Tetrahydroisoquinolines (THIQ) are organic compounds, whose structure includes a benzene ring merged with a nitrogen-containing cycle.
Drug Discovery. Image Credit: metamorworks/Shutterstock.com
These substances are in huge demand in the pharmaceutical sector. They are used for producing antidepressants, myorelaxants, as well as medicines for cough, anti-hypertension, and insomnia While many variations of THIQ structures, are present in natural sources (for instance, as part of phytotoxins), contemporary pharmaceutical manufacturers are also fascinated by their unusual forms, such as spirocyclic THIQs.
Two neighboring cycles share a common atom in the THIQ molecules, producing a highly stable and unusual 3D structure. This aspect is particularly significant for designing drugs: if the spatial structure of a molecule is more stable, it can be aimed more precisely at a protein target in the body.
Most of the current methods used for producing spirocyclic THIQs consume a significant amount of time. These methods also involve complex cycle-forming reactions organized in a linear chain.
A group of chemists from Immanuel Kant Baltic Federal University and Saint Petersburg State University has now identified a new way to simplify this procedure with just three steps and to integrate the first two ones into a single chemical process.
The first step is the supposed Castagnoli-Cushman reaction. Earlier in 2021, the BFU-SPbSU research team had announced a new variant of the Castagnoli-Cushman reaction, in which the product (numerous carboxylic acids) is made from three components, such as ammonium acetate that acts as a source of nitrogen. homophthalic anhydride (an organic compound with a benzene ring attached to an oxygen cycle with a pair of carbonyl groups), and cyclic ketones.
The researchers used cyclohexanone as a ketone to test the new THIQ synthesis process, and a carboxylic acid was formed from the reagents after 16 hours of reaction. The acid included three rings, and two of these rings already shared a common atom. The following steps were to extract the waste products from the reaction while keeping the spirocyclic compound intact.
Initially, the researchers heated the compound in dimethyl sulfoxide to eliminate the-COOH carboxylic group. This method did not involve any purification of the first reaction products. Consequently, the acid changed into THIQ lactam—a compound that varies by just one additional oxygen atom from the target reaction product. The process was completed by a reduction reaction of the lactam with lithium aluminum hydride.
All stages of the procedure continued in high yield: 79% of the original homophthalic anhydride changed into THIQ lactam, while 78% of the lactam yielded spirocyclic THIQ. After verifying the efficiency of the novel technique, the researchers performed the same sequence of reactions using other cyclic ketones.
Among the 14 tested options, most of them also exhibited a high THIQ yield. Hence, the new approach can be applied to extract substances with different structures.
We have developed an effective approach to the synthesis of spirocyclic tetrahydroisoquinolines that is also much easier compared to existing procedures. It can increase our opportunities for the development of THIQ-based compounds for the pharmaceutical industry. Moreover, the same approach can be applied to other compounds that might serve as prototypes for new drugs.”
Mikhail Krasavin, D.Sc., Chemistry, Research Professor, Institute of Living Systems
Krasavin is also the head of the Department of Chemistry of Natural Products (SPbSU).
Safryginab, A. et al. (2020) Synthesis of spirocyclic tetrahydroisoquinolines (spiroTHIQs) via the Castagnoli-Cushman reaction. Tetrahedron Letters. doi.org/10.1016/j.tetlet.2020.152408.