Progress towards the total synthesis of Nemamides, Euglenatides and related analogues

Smith, Tyarna (2025) Progress towards the total synthesis of Nemamides, Euglenatides and related analogues. Doctoral thesis, University of East Anglia.

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Abstract

Euglenatides A-E and nemamides A and B were isolated from Euglena gracilis and Caenorhabditis elegans respectively. Both product families contain similar 5-mer cyclic peptide structures, each including a variant of graciline. Graciline is an amino acid containing a polyketide chain with multiple stereogenic centres. Variants include 2-deoxygraciline as well as others possessing modified chain lengths and saturation. Euglenatides A-D were shown to have anti-fungal effects, alongside tumour supressing output against varying cancer cell lines. Considering the structural similarity, this makes all seven compounds possible therapeutic targets and therefore, the total synthesis of these compound families is desirable.

This thesis focuses on devising a route towards the total synthesis of these two natural product families. Synthetic routes are designed around the key disconnection of the respective graciline variant and the remaining 4-mer linear peptide chain. To allow for generation of all graciline variants, the route was designed to be modified from a late stage intermediate. Approaches outlined within utilise various chiral catalysts and auxiliaries to install the stereogenic centres, and detail initial optimisation strategies towards the synthesis of the late stage intermediate. Initial work using a Brown allylation approach proved to be inefficient, so was redesigned to include other catalytic approaches towards stereo-control. This route utilises a semi-iterative approach which includes an asymmetric aldol directed by a functionalised proline organo-catalyst, and copper catalysed hydroboration for the stereoselective formation of carbon-heteroatom bonds.

Alongside this, the use of model systems to trial the preliminary synthetic steps towards the cyclic peptides is outlined.

Further work is required to complete the total synthesis of nemamides and euglenatides, however, this thesis describes the initial synthetic work, including steps towards graciline and its variants. Preliminary findings suggest that the novel synthetic strategy described herein could lead to successful isolation of the graciline targets with high stereocontrol if substrate specific optimisation of the hydroboration reaction is performed.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Science > School of Chemistry, Pharmacy and Pharmacology
Depositing User:	Chris White
Date Deposited:	13 Apr 2026 07:58
Last Modified:	13 Apr 2026 07:58
URI:	https://ueaeprints.uea.ac.uk/id/eprint/102757
DOI:

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