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 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 , 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 , 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

4. First steps of the synthesis
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc , 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

5. First steps of the synthesis
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc , 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

6. First steps of the synthesis
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc , 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

7. « Aza-Robinson » annulation to form the first indolizidinone ring
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc , 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

8. « Aza-Robinson » annulation to form the first indolizidinone ring
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc , 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

9. McCluskey fragmentation and formation of 9-membered cycle
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc , 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

10. McCluskey fragmentation and formation of 9-membered cycle
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc , 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

11. McCluskey fragmentation and formation of 9-membered cycle
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc , 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

12. McCluskey fragmentation and formation of 9-membered cycle
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc , 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

13. (E,E,E)-Triene formation from the allyl functionality
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc , 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

14. (E,E,E)-Triene formation from the allyl functionality
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc , 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

15. (E,E,E)-Triene formation from the allyl functionality
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc , 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

16. (E,E,E)-Triene formation from the allyl functionality
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc , 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

17. End Game
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc , 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

18. End Game
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc , 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

19. End Game
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc , 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

20. Alternative pathway explored previously…
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc , 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

21. Alternative pathway explored previously…
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc , 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

22. Alternative pathway explored previously…
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc , 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

23. Alternative pathway explored previously…
Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. J. Am. Chem. Soc , 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