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dc.contributor.advisorSteenkamp, J. A.
dc.contributor.advisorBezuidenhout, B. C. B.
dc.contributor.authorJordaan, Lizette
dc.date.accessioned2015-11-24T09:18:02Z
dc.date.available2015-11-24T09:18:02Z
dc.date.copyright2007
dc.date.issued2007
dc.date.submitted2007
dc.identifier.urihttp://hdl.handle.net/11660/1830
dc.description.abstractSince the introduction of synthetic analogues in both the health-related and cosmetic industry, a new generation has emerged in search of beneficial bioactivity compounds. This generation of “natural and green” focuses mainly on natural compounds and their health relating application. This research project focused on the natural polyphenolic compounds, Flavonoids. Flavonoids are known to be strong antioxidants, these are molecules that quenches reactive oxygen species (ROS). This generation of free radicals in the stratum corneum is the main factor in the development of skin damage and premature ageing. The two main sources of antioxidants are our body’s own in-house antioxidants or dietary antioxidants. Vitamins E and C were briefly discussed as antioxidants, but the main focus was the antioxidant activity of flavonoids. Through this study were unraveled the reaction pathways of natural antioxidants and their synthetic analogues, in chemical and biological systems. Emphasis was placed on their structure-activity relationship and correlated to their chemical and biological activities. Rooibos extract, known locally and overseas, was pursued not only for its bioactivity but rather its strong radical scavenging abilities. It is known that rooibos is not only unique to South Africa, but is hitherto the only natural source of the dihydrochalcone aspalathin (proven to be a very strong antioxidant). The uniqueness of this dihydrochalcone prompted the establishment of a viable synthetic route towards the construction of those crucial bonds in this target molecule, aspalathin. The first step would be the construction of the dihydrochalcone, 3,4,2’,4’,6’- pentahydroxy dihydrochalcone, which proved to be a challenging array of chemical reactivity. With acylations like Friedel-Craft and Fries, that is known to be very successful, it was decided to commence with the construction of the dihydrochalcone via an appropriate acylation step. Acylation of phenols can either occur via Cacylation (Friedel-Crafts reaction) or O-acylation (esterfication). This regioselectivity is governed by a set of principles incorporated in a theoretical premise, conveniently named as hard and soft acids and bases (HSAB). A new group of water tolerant Lewis acids, namely the lanthanide triflates have been introduced, and also the use of BF3·(C2H5)2O has proven success as catalyst in C-acylation. Simple phenolic substrates were used in the acylation process to assist the eventual establishment of a viable protocol. With these we were able to synthesize 1-hydroxy- 2-acetonaphthone and 3-(3,4-dihydroxy-phenyl)-1-(1-hydroxy-naphthalen-2-yl)- propan-1-one successfully, but in unsatisfactory yields (36 %). Despite many experiments under different conditions, starting with different model compounds, we were unable to improve the reaction yields. Within these reactions resorcinol produced the O-acylation product, 3’-O-hydroxy-phenyl 3-phenyl-propanoate and the C-acylation product, 2’,4’-dihydroxydihydrochalcone, whereas phloroglucinol only produced the O-acylated product, 3’,5’-dihydroxy-phenyl 3-phenyl-propanoate. From this analysis the conclusion can be made that, first occurring is the O-acylation followed by a Fries rearrangement in some cases. The neighboring hydroxy functionalities of phloroglucinol for example, posed a significant steric challenge for incoming electrophiles From the commencement of the project, replacement of the carboxylic acid group with the related, but with different chemical characteristics, nitrile groups was a necessary alternative. The Hoesch reaction was a good example of the HSAB principle, where in acid medium the nitrogen of the cyano group is protonated to afford the reactive electrophilic