Synthesis of indole alkaloids based on the malagashanine skeleton

This project falls within the EPSRC Synthetic Organic Chemistry research area.

The project aims to develop sustainable, highly modular strategies towards the synthesis of indole alkaloids, enabling rapid construction of these functionally rich, valuable natural product scaffolds.

The malagashanine and myrtoidine alkaloids are polycyclic indole-based natural products that feature a 5,6-trans-fused pyrrolidine ring system.

Building on work in the group towards the Strychnos family of natural products this project explores the use of thiophene-S,S-dioxides along with cascade Michael reactions, to achieve concise asymmetric syntheses of this family.

Access to the tetracyclic indoline core will commence with reaction of N-methyl tryptamine and thiophene S,S-dioxide in an addition elimination reaction, which will then undergo an intramolecular Diels-Alder cascade to afford a dienamine.

Based on our previous work, we have propose that this enamine should be reduced with high stereoselectivity to install the required anti-fused pyrrolidine ring.

Indoline acetylation, followed by DIBALH reduction of the more reactive acyl sultam, will deliver the aldehyde substituted tetracyclic indoline core.

From the indoline core, cyclization of the remaining pyran ring is required for malagashanine, and of the fused pyran-butenolide for myrtoidine. We propose that both might be achieved via a cascade Michael addition reaction.

Specifically, it is hoped that at ambient temperatures it will prove possible to effect addition of dimethyl malonate to an enal, delivering a diester after chemoselective reduction of the aldehyde. If this step proves challenging, an iridium-catalyzed allylic substitution will instead be tested.

A decarboxylative Knoevenagel reaction with acetaldehyde is then planned (possibly via the diacid), where the intermediate alpha-beta-unsaturated enoate undergoes oxa-Michael (6-endo-trig) cyclisation by the proximal alcohol to afford malagashanine.

It is hoped that conducting this reaction under thermodynamic conditions will control the stereochemistry at the two new stereocentres. To access the myrtoidine framework, a Michael addition using a ketolactone is planned.

Following reduction, cyclisation is anticipated, which would complete the asymmetric synthesis of 11-demethoxymyrtoidine in just eight steps.

Further members of this natural product family will be explored as the project progresses, along with late-stage functionalisations to introduce the required methoxy groups.

Phase Two As a potential second phase to the project, thiophene-S,S-dioxides will be used to develop novel cascade routes to related classes of indole alkaloids. These may include the mavacurane alkaloids incorporating a highly strained pentacyclic scaffold.