Progress towards the stereoselective synthesis of cycleanine.

Abstract

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.