MSGID: 1:317/3 64781f0a   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    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   
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   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.   
      
      
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   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   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/05/230531150050.htm   
      
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