'Product Blog'

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.

References:

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)