'Product Blog'

Highly effective ferrocenyl based diphosphine ligands give access to complex chiral organic molecules that generate natural products and drugs

Enantioselective processes promoted by transition metal chiral catalysts play a dominant role in asymmetric synthesis of active pharmaceutical ingredients and natural products [1]. C2-Symmetrical diphosphine ligands are an interesting class of ligands because of the limited number of possible transition states in the asymmetric catalytic reaction [2].

MandyPhos represent a highly modular, bidentate diphosphine ligand having a C2-symmetrical backbone (Fig. 1). The first successful applications were reported in 1998 for the enantioselective Rh-catalyzed hydrogenation of α-acetamidoacrylic acid derivatives [2]. Later, many MandyPhos ligands initiated systematic investigations of various catalytic transformations [3]. The most prominent candidates were selected and commercialized by Solvias.

Fig. 1 MandyPhos ligands

Mandyphos ligands with the (3,5-dimethyl-4-methoxyphenyl)- (26-0248), 1,1'-bis(diphenylphosphino)-(26-0252) and 1,1'-bis(dicyclohexylphosphino)- (26-0240) groups on the side arms, are the most popular ligands and are used in various transition metal (Pd, Rh, Ru, Ir, Cu, Ni) catalyzed coupling reactions (for detailed information see the corresponding technical note).

Moreover, application of NaOTf or KOTf metal salts as a Grignard activator and halide scavenger in the MandyPhos mediated processes helps to overcome inhibitions related to the presence of lithium halide salts [4]. Also, Morken et al described an alternative to the organometallic transmetallation step that is common in many metal-catalyzed reactions, such as Suzuki-Miyaura coupling. Specifically, it was demonstrated that vinyl boronic esterate complexes, prepared by combining organoboronates and organolithium reagents, engage in palladium-induced metalate rearrangement wherein 1,2-migration of an alkyl or aryl group from boron to the vinyl α-carbon occurs concomitantly with C–Pd s-bond formation. This elementary reaction enables a powerful cross-coupling reaction in which a chiral Pd catalyst merges three simple starting materials — an organolithium, an organoboronic ester, and an organotriflate — into chiral organoboronic esters with high enantioselectivity [5].

References:

1.       Chem. Rev. 2006, 106, 2734.
2.       Tetrahedron Lett. 1998, 39, 8073.
3.       Tetrahedron Asymmetry 2004, 15, 2299.
4.       J. Am. Chem. Soc. 2017, 139, 3153.
5.       Science 2016, 351, 70.