The application of soluble supports in the radiochemical asymmetric total synthesis of tea flavanols.

Chua, Ching Ching (2009) The application of soluble supports in the radiochemical asymmetric total synthesis of tea flavanols. PhD thesis, University of Glasgow.

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Flavan-3-ols such as (—)-epicatechin and (+)-catechin are found in significant concentrations in red wine, green and black teas and cocoa. The radiolabelling of flavan-3-ols for feeding studies would require a short high-yielding route from the point of introduction of the label. (E)-1,3-Diarylpropenes had been key intermediates in previous syntheses of flavan-3-ols and so the modified Julia alkenation reaction between a labelled aryl aldehyde and a 2-(2'-arylethylsulfonyl)benzothiazole was proposed as the key step in the preparation of radiolabelled (E)-1,3-diarylpropene. A low molecular weight poly(ethyleneglycol)-monomethyl ether (MPEG, average MW 550) support would be used to improve the efficiency of isolating radiolabelled product after each reaction.

The light MPEG support was attached to the starting aryl bromide by protecting the phenolic hydroxyl group with a new light MPEG α,α’-dioxyxylyl protecting group, introduced by reaction with light MPEG-supported benzylic bromide, to give supported aryl bromide. The aryl bromide was reacted with copper (I) cyanide to give MPEG-supported nitrile. In theory, 14C-labelled cyanide could be used in this step. Reduction and hydrolysis gave the aldehyde. Throughout the sequence MPEG solid-phase extraction (M-SPE) was used to assist purification.

Several approaches to the synthesis of 2-(2'-arylethylsufonyl)benzothiazole were then investigated using a variety of model 2-arylethyl sulfones. The novel addition of phenylcopper to phenyl vinyl sulfone gave 2-phenethyl phenyl sulfone in good yield, but the reaction was less effective for sterically hindered arylcoppers and unsuccessful for the preparation of 2-(2'-arylethylsufonyl)benzothiazoles. Alkylcopper reagents were also suitable substrates for this novel coupling. Heck reaction between aryl iodide and phenyl vinyl sulfone, and reduction of the resulting alkene gave 2-arylethyl phenyl sulfone but the Heck reaction failed with benzothiazolyl analogues. Lithiated 2-(methylthio)benzothiazole reacted with aryl aldehydes to give β-hydroxy sulfides, but reduction to 2-arylethyl derivatives failed, even after oxidation of the sulfide to the sulfone or elimination to give a vinyl sulfide or sulfone. The same problem was encountered when lithiated 2-(trimethylsilylmethylthio)benzothiazole was use to make vinyl sulfides directly. However, alkylation of lithiated 2-(methylthio)benzothiazole with benzyl bromide gave 2-(2'-phenylethylsufonyl)benzothiazole in good yield. Unfortunately, the reaction could not be used to prepare phloroglucinol-derived benzothiazole.

Finally, the benzothiazoles underwent modified-Julia alkenation reaction with electron-rich benzaldehydes to give (E)-1,3-diarylpropenes in high yield.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Flavanols, Soluble supports, MPEG, Modified Julia Alkenation, Copper (1) mediated Michael addition, Sulfones
Subjects: Q Science > QD Chemistry
Colleges/Schools: College of Science and Engineering > School of Chemistry
Supervisor's Name: Hartley, Dr. Richard
Date of Award: 2009
Embargo Date: 30 June 2014
Depositing User: Miss Ching Chua
Unique ID: glathesis:2009-837
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 12 Aug 2009
Last Modified: 19 Apr 2013 07:57

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