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Mass synthesis of bioactive indole alkaloids

A recent survey indicated that almost two-thirds of pharmaceuticals have a natural origin. Exploring the bioactivity of synthetic derivatives has great potential for a wide range of applications, especially when natural compounds are not available in great quantity.
Mass synthesis of bioactive indole alkaloids
The EU-funded STRICTSYN (Collective syntheses and biological evaluation of akuammiline indole alkaloids) project has addressed the production of bioactive indole alkaloids such as strictamine, aspidophylline A and alsmaphorazine C. Researchers evaluated the bioactivity of their intermediates and analogues to explore their full potential. In the case of strictamine and alsmaphorazine C, there had to date been no successful synthesis due to the complexity of their architecture.

Under optimised conditions, the researchers reacted a broad range of azomethine imines with secondary enecarbamates. Using the catalyst SPINOL-derived chiral phosphoric acid, the team produced excellent yields of isoquinoline-fused pyrazolidines. Products of the cycloaddition were confirmed by X-ray analysis.

Z isomers of enecarbamates produced excellent yields of cycloadducts after dipolar cycloaddition with azomethine imines, this time in the presence of H8-BINOL-based chiral phosphoric acid. This is most probably a first for this cycloaddition between azomethine imine and an electron-rich internal double bond.

The team also increased the skeleton diversity of pyrazolidine using diastereoselective post-transformations. Also, a series of standard transformations converted a cycloadduct to aminobenzo[a]quinolizidine, a tricyclic compound used in therapy for diabetes type II.

Pyrazoline derivatives produced by STRICTSYN display a wide range of biological pharmaceutical potential including antibacterial, anti-tumour and anti-inflammatory properties. Project work has merged organic chemistry, medicinal chemistry and biology and promises to form the basis for the discovery of a new generation of potent lead compounds for drug discovery.

Related information

Subjects

Life Sciences

Keywords

Bioactive, indole alkaloids, STRICTSYN, azomethine imines, secondary enecarbamates
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