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Total Synthesis of (-)- Acetylaranotin : A 40-Year Journey

Total Synthesis of (-)- Acetylaranotin : A 40-Year Journey. Malay Doshi. Epidithiodiketopiperazines (ETPs): A Large Class of Compounds. Isolated 40 years ago Fungal metabolities Bio active compounds Viral RNA Polymerase inhibitor, anticancer, anti-proliferative.

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Total Synthesis of (-)- Acetylaranotin : A 40-Year Journey

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  1. Total Synthesis of (-)-Acetylaranotin:A 40-Year Journey Malay Doshi

  2. Epidithiodiketopiperazines (ETPs): A Large Class of Compounds • Isolated 40 years ago • Fungal metabolities • Bio active compounds • Viral RNA Polymerase inhibitor, anticancer, anti-proliferative Codelli, J., Puchlopek, A., Reisman, S., J. Am. Chem. Soc., 2011, DOI: 10.1021/ja209354e

  3. Structural Features Of Common ETPs

  4. Structural Features Of Common ETPs

  5. Looking To Nature For Inspiration (+)-11,11’-Dideoxyverticillin A • Biomimetic synthesis undertaken by Movassagi group • Biosynthesis needed to be understood • Structure is a dimer and has disulfide linkages Kim, J., Ashenhurst, J., Movassaghi, M., Science, 2009, 238-241

  6. Biosynthesis Of Dimer • Formed via tryptamine oxidation • Does not provide full stereocontrol Kim, J., Ashenhurst, J., Movassaghi, M., Science, 2009, 238-241

  7. Alternate Proposal For Dimerization Kim, J., Ashenhurst, J., Movassaghi, M., Science, 2009, 238-241

  8. Biosynthesis Of Disulfide Linkage

  9. Biosynthesis Of Disulfide Linkage • Evidence from biosynthetic gene cluster • Cysteine residue is common source of sulfur Kim, J., Ashenhurst, J., Movassaghi, M., Science, 2009, 238-241

  10. Biosynthesis Of Disulfide Linkage • Pyridoxal phosphate is a key cofactor Kim, J., Ashenhurst, J., Movassaghi, M., Science, 2009, 238-241

  11. Final Proposal Kim, J., Ashenhurst, J., Movassaghi, M., Science, 2009, 238-241

  12. Biomimetic Synthesis Of Dimer Kim, J., Ashenhurst, J., Movassaghi, M., Science, 2009, 238-241

  13. Biomimetic Synthesis Of Dimer Kim, J., Ashenhurst, J., Movassaghi, M., Science, 2009, 238-241

  14. Can We Always Use Biosynthesis As A Starting Point? • Gives a “proven” approach • Johnson’s synthesis to Progesterone • What works for nature may not work for us • Enzymes can do reactions that we can not • Dimerization had to be changed • Source of sulfur had to be changed • Biosynthesis is simply unknown • Can be an arduous process to figure out

  15. What If Biosynthesis Is Not Known? • Similar cores • Clive and his group attempt the synthesis Peng, J., Clive, D., J. Org. Chem., 2009, 74, 513-519

  16. Synthesis Of The Core Peng, J., Clive, D., J. Org. Chem., 2009, 74, 513-519

  17. Synthesis Of The Core Peng, J., Clive, D., J. Org. Chem., 2009, 74, 513-519

  18. Synthesis Of The Core Peng, J., Clive, D., J. Org. Chem., 2009, 74, 513-519

  19. Synthesis Of The Core Peng, J., Clive, D., J. Org. Chem., 2009, 74, 513-519

  20. Synthesis Of The Core Peng, J., Clive, D., J. Org. Chem., 2009, 74, 513-519

  21. Synthesis Of The Core • Core is synthesized; disulfide is incomplete • Overall: linear, 23 steps, 0.4% yield Peng, J., Clive, D., J. Org. Chem., 2009, 74, 513-519

  22. ReismanReterosynthesis • Key late stage S-S coupling Codelli, J., Puchlopek, A., Reisman, S., J. Am. Chem. Soc., 2011, DOI: 10.1021/ja209354e

  23. Synthesis Of Monomer Codelli, J., Puchlopek, A., Reisman, S., J. Am. Chem. Soc., 2011, DOI: 10.1021/ja209354e

  24. Synthesis Of Monomer

  25. Synthesis Of Monomer Codelli, J., Puchlopek, A., Reisman, S., J. Am. Chem. Soc., 2011, DOI: 10.1021/ja209354e

  26. Synthesis Of Monomer Codelli, J., Puchlopek, A., Reisman, S., J. Am. Chem. Soc., 2011, DOI: 10.1021/ja209354e

  27. Synthesis Of Dimer Codelli, J., Puchlopek, A., Reisman, S., J. Am. Chem. Soc., 2011, DOI: 10.1021/ja209354e

  28. Making The S-S bond • What are our choices? • Acidic, basic, radical or enzymes??

  29. S-S Bonds In Biology

  30. General Approaches To Sulfenylation • Reagent examples: O2, I2, DEAD, SO2Cl2 etc… • Can tolerate many functional groups Witt, D., Synthesis, 2008, 16, 2491-2509

