Open Access
Aungst, Jr., Ronald Alan
Graduate Program:
Doctor of Philosophy
Document Type:
Date of Defense:
May 23, 2007
Committee Members:
  • RAYMOND LEE FUNK, Committee Chair
  • Steven M Weinreb, Committee Member
  • Scott Trent Feldman, Committee Member
  • Joseph M Bollinger Jr., Committee Member
  • heterocycloaddition
  • Diels-Alder
  • cycloaddition
  • dioxin
  • natural product
  • 4 + 3 cycloaddition
  • synthesis
  • retrocycloaddition
Reported herein are several approaches for the synthesis of substituted acrolein derivatives via the retrocycloaddition of substituted 4H-1,3-dioxins. Upon thermal or Lewis acid mediated retro hetero Diels-Alder reactions of these substrates, an appropriately substituted acrolein derivative is generated (stereoselectively in most cases) which can be utilized as a substrate for a variety of cycloaddition reactions. These cycloadditions, including Diels-Alder, hetero Diels-Alder, and [4 + 3], have provided access to several ring systems with excellent control over regio- and stereoselectivity. A strategy for the stereocontrolled synthesis of (Z)-2-acylenals has been developed through utilization of a retrocycloaddition reaction of 5-acyl-4-alkyl-4H-1,3-dioxins. This approach has provided concise synthetic routes to several natural products containing the 5-acyl-2H-3,4-dihydropyran substructure. Application of this methodology has been showcased in the natural product syntheses of both the immunosuppressant loganetin and the cytotoxin euplotin A. This methodology has also been investigated in a synthetic approach towards the synthesis of the xenicin core. Similarly, retrocycloadditions of 4H-4-alkyl-5-(trialkylsilyloxy)-1,3-dioxins proceed smoothly in refluxing toluene to afford (Z)-2-(trialkylsilyloxy)-2-alkenals with complete stereoselectivity. These enals undergo Sasaki-type [4 + 3] cyclization with dienes in the presence of Lewis acids, in many instances with excellent regio- and/or stereoselectivity. Also, throughout our investigations of forming 1,3-dioxins it was found that these retrocyloaddition precursors could be formed by a variety of reaction sequences. An example of a deconjugation approach for the formation of dioxins is exemplified in the development of a thermally labile solid-phase linker. A similar approach was also utilized in the synthesis of the 1,3-dioxin precursors for the preparation of the labdane/clerodane ring system. Subsequent thermolysis of this substrate provided clean conversion, via a one-pot retro- hetero Diels-Alder reaction and successive intramolecular Diels-Alder reaction, to provide the requisite trans-decalin ring system with an axial bridgehead aldehyde. Finally, in our studies toward the synthesis of 1,3-dioxins, a Diels-Alder approach to the sesquiterpene illudin C ring system was investigated. Unfortunately, this approach proved unproductive; however, it did lead to an alternative approach to illudin C. A convergent total synthesis of illudin C is described. The tricyclic ring system of the natural product was quickly assembled from cyclopropane and cyclopentene precursors via a novel oxime dianion coupling reaction and a subsequent intramolecular nitrile oxide-olefin cycloaddition.