Total Synthesis and Evaluation of [?[CH2NH]Tpg4] 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 - PowerPoint PPT Presentation

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Total Synthesis and Evaluation of [?[CH2NH]Tpg4] 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

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Title: Total Synthesis and Evaluation of [?[CH2NH]Tpg4] 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


1
Total Synthesis and Evaluation of ?CH2NHTpg4
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)

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 _at_ 230 oC not seen
15
ABCD Synthesis
Thermal equilibration of product _at_ 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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