  31. Using 1-Chlorobenzotriazole • SN2 displacement • Works well for unsymmetrical thiols • Long reaction times and generation of unwanted homo dimer (tough to remove) • Avoided by using correct equivalence • One pot Hunter, R.; Caira, M., Stellenboom, N. J. Org. Chem. 2006, 71, 8268

  32. From OrganophosphorusSulfenyl Halides • Starting material is hard to prepare, purify and is prone to fast degradation • Used for unsymmetrical thiols • Extremly specific for thiols • OH, NH2, carboxyl do not need to be protected • Reaction times are rather small Antoniow, S., Witt, D. Synthesis 2007, 363

  33. From Thiosulfates • Used for symmetericalthiols • Used for glycosidation • Practical and useful in kilo scale Davis, B. G.; Ward, S. J.; Rendle, P. M. Chem. Commun., 2001, 189

  34. What Are The Issues? • Sensitive to oxidative or acid conditions • Need basic conditions

  35. From Elemental Sulfur • First proposal was by Schmidt Ohler, E., Poisel, H., Tataruch, F., Schmidt, U., Chem. Ber., 1972,105, 635-641

  36. Epicoccin G Totokotosopoulos, S., Giuere, D., Sun, Y., Sarlah, D., Nicolau, K. C., J. Am. Chem. Soc., 2011, 133, 8150-8153

  37. Epicoccin G Totokotosopoulos, S., Giuere, D., Sun, Y., Sarlah, D., Nicolau, K. C., J. Am. Chem. Soc., 2011, 133, 8150-8153

  38. Epicoccin G Totokotosopoulos, S., Giuere, D., Sun, Y., Sarlah, D., Nicolau, K. C., J. Am. Chem. Soc., 2011, 133, 8150-8153

  39. Sulfenylation Of 2,5-Diketopiperazines • Syn or anti accommodate well • Polycyclic work well • Mixture of products Totokotosopoulos, S., Giuere, D., Sun, Y., Sarlah, D., Nicolau, K. C., Angew. Chem. Int. Ed., 2011, DOI: 10.1002/anie.201107623

  40. Sulfenylation Of 2,5-Diketopiperazines • Synor anti accommodated well • Polycyclic work well • Mixture of products Totokotosopoulos, S., Giuere, D., Sun, Y., Sarlah, D., Nicolau, K. C., Angew. Chem. Int. Ed., 2011, DOI: 10.1002/anie.201107623

  41. Mechanism Of Sulfenylation Totokotosopoulos, S., Giuere, D., Sun, Y., Sarlah, D., Nicolau, K. C., Angew. Chem. Int. Ed., 2011, DOI: 10.1002/anie.201107623

  42. Mechanism Of Sulfenylation • Initial mixing of NaHMDS and S8 • HRMS shows: major signal at m/z C12H36N2O2S4H+ [M+H+] 449.0908 • (TMS)2N-SSSS-N(TMS)2 • NMR after flash chromatography provided further evidence • 1H NMR (CDCl3, 600 MHz): δ=0.26 ppm • 13C NMR (CDCl3, 600 MHz): δ=2.4 ppm Totokotosopoulos, S., Giuere, D., Sun, Y., Sarlah, D., Nicolau, K. C., Angew. Chem. Int. Ed., 2011, DOI: 10.1002/anie.201107623

  43. Mechanism Of Sulfenylation Totokotosopoulos, S., Giuere, D., Sun, Y., Sarlah, D., Nicolau, K. C., Angew. Chem. Int. Ed., 2011, DOI: 10.1002/anie.201107623

  44. Mechanism Of Sulfenylation Totokotosopoulos, S., Giuere, D., Sun, Y., Sarlah, D., Nicolau, K. C., Angew. Chem. Int. Ed., 2011, DOI: 10.1002/anie.201107623

  45. Completion Of Acetylaranotin • Overall: Convergent, 18 steps, 0.45% yield Codelli, J., Puchlopek, A., Reisman, S., J. Am. Chem. Soc., 2011, DOI: 10.1021/ja209354e

  46. Summary And Conclusion • Structural features of Acetylaranotin • Three fused rings and disulfide linkage • Biomimetic synthesis of 11,11’-dideoxyvertillicin A • Biosynthesis of dimerization via tryptophan • Biosynthesis of disulfide via iminium ion • Synthesis of the core of Acetylaranotin • Linear, 23 steps and 0.4% yield

  47. Summary And Conclusion • Synthesis of Acetylaranotin • Convergent, 18 steps, 0.45% yield • Basic conditions used for sulfenylation • Elemental sulfur and NaHMDS • Used during synthesis of Epiconnin G

  48. Acknowledgements Professor Robert N. Ben • Dr. Mathieu Leclère • ChantelleCapicciotti • Anna Balcerzak • Devin Tonelli • Evan Perley-Robertson • Jennie Briard • Matt Alteen • Alan Grant

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