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Development of enantioselective organocatalytic hydrogenation methods and progress toward the total synthesis of (+)-minfiensine

Citation

Tuttle, Jamison Bryce (2008) Development of enantioselective organocatalytic hydrogenation methods and progress toward the total synthesis of (+)-minfiensine. Dissertation (Ph.D.), California Institute of Technology. http://resolver.caltech.edu/CaltechETD:etd-04292008-113738

Abstract

The development of an enantioselective organocatalytic hydrogenation reaction utilizing the LUMO-lowering activation of α,[beta]-unsaturated aldehydes has been developed. This strategy employs an imidazolidinone catalyst to activate the alkene towards conjugate reduction of the pendant [beta],[beta]-disubstituted alkene by a Hantzsch dihydropyridine. This is the first general methodology that utilizes disubstituted alkenes for iminiuim activation chemistry and stereoconvergently reduces mixtures of olefin geometric isomers to favor an enantioenriched product. Furthermore, the reagents are air and moisture stable making this new process operationally trivial.

By exploiting the aforementioned mode of reactivity, enones have been successfully reduced utilizing a privileged imidazolidinone catalyst. These studies led to the discovery of a novel Hantzsch dihydropyridine that exhibits a dramatic increase in reactivity. Further comparison of these Hantzsch derivatives provides interesting physical and structural data that may account for the observed differences.

A rapid entry into the tetracyclic framework of minfiensine utilizing our group’s organocascade cyclization methodology was undertaken. This strategy demonstrates the first example of a 2,3-dialkyl substituted indole starting material successfully reacting under our pyrroloindoline-forming conditions. Various strategies for introducing an allyl silane moiety for use as a SOMOphile to furnish the final ring of the pentacycle were pursued. Numerous attempts were unsuccessful, and studies for introducing the allylsilane post-cyclization were undertaken. These experiments have led to the construction of a vicinal diol that should be two transformations away from attempting the key SOMO cyclization. If successful, the resulting intermediate will be six steps away from the final natural product.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:conjugate addition; dynamic kinetic resolution; enantioselective; Hantzsch; hydrogenation; imidazolidinone; iminium activation; minfiensine; NADH; organocatalysis; pyrroloindoline; reduction; stereoconvergence
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:
  • Stoltz, Brian M. (chair)
  • MacMillan, David W. C.
  • Okumura, Mitchio
  • Grubbs, Robert H.
Defense Date:18 April 2008
Author Email:jamison (AT) caltech.edu
Record Number:CaltechETD:etd-04292008-113738
Persistent URL:http://resolver.caltech.edu/CaltechETD:etd-04292008-113738
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:1550
Collection:CaltechTHESIS
Deposited By: Imported from ETD-db
Deposited On:30 May 2008
Last Modified:26 Dec 2012 02:39

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