total synthesis and evaluation of [ψ[ch 2 nh]tpg 4 ] vancomycin aglycon: reengineering vancomycin...
TRANSCRIPT
![Page 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](https://reader036.vdocuments.mx/reader036/viewer/2022081512/56649d1b5503460f949f12a1/html5/thumbnails/1.jpg)
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
![Page 2: 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](https://reader036.vdocuments.mx/reader036/viewer/2022081512/56649d1b5503460f949f12a1/html5/thumbnails/2.jpg)
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
![Page 3: 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](https://reader036.vdocuments.mx/reader036/viewer/2022081512/56649d1b5503460f949f12a1/html5/thumbnails/3.jpg)
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
![Page 4: 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](https://reader036.vdocuments.mx/reader036/viewer/2022081512/56649d1b5503460f949f12a1/html5/thumbnails/4.jpg)
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
![Page 5: 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](https://reader036.vdocuments.mx/reader036/viewer/2022081512/56649d1b5503460f949f12a1/html5/thumbnails/5.jpg)
Ring A Formation
5
Dale L. Boger. J. Am. Chem. Soc. 1999, 121, 10004-10011
![Page 6: 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](https://reader036.vdocuments.mx/reader036/viewer/2022081512/56649d1b5503460f949f12a1/html5/thumbnails/6.jpg)
Ring B Formation
6Boger, Dale L. Bioorg. Chem. Lett. 1995, 5, 3091-3096
![Page 7: 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](https://reader036.vdocuments.mx/reader036/viewer/2022081512/56649d1b5503460f949f12a1/html5/thumbnails/7.jpg)
Ring C
7
Vassil P. Vassilev. Tet. Lett. 1995, 36, 4081-4084
![Page 8: 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](https://reader036.vdocuments.mx/reader036/viewer/2022081512/56649d1b5503460f949f12a1/html5/thumbnails/8.jpg)
Ring D: Chiral Auxilary
8Nsenda, T. Tet. Lett. 1998, 39,2191
![Page 9: 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](https://reader036.vdocuments.mx/reader036/viewer/2022081512/56649d1b5503460f949f12a1/html5/thumbnails/9.jpg)
Ring E
9
Boger, Dale L. Bioorg. Chem. Lett. 1995, 5, 3091-3096Boger, Dale L. J. Org. Chem. 1997, 62, 4721-4736
![Page 10: 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](https://reader036.vdocuments.mx/reader036/viewer/2022081512/56649d1b5503460f949f12a1/html5/thumbnails/10.jpg)
Ring E
10
Unlisted RXN
![Page 11: 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](https://reader036.vdocuments.mx/reader036/viewer/2022081512/56649d1b5503460f949f12a1/html5/thumbnails/11.jpg)
Ring D
11Dale. L. Boger. J. Am. Chem. Soc. 1997, 62, 4721
![Page 12: 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](https://reader036.vdocuments.mx/reader036/viewer/2022081512/56649d1b5503460f949f12a1/html5/thumbnails/12.jpg)
BCD Synthesis
12
![Page 13: 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](https://reader036.vdocuments.mx/reader036/viewer/2022081512/56649d1b5503460f949f12a1/html5/thumbnails/13.jpg)
BCD Synthesis
13
![Page 14: 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](https://reader036.vdocuments.mx/reader036/viewer/2022081512/56649d1b5503460f949f12a1/html5/thumbnails/14.jpg)
ABCD Synthesis
14
Thermal equilibration of product @ 230 oC not seen
![Page 15: 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](https://reader036.vdocuments.mx/reader036/viewer/2022081512/56649d1b5503460f949f12a1/html5/thumbnails/15.jpg)
ABCD Synthesis
15
Thermal equilibration of product @ 170 oC not seen
![Page 16: 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](https://reader036.vdocuments.mx/reader036/viewer/2022081512/56649d1b5503460f949f12a1/html5/thumbnails/16.jpg)
ABCD Synthesis: Suzuki Coupling
16
![Page 17: 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](https://reader036.vdocuments.mx/reader036/viewer/2022081512/56649d1b5503460f949f12a1/html5/thumbnails/17.jpg)
ABCD Cyclization
17
![Page 18: 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](https://reader036.vdocuments.mx/reader036/viewer/2022081512/56649d1b5503460f949f12a1/html5/thumbnails/18.jpg)
ABCD Cyclization
18
![Page 19: 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](https://reader036.vdocuments.mx/reader036/viewer/2022081512/56649d1b5503460f949f12a1/html5/thumbnails/19.jpg)
ABCDE Synthesis
19
![Page 20: 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](https://reader036.vdocuments.mx/reader036/viewer/2022081512/56649d1b5503460f949f12a1/html5/thumbnails/20.jpg)
ABCDE Cyclization
20
Again, no thermal equilibration
![Page 21: 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](https://reader036.vdocuments.mx/reader036/viewer/2022081512/56649d1b5503460f949f12a1/html5/thumbnails/21.jpg)
ABCDE
21
![Page 22: 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](https://reader036.vdocuments.mx/reader036/viewer/2022081512/56649d1b5503460f949f12a1/html5/thumbnails/22.jpg)
Final Stretch
22
Global deprotection 4 aryl esters, 2 TBS, NBoc, and 4-methyl carbamate!
![Page 23: 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](https://reader036.vdocuments.mx/reader036/viewer/2022081512/56649d1b5503460f949f12a1/html5/thumbnails/23.jpg)
Conclusion
• Product binds to DAla-DLac
– 100 fold increase
• Product binds to DAla-DAla
– 10 fold decrease
23
![Page 24: 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](https://reader036.vdocuments.mx/reader036/viewer/2022081512/56649d1b5503460f949f12a1/html5/thumbnails/24.jpg)
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