Total synthesis of biselide A and studies towards the synthesis of a chimeric glycopeptide to probe peptide-carbohydrate mimicry

Date created: 
2019-12-11
Identifier: 
etd20650
Keywords: 
Natural products
Total synthesis
Biselide A
Phormidolide A
Antibody
Glycopeptide
Abstract: 

The primary focus of the research described in this thesis deals with the studies geared towards the total synthesis of biselide A and phormidolide A, two tetrahydrofuran containing natural products with potentially useful biological activities. Additionally, efforts towards the synthesis of a chimeric glycopeptide is described. Biselide A, is a chlorinated macrocyclic polyketide isolated from the Okinawan ascidian Didemnidae sp., possessing potent cytotoxicity against a variety of human cancer cell lines. The core molecular structure contains a densely substituted tetrahydrofuran ring and 5 stereogenic centres as a part of 14-membered macrolactone. To access this potentially useful marine macrolide we have utilized an asymmetric aldol reaction with enantiomerically-enriched chlorohydrins that affords a rapid and stereocontrolled access to the tetrahydrofuran core. The macrocycle was constructed through a series of transformations that include a cross metathesis, regioselective enzymatic acetylation, and Reformatsky macrocyclization. In this thesis we highlight a flexible and stereoselective total synthesis of biselide A. Phormidolide A is a complex macrocyclic polyketide isolated from the cyanobacteria Leptolyngbya sp. It possess a highly oxygenated side chain and a macrocyclic core with an embedded substituted tetrahydrofuran. We exploit our previously developed α-chlorination/aldol reaction strategy to access the tetrahydrofuran motif. Synthesis of three model acetonide tetrahydrofuran derivatives allowed for the NMR comparison with the same previously reported triacetonide derivative of phormidolide A. NMR spectroscopic analysis supports a reassignment of seven of the eleven stereogenic centres initially reported for phormidolide A. The second part of this thesis describes the progress made towards the synthesis of a chimeric glycopeptide. Two haptens, a pentasaccharide and a mimetic octapeptide bind with moderate affinity to a monoclonal antibody SYA/J6, specific for the O-polysaccharide of the S.flexneri Y bacterium. Based on the X-ray crystallography data and molecular docking studies, two chimeric glycopeptides (α-glycopeptide and β-glycopeptide) were designed in an attempt to improve the binding affinity to SYA/J6 antibody. Our group has previously synthesized α-glycopeptide and showed no inhibition of SYA/J6 antibody to the O-polysaccharide. Preliminary docking studies indicated that the β-glycopeptide might provide a better fit within the antibody combining site. The molecule consists of a rhamnose trisaccharide linked through a β-glycosidic linkage to an MDW moiety of a mimetic octapeptide. Our strategy involved linking three fragments, synthesized using solution and/or solid phase methodology. The key step in the synthesis was the formation of the thermodynamically less favoured β-linkage between the sugar and peptide. This was achieved following an ulosyl bromide approach. We herein describe our efforts towards the synthesis of a β-glycopeptide.

Document type: 
Thesis
Rights: 
This thesis may be printed or downloaded for non-commercial research and scholarly purposes. Copyright remains with the author.
File(s): 
Senior supervisor: 
Robert A. Britton
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.
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