, 127. Tetrahedron Lett.2004, 45, 4489.

  6. Synthesis of the bicyclo[2.2.2]diazaoctane by SN2’ approach Seebach and coworkers, J. Am. Chem. Soc.1983, 105, 5390. Somei and coworkers, Heterocycles1981, 16, 941.

  7. Synthesis of the bicyclo[2.2.2]diazaoctane by SN2’ approach (2) Brevianamide B

  8. Synthesis of the bicyclo[2.2.2]diazaoctane by SN2’ approach (2) Tight ion pair

  9. Synthesis of the bicyclo[2.2.2]diazaoctane by Diels-Alder approach 2.5:1 2.5:1

  10. Synthesis of the bicyclo[2.2.2]diazaoctane by Diels-Alder Approach Williams et al. Bioorg. Med. Chem., 1998, 6, 1233. 90 % R S

  11. Synthesis of the bicyclo[2.2.2]diazaoctane by Diels-Alder Approach "EXO" "ENDO" R S 90 % S R

  12. William’s synthesis of bicyclo[2.2.2]diazaoctane nucleus NaH SN2’ • 16 steps in 12 % yield overall • High stereoselectivity of alkylation based on the presence or absence of metal chelation Diels-Alder • 4 steps in 17 % yield overall from and • Medium stereoselectivity of cycloaddition based on steric effects

  13. Synthesis of Stephacidin A: formation of the bicyclo[2.2.2]diazaoctane nucleus Based on intermolecular Diels-Alder model reactions ⇒ acidic conditions such as HCl and BF3.OEt2 not as effective as AcCl or HCO2H ⇒ high pression and temperature ⇒ slow rates (6-20 days) Liebscher’ approach AcCl Diels-Alder Liebscher and coll. J. Org. Chem.2001, 66, 3984. + + major

  14. Synthesis of Stephacidin A: formation of the bicyclo[2.2.2]diazaoctane nucleus Liebscher’ approach (2) + Williams and coll. Tetrahedron Lett.2005, 46, 9013. Z-Admpa Lieberknecht and coll. Tetrahedron Lett.1987, 28, 4275.

  15. Synthesis of Stephacidin A: formation of the bicyclo[2.2.2]diazaoctane nucleus Liebscher’ approach (3) R AcCl tBuOK 78 % Diels-Alder rt, 20 days one stereoisomer ! 48 % minimal steric repulsion R defavoring steric repulsion S

  16. Liebscher’s synthesis of bicyclo[2.2.2]diazaoctane nucleus AcCl Diels-Alder • 2 steps in 37 % yield overall from and • Stereospecificity of cycloaddition based on steric effects due to presence of acetoxy group BUT Cycloaddition step achieved in 20 days and in only 48 % yield !!

  17. Synthesis of Stephacidin A: formation of the bicyclo[2.2.2]diazaoctane nucleus Myers’ approach Acyl radical approach J. Am. Chem. Soc.2005, 127, 5342. Abrams and coll. Tetrahedron1991, 47, 3259.

  18. Formation of the bicyclo[2.2.2]diazaoctane nucleus: Myers’ approach Corey and coworkers, Tetrahedron Lett.1991, 32, 5025. Corey E. J., Bakshi R. K., Shibata S. J. Am. Chem. Soc.1987, 109, 5551.

  19. Formation of the bicyclo[2.2.2]diazaoctane nucleus: Myers’ approach R S

  20. Formation of the bicyclo[2.2.2]diazaoctane nucleus: Myers’ approach Ghaffar T., Parkins A. W. J. Mol. Cat. A2000, 160, 249. S = H2O X 7-membered ring !

  21. Formation of the bicyclo[2.2.2]diazaoctane nucleus: Myers’ approach Jackson L. V., Walton J. C. Chem. Commun. 2000, 2327.

  22. Formation of the bicyclo[2.2.2]diazaoctane nucleus: Myers’ approach 62 % BUT

  23. Myers’ synthesis of bicyclo[2.2.2]diazaoctane nucleus Enantioselective synthesis of the desired nucleus 12 steps in 19 % yield overall from and Product used as precursor for synthesis of Stephacidin B

  24. Synthesis of Stephacidin A: formation of the bicyclo[2.2.2]diazaoctane nucleus Three steps: 1/ Synthesis of a model of the bicyclo[2.2.2]diazaoctane nucleus 2/ Application of the strategy to a functionalized system for eventual elaboration into Stephacidin A 3/ Formation of Stephacidin A Baran’ s approach J. Am. Chem. Soc.2006, 128, 8678.

  25. - Baran’s Synthesis of Stephacidin A –- First step: Preparation of a model of the bicyclo[2.2.2]diazaoctane nucleus - Intramolecular vinyl radical cyclisation Intramolecular Diels-Alder Intramolecular oxidative enolate heterocoupling

  26. - Baran’s Synthesis of Stephacidin A –- First step: Preparation of a model of the bicyclo[2.2.2]diazaoctane nucleus - First strategy: Ring closure by intramolecular Diels-Alder reaction Dehydrogenation Peptide coupling N-Boc-L-Trp Dehydrogenation

  27. - Baran’s Synthesis of Stephacidin A –- First step: Preparation of a model of the bicyclo[2.2.2]diazaoctane nucleus - First strategy: Ring closure by intramolecular Diels-Alder reaction (2) Dehydrogenation: 92 % ⇒ Study of direct dehydrogenation of simplified Trp derivatives Yamamoto and coll. J. Am. Chem. Soc. 2004, 126, 5962.

