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  • Enantioselective Organocatalytic Friedel-Crafts Alkylations of

    Heterocycles and Electron-Rich Benzenes

    Thesis by Nick A. Paras

    In Partial Fulfillment of the Requirements For the Degree of

    Doctor of Philosophy

    California Institute of Technology

    Pasadena, California 2004 (Defended February 19, 2004)

  • ii

    Acknowledgements

    A graduate degree in organic chemistry comes not without a little help. First, I

    would like to thank my graduate advisor, Prof. David MacMillan. Dating back to the first

    days of our association, when he took me under his wing as a postdoc at Harvard, he

    taught me just about everything I know about organic synthetic methodology. I need to

    also thank my undergraduate research advisor, Prof. David Evans, for giving me a start in

    research and for the invaluable experience of sitting in on 2 years of Evans’ group

    meetings. I’d wager that I learned more about chemistry over beer and pretzels once a

    week than I had before or have since.

    I have benefited from working in a unique environment of brilliant minds and

    fierce competitors within the group. I would like to thank Kateri Ahrendt, Chris Borths,

    and Wendy Jen for taking the first crucial steps in the pursuit of iminium catalysis. I also

    very much enjoyed collaborating with Sean Brown and Joel Austin as asymmetric

    Friedel-Crafts really got off the ground. Above all, within the group, I was fortunate to

    have a superb baymate in Vy Dong. She was always supportive, always insightful and,

    more often than not, let me play any kind of music I liked. Vy and Wilmer were also

    largely responsible for keeping me sane and (within limits of experimental error) healthy.

    In that regard, I also want to thank the “LA Greeks” who along with V & W have taken

    me in as family and helped me maintain perspective.

    Finally, and most importantly, I thank my parents, James and Koula Paras. They

    made do with less so Andy and I could have more, and their high expectations of us were

    always backed up with the support to help us realize them. This dissertation is dedicated

    to them.

  • iii

    Abstract

    The development of the first organocatalytic asymmetric Friedel-Crafts alkylation is described in

    the context of conjugate additions of pyrroles to α,β-unsaturated aldehydes. Catalytic amounts of chiral

    imidazolidinone salts are used to activate the electrophile component via reversible formation of iminium

    ions. Ensuing conjugate additions of pyrroles afford aldehyde products in good yield and high

    enantiopurity using a range of alkyl–, aryl–, and heteroatom-substituted enals and nucleophiles. This

    reaction demonstrates the feasibility of using iminium catalysis to promote reactions of electron-deficient

    olefins beyond simple cycloaddition reactions. Observations were also made regarding the role of Brønsted

    acid cocatalysts in these organocatalytic reactions. The synthetic utility of asymmetric conjugate additions

    of pyrroles was demonstrated in a concise, enantioselective synthesis of the analgesic Ketorolac.

    An enantioselective organocatalytic conjugate addition of electron-rich benzenes to α,β-

    unsaturated aldehydes has been developed. A new chiral secondary amine promotes exclusive para-

    alkylation of dialkylamino-substituted benzenes in good yield and with a high degree of stereocontrol. The

    process tolerates a range of substitutents on the electrophile component as well as a high degree of

    flexibility in the ortho- and meta-positions on the benzene ring. Particularly, the unique ability of this

    methodology to efficiently generate bisbenzyllic stereocenters by addition of electron-rich benzenes to

    cinnamaldehyde derivatives is demonstrated.

    A general procedure for the cleavage of dialkylamino substituents from aromatic rings has also

    been developed. To accomplish this cleavage, a dialkylaniline is first converted to the corresponding

    quaternary ammonium salt with methyl iodide or methyl trifluromethanesulfonate. In a second step,

    dissolving metal reduction of the salt liberates the deaminated arene in high yields for the overall process.

    A range of alkyl, aryl, and heteroatom substitutions at the ortho, meta, and para positions were tolerated

    without significant decrease in reaction efficiency or yield. Deamination of aniline substrates bearing

    stereogenic centers para to the dialkylamino functionality proceeded with complete retention of

    enantiopurity. The combined utility of the asymmetric aniline alkylation and the new deamination

    methodology was demonstrated in the first enantioselective synthesis of the anticholinergic drug (R)-

    Tolterodine.

  • iv

    TABLE OF CONTENTS

    LIST OF FIGURES......................................................................................................................................... V LIST OF SCHEMES....................................................................................................................................... VI

    CHAPTER 1 ..................................................................................................................................................1

    INTRODUCTION............................................................................................................................................1 DESIGN OF A NEW MECHANISM FOR ORGANOCATALYSIS...........................................................................6 DEVELOPMENT OF A HIGHLY SELECTIVE SECONDARY AMINE CATALYST..................................................9 ORGANOCATALYTIC ASYMMETRIC CONJUGATE ADDITION REACTIONS ...................................................13

    CHAPTER 2 ................................................................................................................................................18

    REACTION DESIGN ....................................................................................................................................18 RESULTS AND DISCUSSION........................................................................................................................23

    Identification of a suitable nucleophile................................................................................................23 Optimization of pyrrole additions........................................................................................................26 Investigation of transition state topology.............................................................................................37 Application: enantioselective synthesis of (R)-Ketorolac (18) ............................................................44

    CONCLUSION.............................................................................................................................................47 EXPERIMENTAL SECTION ..........................................................................................................................48

    CHAPTER 3 ................................................................................................................................................70

    REACTION DESIGN ....................................................................................................................................70 RESULTS AND DISCUSSION........................................................................................................................72

    Initial results........................................................................................................................................72 Scope and limitations...........................................................................................................................73 Kinetics studies ....................................................................................................................................78 Determination of absolute stereochemical configuration of products.................................................82

    CONCLUSION.............................................................................................................................................86 EXPERIMENTAL SECTION ..........................................................................................................................87

    CHAPTER 4 ..............................................................................................................................................111

    REACTION DESIGN ..................................................................................................................................111 RESULTS AND DISCUSSION......................................................................................................................113

    Design of a new method for direct cleavage of dialkylamines...........................................................115 Initial attempts and substrate scope ..................................................................................................118 Application: enantioselective synthesis of (R)-tolterodine (14) .........................................................121

    CONCLUSION...........................................................................................................................................127 EXPERIMENTAL SECTIO

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