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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.

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Catalytic, Asymmetric Synthesis of β-Lactams

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  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

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