Changing proton source in asymmetric decarboxylation unexpectedly delivers opposite configuration


Using the same catalyst and ligand but different acid reagents directs which enantiomer is made

Organic chemists in Ireland have developed a pair of reactions they think are unique in controllably producing predominantly one of two mirror-image products without a change of catalyst.1 Instead, Pat Guiry and his University College Dublin team’s choice of acid directs their asymmetric decarboxylation’s pathway. ‘We just expected the change in proton source to either help enantioselectivity or not – we certainly did not expect a total reversal,’ Guiry admits.

Guiry’s team had been working towards synthesising sativanone, an isoflavanone first isolated from Honduras rosewood that has shown cancer-fighting and bacteria-killing potential in lab tests. They needed to attach a substituted benzene ring to the molecule’s bicyclic core, at a carbon where two enantiomers could form depending on whether the attachment points upwards or downwards.

The chemists had first developed a route to their desired enantiomer on a molecule similar to sativanone, but simpler. They added an allyl ester onto the critical carbon, then the substituted benzene, giving a mixture of both enantiomers. Removing the ester using Meldrum’s acid (2,2-dimethyl-1,3-dioxane-4,6-dione) and a palladium catalyst with a chiral ligand gave almost exclusively the desired enantiomer.2

But when the team used that approach to make sativanone, they got hardly any enantioselectivity. Guiry’s student Robert Doran then found formic acid restored high selectivity, but for the opposite enantiomer to that expected.

Taking the formic acid reaction back to their model molecule Guiry’s team again got the opposite enantiomer to Meldrum’s acid with high selectivity, in enantiomeric excesses over 90%. The chemists have also found a similar but less pronounced effect on other molecules3 with Guiry adding that further unpublished work shows ‘it’s quite general’.

Brian Stoltz from California Institute of Technology in Pasadena says he is ‘very excited’ by the finding, in part because his team developed the decarboxylative protonation involved. ‘Anytime there is complete reversal in stereoselectivity of a highly enantioselective catalytic reaction by means other than changing the enantiomer of the catalyst, it is unusual and interesting,’ he enthuses.

While Guiry and his coworkers are yet to fully explain the strange result, they are investigating it. ‘We think that formic acid might form a tight ion-pair with the palladium complex leading to attack by one face whereas the proton from Meldrum’s acid is attacked by the other face,’ he says. ‘But that’s a bit hand-wavy, so we’re trying to pin it down.’