Presented by, Michael Elbaum

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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. 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 92037Presented by,Michael Elbaum

  • Dale L. BogerB.S. University of Kansas, 1975Ph.D. Harvard University, 1980Assistant / Associate Professor of Medicinal Chemistry, University of Kansas 1979-1985Associate Professor / Professor of Chemistry, Purdue University, 1985-1991Professor, The Scripps Research Institute, 1991-PresentMember, The Skaggs Institute for Chemical Biology, 1996-presentEditor-in-Chief, Bioorganic and Medicinal Chemistry Letter, 1990-presentACS Medicinal Chemistry Division, Councilor, 1996-1999ACS Aldrich Award for Creativity in Organic Synthesis, 1999ISI Highly Cited (top 100 chemists)*

  • VancomycinFirst isolated 1953 by Edmund Kornfeld (Eli Lilly) from soil bacteriaTreat Gram-positive bacteriaDrug of Last ResortIntravenousResistanceRoughly 1000x less bioactivity

    *

  • Retrosynthesis5 amide bonds / 5 peptide couplings, 6 alpha-AA derivativesAtropodiastereomers, DE = 18.7 kcal/molAB = 25.1 kcal/molCD = 30.4 kcal/molCyclization order, CD, AB, DEPermits recycling of undesired atropisomer thermal equilibrationBiaryl, 2 nucleophilic substitutionsFormation CD / DEActivating nitro also serves as a precursor for arylchloride*

  • Ring A Formation*Dale L. Boger. J. Am. Chem. Soc. 1999, 121, 10004-10011

  • Ring B Formation*Boger, Dale L. Bioorg. Chem. Lett. 1995, 5, 3091-3096

  • Ring C*Vassil P. Vassilev. Tet. Lett. 1995, 36, 4081-4084

  • Ring D: Chiral Auxilary*Nsenda, T. Tet. Lett. 1998, 39,2191

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

  • Ring E*Unlisted RXN

  • Ring D*Dale. L. Boger. J. Am. Chem. Soc. 1997, 62, 4721

  • BCD Synthesis*

  • BCD Synthesis*

  • ABCD Synthesis*Thermal equilibration of product @ 230 oC not seen

  • ABCD Synthesis*Thermal equilibration of product @ 170 oC not seen

  • ABCD Synthesis: Suzuki Coupling*

  • ABCD Cyclization*

  • ABCD Cyclization*

  • ABCDE Synthesis*

  • ABCDE Cyclization*Again, no thermal equilibration

  • ABCDE*

  • Final Stretch*Global deprotection 4 aryl esters, 2 TBS, NBoc, and 4-methyl carbamate!

  • ConclusionProduct binds to DAla-DLac100 fold increase

    Product binds to DAla-DAla10 fold decrease

    *

  • 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

    1000 fold*Note Rings C and E are setting up hinges with enantiomers*Sharpless Asymmetric Aminohydroxylation, Amine coordinates to OsO3

    *Generating Titanium Enolate**Sharpless Asymmetric Aminohydroxylation*1) Oxidize primary alcohol 2) Reductive amination coupling, acid / hydride3) Protection of amine via formation of amide.. 4) Remove BnO MeEster Carboxylic acid*1) Nu attack Phospho, 2) Phos leaves, O attacks carbonyl*Remove TBSRemove CbzEster to acid*O Attacks phosphorus and leaves, anion on tri nitrogen oxygen attacks carbonyl*Peptide Coupling**Reduce nitroAryl chlorideTBS protect*35 EqHard Acid, Soft Nucleophile*