total synthesis and evaluation of [ψ[ch 2 nh]tpg 4 ] vancomycin aglycon: reengineering vancomycin...
TRANSCRIPT
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