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Development of Organocatalytic Direct Aldol Transformations, Total Syntheses of Brasoside and Littoralisone, and Progress Toward the Total Synthesis of Diazonamide A


Mangion, Ian Kyle (2006) Development of Organocatalytic Direct Aldol Transformations, Total Syntheses of Brasoside and Littoralisone, and Progress Toward the Total Synthesis of Diazonamide A. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/1TPK-9277.


The enantioselective amine-catalyzed direct aldol reaction of aldehdyes has been accomplished for the first time using an imidazolidinone organocatalyst. That imidazolidinone catalyst, initially developed for LUMO-lowering activation of alpha, beta-unsaturated aldehydes, provides new insight into amine-mediated aldol transition states. The concepts developed in this study have been applied toward the development of an unprecedented enantioselective Type II direct aldol. In the course of these studies the amino acid proline was also found to be a highly effective catalyst for this transformation. These catalyst systems form the basis for a novel approach to polyketide and polyglycolate architectures, structural motifs having broad representation amongst natural product isolates.

This enamine catalysis strategy was then applied towards the total synthesis of the iridoid natural products brasoside and littoralisone. Direct aldol chemistry was applied towards the synthesis of a substituted carbohydrate structure, and a recently developed enantioselective oxyamination reaction installed a key stereocenter. Stereocontrolled synthesis of the bicyclic core common to the iridoid class of natural products required the development of a new, kinetically controlled organocatalytic intramolecular Michael reaction. A [2+2] photocycloaddition completed the first total synthesis of littoralisone, and demonstrated a likely biosynthetic link to brasoside, which may well be a natural precursor.

An iminium-mediated addition-cyclization cascade reaction has been applied toward the total synthesis of the marine natural product diazonamide A. This strategy has provided stereoselective, catalytic access to the crucial C-10 quaternary carbon stereocenter for the first time. A novel intramolecular soft enolization aldol macrocyclization formed a precursor to the A-ring oxazole, which was subsequently completed in a newly discovered DAST-mediated cyclodehydration. Closure of the fourteen-membered biaryl macrocycle has been accessed through an unusual Suzuki macrocyclization, and completion of diazonamide A should be accessible in four further steps.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:brasoside; diazonamide; direct aldol; littoralisone; macrocyclization; organocatalysis
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Awards:The Herbert Newby McCoy Award, 2006.
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • MacMillan, David W. C.
Thesis Committee:
  • Stoltz, Brian M. (chair)
  • MacMillan, David W. C.
  • Peters, Jonas C.
  • Grubbs, Robert H.
Defense Date:25 May 2006
Record Number:CaltechETD:etd-05232006-210214
Persistent URL:
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:1981
Deposited By: Imported from ETD-db
Deposited On:24 May 2006
Last Modified:15 Apr 2020 22:30

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