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Strategies for the Stereoselective Synthesis of Carbon Quaternary Centers via Transition Metal-Catalyzed Alkylation of Enolate Compounds

Citation

Reeves, Corey Michael (2015) Strategies for the Stereoselective Synthesis of Carbon Quaternary Centers via Transition Metal-Catalyzed Alkylation of Enolate Compounds. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z9VX0DGH. http://resolver.caltech.edu/CaltechTHESIS:05192015-131629900

Abstract

Notwithstanding advances in modern chemical methods, the selective installation of sterically encumbered carbon stereocenters, in particular all-carbon quaternary centers, remains an unsolved problem in organic chemistry. The prevalence of all-carbon quaternary centers in biologically active natural products and pharmaceutical compounds provides a strong impetus to address current limitations in the state of the art of their generation. This thesis presents four related projects, all of which share in the goal of constructing highly-congested carbon centers in a stereoselective manner, and in the use of transition-metal catalyzed alkylation as a means to address that goal.

The first research described is an extension of allylic alkylation methodology previously developed in the Stoltz group to small, strained rings. This research constitutes the first transition metal-catalyzed enantioselective α-alkylation of cyclobutanones. Under Pd-catalysis, this chemistry affords all–carbon α-quaternary cyclobutanones in good to excellent yields and enantioselectivities.

Next is described our development of a (trimethylsilyl)ethyl β-ketoester class of enolate precursors, and their application in palladium–catalyzed asymmetric allylic alkylation to yield a variety of α-quaternary ketones and lactams. Independent coupling partner synthesis engenders enhanced allyl substrate scope relative to allyl β-ketoester substrates; highly functionalized α-quaternary ketones generated by the union of our fluoride-triggered β-ketoesters and sensitive allylic alkylation coupling partners serve to demonstrate the utility of this method for complex fragment coupling.

Lastly, our development of an Ir-catalyzed asymmetric allylic alkylation of cyclic β-ketoesters to afford highly congested, vicinal stereocenters comprised of tertiary and all-carbon quaternary centers with outstanding regio-, diastereo-, and enantiocontrol is detailed. Implementation of a subsequent Pd-catalyzed alkylation affords dialkylated products with pinpoint stereochemical control of both chiral centers. The chemistry is then extended to include acyclic β-ketoesters and similar levels of selective and functional group tolerance are observed. Critical to the successful development of this method was the employment of iridium catalysis in concert with N-aryl-phosphoramidite ligands.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Catalysis, Allylic Alkylation, Asymmetric, Alkylation, Palladium, Methodology, Reaction Development, Quaternary, Quaternary Stereocenter, All-carbon Quaternary Center
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:
  • Dervan, Peter B. (chair)
  • Reisman, Sarah E.
  • Hsieh-Wilson, Linda C.
  • Stoltz, Brian M.
Defense Date:13 May 2015
Record Number:CaltechTHESIS:05192015-131629900
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:05192015-131629900
DOI:10.7907/Z9VX0DGH
Related URLs:
URLURL TypeDescription
http://pubs.acs.org/doi/abs/10.1021/ol500355zPublisherArticle related to Chapter 2
http://pubs.acs.org/doi/abs/10.1021/ja4097829PublisherArticle related to Chapter 4
http://pubs.acs.org/doi/pdf/10.1021/ja4052075PublisherArticle related to Chapter 3
http://onlinelibrary.wiley.com/doi/10.1002/anie.201301815/abstractPublisherArticle related to Chapter 1
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:8869
Collection:CaltechTHESIS
Deposited By: Corey Reeves
Deposited On:28 May 2015 19:30
Last Modified:12 Apr 2016 19:00

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