Ligands BIPHEP

Scheme 15 Iridium-catalyzed hydrogen-mediated coupling of alkyl-substituted alkynes to activated ketones and aldehydes. Conditions a ligand = BIPHEP, solvent = toluene, T = 80 °C b ligand = DPPF, solvent = toluene, T = 60 °C c ligand = BIPHEP, solvent = DCE,...

Hoffmann-La Roche (Roche) Strong and early efforts to integrate enantioselective catal3d ic steps in the synthesis of chiral vitamins, fine chemicals, and pharmaceuticals. Development of a proprietary family of biphenyl diphosphine ligands (biphep) many pilot and bench-scale processes. Ligands licensed to PPG-Sipsy and Solvias. 

The in situ generation of CuH from organosilanes in the presence of either a BIPHEP (99) or a SEGPHOS (100) type ligand represents a general method for the asymmetric hydrosilylation of aryl alkyl ketones at low temperatures. 

Modification of the electronic and steric properties of BINAP, BIPHEMP, and MeO-BIPHEP can lead to the development of new efficient atropisomeric ligands (Figure 1). In fact, Takaya has found that a modified BINAP... 

Figure 2 Water-soluble biphep ligand and polymer-supported BINAP ligands.

Using Ir/MeO-Biphep/l2 catalyst system, a variety of substituted quinoline derivatives were hydrogenated in 95% yield and up to 96% ee. This method provided an efficient accesss to three naturally occurring alkaloids (Scheme 17).328 Ferrocene N, P ligand 108 is also effective for the asymmetric hydrogenation of quinolines with up to 92% ee.188a... 

The sense of diastereoselectivity in the dynamic kinetic resolution of 2-substi-tuted / -keto esters depends on the structure of the keto ester. The ruthenium catalyst with atropisomeric diphosphine ligands (binap, MeO-biphep, synphos, etc.) induced syn-products in high diastereomeric and enantiomeric selectivity in the dynamic kinetic resolution of / -keto esters with an a-amido or carbamate moiety (Table 21.21) [119-121, 123, 125-127]. In contrast to the above examples of a-amido-/ -keto esters, the TsOH or HC1 salt of /l-keto esters with an a-amino unit were hydrogenated with excellent cwti-selectivity using ruthenium-atropiso-... 

The success of BINAP and the associated ligands families has led to many variations, and most have shown improved properties for specific applications (Fig. 23.1). Examples include derivatives of the naphthyl system of BINAP, as well as those derived from BIPHEP. 

CHEP ligand, which was successfully applied in both Rh- and Ru-catalyzed en-antioselective hydrogenation [7]. Schmid et al. reported BIPHEMP [8] and MeO-BIPHEP [9] ligands, both of which were successfully applied in many Ru-cata-lyzed hydrogenations. Achiwa also developed several atropisomeric ligands such as BIMOP [10], FUPMOP [11], and MOC-BIMOP (Fig. 26.1) [12]. 

A PYRPHOS ligand was found to be effective for the hydrogenation of a / -aryl- or alkyl-substituted monoamido itaconate [107]. A MeO-BIPHEP-Ru catalyst was successfully applied for the enantioselective hydrogenation of an intermediate for the drug candoxatril in a mixed solvent (THF/H20) (Scheme 26.12) [108]. 

The most common chiral auxiliaries are diphosphines (biphep, binap and analogues, DuPhos, ferrocenyl-based ligands, etc.) and cinchona and tartaric acid-derived compounds. It is clear that the optimal chiral auxiliary is determined not only by the chiral backbone (type or family) but also by the substituents of the coordinating groups. Therefore, modular ligands with substituents that can easily be varied and tuned to the needs of a specific transformation have an inherent advantage (principle of modularity). 

Earlier examples of pilot- and bench-scale processes are summarized in [14]. Several cases with high ee-values and medium activity using Rh-bpm ligands were reported by Hoechst (now Sanofi Aventis) [46] Ru-binap and Ru-biphep... 

The hydrogenation of a-amino ketones was also a key step for the synthesis of three more pharma actives (Fig. 37.25). Roche [95] divulged a pilot process involving the hydrogenation/dynamic kinetic resolution of a cyclic a-amino ketone using an optimized MeO-biphep ligand. The Ru-catalyzed reaction was carried out on a 9-kg scale with excellent enantio- and diastereoselectivities, and very... 

The ruthenium catalyst was prepared at room temperature by reaction of [(COD)Ru(2-(methylallyl)2] with ligand P P in this case (R)-MeO-BIPHEP (1.2 eq) in acetone (2mL). 

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