1 / 45

Catalytic, Asymmetric Synthesis of β-Lactams

Catalytic, Asymmetric Synthesis of β-Lactams. Matt Windsor Gellman Group 10/19/06. Outline. Background and Applications Synthesis Gilman-Speeter Kinugasa Staudinger Potential Industrial Uses Conclusions. Synthesis by Staudinger.

lorant
Download Presentation

Catalytic, Asymmetric Synthesis of β-Lactams

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Catalytic, Asymmetric Synthesis of β-Lactams Matt Windsor Gellman Group 10/19/06

  2. Outline • Background and Applications • Synthesis • Gilman-Speeter • Kinugasa • Staudinger • Potential Industrial Uses • Conclusions

  3. Synthesis by Staudinger • First to synthesize β-lactam core from diphenylketene and benzylideneaniline - +

  4. Discovery of Penicillin • Discovered in 1928 • First used to treat patients in 1942 • Significantly lowered number of deaths and amputations caused by infected wounds in WWII

  5. Penicillin’s Mode of Action • Prevents crosslinking of bacteria’s cell wall polymer strands (peptidoglycan) http://en.wikipedia.org/wiki/Peptidoglycan

  6. Mechanism of Activity • -lactams act as inhibitors of serine proteases: • -lactamases • Prostate Specific Antigen • Thrombin • Human Cytomegalovirus • Elastase

  7. Antibiotic Resistance via -Lactamases • -Lactamases able to remove acyl group, regenerate serine sidechain

  8. Outline • Background and Applications • Synthesis • Gilman-Speeter • Kinugasa • Staudinger • Potential Industrial Uses • Conclusions

  9. Common Methodologies • Enantiomerically pure substrates • Chiral auxiliaries

  10. Gilman-Speeter

  11. Gilman-Speeter Selectivity • Ternary complex: Li amide, chiral ligand, Li enolate ester • Screening of new, tridentate catalysts to replace amide base in complex

  12. Comparison of Catalytic Ligand

  13. Kinugasa: Background • First reaction to give exclusively cis-lactam • Stoichiometeric use of copper under nitrogen

  14. First Catalytic Kinugasa Reaction • Significant isomerization to trans lactam under basic conditions • Imine byproduct

  15. Isomerization from cis to trans Isomerization rate depends on R: Ester > aryl > alkyl

  16. New Kinugasa Mechanism

  17. Bulky Base Prevents Isomerization

  18. Tricyclic Systems

  19. Quaternary Center Hypothesis • Introduce electrophile and get quaternary center • Addition should be trans to C-4 substituent

  20. Initial Quaternary Conditions • Standard reaction conditions gave negligible amount of product

  21. Development of New Proton Sink • Replaced R3N base • New system generates acetophenone • Poor proton donor compared to trialkylammonium salt

  22. Air Stable Kinugasa Catalyst • Cu(II) reagent stable under air • Cu(I) catalytic species

  23. Kinugasa Stereochemical Model

  24. More Evidence for New Mechanism • Intermediate stabilized by electron withdrawing group (EWG)

  25. Staudinger Mechanism • One of the most common methods toward -lactams • cis-Lactam predominant product in most reactions (can isomerize to get trans) • High background rate (spontaneous)

  26. Reaction Control • In order to control reaction, had to first prevent spontaneous cyclization • Requires development of electron-deficient imine • Catalyst needed for reaction to proceed

  27. Lectka’s Imine

  28. Diastereoselective Catalyst • Rigidify transition state by using catalyst that is H-bond donor and acceptor • Selectivity lost in H-bonding solvent

  29. Enantioselective Catalyst • Cinchona alkaloids used previously as enantioselective catalyst

  30. Staudinger Stereochemical Model

  31. Ketene Generation • Commonly use trialkylamine to dehydrohalogenate acyl chloride • Base can act as nucleophile to catalyze reaction racemically • Need non-nucleophilic, but strong thermodynamic base

  32. Shuttle Deprotonation • Use weaker but faster base, have PS remove HCl and precipitate • BQ plays role of kinetically active base

  33. Synthesis with Unique Ketenes • Oxygen substituted ketenes can not be synthesized with chiral auxiliaries

  34. Will a Lewis Acid (LA) Increase Yield? • Intermediate reacting promiscuously • Need to activate imine or make intermediate more chemoselective • Four scenarios: coordinate to imine (A), enolate (B), both (C) or catalyst (D)

  35. Indium as Lewis Acid • Increase in yield, small loss in diastereoselectivity

  36. Variation of the Imine Substituent • Range of ketene and imine substituents in very good yield, ee

  37. Control of cis or trans Product • cis/trans selection depends on N-protecting group!

  38. trans Products From Anionic Catalyst • Negative charge, bulky counterion are key • No alkyl groups, work ongoing

  39. Summary of Substrate Scope

  40. Outline • Background and Applications • Synthesis • Rhodium Catalyzed • Gilman-Speeter • Kinugasa • Staudinger • Potential Industrial Uses • Conclusions

  41. Industrial Uses: Zetia   • Inhibitor of intestinal cholesterol absorption • Combined with Merck statin (ZOCOR ) and sold as Vytorin 

  42. Industrial Uses: Zetia

  43. Industrial Uses: Taxol

  44. Conclusions • Field still in its infancy • Primarily limited by substrate specificity • Enolate for Gilman-Speeter • Imine for Staudinger • Nitrone for Kinugasa • Better catalysts to maximize selectivity, yield

  45. Shout Outs • Professor Sam Gellman • Gellman Group • Practice Talk Attendees • Lauren Boyle Claire Poppe • Maren Buck Chris Shaffer • Julee Byram Becca Splain • Alex Clemens Katherine Traynor • Richard Grant

More Related