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

Ala-D-Ala and D-Ala-D-Lac Binding

Brendan M. Crowley and Dale L. BogerJ. 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

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) 2

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

3

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

4

Ring A Formation

5

Dale L. Boger. J. Am. Chem. Soc. 1999, 121, 10004-10011

Ring B Formation

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

Ring C

7

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

Ring D: Chiral Auxilary

8Nsenda, T. Tet. Lett. 1998, 39,2191

Ring E

9

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

Ring E

10

Unlisted RXN

Ring D

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

BCD Synthesis

12

BCD Synthesis

13

ABCD Synthesis

14

Thermal equilibration of product @ 230 oC not seen

ABCD Synthesis

15

Thermal equilibration of product @ 170 oC not seen

ABCD Synthesis: Suzuki Coupling

16

ABCD Cyclization

17

ABCD Cyclization

18

ABCDE Synthesis

19

ABCDE Cyclization

20

Again, no thermal equilibration

ABCDE

21

Final Stretch

22

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

Conclusion

• Product binds to DAla-DLac

– 100 fold increase

• Product binds to DAla-DAla

– 10 fold decrease

23

Thank You

24

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