Chemists at Scripps Research have addressed one of the most formidable challenges 

in  synthetic  chemistry  by  inventing a method for "enantioselective remote meta-CH 

activation," which enables the making of chiral molecules that were previously difficult 

or impossible to synthesize.

The method, reported today in Nature, is likely to be adopted widely for the making of 

prospective drugs and other chemical products.

"This new method should allow us to explore a large 'chemical space' that had been 

essentially off-limits," says Jin-Quan Yu, Ph.D., senior investigator and Frank and Ber

tha Hupp Professor of Chemistry at Scripps Research.

Chiral molecules are asymmetric, with "right hand" and "left hand" forms. Often only 

one of these forms (called enantiomers) has the desired biological or chemical activity

, while the other is inert or even has unwanted side effects—and most ordinary reactio

ns yield an impure, 50:50 mix of both.

There are methods for turning a symmetric molecule into a chiral one and obtaining p

ure quantities of one enantiomer rather than the other. However, these methods typica

lly involve the attachment of a reactive cluster of atoms called a functional group to the 

starting molecule at the point that becomes the center of asymmetry: the so-called chiral center. The new method attaches a new functional group relatively far from the chiral cen

ter—a feat previously achievable only by enzymes in living cells. Since the chiral center 

typically contains another functional group, the resulting chiral molecule ends up with two 

widely spaced functional groups, potentially conferring unique and potent bioactivity.

"The chiral molecules we can make with this method can be designed to interact with widely 

spaced binding sites on a target protein, for example," Yu says.

Key to the new method is a specially designed helper molecule, a "transient chiral mediator," 

based on the organic compound norbornene. It enables the crucial step of attaching the 

new functional group asymmetrically to an initially symmetric starting compound—far from the 

chiral center on the molecular backbone but, even so, yielding nearly 100 percent pure 

quantities of the desired enantiomer.

Yu's  team  demonstrated  the  technique  by  using  it  for  the "remote chiral induction" of 

benzylamines and phenylethyl amines, broad classes of molecules that form the bases for 

many modern drugs as well as many biologically active compounds in plant and animal cells. 

The resulting chiral molecules typically comprised more than 95 percent of the desired 

enantiomer and less than 5 percent of the unwanted enantiomer.