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Title: Evaluating the use of chiral anthracene templates to access pyroglutamic acid
Author: Hasbullah, Siti Aishah Binti
ISNI:       0000 0004 2725 2371
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2010
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Approaches to prepare pyroglutamic acid derivatives using a chiral anthracene moiety have been carried out using a nucleophilic carboxylic acid synthon. A model study to prepare five membered ring lactams bearing a quaternary centre via a Ugi-3CR reaction using commercially available levulinic acid 162 was successful, giving the five-membered ring lactams 164a -164g in 72 - 86% yield. A Pd catalysed ring opening of an anthracene anhydride 184 cycloadduct was used to prepare a key keto-acid that unfortunately was a poor substrate for the Ugi reaction due to the geometry of keto acid to give alkene product 198. Introduction of a furan ring as a masked carboxylic acid moiety proceeded with excellent levels of diastereoselectivity, follmved by conversion into a carboxylate ester (71 - 80% yield). Flash vacuum pyrolysis (FVP) followed by reduction gave pyroglutamate esters 243 and 256 - 261 in 21 - 26% yield but poor enantioselectivity, which was found to be dependant on the electronic nature of the N-protecting group. Constructing a quaternary carbon centre using the same methodology was successful to give pyroglutamate 273 in 63% yield and 95% enantioselectivity after FVP. Other analogues gave enamides 275a-j in good to excellent yield (63 - 90%). Dimethyl dioxirane (DMDO) oxidation of enamide 275f gave hydroxy-ketone 285 in excellent yield. Subsequent double reduction with Et3SiH and NaBH4 gave two diastereoisomers in moderate yield. FVP of both diastereoisomers gave pyroglutamate ester 295 and 296 in 40% and 60% respectively.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available