Scientists design remarkably stable chiral molecules

Like a right hand and a left hand, two molecules can have the same composition, but a different shape and arrangement in space — and understanding and controlling this phenomenon is crucial to drug design.

A molecule (or any object) is said to be ‘chiral’ if it cannot be superimposed on its mirror image by any combination of rotations, translations and geometric changes; this universal molecular asymmetry requires chemists to design chiral molecules capable of interacting precisely with living systems. Now a team from the University of Geneva (UNIGE), in collaboration with the University of Pisa, has developed a new family of remarkably stable chiral molecules, opening up new prospects for the design of geometry-controlled drugs. Their work has been published in the Journal of the American Chemical Society.

Within a molecule, chirality often arises from the presence of one or more asymmetry centres, known as stereogenic centres. These are often made up of a central carbon atom, itself linked to four different groups or chains of atoms, usually carbon as well. The UNIGE team has created a new type of stereogenic centre. This time, the central carbon atom is not surrounded by carbon chains, but only by oxygen and nitrogen atoms — understood to be a first in the field of chemistry.

“Molecules with this new type of stereogenic centre had never before been isolated in a stable form,” said group leader Professor Jérôme Lacour, from UNIGE. “Their synthesis and characterisation mark a major conceptual and experimental breakthrough.”

The stability of chiral molecules is a particularly important parameter. Mirror molecule pairs are structurally very close, and in many cases spontaneous switching from one to the other is possible — for example, under the effect of temperature — as if a left hand were suddenly transformed into a right hand. In this way, we could switch from a drug to an inactive or even toxic molecule. The new molecular structures developed by the UNIGE team feature exceptional chiral stability, meaning that the switch from one molecule to its mirror sister is particularly unlikely.

“Using dynamic chromatography techniques and quantum chemistry calculations, we have shown that, for the first molecule developed, it would take 84,000 years at room temperature for half a sample to transform into its mirror molecule,” said first author Olivier Viudes, a PhD student at UNIGE. For a drug, such stability guarantees safe storage, without the need for specific conditions.

The new stereogenic centres developed by the team should thus enable the design of stable, controlled, three-dimensional chiral molecules. These structures open up new possibilities for drug design and the creation of new materials.

“These novel stereogenic centres offer a new way of organising molecular space,” said Professor Gennaro Pescitelli from the University of Pisa, co-principal investigator on the study. “They open up a whole new degree of freedom and imagination in chemical synthesis.”

Image caption: Mirror molecules synthesised in this study, featuring an asymmetric carbon fully substituted by oxygen atoms, a novel configuration in molecular chirality. The carbon atoms are in grey, oxygen atoms in red, and hydrogen atoms in white. Image ©Pierrick Berruyer.