Catalytic asymmetric synthesis of lactams
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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

Matt Windsor

Gellman Group


Outline l.jpg

  • Background and Applications

  • Synthesis

    • Gilman-Speeter

    • Kinugasa

    • Staudinger

  • Potential Industrial Uses

  • Conclusions

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Synthesis by Staudinger

  • First to synthesize β-lactam core from diphenylketene and benzylideneaniline



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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

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Penicillin’s Mode of Action

  • Prevents crosslinking of bacteria’s cell wall polymer strands (peptidoglycan)

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Mechanism of Activity

  • -lactams act as inhibitors of serine proteases:

    • -lactamases

    • Prostate Specific Antigen

    • Thrombin

    • Human Cytomegalovirus

    • Elastase

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Antibiotic Resistance via -Lactamases

  • -Lactamases able to remove acyl group, regenerate serine sidechain

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  • Background and Applications

  • Synthesis

    • Gilman-Speeter

    • Kinugasa

    • Staudinger

  • Potential Industrial Uses

  • Conclusions

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Common Methodologies

  • Enantiomerically pure substrates

  • Chiral auxiliaries

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Gilman-Speeter Selectivity

  • Ternary complex: Li amide, chiral ligand, Li enolate ester

  • Screening of new, tridentate catalysts to replace amide base in complex

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Kinugasa: Background

  • First reaction to give exclusively cis-lactam

  • Stoichiometeric use of copper under nitrogen

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First Catalytic Kinugasa Reaction

  • Significant isomerization to trans lactam under basic conditions

  • Imine byproduct

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Isomerization from cis to trans

Isomerization rate depends on R:

Ester > aryl > alkyl

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Quaternary Center Hypothesis

  • Introduce electrophile and get quaternary center

  • Addition should be trans to C-4 substituent

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Initial Quaternary Conditions

  • Standard reaction conditions gave negligible amount of product

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Development of New Proton Sink

  • Replaced R3N base

  • New system generates acetophenone

    • Poor proton donor compared to trialkylammonium salt

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Air Stable Kinugasa Catalyst

  • Cu(II) reagent stable under air

  • Cu(I) catalytic species

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More Evidence for New Mechanism

  • Intermediate stabilized by electron withdrawing group (EWG)

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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)

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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

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Diastereoselective Catalyst

  • Rigidify transition state by using catalyst that is H-bond donor and acceptor

  • Selectivity lost in H-bonding solvent

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Enantioselective Catalyst

  • Cinchona alkaloids used previously as enantioselective catalyst

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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

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Shuttle Deprotonation

  • Use weaker but faster base, have PS remove HCl and precipitate

  • BQ plays role of kinetically active base

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Synthesis with Unique Ketenes

  • Oxygen substituted ketenes can not be synthesized with chiral auxiliaries

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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)

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Indium as Lewis Acid

  • Increase in yield, small loss in diastereoselectivity

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Variation of the Imine Substituent

  • Range of ketene and imine substituents in very good yield, ee

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Control of cis or trans Product

  • cis/trans selection depends on N-protecting group!

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trans Products From Anionic Catalyst

  • Negative charge, bulky counterion are key

  • No alkyl groups, work ongoing

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  • Background and Applications

  • Synthesis

    • Rhodium Catalyzed

    • Gilman-Speeter

    • Kinugasa

    • Staudinger

  • Potential Industrial Uses

  • Conclusions

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Industrial Uses: Zetia

  • Inhibitor of intestinal cholesterol absorption

  • Combined with Merck statin (ZOCOR ) and sold as Vytorin

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  • 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

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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