  28. - Baran’s Synthesis of Stephacidin A –- First step: Preparation of a model of the bicyclo[2.2.2]diazaoctane nucleus - First strategy: Ring closure by intramolecular Diels-Alder reaction (3) X X

  29. - Baran’s Synthesis of Stephacidin A –- First step: Preparation of a model of the bicyclo[2.2.2]diazaoctane nucleus - Second strategy: Ring closure by intramolecular vinyl radical cyclization X

  30. - Baran’s Synthesis of Stephacidin A –- First step: Preparation of a model of the bicyclo[2.2.2]diazaoctane nucleus - Third strategy: Ring closure by intramolecular oxidative enolate coupling Intramolecular Oxidative Coupling Baran and coll. Angew. Chem. Int. Ed.2005, 44, 609.

  31. - Baran’s Synthesis of Stephacidin A –- First step: Preparation of a model of the bicyclo[2.2.2]diazaoctane nucleus - Third strategy: Ring closure by intramolecular oxidative enolate coupling 6R 7 6 4 4 Diastereoselectivity Mechanism ?

  32. - Baran’s Synthesis of Stephacidin A –- Second step: Application to the elaboration of a suitable functionalized system - Amide bond formation Benzopyran Tryptophan Synthesis: Reider and coll. J. Org. Chem. 1997, 62, 2676.

  33. - Baran’s Synthesis of Stephacidin A –- Third step: Final formation of Stephacidin A - Benzopyran Tryptophan Synthesis (2): Proline Synthesis:

  34. - Baran’s Synthesis of Stephacidin A –- Third step: Final formation of Stephacidin A - Union of Tryptophan and Proline Fragments Ohfune and coll. J. Org. Chem. 1990, 55, 870.

  35. - Baran’s Synthesis of Stephacidin A –- Third step: Final formation of Stephacidin A - Union of Tryptophan and Proline Fragments (2) Yield: 4.5 % from 1 in 8 steps Comparison with natural Stephacidin A (spectra and optical data)

  36. - Baran’s Synthesis of Stephacidin A –- Third step: Final formation of Stephacidin A - ? Determination of absolute configuration • 1H and 13C NMR: identical in all respects to natural Stephacidin A • Optical properties R R + + S S Stephacidin A

  37. Synthesis of Stephacidin B DIMERIZATION Stephacidin A Double Michael addition pathway Cationic pathway c d c a b d

  38. Synthesis of Stephacidin B Myers’ approach: Three steps: 1/ Preparation and reactivity study of a model of Avrainvillamide 2/ Enantioselective synthesis of Avrainvillamide from bicyclodiazaoctane nucleus 3/ Formation of Stephacidin B J. Am. Chem. Soc.2003, 125, 12041. Oxidation 2 X J. Am. Chem. Soc.2005, 127, 5342.

  39. Myer’s Synthesis of Stephacidin B –- First step: Preparation and reactivity study of a model of avrainvillamide - Shimizu and coworkers, Tetrahedron Lett. 1993, 34, 3421. Oxidative addition 1,1-reductive elimination Formation of aryl copper derivative

  40. Myer’s Synthesis of Stephacidin B –- First step: Preparation and reactivity study of a model of avrainvillamide (2) - Identification of the Mickael acceptor group T = 23 °C A:B = 2:1 T = -20 °C A:B = 10:1 B A

  41. Myer’s Synthesis of Stephacidin B –- First step: Preparation and reactivity study of a model of avrainvillamide (2) - !!! X

  42. Myer’s Synthesis of Stephacidin B –- Second step: Synthesis of Avrainvillamide from bicyclodiazaoctane nucleus - Knochel and coll. Angew. Chem. Int. Ed. 2002, 41, 1610.

  43. Myer’s Synthesis of Stephacidin B –- Second step: Synthesis of Avrainvillamide from bicyclodiazaoctane nucleus - Avrainvillamide Nicolaou and coll. Angew. Chem. Int. Ed. 2005, 44, 3736.

  44. Myer’s Synthesis of Stephacidin B -- Third Step: Final Formation of Stephacidin B - Optical property: Synthetic aD25 = -35,1 (c 1,0; CHCl3) Natural aD25 = + 10,6 (c 1,0; CHCl3) Comparison 1H and 13C NMR spectra: 1H NMR: lack of correspondence in the region d 2.45-2.60 13C NMR: identical spectra Avrainvillamide Stephacidin B Optical property: Synthetic aD25 = +91,0 (c 1,0; CHCl3) Natural aD25 : unknown Comparison 1H and 13C NMR spectra: ⇒ Exact correspondence Interconversion in various solvent-acetonitrile systems: T = 38 °C AVR : SPC B = 2 : 1 T = 23 °C AVR : SPC B = 1 : 2 after 48h

  45. Synthesis of Stephacidin B - Baran’s approach: Increasing Oxidation State J. Am. Chem. Soc.2006, 128, 8678.

  46. Synthesis of Stephacidin B - Baran’s approach: X X X

  47. Synthesis of Stephacidin B - Baran’s approach: 1/ Initial oxidation studies performed on simplified Stephacidin A models 2/ Total synthesis of Stephacidin B starting from Stephacidin A via Avrainvillamide 3/ Biological evaluation of Avrainvillamide and simplified mimics J. Am. Chem. Soc.2006, 128, 8678. Angew. Chem. Int. Ed.2005, 44, 3892.

  48. Synthesis of Stephacidin B -- First Step: Initial Oxidation Studies performed on Simplified Stephacidin A models - Synthesis of a Stephacidin A model : Stephacidin A model

  49. Synthesis of Stephacidin B -- First Step: Initial Oxidation Studies performed on Simplified Stephacidin A models - Oxidation of Stephacidin A models:

  50. Synthesis of Stephacidin B -- Second Step: Formation of Stephacidin B starting from Stephacidin A via Avrainvillamide - X • Identical in all respects to the natural Stephacidin B: • LCMS • TLC in several solvent mixtures • 1H NMR • Optical rotation

More Related