Total Synthesis of (

±

)-Indolizomycin

A presentation by Guillaume Pelletier November 22 th 2012

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 molecule even at 25 arrangment ° C!

of the hemi-aminal functionality (stereochemistry not defined) makes the indolizomycin a very labile 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.

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.

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.

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.

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.

« 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.

« 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.

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.

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.

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.

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.

(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.

(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.

(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.

(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.

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.

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.

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.

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.

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.

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.

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.