1. 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, 2885-2892 Contribution 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) 1

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 2

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 3

5. Ring A Formation 4 Dale L. Boger. J. Am. Chem. Soc. 1999, 121, 10004-10011

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

7. Ring C 6 Vassil P. Vassilev. Tet. Lett. 1995, 36, 4081-4084

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

9. Ring E 8 Boger, Dale L. Bioorg. Chem. Lett. 1995, 5, 3091-3096 Boger, Dale L. J. Org. Chem. 1997, 62, 4721-4736

10. Ring E 9 Unlisted RXN

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

12. BCD Synthesis 11

13. BCD Synthesis 12

14. ABCD Synthesis 13 Thermal equilibration of product @ 230 o C not seen

15. ABCD Synthesis 14 Thermal equilibration of product @ 170 o C not seen

16. ABCD Synthesis: Suzuki Coupling 15

17. ABCD Cyclization 16

18. ABCD Cyclization 17

19. ABCDE Synthesis 18

20. ABCDE Cyclization 19 Again, no thermal equilibration

21. ABCDE 20

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

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

24. Thank You 23 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