Cresswell, Mark (2013) The stereoselective Pictet-Spengler reaction and studies towards the total synthesis of ajmaline. Doctoral thesis, Keele University.

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Due to their extensive and important medicinal properties, the indole alkaloids are an important class of natural products. A key step towards the total synthesis of indole alkaloids is the diastereoselective Pictet-Spengler reaction, which has enabled the total syntheses of a number of these natural products to be reported, one of which is the medicinally-important alkaloid ajmaline. Ajmaline is well studied and the previous attempts towards its synthetic preparation are described.

During our investigations towards the asymmetric syntheses of ajmaline and other related indole alkaloids, it was found that the kinetically-controlled Pictet-Spengler cyclisations of L-tryptophan allyl ester gave cis-3,5-disubstituted tetrahydro-β- carbolines with enhanced stereoselectivities of up to 20:1. The Pictet-Spengler reaction of L tryptophanamide was also studied and the cis/trans tetrahydro-β- carbolines were formed in a ratio of 3:1, typical of that for other ineticallycontrolled Pictet Spengler cyclisations reported previously.

Studies towards our total synthesis of ajmaline are also described. The synthesis features the kinetically-controlled Pictet-Spengler reaction, a highly stereoselective intramolecular Michael cyclisation and a one-pot indole cyclisation/reduction procedure, which was used to introduce three stereocentres simultaneously. It was found that the nitrogen protecting group has a defining role to play in both the indole cyclisation step, and during reduction of the subsequent iminium ion through remote steric induction. Despite installing seven of the nine stereocentres with high levels of stereocontrol, an inability to remove the robust nitrogen amide protecting group prevented completion of a total synthesis. The final ring-closing protocol could be carried out using semi-synthetic material derived from ajmaline. Cyclisation was achieved by the selective oxidation of a primary alcohol to the aldehyde, which spontaneously ring closed under the conditions of the reaction to complete the ajmaline framework.

Item Type: Thesis (Doctoral)
Subjects: Q Science > QD Chemistry
Divisions: Faculty of Natural Sciences > School of Chemical and Physical Sciences
Depositing User: Lisa Bailey
Date Deposited: 26 Jul 2017 09:46
Last Modified: 17 Aug 2022 15:54

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