Crossing the ring: New method enables C-H activation across saturated carbocycles

Date:
May 31, 2023
Source:
Scripps Research Institute
Summary:
Chemists add another powerful tool to their 'molecular editing'
toolkit for crafting pharmaceuticals and other valuable compounds.


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FULL STORY ==========================================================================
A new "molecular editing" technique from Scripps Research enables chemists
to add new elements to organic molecules at locations that were previously
out of reach.

The researchers described their new method in a paper that appeared on May
31, 2023, in Nature. The method uses a designer molecule called a ligand
that helps a palladium-atom catalyst reach from one side of a carbon-atom
ring to break a carbon-hydrogen bond on the other side, allowing a new
set of molecules to join at that site. This molecule-building feat was previously impossible for so- called "saturated" rings of carbon atoms,
which are common features in drug molecules.

"Previously, to achieve the same result, one would have to undertake a
de novo approach -- what we call a cyclization reaction -- involving the formation of a new ring structure from an acyclic chain, using this new
method, we can directly modify an existing ring to avoid a cyclization
process that can often prove challenging," says study senior author
Jin-Quan Yu, PhD, the Bristol Myers Squibb Endowed Chair in Chemistry
and the Frank and Bertha Hupp Professor in the Department of Chemistry
at Scripps Research. "In addition to saving steps, this unprecedented
synthetic strategy can introduce new chemical space for drug discovery
as structurally distinct substrates are incorporated into the ring."
Yu and his laboratory are already known for their innovations in C- H functionalization, which is a powerful way of building complex organic molecules to make new pharmaceuticals and other valuable commercial
compounds.

In this approach, chemists use ligands and catalysts to disconnect a
hydrogen (H) atom from a carbon (C) atom at a desired position on an
organic molecule.

This disconnection allows a new cluster of molecules, known as a
functional group, to bond where the hydrogen atom had been.

Most molecules that are used to build new drugs include rings of
carbon atoms, also called carbocycles. Thanks in part to Yu's group,
the C- H functionalizations of carbon atoms on these rings have become relatively easy in many cases. This approach is often not applicable,
though, in cases where the existing functional group needed to anchor
the ligand and catalyst is directly across the ring from the desired
C-H functionalization site.

"We call this scenario 'crossing the river,' and it has been extremely challenging because the palladium catalyst must form a strained 'bridge' connecting the existing functional group and the desired carbon site on
the other side of the ring," Yu says.

The most challenging cases are those in which the carbon-ring structures
are "saturated," which means their carbons are connected only with single carbon- carbon bonds. Saturated carbon rings are common in pharmaceutical chemistry, but are harder targets for C-H functionalization, in part
because the C-H bonds have less affinity for metal catalysts, compared
to the double C-C bonds of unsaturated carbon rings. The Yu lab has
achieved C-H functionalization across unsaturated rings, but there has
been no way to do this across a saturated ring -- until now.

In the study, Yu and his team, including co-first authors Guowei Kang,
PhD, Daniel Strassfeld, PhD, and Tao Sheng, PhD, all postdoctoral
research associates in the Yu lab, were able -- after months of trial
and error -- to develop quinuclidine-pyridone and sulfonamide-pyridone
ligands enabling cross- ring functionalization with saturated carbon
rings. They showed that the approach can work for rings containing from
four to eight carbon atoms, within a wide variety of molecules.

The researchers demonstrated the new technique by easily functionalizing molecules that are being used to develop future drugs, including compounds called histone deacetylase inhibitors, which are under investigation as potential cancer treatments.

"We anticipate that this new tool will greatly simplify the synthesis of
a large class of carbocyclic molecules used in pharmaceutical chemistry, expanding chemical space for the discovery of new and better drugs,"
Yu says.

The research was supported by grants from the National Institute of
General Medical Sciences (2R01GM084019 and F32GM143921).

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========================================================================== Story Source: Materials provided by Scripps_Research_Institute. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Kang, G., Strassfeld, D.A., Sheng, T. et al. Transannular C-
H functionalization of cycloalkane carboxylic acids. Nature,
2023 DOI: 10.1038/s41586-023-06000-z ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/05/230531150050.htm

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