Strategies for the synthesis of bioactive compounds: biomimetic approaches to the Salinosporamides and the hexadehydro-Diels-Alder reaction
type: CreativeWork
description: Part I: The salinosporamides are a subset of polyketide-derived marine natural products that have as their key structural feature a fused γ-lactam/β-lactone moiety. These molecules are known to inhibit the 20S proteasome (20SP) by utilizing the β-lactone reactivity, a promising target for cancer therapeutics. We propose that salinosporamide A may be formed biosynthetically by a non-enzymatic bis-cyclization event involving an uncatalyzed intramolecular ketene-ketone [2+2] cycloaddition of an amidoketene precursor. We also propose a transition state that places the C2 substituent pseudo-equatorial, allowing for enhanced stereoselectivity during bis-cyclization. Enolate formation from a thioester followed by internal acylation and concurrent loss of thiolate would form a 5(4H)-oxazolone. It is known that 5(4H)-oxazolones readily tautomerize to 4-hydroxyoxazoles, which are in equilibrium with their mesoionic Münchnone forms. Valence bond isomerism interconverts Münchnones to amidoketenes. Spontaneous ketene-ketone [2+2] cycloaddition would siphon the precursors through such a tautomeric manifold to give the natural product. Progress toward the synthesis of the biosynthetic precursors to salinosporamide A is disclosed in Chapters 3-5. Part II: The second part of this Thesis describes our recent, serendipitous encounter with the hexadehydro-Diels-Alder (HDDA) reaction. The HDDA reaction is a mode of the Diels-Alder reaction that involves [4+2] cycloaddition between a diyne and an alkyne to form aryne reactive intermediate. In Part II we show the scope of substrates that are capable of generating an aryne via the HDDA reaction. Additionally, we show that HDDA-mediated generation of arynes allows for the discovery of new modes of aryne trapping, for example, the desaturation of hydrocarbons.
abstract: Part I: The salinosporamides are a subset of polyketide-derived marine natural products that have as their key structural feature a fused γ-lactam/β-lactone moiety. These molecules are known to inhibit the 20S proteasome (20SP) by utilizing the β-lactone reactivity, a promising target for cancer therapeutics. We propose that salinosporamide A may be formed biosynthetically by a non-enzymatic bis-cyclization event involving an uncatalyzed intramolecular ketene-ketone [2+2] cycloaddition of an amidoketene precursor. We also propose a transition state that places the C2 substituent pseudo-equatorial, allowing for enhanced stereoselectivity during bis-cyclization. Enolate formation from a thioester followed by internal acylation and concurrent loss of thiolate would form a 5(4H)-oxazolone. It is known that 5(4H)-oxazolones readily tautomerize to 4-hydroxyoxazoles, which are in equilibrium with their mesoionic Münchnone forms. Valence bond isomerism interconverts Münchnones to amidoketenes. Spontaneous ketene-ketone [2+2] cycloaddition would siphon the precursors through such a tautomeric manifold to give the natural product. Progress toward the synthesis of the biosynthetic precursors to salinosporamide A is disclosed in Chapters 3-5. Part II: The second part of this Thesis describes our recent, serendipitous encounter with the hexadehydro-Diels-Alder (HDDA) reaction. The HDDA reaction is a mode of the Diels-Alder reaction that involves [4+2] cycloaddition between a diyne and an alkyne to form aryne reactive intermediate. In Part II we show the scope of substrates that are capable of generating an aryne via the HDDA reaction. Additionally, we show that HDDA-mediated generation of arynes allows for the discovery of new modes of aryne trapping, for example, the desaturation of hydrocarbons.
author: Willoughby, Patrick
language: en
keywords: Natural products, Synthetic methodology, Total synthesis, Chemistry
date published: 2013-08
date modified: 2026-07-24T05:20:09Z
provider: University of Minnesota
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Minnesota

PropertyValue
property ID: Handle
value: http://hdl.handle.net/11299/167685