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The development of an asymmetric palladium-catalyzed conjugate addition and its application toward the total syntheses of taiwaniaquinoid natural products

Citation

Holder, Jeffrey Clinton (2014) The development of an asymmetric palladium-catalyzed conjugate addition and its application toward the total syntheses of taiwaniaquinoid natural products. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechTHESIS:05132014-111254056

Abstract

The asymmetric synthesis of quaternary stereocenters remains a challenging problem in organic synthesis. Past work from the Stoltz laboratory has resulted in methodology to install quaternary stereocenters α- or γ- to carbonyl compounds. Thus, the asymmetric synthesis of β-quaternary stereocenters was a desirable objective, and was accomplished by engineering the palladium-catalyzed addition of arylmetal organometallic reagents to α,β-unsaturated conjugate acceptors.

Herein, we described the rational design of a palladium-catalyzed conjugate addition reactions utilizing a catalyst derived from palladium(II) trifluoroacetate and pyridinooxazole ligands. This reaction is highly tolerant of protic solvents and oxygen atmosphere, making it a practical and operationally simple reaction. The mild conditions facilitate a remarkably high functional group tolerance, including carbonyls, halogens, and fluorinated functional groups. Furthermore, the reaction catalyzed conjugate additions with high enantioselectivity with conjugate acceptors of 5-, 6-, and 7-membered ring sizes. Extension of the methodology toward the asymmetric synthesis of flavanone products is presented, as well.

A computational and experimental investigation into the reaction mechanism provided a stereochemical model for enantioinduction, whereby the α-methylene protons adjacent the enone carbonyl clashes with the tert-butyl groups of the chiral ligand. Additionally, it was found that the addition of water and ammonium hexafluorophosphate significantly increases the reaction rate without sacrificing enantioselectivity. The synergistic effects of these additives allowed for the reaction to proceed at a lower temperature, and thus facilitated expansion of the substrate scope to sensitive functional groups such as protic amides and aryl bromides. Investigations into a scale-up synthesis of the chiral ligand (S)-tert-butylPyOx are also presented. This three-step synthetic route allowed for synthesis of the target compound of greater than 10 g scale.

Finally, the application of the newly developed conjugate addition reaction toward the synthesis of the taiwaniaquinoid class of terpenoid natural products is discussed. The conjugate addition reaction formed the key benzylic quaternary stereocenter in high enantioselectivity, joining together the majority of the carbons in the taiwaniaquinoid scaffold. Efforts toward the synthesis of the B-ring are presented.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Asymmetric catalysis, Palladium, Conjugate Addition
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Stoltz, Brian M.
Thesis Committee:
  • Reisman, Sarah E. (chair)
  • Agapie, Theodor
  • Grubbs, Robert H.
  • Stoltz, Brian M.
Defense Date:5 May 2014
Record Number:CaltechTHESIS:05132014-111254056
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:05132014-111254056
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/ja200664xDOIArticle adapted for ch. 2
http://dx.doi.org/10.1002/chem.201203643DOIArticle adapted for ch. 3
http://dx.doi.org/10.1021/ja401713gDOIArticle adapted for ch. 4
http://dx.doi.org/10.3762/bjoc.9.187DOIArticle adapted for ch. 5
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:8231
Collection:CaltechTHESIS
Deposited By: Jeffrey Holder
Deposited On:20 May 2014 16:43
Last Modified:20 May 2014 16:43

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