The Regioselective Synthesis of Deuterated 4-Alkyl-y-Lactones: a thesis presented in partial fulfilment of the requirements for the degree of Master of Science in Chemistry at Massey University
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Date
2001
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Massey University
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Abstract
γ-Lactones are important flavour compounds that occur naturally in foodstuffs such as fruit and dairy products. Their presence, or absence, has a considerable influence on the perceived quality of these products. It is therefore important to be able to accurately measure the concentrations of certain γ-lactones. Deuterium labelled compounds offer the possibility of achieving this through stable isotope dilution assays (SIDA). To achieve maximum sensitivity in SIDA of γ-lactones requires two to four deuterium atoms to be placed regioselectively within the lactone ring, where they are retained in the base peak of the labelled analogue upon electron ionisation mass spectroscopy. To this end. two syntheses of regioselectively deuterium ring labelled γ-lactones have been developed. Initially, three tetradeuterated 2,2,3,3-²H₄-γ-lactones were prepared. The key step in these syntheses involved the reduction of a doubly protected hydroxy acetylenic acid with deuterium gas in the presence of Wilkinson's catalyst. 2,2,3,3-²H₄-γ-Dodecalactone was prepared in 25% overall yield with 95% deuterium incorporation, 2,2,3,3-²H₄-γ-decalactone in 46% yield with 89% deuterium incorporation and 2,2,3,3-²H₄-γ-octalactone in 36% yield with 90% deuterium incorporation. While higher catalyst loadings (10 mol%) resulted in shorter reduction times, a higher degree of deuterium incorporation was achieved at lower catalyst loadings (5 mol%). A second, one-pot radical synthesis of ring-labelled γ-lactones was also developed which involved the addition of a two-carbon acetoxy radical to an appropriate 1,1,2-deuterated 1- alkene. This synthesis produced trideuterated γ-lactones without deuterium in the potentially exchangeable position α to the carbonyl moiety. Extensive GC optimisation for this process was undertaken using unlabelled precursors. A combination of 1-alkene (1.5 mmol). 2-iodoacetamide (0.5 mmol), 1,1'-azo-bis-cyclohexanecarbonitrile (radical initiator) (1.0 mmol) and water (50 mmol) in benzene (10 mL) was found to be optimal. The synthesis of 1,1,2-²H₃-1-decene, 1,1,2-²H₃-1-octene and 1,1,2-²H₃-1-hexene was pursued via the reduction of appropriate 1-²H-1-alkynes with deuterium gas over Lindlar's catalyst. This apparently simple transformation, proved difficult due to the volatility of the target l,l,2-²H₃-1-alkenes. Nonetheless, under the optimised radical conditions. 3,3,4-²H₃-γ-dodecalactone was prepared in a 69% isolated yield from 1,1,2-²H₃-decene with 96% deuterium incorporation. 3,3,4-²H₃-γ-Octalactone was prepared in 17% yield from 1,1,2-²H₃-1-hexene with 92% deuterium incorporation. It is suggested the efficiency of the radical lactonisation process was dependant upon the purity of the 1,1,2-²H₃-1-alkene as under the optimised conditions, unlabelled γ-decalactone and γ-octalactone were prepared in 91% and 94% isolated yields respectively. Application of the radical strategy for the synthesis of 3,3,4-²H₃-(Z)-6-dodecen-γ-lactone was envisaged but the required deuterated precursor was not accessible. The alternative dideuterated 6,7-²H₂-(Z)-6-dodecen-γ-lactone was. however, prepared in 75% yield with 96% deuterium incorporation via the partial reduction of 6-dodecyn-γ-lactone with deuterium gas over Lindlar's catalyst. The deuterated lactones prepared in this thesis have since proved of value as internal standards for SIDA.
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Lactones -- Synthesis, Radioactive tracers, Deuterium