Domino-effect Stereocontrol

By taking advantage of a series of freely rotating amide substituents on a rigid molecule, a team of chemists in England has demonstrated that the stereochemistry at a chiral center at one end of the molecule can influence the stereochemistry at another chiral center up to 22 bonds away--almost twice the distance previously achieved in a synthetic system. This type of remote stereochemical control potentially could be used to transmit information in a variety of chemical and biological systems.

Chemistry professor Jonathan Clayden and coworkers at the University of Manchester use amide-substituted xanthenes as the backbone of their communicative systems [Nature, 431, 966 (2004)]. Each three-ring xanthene has two amide groups attached, one on each side of the oxygen heteroatom in the center ring. The carbonyl oxygen atoms of the amide groups point up or down relative to the plane of the xanthene rings, and they always point in opposite directions relative to one another, in an anti conformation.

The researchers initially modified a single xanthene by condensing an ephedrine molecule with an aldehyde attached to one side of the xanthene, forming an S oxazolidine ring substituent. The asymmetry of the oxazolidine caused the nearest amide group on the xanthene to twist to its less hindered orientation. This twist triggered a domino effect in which the remaining amide group took up an anti conformation relative to the first one. When the opposite end of the xanthene was functionalized, by adding an aldehyde and then converting it to an alcohol, the orientation of the amide groups induced better than 95% diastereoselectivity for the S alcohol. The alcohol and the amide group next to it take up a syn conformation relative to one another.

Clayden and coworkers then carried out similar chemistry on bisxanthene and trisxanthene systems. They found that the amide twist induced by the oxazolidine ring allowed stereochemical information to be relayed from one amide group to the next across all of the xanthene rings. In the case of the trisxanthene, the oxazolidine ring exercises its control for the diastereoselectivity of the alcohol across an unprecedented 22 bonds. The barrier to extending the stereocontrol to longer distances so far has been the Manchester group's inability to synthesize longer xanthene oligomers, rather than any limitation to the transfer of stereochemical information, they note.

"From a purely synthetic perspective, this is a remarkable paper," notes Adam Nelson, a senior lecturer at the University of Leeds, in England. "The importance is increased by the possible application of these stereocontrol concepts outside of synthetic chemistry to information processing and nanotechnology." The relay of information is similar to that in an allosteric protein where structural information is exchanged between remote sites, such as across a membrane, he says.

Other potential applications are in nanotechnology where xanthene or related systems could link together molecular machines, Clayden notes.

"The work certainly shows that organic chemists can design systems, different from nature's, that achieve the remote control that we usually think of as being nature's preserve," adds Ian Fleming, emeritus professor of chemistry at the University of Cambridge.