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N-Phenylazole-Based Phosphine Ligands for Asymmetric C-H Functionalization

Phosphines with an imidazole or pyrrole rings lead to the effective enantioselective synthesis of 𝜷2- and 𝜷3- amino acids

β2- and β3-amino acids represent important chiral components for the synthesis of the pharmaceuticals and peptidomimetics found in natural products. In particular, the incorporation of β-amino acids into peptides allows modulation of their secondary structure and increase of their proteolytic stability, hence furnishing peptidomimetics with improved pharmacological value [1].


       15-3360                                                        15-3365

Fig. 1. N-phenylazole-based phosphine ligands

Already in earlier reports, N-phenylazole-based phosphine ligands (Fig. 1) bearing an imidazole (15-3360) or pyrrole (15-3365) rings were showing an effective performance in the palladium-catalyzed ligand-controlled α- and β-arylation of acyclic N-Boc amines [2] and in Barbier-Negishi coupling of secondary alkyl bromides with aryl and alkenyl triflates and nonaflates [3].

This useful behavior of the ligands led to the straightforward regio- and enantiodivergent access of the β2- and β3-amino acids via one-pot reaction composed of sparteine-mediated enantioselective lithiation of a Boc-1,3-oxazinane, transmetallation to zinc and direct or migratory Negishi coupling with an organic electrophile (Fig. 2) [1].


Fig. 2. N-phenylazole-based phosphine ligands

The regioselectivity of the Negishi coupling was highly ligand-controlled and switch-able to obtain the C4- or the C5-functionalized product exclusively. High enantioselectivities were achieved on a broad range of examples, and a catalytic version in chiral diamine was developed using the (+)-sparteine surrogate. Selected C4- and C5-functionalized Boc-1,3-oxazinanes were subsequently converted to highly enantioenriched β2- and β3-amino acids with the (R) or (S) configuration, depending on the sparteine enantiomer employed in the lithiation step.


  1.       Nat. Catal. 2019, 2, 882.
  2.       Angew. Chem. Int. Ed. 2014, 53, 2678.
  3.       Angew. Chem. Int. Ed. 2018, 57, 1982.


Featured Products

15-3360 1-[2,6-Bis(cyclohexyloxy)phenyl]-2-(di-tertbutylphosphaneyl)-1H-imidazole, min. 95% (2179272-79-6)

15-3365  2-[Bis(1-methylethyl)phosphino]-1-phenyl-1H-pyrrole, min. 95% (1257847-61-2)



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