Publication Date:
2016-02-18
Description:
Discovering pharmaceutical candidates is a resource-intensive enterprise that frequently requires the parallel synthesis of hundreds or even thousands of molecules. C-H bonds are present in almost all pharmaceutical agents. Consequently, the development of selective, rapid and efficient methods for converting these bonds into new chemical entities has the potential to streamline pharmaceutical development. Saturated nitrogen-containing heterocycles (alicyclic amines) feature prominently in pharmaceuticals, such as treatments for depression (paroxetine, amitifadine), diabetes (gliclazide), leukaemia (alvocidib), schizophrenia (risperidone, belaperidone), malaria (mefloquine) and nicotine addiction (cytisine, varenicline). However, existing methods for the C-H functionalization of saturated nitrogen heterocycles, particularly at sites remote to nitrogen, remain extremely limited. Here we report a transannular approach to selectively manipulate the C-H bonds of alicyclic amines at sites remote to nitrogen. Our reaction uses the boat conformation of the substrates to achieve palladium-catalysed amine-directed conversion of C-H bonds to C-C bonds on various alicyclic amine scaffolds. We demonstrate this approach by synthesizing new derivatives of several bioactive molecules, including varenicline.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Topczewski, Joseph J -- Cabrera, Pablo J -- Saper, Noam I -- Sanford, Melanie S -- F32 GM109479/GM/NIGMS NIH HHS/ -- GM073836/GM/NIGMS NIH HHS/ -- R01 GM073836/GM/NIGMS NIH HHS/ -- England -- Nature. 2016 Mar 10;531(7593):220-4. doi: 10.1038/nature16957. Epub 2016 Feb 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26886789" target="_blank"〉PubMed〈/a〉
Keywords:
Amines/*chemistry
;
Carbon/*chemistry
;
Catalysis
;
*Chemistry Techniques, Synthetic
;
Heterocyclic Compounds/chemistry
;
Hydrogen/*chemistry
;
Nitrogen/chemistry
;
Palladium/*chemistry
;
Pharmaceutical Preparations/chemical synthesis/chemistry
;
Piperidines/chemical synthesis/chemistry
;
Varenicline/chemical synthesis/chemistry
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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