Synthesis and evaluation of narciclasine analogues

Abstract

Narciclasine was isolated from the common daffodil in 1967 and was shown to exhibit potent and selective anti-cancer activity. However, current synthetic routes are generally long and low yielding, hampering its progress as a clinical candidate. This project aims to synthesise bioactive analogues using a short, elegant and scalable synthesis.

A one-pot procedure has been developed whereby a carboxylic acid is converted to an isocyanate using a modified Curtius rearrangement, which is then captured by a tethered electron-rich aromatic ring in a Lewis-acid mediated intramolecular Friedel Crafts acylation. This methodology was then applied to produce a series of dihydroisoquinolinones as simplified AB-ring analogues in 73-90 % yields. Interestingly, the cyclisation of 3,4,5-(trimethoxyphenyl)propionic acid proceeds with selective demethylation at the 8-position when BF3·OEt2 is employed as the Lewis acid. To mimic the sp2 centre at the 10b position of narciclasine, the analogues were oxidised using palladium on activated carbon in 39-89 % yields.

This synthetic methodology has been applied to the synthesis of the more complex ABC-ring analogues. Acetophenones were readily converted to β-ketoesters, which were then condensed with methyl vinyl ketone using a Robinson annulation reaction to generate modified Hagemann’s esters. Reduction followed by saponification of this ester provided the corresponding acid for cyclisation using the Curtius rearrangement and Friedel-Crafts acylation. Three analogues have been synthesised using this approach in 6 steps and overall yields of 10-18 %. These analogues have been evaluated against HT29 colon cancer cell lines, showing a range of activities from 715 μM to 15 μM, with patterns in the structure activity relationship that mirror those in the natural products.

The prenyl and chroman groups are medicinally important functional groups found in a number of natural products. During our investigations, a mild method of prenylating an aromatic ring using Bi(OTf)3 as a catalyst was discovered. The procedure was optimised and applied to a range of aryl rings to identify the scope and limitations of the reaction. It was also found that applying the same procedure to phenols gave chromans as the products. This reaction was applied to the synthesis of the natural product 2-(3-methyl-2-butenyl)-3,4,5-trimethoxyphenol, in 34 % overall yield.

Date of Award	1 Feb 2011
Original language	English
Awarding Institution	University of Bath
Supervisor	Lorenzo Caggiano (Supervisor)