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Total Synthesis of (±)-Indolizomycin

Total Synthesis of (±)-Indolizomycin. A presentation by Guillaume Pelletier November 22 th 2012. Structural and biological analysis.

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Total Synthesis of (±)-Indolizomycin

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  1. Total Synthesis of (±)-Indolizomycin A presentation by Guillaume Pelletier November 22th 2012

  2. Structural and biological analysis • A fusion between Streptomyces strains NM16 and NP1-1 produced a particularly active clone SK2-52 which produced Indolizomycin as a potent antibiotic unstable indolizidine. • The particular arrangment of the hemi-aminal functionality (stereochemistry not defined) makes the indolizomycin a very labile molecule even at 25°C! • Total synthesis of the racemic compound was achieved by the Danishefsky group in 1990. Albert I. Meyers’ group intercepted the Danishefsky synthesis with an enantioenriched intermediate in 1999. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30. Gomi, S. et al. J. Antibiot. 1984, 37, 1491. Groaning, M. D.; Meyers, A. I. Tetrahedron Lett. 1999, 40, 4639.

  3. Retrosynthetic approach Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30. Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.

  4. First steps of the synthesis Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30. Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.

  5. First steps of the synthesis Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30. Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.

  6. First steps of the synthesis Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30. Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.

  7. « Aza-Robinson » annulation to form the first indolizidinone ring Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30. Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.

  8. « Aza-Robinson » annulation to form the first indolizidinone ring Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30. Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.

  9. McCluskey fragmentation and formation of 9-membered cycle Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30. Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.

  10. McCluskey fragmentation and formation of 9-membered cycle Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30. Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.

  11. McCluskey fragmentation and formation of 9-membered cycle Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30. Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.

  12. McCluskey fragmentation and formation of 9-membered cycle Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30. Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.

  13. (E,E,E)-Triene formation from the allyl functionality Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30. Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.

  14. (E,E,E)-Triene formation from the allyl functionality Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30. Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.

  15. (E,E,E)-Triene formation from the allyl functionality Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30. Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.

  16. (E,E,E)-Triene formation from the allyl functionality Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30. Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.

  17. End Game Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30. Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.

  18. End Game Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30. Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.

  19. End Game Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30. Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.

  20. Alternative pathway explored previously… Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30. Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.

  21. Alternative pathway explored previously… Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30. Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.

  22. Alternative pathway explored previously… Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30. Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.

  23. Alternative pathway explored previously… Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc. 1990, 112, 2003. Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem. Soc. 1993, 115, 30. Nicolaou, K. C.; Sorensen, E. J. in Classics in Total Synthesis, VCH Publishers, 1996, Ch. 28, p. 471-484.

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