Kerr’s highly selective catalysts for deuterium and tritium exchange operate at low-catalyst loadings with excellent functional group tolerance

Kerr’s highly selective catalysts for deuterium and tritium exchange operate at low-catalyst loadings with excellent functional group tolerance

                                          Kerr’s Catalysts for Hydrogen Isotope Exchange (HIE)

 

 

                                                                                                                   Scheme 1.  General reaction scheme for hydrogen isotope exchange (HIE).

Isotopic enrichment of candidate drug molecules is critical for investigation of metabolic processes and the underlying pharmacokinetics and pharmacodynamics properties. Over the past 25 years, significant developments in hydrogen isotope exchange (HIE) catalysis have enabled incorporation of tritium and deuterium into complex molecules in a single step, thereby circumventing the need for additional synthetic steps and costly starting materials.  Among HIE catalysts, air-stability and ortho-directed selectivity of Crabtree’s catalyst [See Crabtree Blog]  have made that system the most widely used in industry and academia (scheme 1).1,2 Unfortunately, low catalyst lifetimes with Crabtree’s system often require very high catalyst loadings.  Furthermore, the participation of Crabtree’s catalyst in reduction of unsaturated C-C bonds typically restricts utility of Crabtree’s catalyst (Strem #77-9500) to aryl C-H groups.3

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Scheme 2. Modular synthesis of Kerr’s catalysts enables facile preparation of a broad array of catalysts from the [Ir(COD)Cl]2 starting material.1

 

Iridium  Catalysts

Kerr's Blog Image3

                                                                                                                              Figure 1.  Kerr’s catalysts available from Strem Chemicals.

 

More recently, Kerr and co-workers sought to address limitations by substituting the pyridine ligand utilized in Crabtree’s catalyst with more sterically encumbering N-heterocyclic carbene (NHC) ligands.1  The modular synthesis of these compounds has enabled preparation of a wide array of catalysts which can be screened to optimize selectivity for HIE for the substrate of interest (scheme 2, figure 1). A general feature of these sterically protected Ir(I) catalysts is enhanced catalyst efficiency compared to other well-known HIE catalysts.  Accordingly, Kerr’s catalysts have been shown to provide high yields of isotopically enriched products at low catalyst loadings (0.1-0.5 mol%) and short reaction times (60-90 min) (scheme 3).4

                                                                                                                   Scheme 3. Efficient and selective catalysis with Kerr’s catalyst #77-1830.

 

Furthermore, the use of Kerr’s catalysts has enabled selective HIE across new substrate platforms. In the example below, Kerr’s triphenylphosphine catalyst (Strem #77-1825) readily delivered the b-labeled enone with 94% selectivity (scheme 4).  In contrast, Crabtree’s catalyst failed to differentiate between HIE and the reductive pathway, giving a 46:54 mixture of the two products, respectively.3

                                                 Scheme 4. Kerr’s catalyst (#77-1825) provides enhanced selectivity for b-labeled enone product [1] compared to Crabtree’s catalyst (#77-9500).3

More remarkably, conditions were recently reported for the exchange of un-activated C(sp3)-H bonds.5 This methodology utilized Kerr’s triphenylphosphine catalyst #77-1840 to isotopically label aliphatic amides.   In this work, more than 28 examples were reported with up to 99% deuterium incorporation.  Below are two examples from this work which demonstrate the versatility and functional group tolerance of this system (figure 2).

                                                                             Figure 2.  HIE products obtained by C(sp3)-H bond activation catalyzed Kerr’s triphenylphosphine catalyst #77-1840.5

References:

  1.  J. Label. Compd. Radiopharm. 2010, 53, 662-667.
  2.  Acc. Chem. Res. 1979, 12, 9, 331-337.
  3.  Chem. Eur. J. 2014, 20, 14604 – 14607.
  4. Chem. Commun. 2008, 1115-1117.
  5. Angew. Chem. Int. Ed. 2018, 57, 8159 –8163.

 

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