The objectives of this project were to investigate the application of new
methodologies for the preparation of benzyltetrahydroisoquinoline monomers and
secondly, to synthesise the bisbenzyltetrahydroisoquinoline neferine and its
analogues. Neferine was isolated from the roots of Nelumbo nucifera. This
compound has been reported to exhibit important biological activities, which
include anti-arrhymia, anti-platelet aggregation, anti-thrombosis, anti-cancer as
well as anti-HIV activities. Moreover, neferine showed lower cytotoxicity compared
to other isoquinolines. However, the total synthesis of this compound has not been
reported.
Two methodolologies based on the intramolecular hydroamination of
aminostilbenes and aminoalkynes were investigated for the preparation of
benzyltetrahydroisoquinolines with different oxygenation patterns. In these
strategies, the aminostilbene and aminoalkyne precursors were successfully
synthesised by the Heck and Sonogashira coupling reactions, respectively. The
attempts to cyclise the aminostilbenes into the corresponding
tetrahydroisoquinolines under base-catalysed, metal-catalysed and acid-catalysed
conditions were unsuccessful. On the other hand, cyclisation of aminoalkynes into
dihydroisoquinolines was achieved with the aid of titanium catalysts. Different
titanium catalysts were tested for this hydroaminationation reaction. Optimum
results were obtained with bis-(cyclopentadienyl)dimethyl titanium(IV) catalyst,
albeit the yields were inconsistent when the reaction was performed on a larger
scale.
Induction of the desired stereochemistry on the dihydroisoquinolines prepared by
the hydroamination of aminoalkynes was attempted with the chiral BINOL
phosphoric acid catalyst without success. The catalyst was prepared in good
yields and high enantiomeric excess from cheap and readily-available starting
materials. Had this reaction been successful, this would have been a breakthrough
in the stereoselective reduction of dihydroisoquinolines as most chiral catalysts,
which are currently employed are expensive, difficult to prepare and some are air
and moisture-sensitive.
Although the first objectives of this project are not fully met, the results obtained in
the synthesis of benzyltetrahydroisoquinolines by the hydroamination of
aminostilbenes and aminoalkynes contribute greatly to the prevailing literature on
the synthesis of benzyltetrahydroisoquinolines by these reactions. Presently, there
is limited literature on the synthesis of benzyltetrahydroisoquinolines by these
methods. Moreover, there is a need for the development of new synthetic
strategies that would render benzyltetrahydroisoquinolines in minimum steps and
good yields.
It was planned that, upon successful synthesis of benzyltetrahydroisoquinolines
from aminostilbene and aminoalkyne precursors, these modern methodologies
would be applied in the synthesis of the two benzyltetrahydroisoquinoline scaffolds
of neferine. However, these routes could not be pursued due to failure to ringclose
the aminostilbenes and irreproducibility of results in the preparation of
dihydroisoquinolines from aminoalkynes. Therefore, classical procedures were
employed for the preparation of benzylisoquinoline nuclei of neferine.
Three different synthetic routes were followed for the synthesis of neferine and its
analogues. The first two methods were based on the Ullmann coupling reaction for
the formation of the diaryl ether bond. The first method entailed an early
construction of the ether link and late construction of the two isoquinoline rings on
the ether bridge. The second method involved synthesis of the two isoquinoline
nuclei, and coupling of the two units by the Ullmann reaction in the late stages of
the synthesis. In the last synthetic strategy, the diaryl ether bridge was constructed
by the nucleophilic aromatic substitution reaction. In all the three methods, the two
isoquinoline rings were formed by the Bischler-Napieralski cyclisation reaction.
In the first route, we succeeded in preparing the two major building blocks, which
were N-(3,4-dimethoxyphenylethyl)-4-benzyloxy-3-iodophenylacetamide and [2-
(4’-hydroxy-3’-methoxyphenyl)ethyl]carbamic acid tert-butyl ester. The Ullmann
coupling of the two compounds afforded the diphenyl ether N-(3,4-
dimethoxyphenylethyl)-4-benzyloxy-3-(4-(3-methoxyphenoxy)ethyl-tertbutylcarbamate)
phenylacetamide, albeit in low yields. Although N-(3,4-
dimethoxyphenylethyl)-4-benzyloxy-3-(4-(3-methoxyphenoxy)ethyl-tertbutylcarbamate)
phenylacetamide was obtained in low yields, the successful
formation of the diaryl ether bond from electron-rich haloacetamide and
hydroxyphenethylamine is a great advancement in the synthesis of
bisbenzyltetrahydroisoquinolines. In the second approach, the two
benzyltetrahydroisoquinoline precursors for the Ullmann coupling reaction were
successfully synthesised. These were the 7-hydroxybenzyltetrahydroisoquinoline
and the 3’-iodobenzyltetrahydroisoquinoline. The Ullmann coupling reaction of the
two isoquinolines did not give any fruitful results. In the last synthetic strategy, the
formation of the diaryl ether bridge was based on the nucleophilic aromatic
substitution reaction. In this route, we managed to synthesise the two coupling
partners for the nucleophilic aromatic substitution reaction leading to Omethylneferine.
One of the building blocks was the natural
benzyltetrahydroisoquinoline, hydroxylaudanidine, and its coupling partner was N-
[2-(4-fluoro-3-nitrophenyl)ethyl]-2-(4-methoxyphenyl)-N-methylacetamide. The
major challenges in this route were encountered in the preparation the
fluoroacetamide, which involved several low-yielding synthetic steps and tedious
chromatographic purifications. The nucleophilic aromatic substitution reaction of
the two precursors was attempted in vain.
Even though the total synthesis of neferine could not be accomplished, it is
strongly believed that the developed synthetic routes will enable us to complete
the synthesis of the targeted compound and other naturally-occurring
bisbenzyltetrahydroisoquinolines. The results obtained herein represent a
significant advance considering the importance of the
bisbenzyltetrahydroisoquinolines as biologically active compounds. / Thesis (Ph.D.)-University of KwaZulu-Natal, Pietermaritzburg, 2011.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:ukzn/oai:http://researchspace.ukzn.ac.za:10413/8080 |
| Date | January 2011 |
| Creators | Sonopo, Molahlehi Samuel. |
| Contributors | Van Heerden, Fanie R. |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | English |
| Type | Thesis |
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