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

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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

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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

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*