Development of Versatile Methodology for Hetero- and Carbocycle Construction: Application in Complex Natural Product Synthesis
Open Access
- Author:
- Greshock, Thomas J
- Graduate Program:
- Chemistry
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- February 28, 2006
- Committee Members:
- Raymond Lee Funk, Committee Chair/Co-Chair
Steven M Weinreb, Committee Member
Blake R Peterson, Committee Member
Squire J Booker, Committee Member - Keywords:
- welwistatin
dioxin
lepadiformine
amidoacrolein
indole
electrocyclic
Diels-Alder
Michael addition
halomethyl vinyl ketone equivalent
heterocycle
carbocycle
welwitindolinones - Abstract:
- The total synthesis of the cytotoxin lepadiformine is discussed in Part I. The key transformation in this synthesis involves methodology previously developed in the Funk group, namely, a regio- and endo-selective cycloaddition of a 2-amidoacrolein with the dimethyl acetal of 4,6-heptadienal. This Diels-Alder reaction not only established the C(5)-C(10) relative stereochemistry of lepadiformine, but was also strategically functionalized for elaboration to the tricyclic ring system. These steps included a diasteroselective addition of an organoytterbium reagent to an aldehyde, cyclization to the trans-perhydroquinoline substructure via a Mitsonobu reaction, and an iodine-promoted amine cyclization with an alkene to introduce the pyrrolidine ring. Part II discusses the development of 6-haloalkyl-4H-1,3-dioxins and their utility as haloalkyl vinyl ketone equivalents for the construction of hetero- and carbocyclic ring systems. In particular, 6-bromomethyl-4H-1,3-dioxin has proven to be useful for the preparation of complex bicyclo[4.3.1]decane-3,10-diones. In addition, a novel method for the construction of both aromatic rings of indoles from readily available α-haloenones and α-(trialkylstannyl)enecarbamates using a 5-step sequence that features facile electrocyclic ring closures of trienecarbamates is described. This method has proven to be most useful for the preparation of indoles possessing complex or difficult substitution patterns. Finally, these two methods have been successfully employed in a stereoselective synthesis of a fully functionalized welwistatin ring system. The key transformation in this synthesis is a sterically encumbered 7-endo intramolecular conjugate addition reaction of a β-ketonitrile to deliver the strained bicyclo[4.3.1]decanone ring system present in welwistatin.