Pseudo-natural substances: breakthrough research from the Faculty of Pharmacy in Nature Synthesis

Scientists from the Department of Chemical Drugs at the Faculty of Pharmacy have just published their latest paper in the prestigious journal Nature Synthesis. The article presents important findings that may open new perspectives in the field of medicinal chemistry and contribute to future discoveries in medical research.

15 Nov 2023

Although chiral bioactive molecules containing seven- and eight-membered cycles are relatively abundant among substances of natural or synthetic origin, their abundance decreases steeply with increasing ring size due to thermodynamic factors adversely affecting their formation (rings with more than 11 atoms are easier to synthesize). At the same time, cyclic compounds with complex structures find interesting applications, for example, as so-called pseudo-natural substances, which combine fragments of natural products, but in contexts that are not achievable by biosynthetic processes in living organisms. Thanks to alternative arrangements of structural components, they can then exhibit novel or optimised activity in a range of biological models, thus opening the way to entirely new classes of drugs.

Crucial to the laboratory preparation of the above compounds was the discovery of higher order asymmetric cycloadditions that allow the construction of an incredibly complex organic molecule in a single transformation. By the term cycloaddition, most of us probably imagine in particular the Diels-Alder reaction, which is chemically classified as a [4+2] cycloaddition, i.e. with a shift of 6 π-electrons. Higher order cycloadditions then involve the movement of more than 6 electrons, e.g. [6+4], [8+2], etc., and thus offer an elegant solution to the problematic preparation of cyclic molecules containing medium-sized rings (i.e. 7-11 membered).

Even before 2017, virtually no one would have believed that higher-order cycloadditions could also be successfully catalyzed by substances derived from the amino acid proline. It was Prof. Karl Anker Jørgensen's group that pioneered in this respect, and together with Prof. Kendall Houk, they have been working on cycloadditions for a long time not only on a synthetic but also on a theoretical level.

A critical analysis of the possibilities and limitations of current higher order organocatalytic cycloaddition methods applied to the preparation of chiral cyclic compounds was published in the prestigious journal Nature Synthesis. During his postdoctoral fellowship co-funded by the Erasmus+ programme, Jan Otevřel from the Department of Chemical Drugs, also contributed to it. The work was done in collaboration with Macarena Eugui, Sebastijan Rick and Karl Anker Jørgensen from Aarhus University, Denmark.

Read the full article here.


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