ORDECHASYN

Organocatalytic Desymmetrization and C-H Bond Activation in Complex Natural Product Synthesis

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 Obiettivo del progetto (Objective)

'The aim of this research is to develop novel organocatalytic desymmetrizatoin and novel C-H bond formation reaction, and to apply these methodologies to the total synthesis of bioactive lueconicine A, B and strychnan alkaloids. These organocatalytic desymmetrizatoin and C-H bond activation provide an excellent method for the rapid construction of complex ring systems, such as the octahydro-1,6-ethanoindole with good streocontrol. However, despite the great potential of these kinds of organocatalytic desymmetrization and C-H bond activation reaction, only small number of results have been reported. Therefore, these types of reactions are highly innovative and would constitute an extremely powerful example of the possibilities offered by organocatalysis. Definitely, to apply these methodologies to the total synthesis of bioactive natural products such as leuconicines and other strychnan alkaloids would provide sufficient material for thorough biological studies and would also constitute a milestone for the study of structure-activity relationship.'

Introduzione (Teaser)

Alkaloids are a large class of cyclic organic compounds found in plants and having profound physiological effects on humans. Scientists successfully implemented underexplored synthetic routes to their production, paving the way to expanded structure-function studies.

Descrizione progetto (Article)

Drugs such as cocaine and morphine, poisons such as strychnine, natural substances of pharmacological value, and even caffeine and nicotine are all alkaloids. Organocatalytic desymmetrisation and carbon-hydrogen (C-H) bond activation is an excellent route to complex ring systems but, despite their potential importance, these reactions have not been widely studied.

EU-supported scientists conducted successful investigations exploiting these reactions within the scope of the project ORDECHASYN (Organocatalytic desymmetrization and C-H bond activation in complex natural product synthesis). They set out to synthesise a seven-membered ring and pentacyclic (five-ring) skeleton of a target natural product.

Researchers focused first on synthesis of the molecule's tricyclic core. This would be formed by a coupling reaction between spirocyclic aminoeneone and cyanic acid followed by a Michael addition strategy.

Spirocyclic structures are characterised by a (quaternary) carbon in the centre of two fused rings. Spirocyclic aminoeneone is synthetically challenging. The team carried out a model study to determine the appropriate reaction conditions. Following extensive experimentation, the team successfully synthesised the desired model spirocyclic aminoeneone. The carboxyl acid (cyanoacid) was smoothly prepared from optically pure iodoalcohol.

The coupling of these steps led to the successful synthesis of the tricyclic core of the target alkaloid in excellent yield in 10 steps via a Michael addition strategy. The team is currently working on the C-C bond formation that will enable researchers to realise the seven-membered ring and pentacyclic skeleton of the target natural product at the same time.

ORDECHASYN scientists are well on their way to synthesis in high yield of commercially important alkaloids with good control. The project could have major impact on production of natural agents, creating the ability to study structures and effects in depth, with broad applications in health and medical treatment.