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Applications of palladium-catalyzed enantioselective decarboxylative alkylation in natural products total synthesis

Citation

McFadden, Ryan Michael (2008) Applications of palladium-catalyzed enantioselective decarboxylative alkylation in natural products total synthesis. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechETD:etd-12172007-134752

Abstract

The catalytic enantioselective preparation of all-carbon quaternary stereocenters within rings via alkylation is a major challenge in synthetic organic chemistry. Many important natural products and biologically active pharmaceuticals contain this motif. We have developed palladium-catalyzed decarboxylative alkylations capable of generating all-carbon quaternary stereocenters in good yield with high enantioselectivity.

Alkylated products are readily elaborated to synthetically useful cyclic scaffolds. The enantioselective decarboxylative alkylation is thus utilized to prepare intermediates previously reported in the total syntheses of classic natural products. Herein, we disclose modern formal syntheses of (–)-Thujopsene, (-–)-Dysidiolide, and (–)-Aspidospermine.

The longer-term goal was to apply this new enantioselective catalysis to the total syntheses of natural products with novel carbocyclic architectures. Our methodology is demonstrated during the first protecting group-free enantioselective total synthesis of (+)-dichroanone, a 4a-methyltetrahydrofluorene. The [6-5-6] tricyclic natural products family has members with important biological activity, and our route to (+)-dichroanone may provide general access to related compounds. During our synthetic endeavors, a novel Kumada-benzannulation approach to the aromatic portion of (+)-dichroanone was developed, along with a unique synthesis of a hydroxy-p-benzoquinone from a phenol. The absolute stereochemistry of the natural product was verified for the first time during our total synthesis.

Significant progress has been made toward the total synthesis of the marine meroterpenoid liphagal, a potent and selective phosphatidylinositol 3-kinase alpha inhibitor. The enantioselective decarboxylative alkylation has been employed, and an acetylene [2 + 2] photoaddition / ring-opening sequence is used to construct the 7-membered ring. New understanding about the reactivity of [6-7] bicyclic scaffolds has been gathered, and the information applied during preparation of liphagal’s benzofuran motif. Our efforts have led to a functionally diverse array of liphagal analogues, which may be used for structure-activity-relationship studies with phosphatidylinositol 3-kinases.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Catalyzed; Enantioselective; Palladium; Total Synthesis
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Restricted to Caltech community only
Research Advisor(s):
  • Stoltz, Brian M.
Thesis Committee:
  • Grubbs, Robert H. (chair)
  • Stoltz, Brian M.
  • Hsieh-Wilson, Linda C.
  • Goddard, William A., III
Defense Date:11 December 2007
Record Number:CaltechETD:etd-12172007-134752
Persistent URL:http://resolver.caltech.edu/CaltechETD:etd-12172007-134752
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:5035
Collection:CaltechTHESIS
Deposited By: Imported from ETD-db
Deposited On:15 Jan 2008
Last Modified:26 Dec 2012 03:14

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