Total Synthesis and Evaluation of
[ψ[CH2NH]Tpg4] Vancomycin Aglycon:
Reengineering Vancomycin for Dual D-Ala-DAla 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
Dale L. Boger
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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)
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Vancomycin
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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
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Retrosynthesis
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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
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Ring A Formation
Dale L. Boger. J. Am. Chem. Soc. 1999, 121, 10004-10011
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Ring B Formation
Boger, Dale L. Bioorg. Chem. Lett. 1995, 5, 3091-3096
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Ring C
Vassil P. Vassilev. Tet. Lett. 1995, 36, 4081-4084
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Ring D: Chiral Auxilary
Nsenda, T. Tet. Lett. 1998, 39,2191
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Ring E
Boger, Dale L. Bioorg. Chem. Lett. 1995, 5, 3091-3096
Boger, Dale L. J. Org. Chem. 1997, 62, 4721-4736
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Ring E
Unlisted RXN
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Ring D
Dale. L. Boger. J. Am. Chem. Soc. 1997, 62, 4721
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BCD Synthesis
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BCD Synthesis
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ABCD Synthesis
Thermal equilibration of product @ 230 oC not seen
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ABCD Synthesis
Thermal equilibration of product @ 170 oC not seen
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ABCD Synthesis: Suzuki Coupling
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ABCD Cyclization
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ABCD Cyclization
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ABCDE Synthesis
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ABCDE Cyclization
Again, no thermal equilibration
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ABCDE
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Final Stretch
Global deprotection 4 aryl esters, 2 TBS, NBoc, and 4-methyl carbamate!
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Conclusion
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Product binds to DAla-DLac
– 100 fold increase
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Product binds to DAla-DAla
– 10 fold decrease
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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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