New Routes in Drug Discovery
Compound libraries inspired by serotonin and other pharmacologically relevant indole alkaloids have been developed via novel catalytic reactions.
Alkaloids are compounds which contain nitrogen atoms. They constitute a class of compounds that generally shows interesting pharmacological properties. Alkaloids are produced by many organisms in nature, e.g. bacteria, fungi, plants, and animals, but they can also be produced synthetically. The biosynthetic route to indole alkaloids generally starts from the amino acid L-tryptophan. The thesis focusses on indole alkaloids which are one of the largest sub-groups. Examples of naturally occurring indole alkaloids are serotonin, harmine, heptaphylline, and lysergic acid, all of pharmacological relevance.
The pursuit of new synthetic methodologies for the next generation of compound libraries is ongoing. In particular, incorporation of scaffolds which are inspired by naturally occurring products is of high interest. The project investigates new routes for the synthesis of indole-containing small molecules that carry structural features similar to or reminiscent of naturally occurring alkaloids.
Synthesis of 1,2,3,4-tetrahydro-β-carbolines (TBHCs) was based on a transition metal/ Brønsted acid-catalyzed tandem isomerization/N-acyliminium ion cyclization of N-acylated allylic tryptamines. In order to optimize reaction conditions a ruthenium hydride catalyst RuHCl(CO)(PPh3)3 was combined with diphenyl phosphate at elevated temperature (refluxing tolune). This led to good yields (68-96 %) of the desired products. Further, the substituent α to the nitrogen in the allylic system proved to be highly important for the enantio-selectivity. Enantiomeric excesses up to 57 % were obtained.
Further, 1,2,3,4-tetrahydrocarbazoles were synthesized using three different types of novel Brønsted acid- catalyzed Friedel-Crafts-type reactions. Type 1 reactions involved direct intramolecular cyclization from an indole moiety to an aldehyde resulting in the corresponding alcohols. Type 2 reactions were based on addition of nucleophiles, either to cyclized alcohols or directly to the carbonyl followed by cyclization. In type 3 reactions organometallic reagents were added to the carbonyl with subsequent cyclization.
A two-step synthetic route via the alcohols was investigated. The route was found to be most efficient when carbocation stabilizing groups were present around the alcohol, favoring type 3 reactions. Three final type 3 products were synthesized in good yields (64-95 %).