Total Synthesis of an Oxidation Product of gamma-Carotene - a ProVitamin A Food Carotenoid

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dc.contributor.advisorKhachik, Fredericken_US
dc.contributor.advisorKahn, Jasonen_US
dc.contributor.authorCrawford, Kristine Sheilaen_US
dc.contributor.departmentChemistryen_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.date.accessioned2012-07-07T05:30:45Z
dc.date.available2012-07-07T05:30:45Z
dc.date.issued2011en_US
dc.description.abstractHuman serum carotenoids and their metabolites are known to function as antioxidants and inflammation mediators. In 1992, two oxidative metabolites of lycopene were isolated from human serum and tomato-based food products. These substances were subsequently prepared by partial synthesis from lycopene and characterized as a diastereomeric mixture of 2,6-cyclolycopene-1,5-diols I and II. Results of in vitro studies have demonstrated that the diols were more effective at inhibiting the growth of solid human tumor cells than lycopene. While the metabolisms of prominent hydrocarbon carotenoids such as lycopene and beta-carotene have been extensively studied, the functional role of gamma-carotene remains unexplored. Because the chemical structure of gamma-carotene is a hybrid of lycopene and beta-carotene, the total synthesis of the analogous metabolite of gamma-carotene 2,6-cyclo-gamma-carotene-1,5-diol was undertaken. The total synthesis 2,6-cyclo-gamma-carotene-1,5-diol was accomplished using a C15+C10+C15 Wittig coupling strategy. The C15-dihydroxyaldehdye key synthon with a defined stereochemistry, a protected C10-Wittig salt, and the beta-ionylidene-ethyltriphenylphosphonium chloride C15-Wittig salt provided the three building blocks in this synthesis. To arrive at the C15-dihydroxyaldehyde, citral epoxide was elongated to a C15-epoxynitrile which underwent acid-catalyzed cyclization to afford a C15-dihydroxynitrile. After reduction with DIBAL-H, the key C15-dihydroxyaldehdye was produced in 16% yield in three steps from citral epoxide. The major drawback of this synthesis was the cyclization step. According to this approach, 2,6-cyclo-gamma-carotene-1,5-diol was prepared in high purity in 5 steps in 2.4% overall yield. In a semi-synthetic approach, 12'-apo-beta-carotene-12'-al was transformed into a C25-Wittig salt and coupled to the C15-dihydroxyaldehyde synthon to afford 2,6-cyclo-gamma-carotene-1,5-diol in 16.8% overall yield in 3 steps. A third strategy involved the epoxidation of 12'-apo-psi-carotene-12'-al followed by cyclization to a C25-dihydroxyaldehyde upon silica gel chromatography. Final coupling of C25-dihydroxyaldehyde with the beta-ionylideneethyltriphenylphosphonium chloride C15-Wittig salt produced 2,6-cyclo-gamma-carotene-1,5-diol in 6.0% overall yield in 2 steps. This strategy does not require access to large amounts of pure C15-dihydroxyaldehdye and takes advantage of the commercial availability of 12'-apo-psi-carotene-12'-al, and is by far the most practical route to 2,6-cyclo-gamma-carotene-1,5-diol. The present methodologies provide novel access to an oxidation product of gamma-carotene that could be potentially formed in humans or biological systems.en_US
dc.identifier.urihttp://hdl.handle.net/1903/12586
dc.subject.pqcontrolledOrganic chemistryen_US
dc.subject.pquncontrolledCarotenoidsen_US
dc.subject.pquncontrolledgamma-Caroteneen_US
dc.subject.pquncontrolledTotal Synthesisen_US
dc.titleTotal Synthesis of an Oxidation Product of gamma-Carotene - a ProVitamin A Food Carotenoiden_US
dc.typeDissertationen_US

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