title: Exploring the Use of a Horner-Wadsworth-Emmons Reaction in the Synthesis of Higher Order Sugars
Creators: name: Everson, Jack G
Publisher: name: Griffith University
Year: 2022
Subjects: subject: 2-keto-3-deoxy-D-manno-octulosonic acid (KDO)
subject: tetradeoxynonulosonic acids
subject: synthesis
subject: acyclic sugar
subject: ulosonic acids
subject: higher order sugars

description: Higher order sugars are typically defined as sugars with a carbon backbone consisting of more than 6 carbons. A category of higher order sugars are ulosonic acids, these sugars are typically eight or nine carbons in length and are denoted by their 1-carboxylic acid, 2-keto and 3 deoxy moiety. Of interest to us are two categories of ulosonic acids, the first being 2-keto-3-deoxy-D-manno-octulosonic acid (KDO). KDO is an 8-carbon acidic sugar which is mostly known as a linker component in LPS and lipid A found in Gram negative bacteria.1,2 The second category of ulosonic acids we are interested in are the 3,5,7,9-tetradeoxynon-2-ulosonic acids (tetradeoxynonulosonic acids). These tetradeoxynonulosonic acids can be identified easily due to their 9-carbon backbone and acylamido groups at the C5 and C7 positions.3,4 Some naturally occurring examples of tetradeoxynonulosonic acids include legionaminic acid, pseudaminic acid and acinetaminic acid. These sugars are found exclusively in bacteria and have been linked to the virulence and motility of some species such as Campylobacter jejuni.5 With both KDO and tetradeoxynonulosonic acids being linked to the virility of a range of pathogenic bacteria there has been great interest into investigating their biological function. However, one issue is the limited access to these sugars, with the sugars either being too expensive or very difficult to synthesize. This project therefore aimed to explore the potential for a new and potentially efficient way to make naturally and synthetically derived versions of both KDO and tetradeoxynonulosonic acids. Chapter 1 explores the literature behind the synthesis of KDO and KDO derivatives as well as tetradeoxynonulosonic acids and a number of their derivatives. In addition to providing a comprehensive account of the various approaches towards these higher order ulosonic acids, the chapter concludes with a section setting the scene for what follows within the thesis. Chapter 2 will start to look at our investigations and exploration of a method by Feng et al. using a Horner-Wadsworth-Emmons (HWE) reaction.6 The method starts with readily available ᴅ-mannose and in three steps reacts it with a two carbon building block (a phosphonate) to give KDO. This reaction is marvellous in its simplicity of turning a 6-carbon sugar into an 8-carbon acidic sugar via a [6+2] approach. We expand on the work by Feng et al. by exposing a range of C6 mannose derivatives to the HWE reaction and in doing so synthesize a number of novel C8 KDO derivatives. Chapter 3 is based on an unexpected outcome from a HWE reaction conducted on a simple aromatic aldehyde, and refers to our publication refers to our publication, ‘Synthesis of butenolides via a Horner-Wadsworth-Emmons cascading dimerization reaction.’7 Within this work we look at the consequence of performing the HWE reaction on simple aliphatic and aromatic aldehydes. We found that all the simple aliphatic aldehydes successfully react, giving proof that the same should be true of sugars providing they are in an acyclic (i.e. aldehyde exposed) form. However we also found that simple aromatic aldehydes successfully react in a HWE reaction but then undergo a dimerization reaction to form a class of compounds called butenolides. Beyond our published work we also performed a mass spectrometry α-synuclein binding assay and an α-synuclein aggregation inhibition assay with a number of our synthesized butenolides. α-synuclein is a protein that plays a role in a number of neurodegenerative diseases, the most notable being Parkinson’s disease.8 We found that a number of our butenolides do indeed bind with α-synuclein but do not prevent its aggregation to form Lewy bodies. Chapter 4 then looks at our attempts to produce acyclic sugar derivatives. After determining that the HWE reaction worked on all the simple aldehydes we tested, we concluded that our sugar derivatives should also work. The HWE reaction requires an aldehyde functional group exposed on the substrate to work and we believed that the limiting factor for a number of our sugars was their propensity to mask their aldehyde group in an acyclic form. We therefore set out to produce a range of acyclic sugars, primarily focusing on the use of oximes to protect the C1 aldehyde. While making a good deal of progress we did have some issues with the final removing of the oxime groups. Nonetheless, we have set a strong foundation for what could be a good approach towards successfully reacting a number of ‘un-willing’ sugar derivatives. Chapter 5 finally looks at a number of alternative approaches we explored in our quest to use the HWE reaction in the synthesis of higher order sugars. This covers two topics, the first being the synthesis of heptanose (7-carbon sugar) compounds. The HWE reaction we are investigating adds a 2-carbon building block to the substrate sugar. In the case of mannose (a 6-carbon sugar) this can be seen as a [6+2] reaction to give the 8-carbon sugar KDO. In order to make nonulosonic acids (9-carbon sugars) we would therefore need to start with a seven (7) carbon sugar. We therefore investigated a [6+1] approach so that we can then perform a [7+2] reaction to give us our desired nonulosonic acids. Our investigation allowed us to make a number of heptanose sugars but we failed to get them to react successfully in the HWE reaction. The second topic covered in chapter 5 relates to the use of the HWE reaction on the C6 position of a number of sugars. The key step in this approach involved oxidation using IBX on C6 to turn it into an aldehyde group, bypassing the need for forcing a sugar into its acyclic form. We then conducted the HWE reaction on this sugar and found that this too is a practical approach to the synthesis of ulosonic acids. Chapter 6 presents a summary of the main points developed during this research, and gives some insight into potential future research towards the synthesis of these higher order ulosonic acids. The final chapter in the thesis, chapter 7, brings together all of the experimental protocols and compound characterisation data. There is also an Appendix at the end of the thesis providing the raw spectra obtained during this research.