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Enantioselective Organocatalytic Friedel-Crafts Alkylations of Heterocycles and Electron-Rich Benzenes


Paras, Nick Anthony (2004) Enantioselective Organocatalytic Friedel-Crafts Alkylations of Heterocycles and Electron-Rich Benzenes. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/EFG2-7V87.


The development of the first organocatalytic asymmetric Friedel-Crafts alkylation is described in the context of conjugate additions of pyrroles to a,b-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 Bronsted 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 a,b-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.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:asymmetric catalysis; conjugate addition; Friedel-Crafts alkylation; organocatalysis
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • MacMillan, David W. C.
Thesis Committee:
  • Dervan, Peter B. (chair)
  • MacMillan, David W. C.
  • Bercaw, John E.
  • Grubbs, Robert H.
Defense Date:19 February 2004
Record Number:CaltechETD:etd-06012004-190154
Persistent URL:
Paras, Nick Anthony0000-0001-5742-4056
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:2353
Deposited By: Imported from ETD-db
Deposited On:02 Jun 2004
Last Modified:02 Feb 2021 23:29

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