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Title: The synthesis of precursors and chiral intermediates of lipoic acid
Author: Howes, David Anthony
ISNI:       0000 0001 3582 7911
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 1981
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This thesis describes the synthesis of optically active precursors and intermediates to enantiomers of lipoic acid - a biologically important molecule present in almost all living organisms. Chapter 1 comprises an up-to-date review of the information gained about lipoic acid since its discovery in 1951. Various syntheses of racemic (including radio labelled) lipoic acid are included. The medicinal use of lipoic acid, its chemotherapeutic potential, biological function and a possible role in oxidative phosphorylation are also discussed. In Chapter 2 the reasons for, and objectives of, the work are stated and the rationale used in designing the various syntheses is examined. The concept is introduced of making the lipoic acid skeleton by coupling a four carbon protected carboxylic acid capable of formation of a terminal carbanion with a 4-carbon optically active 1,2-oxirane containing a terminal hydroxy group. Suitable starting materials are listed for the oxirane and means of protecting the carboxyl functions are discussed. A strategy for the synthesis of (R)- and (S)-8-alkyl lipoic acids is also outlined. Chapter 3 examines the potential of 1-methyl-2,6,7-trioxabicyclo[2,2,2]octanes as carboxyl protecting groups. Although a number of derivatives were successfully synthesised and showed ideal properties for the protection of carboxylic acids, the 4-haloalkyl derivatives were inert to carbanion formation. As 2-(3'-chloropropyl)-2-methyl-1,3-dioxolane easily formed a Grignard reagent which readily reacted with oxiranes it was decided to use it as the acid containing fragment in the synthesis of (R)- and (S)-lipoic acid (the acid function being generated by hydrolysis of the dioxolane group and oxidation of the resulting methyl ketone). Chapter 4 describes the synthesis of (R)-4-(2'-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane, a precursor to an optically active oxirane of use in the synthesis of (R)- and (S)-lipoic acid. (2R,3R)-Di-n-butyltartrate is the starting material used and the optical purity of an intermediate, (R)-1,2-dihydroxybut-3-ene is determined. Chapter 5 contains details of the synthesis of (S)-(2-benzyloxyethyl)oxirane from (S)-malic acid via the intermediate (S)-4-(2'-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (the (R)-isomer of which was obtained in Chapter 4 from (2R,3R)-di-n-butytartrate). The optical purity of (S)-(2-benzyloxyethyl)oxirane is determined. The remainder of the Chapter deals with the successful coupling of (2-benzyloxyethyl)oxirane with the Grignard derivatives of 2-(3'-chloropropyl)-2-methyl-1,3-dioxolane to give the lipoic acid skeleton in optically active form. Preliminary experiments for the remainder of the synthesis of (S)-lipoic acid are then outlined. An alternative route was not successful as an intermediate proved difficult to react with the Grignard derivative- of 2-(3’-chloropropyl)-2-methyl-1.3- dioxolane. Chapter 6 covers an attempt to synthesise an optically active oxirane from (S)-methionine. (S)-4-Methylthiobutane-1,2-diol is successfully synthesised but attempts to convert it into the oxirane derivatives failed and led to an unexpected product, (S)-S-methyl-3-hydroxytetrahydrothiophenium bromide. This compound exhibited some interesting chemical properties, but initial attempts to obtain the oxirane derivatives from it by treatment with base were unsuccessful. In Chapter 7 a proposed route to (R)- and (S)-methyllipoic acid from (R)- and (S)-ethyl lactate is outlined. The critical stereoselective reduction of an hydroxyketone intermediate is investigated using 4-hydroxy-2-oxopentane as a model. A method of investigating the nature of the product from reducing 4-hydroxy-2-oxopentane is developed and used for a number of different reducing agents.
Supervisor: Not available Sponsor: Science Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry