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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

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Litterature Meeting

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  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

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