intermediate, the carbon of which is clearly a “softer” acidic site according to the HSAB theory. The C-acylated product, 2’,4’,6’- trihydroxy dihydrochalcone was produced in an impressive yield (73 %). During this reaction, an interesting result was also obtained, where the phenolic oxygen (“hard” base) as well as the aromatic ring (“soft” base) reacted with the nitrile to produce the product, 3’,5’-dihydroxy-4’-phenyl-propionic acid 1’-3-phenyl-propanoate. It is noteworthy to mention the fact that phloroglucinol was by far the most potent Cand O-nucleophile in a ‘normal’ series of model phenolic entries (phenol, resorcinol, catechol etc.) and resulted in the formation of the biphenyl, 3,5-dihydroxy-phenyl- 2’,4’,6’-trihydroxy-phenylether. Since the formation of a biphenyl ether is a rare occurrence, extensive methylation was employed to confirm the structure. Another part of this study includes the investigation and comparison of similar reactions under the influence of microwaves. Microwave reactions are known for their very short reaction times, higher product yields, less solvent utilized and more cost-effective energy consumption, but it was proved that selectivity was not increased. BF3·(C2H5)2O was the catalyst of choice for the selective C-acylation of phloroglucinol, rather than the water soluble Hf(OTf)4 Lewis acid. Different carboxylic acids were reacted with resorcinol and phloroglucinol with both Lewis acids as catalyst. In the one reaction between resorcinol and 3-phenylpropanoic acid with Hf(OTf)4 as catalyst, a reaction mixture was produced. The reaction mixture was acetylated to give both the O- and C-acetylated products, and from this result it was indicated that Hf(OTf)4 can act as both a Brønsted and Lewis acid in a catalytic cycle. The use of protecting groups was not only to optimize the yields obtained but also to understand BF3·(C2H5)2O and Hf(OTf)4 as catalysts. The low yields for the synthesis of the unprotected dihydrochalcones can be ascribed to: the formation of 3,5- dihydroxy-phenyl-2’,4’,6’-trihydroxy-phenylether, and the formation of 6,7- dimethoxy-indan-1-one and 5,6-dihydroxy-indan-1-one (intramolecular cyclization). At last the C-glycosylated flavonoid, aspalathin was synthesized. The best reaction result of phloroglucinol and 3,4-dihydroxyhydrocinnamic acid was catalyzed by BF3·(C2H5)2O to produce 3,4,2’,4’,6’-pentahydroxy dihydrochalcone, which resulted in a 20 % yield. A reliable method for the direct C-glycosylation of 3,4,2’,4’,6’- pentahydroxy dihydrochalcone with an unprotected sugar, D-glucose in aqueous media was used and yielded synthetic aspalathin (10.7%). Not only was this reported as the first 2 step synthesis of aspalathin, but was distinguished as the first complete free phenolic synthesis of a C-glycosylated flavonoid being reported. Combining this unique synthesis with a global industry such as cosmetics was possible. A study was conducted by Miao-Juei Huang and according to their results it was confirmed that aspalathin would be ideal for the use in topically applied cosmetic products, due to the accumulation of aspalathin in the stratum corneum. This causes a barrier on the skin with strong antioxidant properties, which protects the skin from harmful UV rays, reduce reactive oxygen species and slow down the aging process. Finally the potential of the desired compound to act as an active ingredient in commercial products was confirmed.en_ZA
dc.description.sponsorshipNational Research Foundation (NRF)en_ZA
dc.language.isoenen_ZA
dc.publisherUniversity of the Free Stateen_ZA
dc.subjectDissertation (M.Sc. (Chemistry))--University of the Free State, 2007en_ZA
dc.subjectPolyphenols -- Synthesisen_ZA
dc.subjectRooibos teaen_ZA
dc.subjectFlavonoidsen_ZA
dc.subjectAspalathusen_ZA
dc.subjectCosmetics industryen_ZA
dc.subjectChemistry, Organicen_ZA
dc.titleDevelopment of a viable protocol aimed at the synthesis of a selected natural product with possible application in the industryen_ZA
dc.typeDissertationen_ZA
dc.rights.holderUniversity of the Free Stateen_ZA


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