Palladium-catalysed transannular C-H functionalization of alicyclic amines

Joseph J. Topczewski, Pablo J. Cabrera, Noam I. Saper, Melanie S. Sanford

Research output: Contribution to journalArticlepeer-review

167 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)220-224
Number of pages5
JournalNature
Volume531
Issue number7593
DOIs
StatePublished - Mar 10 2016

Bibliographical note

Funding Information:
We acknowledge J. W. Kampf for X-ray crystallographic analyses of 4a, 11b, an analogue of 11g, 11h and 14a. J.T.T. was supported by an NIH post-doctoral fellowship (F32 GM109479). This work was supported by NIGMS grant GM073836. We acknowledge funding from NSF grant CHE-0840456 for X-ray instrumentation.

Publisher Copyright:
© 2016 Macmillan Publishers Limited. All rights reserved.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

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