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Design and Development of New Enantioselective Organocatalytic Transformations, a Two-Step Synthesis of Carbohydrates, and Progress toward the Total Synthesis of Callipeltoside C


Northrup, Alan Bowers (2005) Design and Development of New Enantioselective Organocatalytic Transformations, a Two-Step Synthesis of Carbohydrates, and Progress toward the Total Synthesis of Callipeltoside C. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/g84s-an43.


The LUMO-lowering activation of a,b-unsaturated ketones has been accomplished through the development of a new imidazolidinone organocatalyst. That new imidazolidinone catalyst provided the first enantioselective catalytic Diels-Alder reaction with simple ketone dienophiles. Significantly, that catalyst is able to activate both cyclic and acyclic a, b-unsaturated ketones in this cycloaddition process.

A new strategy for the synthesis of two privileged structural motifs, the polyketide and polyglycolate architectures, has been developed based on the direct aldehyde aldol reaction. Two different catalysts are presented that are capable of performing the enantioselective direct aldol cross coupling of two distinct aldehyde components. Imidazolidinones have been shown for the first time to initiate the HOMO-raising activation of both saturated and a, b-unsaturated aldehyde substrates. Using an imidazolidinone catalyst, the first direct enantioselective catalytic aldol coupling of two aldehydes is described and provides synthetically valuable b-hydroxy dimethylacetals. Later, proline was found to be an exceptionally effective catalyst for the direct aldehyde aldol reaction. In contrast to imidazolidinone catalysts, proline affords b-hydroxyaldehyde products that are primed for use directly in subsequent aldol reactions.

Utilizing those direct aldehyde aldol methodologies, a two-step synthesis of 2,4,6-O-protected carbohydrates has been developed. Importantly, this modular strategy is capable of producing highly enantioenriched differentially protected forms of glucose, mannose, allose, mannosamine, as well as unnatural hexose derivatives. Furthermore, this method for sugar synthesis has been applied to the construction of differentially protected 13C6-labeled glucose, mannose, and allose in just four steps from labeled ethylene glycol.

The enantioselective catalytic direct aldehyde aldol reaction was further applied toward the total synthesis of the marine natural product callipeltoside C. Several key fragments have been successfully synthesized and coupled to form macrolactone precursors. Nozaki-Hiyama-Kishi ring closure across the C-9/C-10 bond, however, affords exclusively the undesired C-9 epimer. Therefore, completion of the total synthesis will require a revised order for fragment assembly.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:aldol; callipeltoside; carbohydrate; Diels-Alder; enantioselective catalysis; 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.
  • Dougherty, Dennis A.
  • Hsieh-Wilson, Linda C.
Defense Date:9 September 2004
Record Number:CaltechETD:etd-09242004-095741
Persistent URL:
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:3742
Deposited By: Imported from ETD-db
Deposited On:27 Sep 2004
Last Modified:16 Apr 2021 22:27

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