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Total Synthesis and Evaluation of [ψ[CH2NH]Tpg4] Vancomycin Aglycon: Reengineering Vancomycin for Dual D-Ala-D-Ala and D

This study presents the total synthesis and evaluation of [ψ[CH2NH]Tpg4] Vancomycin Aglycon, which aims to reengineer Vancomycin for dual D-Ala-D-Ala and D-Ala-D-Lac binding. The synthesis involves multiple amide bonds and peptide couplings, as well as biaryl and nucleophilic substitutions. The reengineered product shows a 100-fold increase in binding to D-Ala-D-Lac and a 10-fold decrease in binding to D-Ala-D-Ala.

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Total Synthesis and Evaluation of [ψ[CH2NH]Tpg4] Vancomycin Aglycon: Reengineering Vancomycin for Dual D-Ala-D-Ala and D

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  1. Total Synthesis and Evaluation of [ψ[CH2NH]Tpg4] Vancomycin Aglycon: Reengineering Vancomycin for Dual D-Ala-D-Ala and D-Ala-D-Lac BindingBrendan M. Crowley and Dale L. BogerJ. Am. Chem. Soc.2006, 128, 2885-2892Contribution from the Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037 Presented by, Michael Elbaum

  2. Dale L. Boger • B.S. University of Kansas, 1975 • Ph.D. Harvard University, 1980 • Assistant / Associate Professor of Medicinal Chemistry, University of Kansas 1979-1985 • Associate Professor / Professor of Chemistry, Purdue University, 1985-1991 • 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, 1996-1999 • ACS Aldrich Award for Creativity in Organic Synthesis, 1999 • ISI Highly Cited (top 100 chemists)

  3. 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

  4. 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

  5. Ring A Formation Dale L. Boger. J. Am. Chem. Soc.1999, 121, 10004-10011

  6. Ring B Formation Boger, Dale L. Bioorg. Chem. Lett. 1995, 5, 3091-3096

  7. Ring C Vassil P. Vassilev. Tet. Lett. 1995, 36, 4081-4084

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

  9. Ring E Boger, Dale L. Bioorg. Chem. Lett. 1995, 5, 3091-3096 Boger, Dale L. J. Org. Chem.1997, 62, 4721-4736

  10. Ring E Unlisted RXN

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

  12. BCD Synthesis

  13. BCD Synthesis

  14. ABCD Synthesis Thermal equilibration of product @ 230 oC not seen

  15. ABCD Synthesis Thermal equilibration of product @ 170 oC not seen

  16. ABCD Synthesis: Suzuki Coupling

  17. ABCD Cyclization

  18. ABCD Cyclization

  19. ABCDE Synthesis

  20. ABCDE Cyclization Again, no thermal equilibration

  21. ABCDE

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

  23. Conclusion • Product binds to DAla-DLac • 100 fold increase • Product binds to DAla-DAla • 10 fold decrease

  24. Thank You Dale. L. Boger. J. Am. Chem. Soc. 2006, 128, 2885-2892 Dale. L. Boger. J. Am. Chem. Soc.2003, 126, 4310-4317 - Total synth Ristocetin Dale. L. Boger. J. Am. Chem. Soc. 1999, 121, 10004-10011 - Original total synth Vancomycin Aglycon Dale. L. Boger. J. Org. Chem. 1997, 62, 4721-4736 Dale. L. Boger. Bioorg. Med. Chem. Lett. 1995, 5, 3091-3096

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