The emergence of multi-drug resistance (MDR) to antimalarial and anticancer drugs has
stimulated a search for novel MDR inhibitors/reversers. Bisbenzylisoquinoline alkaloids
(BBIQ) are potential agents for reversing MDR, especially when used as synergistic enhancers
of anticancer and antimalarial drugs with improved therapeutic efficacy. Despite numerous
useful biological activities reported for BBIQ’s, the various syntheses of individual members
remained cumbersome and the overall yields are low. In addition, published methods are nonstereospecific
and produced racemates.
The aim of this project was to develop a synthetic pathway for the preparation of cycleanine, a
natural BBIQ with a symmetrical structure. The protocols developed for the synthesis of
cycleanine will serve as a template for the synthesis of other BBIQ’s with more complex
structures. The only published total synthesis of cycleanine did not address regioselectivity and
stereoselectivity, furthermore, key steps suffered from extremely low yields of the products.
Our synthetic pathway is a chiral auxiliary-based asymmetric synthesis that generates
enantioselectively a 1,2,3,4-tetrahydroisoquinolines (THIQ) monomers. Cheap, commerciallyavailable
starting materials were used to prepare monomers in a regioselective as well as
stereoselective manner in good yields. The key feature of this method entails coupling of a
chiral β-phenethylamine and halophenylacetaldehyde using the Pictet-Spengler reaction. Due
to the difficulties encountered during the course of the preparation of monomers, different
methods were tried and formation of unanticipated products rationalised. Dimeric BBIQ’s are
constituted of monomeric THIQ’s which are reported to have array of biological properties
including MDR reversing activities, therefore, the total synthesis of cycleanine will serve two
purposes.
In this investigation, the THIQ monomers were synthesised by a pathway that avoid harsh
reaction conditions. Major reactions employed include nucleophilic aromatic substitutiton,
Wittig reaction, hydroboration and IBX oxidation. Some of the steps were attempted on model
compounds to optimise the conditions prior to attempting the reaction on cycleanine
precursors. Two major contributions toward the synthesis of BBIQ’s were made in this study.
The reaction conditions to control the regioselectivity and enantioselectivity of the Pictet-
Spengler reaction for the preparation of THIQ moiety were developed. A major drawback of
the published syntheses of BBIQ’s is the harsh conditions and low yields associated with the
Ullmann reaction, which is used in the formation of the diaryl ether bonds. We have shown
that the microwave-assisted nucleophilic aromatic substitution of aryl fluorides provide a much
superior method for the formation of the key diaryl ether bond.
Although we failed to form the final diaryl ether bond, the pitfalls encountered in the synthetic
pathway are discussed and potential solutions are presented. The developed synthetic
pathways are of general applicability and therefore can also be employed in the synthesis of
other macrocyclic natural products containing diaryl ethers. / 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:10413/7982 |
| Date | January 2011 |
| Creators | Litedu, Eunice Madira. |
| Contributors | Van Heerden, Fanie R. |
| Source Sets | South African National ETD Portal |
| Language | en_ZA |
| Detected Language | English |
| Type | Thesis |
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