Canadian chemists have discovered a surprising conformational effect using cyclopropane that provides a way to influence the position of substituents on six-membered rings. Here the groups favor the axial orientation, which is typically more unstable, and the effect “becomes more significant as the alkyl groups get larger, which is quite different and unique,” he says James Gleasonwho led the work at McGill University. He believes that “the truly unusual stereocontrol element will be useful in a wide range of applications,” particularly in medicinal chemistry, “where the ability to span groups in specific conformational space is crucial in the development of potent molecules.”

Cyclohexane is a volatile, alicyclic hydrocarbon consisting of six carbon atoms. Its functionally substituted derivatives have diverse biological properties and unique conformations, making them the target of drug development studies worldwide. For example, many anticonvulsant, anti-inflammatory and antidepressant drugs contain cyclohexane rings.

The chair is the most stable conformation that a cyclohexane ring can adopt. Each face of the ring alternates between axial bonds, which are parallel to the axis of the ring, and equatorial bonds, which are located at the periphery. The cyclohexane substituents can adopt either position, but steric hindrance at the axial location means that the equatorial conformer often predominates in equilibrium. However, during an organocatalytic Cope rearrangement, Gleason and his colleague Anthony Izzotti made an unusual observation.

They found that alkyl groups adjacent to cyclopropane in chair-like transition states preferred axial orientation. “The reaction had the complete opposite stereochemistry to our prediction, requiring a band substituent to occupy an axial position. This was completely unexpected,’ says Gleason. Although other chemists have previously observed that α-ethers and acetates adjacent to spirocyclopropanes prefer to be in an axial position, the team set out to explore whether this effect might apply to a wider range of groups.

With this in mind, they synthesized various alkyl-substituted spirocyclopropanes such as those with methyl, ethyl and third-butyl groups, through olefination and cyclopropanation. The energy difference between the alkyl group in both conformations was more negative when the groups were adjacent to spirocyclopropane compared to simple cyclohexane or when adjacent to a dimethyl substituent. Apart from the methyl group, where both conformations were approximately equal in energy, all alkyl groups preferred the axial conformer.

Furthermore, larger alkyl groups experienced a greater shift toward the axial position due to increased torsional strain and, in some cases, hyperconjugation with the spirocyclopropane. In fact, isopropyl and third-butyl were exclusively axial. “I was surprised by the huge conformational effect observed for a third-butyl group’, he says Jonas Brånaltsenior synthetic chemist at AstraZeneca in Sweden. “The team also compared the results with the corresponding dimethyl substituent, which was nice to see, and there I don’t really see a big difference compared to the unsubstituted case.”

Heteroatoms and a range of π- and electron-withdrawing groups also favored the axial conformer when adjacent to the spirocyclopropane. However, along with steric effects, intersubstituent stereoelectronic factors contributed. “The differential behavior of alkyl-substituted cyclohexanes and halogens, in terms of torsion versus stereoelectronic factors, is particularly fascinating and deserves further investigation,” says Margherita Brindisiexpert in medicinal chemistry from the University of Naples Federico II in Italy. “Elucidation of these elements will have key relevance not only for medicinal chemistry, but also for the design and application of cyclic catalysts.”

Brånalt adds that the concept provides “a useful tool for drug designers to modify the conformation of some of the most common scaffolds used in medicinal chemistry.” The McGill team is interested in seeing if the effects can apply to larger rings in the future.