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Content archived on 2024-05-29

Pharmaceuticals from renewable resources

Final Activity Report Summary - RENEWRES (Pharmaceuticals from renewable resources)

The synthesis of polyprenylated phloroglucinol natural products, including clusianone, nemorosone and garsubellin A was pursued by a strategy involving construction of a core bicyclo[3.3.1]nonane-trione structure, and subsequent elaboration via organolithium intermediates. Appropriate bridged core structures were obtained through the cyclisation of a suitably substituted cyclohexanone enol ether or enol silane with malonyl dichloride. Additional substituents were then introduced by means of regioselective lithiation reactions, including the generation of bridgehead enolates, thus enabling the total synthesis of clusianone, and also of an advanced intermediate towards nemorosone. These compounds have important anti-cancer potential and the work is being pursued with a German company Diagenics.

In addition, a chiral base kinetic resolution of an advanced bicyclic intermediate enabled access to the polyprenylated phloroglucinol natural product (+)-clusianone in enantiomerically pure form. X-ray structure determination of another product obtained by the same method then allowed the absolute stereochemistry of (+)-clusianone to be assigned. This is important since the absolute structures of very few of such natural products are known, but this can be very significant for their mode of action as pharmaceuticals.

Additionally we attempted to convert renewable materials such as catechin into the same types of structures as clusianone and nemorosone. Bridgehead lithiations were successfully carried out on substrates derived from catechinic acid, which possess the core bicyclo[3.3.1]nonane-1,3,5-trione structure present in garsubellin A. Using an external quench method, various electrophiles have been incorporated at the C-5 bridgehead position in a one-step process that appears to be sensitive to the substitution pattern on the bicyclic system. Regioselective lithiation at the C-3 sp2 centre was achieved by changing the base used from LDA to LTMP. Following the introduction of a prenyl substituent by bridgehead substitution, annulations of a THF ring, analogous to that in garsubellin A, was possible via an epoxidation-ring opening sequence. Oxidative modification of the catechol substituent of the catechinic acid core was possible to give systems with muconic acid, ortho-quinone or furan 2-carboxylic acid side chains.