Total Synthesis and Evaluation of [ψ[CH 2 NH]Tpg 4 ] Vancomycin Aglycon: Reengineering Vancomycin for Dual D -Ala- D - Ala and D -Ala- D -Lac Binding Brendan.

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Presentation transcript:

Total Synthesis and Evaluation of [ψ[CH 2 NH]Tpg 4 ] Vancomycin Aglycon: Reengineering Vancomycin for Dual D -Ala- D - Ala and D -Ala- D -Lac Binding Brendan M. Crowley and Dale L. Boger J. Am. Chem. Soc. 2006, 128, Contribution from the Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, North Torrey Pines Road, La Jolla, California Presented by, Michael Elbaum

Dale L. Boger B.S. University of Kansas, 1975 Ph.D. Harvard University, 1980 Assistant / Associate Professor of Medicinal Chemistry, University of Kansas Associate Professor / Professor of Chemistry, Purdue University, Professor, The Scripps Research Institute, 1991-Present Member, The Skaggs Institute for Chemical Biology, 1996-present Editor-in-Chief, Bioorganic and Medicinal Chemistry Letter, 1990-present ACS Medicinal Chemistry Division, Councilor, ACS Aldrich Award for Creativity in Organic Synthesis, 1999 ISI Highly Cited (top 100 chemists) 1

Vancomycin First isolated 1953 by Edmund Kornfeld (Eli Lilly) from soil bacteria Treat Gram-positive bacteria Drug of Last Resort –Intravenous –Resistance Roughly 1000x less bioactivity 2

Retrosynthesis 5 amide bonds / 5 peptide couplings, 6 alpha-AA derivatives Atropodiastereomers, –DE = 18.7 kcal/mol –AB = 25.1 kcal/mol –CD = 30.4 kcal/mol Cyclization order, CD, AB, DE –Permits recycling of undesired atropisomer… thermal equilibration Biaryl, 2 nucleophilic substitutions –Formation CD / DE Activating nitro also serves as a precursor for arylchloride 3

Ring A Formation 4 Dale L. Boger. J. Am. Chem. Soc. 1999, 121,

Ring B Formation 5 Boger, Dale L. Bioorg. Chem. Lett. 1995, 5,

Ring C 6 Vassil P. Vassilev. Tet. Lett. 1995, 36,

Ring D: Chiral Auxilary 7 Nsenda, T. Tet. Lett. 1998, 39,2191

Ring E 8 Boger, Dale L. Bioorg. Chem. Lett. 1995, 5, Boger, Dale L. J. Org. Chem. 1997, 62,

Ring E 9 Unlisted RXN

Ring D 10 Dale. L. Boger. J. Am. Chem. Soc. 1997, 62, 4721

BCD Synthesis 11

BCD Synthesis 12

ABCD Synthesis 13 Thermal equilibration of 230 o C not seen

ABCD Synthesis 14 Thermal equilibration of 170 o C not seen

ABCD Synthesis: Suzuki Coupling 15

ABCD Cyclization 16

ABCD Cyclization 17

ABCDE Synthesis 18

ABCDE Cyclization 19 Again, no thermal equilibration

ABCDE 20

Final Stretch 21 Global deprotection 4 aryl esters, 2 TBS, NBoc, and 4-methyl carbamate!

Conclusion Product binds to D Ala- D Lac –100 fold increase Product binds to D Ala- D Ala –10 fold decrease 22

Thank You 23 Dale. L. Boger. J. Am. Chem. Soc. 2006, 128, Dale. L. Boger. J. Am. Chem. Soc. 2003, 126, Total synth Ristocetin Dale. L. Boger. J. Am. Chem. Soc. 1999, 121, Original total synth Vancomycin Aglycon Dale. L. Boger. J. Org. Chem. 1997, 62, Dale. L. Boger. Bioorg. Med. Chem. Lett. 1995, 5,