Stereochemical Control in Complex Molecule Synthesis
Creators: name: White, Lorenzo
Publisher: name: The Australian National University
Year: 2015
Subjects: subject: Chemistry
subject: Organic Chemistry
subject: FOS: Chemical sciences
subject: Synthesis
subject: Natural Products
subject: Stereochemistry
subject: Stereoselective
subject: Radical Chemistry

description: The body of this thesis is comprised of eight scientific articles and is preceded by an overview that contextualises all of this submitted/published work. The work described in this thesis contributes to the chemical methodologies that can be deployed when attempting to exert stereochemical control in complex molecule synthesis. Such contributions are desirable given the often profoundly different chemical, physical and/or biological properties that the varying stereoisomeric forms of a given molecular framework can possess. The methodologies detailed herein can be divided into three parts: The first part is comprised of Publications 1-4 and is concerned with the development of a chemoenzymatic total synthesis of the natural enantiomeric form of vindoline (A) from the enantiomerically pure cis-1,2-dihydrocatechol B, itself a metabolite generated stereospecifically via the whole-cell biotransformation of bromobenzene. Specifically, Publication 1 represents the first (and extensive) literature review of the chemistry of RANEY®-cobalt, a readily generated catalyst that when used in the presence of dihydrogen facilitates the chemoselective reduction of C-N and N-O multiple bonds. This catalyst can be exploited to great effect in the stereoselective assembly, through tandem reductive cyclisation processes, of polycyclic, nitrogen-containing molecular frameworks. Publication 2 describes the results of synthetic studies that exploit RANEY®-cobalt for the purposes of converting compound B into a pentacyclic system, C, embodying most of the key structural features of vindoline (A). Publication 3 describes novel gold-catalysed cyclisation and [2+2]cycloaddition reactions developed as part of related efforts to assemble the 2 vindoline framework. Two key products resulting from these studies are the pentacyclic compounds D and E. Publication 4 represents another invited review article and contextualises the work reported in the first part of the thesis by describing various of the contemporary ways in which cis-1,2- dihydrocatechols such as B have been exploited as starting materials for the stereochemically controlled synthesis of a range of natural products. The second part of this thesis is comprised of Publications 5 and 6. These detail the synthesis and/or manipulations of the chirons F, G and H. The first two of these were obtained through chemical modifications, developed by the author, of congener B while compound E is the product of the large-scale pyrolytic degradation of acidified biomass, most notably waste paper and sawdust. So, Publication 5 describes the preparation of synthon F via an initial reaction between the conjugate base of p-methoxybenzyl alcohol and an epoxide derived from cis-1,2- dihydrocatechol B with trapping of the oxy-anion so formed using MOM-chloride. The reaction was extended to the generation of enone G and thereby establishing a significantly improved protocol for the production of chirons of demonstrated utility in the total synthesis biologically active natural products. Publication 6 describes various novel manipulations of 3 levoglucosenone (H), including those involving Wharton rearrangement chemistry, to produce isolevoglucosenone and related compounds of likely synthetic utility. The third and final part of this thesis is comprised of Publications 7 and 8. It details work focused on exploiting, via radical transfer processes, xanthates in the stereoselective synthesis of either E- or Z-configured olefins. Two types of xanthate, I and J, were employed for such purposes, with manipulations of the former allowing for the introduction of Z-configured olefins into complex molecular frameworks while the latter served as a precursor to a range of E-configured olefins. Specifically, then, Publication 7 describes the synthesis of compound I and its addition, via a radical-based xanthate transfer reaction, to various olefins. The adducts of this process were engaged in Favorskii chemistry that allowed for the stereoselective synthesis of Z-alkenoates. Publication 8 reviews the literature concerned with xanthate J and details the capacity of radical adducts of this species to add to double bonds and so providing a means for effecting Horner-Wadsworth-Emmons reactions with aldehydes and thereby generating E-alkenoates.