This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Cyclopropanes are organic chemistry's smallest rings. Three carbon atoms are joined in a triangle, creating a compact and unusually strained structure.
Despite—or partly because of—this unusual geometry, cyclopropanes are found in many biologically active natural products and have important applications in medicines and drug discovery, from antidepressants to antibiotics and antiviral research. Connect these carbon triangles to an amine, a functional group with a nitrogen at its center, and you get aminocyclopropanes. They are of particular interest in pharmaceutical research because they can be used to replace another substructure commonly found in drug molecules: α,α-gem-dimethylamines (compounds in which the aminocyclopropane's triangle is "opened" by disconnecting one edge).
Such molecular substitutes that resemble an existing part of a drug but can alter important properties, such as biological activity and metabolic stability, are referred to as bioisosteres and have shown beneficial effects in countless cases. Aminocyclopropanes are therefore attractive building blocks for drug discovery. But making them can be difficult: Established approaches can require highly reactive chemicals, metal reagents, multiple synthetic steps or starting materials that are themselves difficult to prepare.
These routes also typically require strict air- and water-free setups. Additionally, such harsh conditions limit which other chemical groups can be present in a molecule during the reaction. This becomes particularly important in medicinal chemistry, where researchers often need to modify already complex molecules without disturbing the rest of their structure.
The research group of Nuno Maulide, professor of organic synthesis at the University of Vienna and adjunct principal investigator at CeMM, introduced a new method for producing aminocyclopropanes under exceptionally mild conditions. In a so-called "hydroaminoalkylation," they used an easily accessible and bench-stable starting material known as a hemiaminal. For many substrates, simply dissolving this compound in the appropriate solvent is enough to initiate the reaction at room temperature—without the need to rigorously exclude air or moisture.
The researchers successfully produced aminocyclopropanes containing unprotected alcohol groups, carbonyl groups and phthalimides—all of which are functional groups that pose significant problems for established approaches. The method also worked on a structurally complex molecule derived from the hormone estrone. In one experiment, the reaction was scaled to more than 1 gram in a single run while still providing an excellent 84% yield.
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