Since 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 ânatural and greenâ 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 bodyâs 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, 3,4,2â,4â,6â-
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, 3â-O-hydroxy-phenyl 3-phenyl-propanoate and the
C-acylation product, 2â,4â-dihydroxydihydrochalcone, whereas phloroglucinol only
produced the O-acylated product, 3â,5â-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 âsofterâ
acidic site according to the HSAB theory. The C-acylated product, 2â,4â,6â-
trihydroxy dihydrochalcone was produced in an impressive yield (73 %). During this
reaction, an interesting result was also obtained, where the phenolic oxygen (âhardâ
base) as well as the aromatic ring (âsoftâ base) reacted with the nitrile to produce the
product, 3â,5â-dihydroxy-4â-phenyl-propionic acid 1â-3-phenyl-propanoate. It is noteworthy to mention the fact that phloroglucinol was by far the most potent Cand
O-nucleophile in a ânormalâ series of model phenolic entries (phenol, resorcinol,
catechol etc.) and resulted in the formation of the biphenyl, 3,5-dihydroxy-phenyl-
2â,4â,6â-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-2â,4â,6â-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 3,4,2â,4â,6â-pentahydroxy dihydrochalcone, which resulted
in a 20 % yield. A reliable method for the direct C-glycosylation of 3,4,2â,4â,6â-
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.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:ufs/oai:etd.uovs.ac.za:etd-09022013-094546 |
| Date | 02 September 2013 |
| Creators | Jordaan, Lizette |
| Contributors | Prof BCB Bezuidenhoudt, Prof JA Steenkamp |
| Publisher | University of the Free State |
| Source Sets | South African National ETD Portal |
| Language | en-uk |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.uovs.ac.za//theses/available/etd-09022013-094546/restricted/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University Free State or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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