Chiral molecules are those whose structural complexity allows them
to have mirror-image, "left-handed" and "right-handed" forms. For drug
molecules, usually only one of those forms works - the other may even
have unwanted side-effects - and thus pharmaceutical chemists have a
great need for methods to build molecules in a single chiral form,
rather than an even mix of both.
Chemists at The Scripps Research Institute (TSRI) have invented a new technique for constructing chiral drug molecules.
‘A newly developed technique mimics the ability of the enzymes in our cells to turn simple organic molecules into chiral molecules.’
The new molecular construction technique, unveiled in a Science
online First Release paper on February 2, 2017, represents a
significant milestone in chiral chemistry. It creates a structure that
chemists call an α-chiral center, thereby enabling the synthesis of a
great variety of potentially valuable chiral drugs and other products.
At the same time - unlike most previous chirality-inducing
reactions - it requires only inexpensive and widely available starting
"This method essentially mimics the ability of the enzymes in our
cells to turn simple organic molecules into chiral molecules," said
senior author Jin-Quan Yu, Frank and Bertha Hupp Professor in the
Department of Chemistry at TSRI.
Over the past decade or so, Yu and his laboratory have invented
dozens of new molecule-building reactions that have been adopted widely
by chemists in academia and industry. Most are C-H activation reactions,
which remove a hydrogen (H) atom - the simplest and most common feature
of organic molecules - from one of the carbon (C) atoms of the
molecular backbone, and replace it with a more complex cluster of atoms
called a functional group.
Increasingly, Yu and his colleagues have designed these reactions to create the asymmetry needed for chiral drugs.
In a paper in Science
last August, for example, they
described a set of chiral asymmetry-making reactions that work by
selectively activating just one of the two hydrogen atoms on a methylene
group (CH2), a feature of many organic molecules. Like most of the C-H
activations developed by the Yu Laboratory, this reaction employs a
palladium atom to break the targeted C-H bond, and a special "ligand"
molecule to steer the palladium atom precisely where it needs to go.
The new set of reactions has an even more challenging target: a
cluster of carbon and hydrogen atoms known as an isopropyl group,
another feature of many organic molecules. The ligands developed for the
reaction, derivatives of aminomethyl oxazoline, effectively select a
carbon at just one side of the isopropyl group and replace one of its
hydrogen atoms with a functional group.
Yu's team showed that they can use the ligands to add aryl, alkene
and alkyne functional groups - common building-blocks in the construction
of drug molecules.
The intended starting material for the new reactions is an
isopropyl-bearing molecule called isobutyric acid, although the
reactions also work well on related molecules. Isobutyric acid is
cheaply produced in very large quantities using standard industrial
methods, and it can also can be generated from waste biomass such as
crushed sugar cane - making it a more environmentally friendly ingredient
for chemical reactions.
Isobutyric acid is also found in nature, and bacteria and other
organisms have evolved enzymes that convert it to natural chiral
molecules. In the past few decades, pharmaceutical chemists have learned
to harness some of these natural enzyme reactions - using genetically
engineered bacteria--to help them build chiral drug molecules. However,
these enzyme-driven reactions are restricted to isobutyric acid as a
starting molecule and are very limited in the chiral molecules they can
yield. The new ligand/catalyst, while essentially mimicking nature's
synthetic feat, is much more versatile.
"Now that we know how to selectively break that one C-H bond with a
palladium catalyst, we're not limited to the reactions that enzymes can
do," Yu said.
He added that researchers at Bristol-Myers Squibb, which has a
research collaboration agreement with the Yu Laboratory, are already
using the new reactions to make potential new drug molecules.