Rhodium-DuPhos catalysts

The Application of DuPHOS Rhodium ( ) Catalysts for Commercial Scale Asymmetric Hydrogenation 2.2.22. N-Acetyl-3-fluorophenylalanine 9... 

The use of rhodium catalysts for the synthesis of a-amino acids by asymmetric hydrogenation of V-acyl dehydro amino acids, frequently in combination with the use of a biocatalyst to upgrade the enantioselectivity and cleave the acyl group which acts as a secondary binding site for the catalyst, has been well-documented. While DuPhos and BPE derived catalysts are suitable for a broad array of dehydroamino acid substrates, a particular challenge posed by a hydrogenation approach to 3,3-diphenylalanine is that the olefin substrate is tetra-substituted and therefore would be expected to have a much lower activity compared to substrates which have been previously examined. 

Chiral l,T-diphosphetanylferrocene Et-FerroTANE serves as an effective ligand for the rhodium-catalyzed hydrogenation of y9-aryl- and /9-alkyl-substituted monoamido ita-conates (Eqs. 19 and 20) [54]. The Et-DuPhos-Rh catalyst was utihzed for the asymmetric hydrogenation of the trisubstituted olefin derivative in the preparation of an important intermediate for the drug candoxatril (>99% ee) [110]. 

FIGURE 13.4 Elaborate amino acids accessible with DuPhos or BPE rhodium catalysts. 

Indeed, we quickly affirmed that the cationic Et-DuPHOS-Rh catalysts allowed smooth reduction of the A -benzoylhydrazones 32 in up to 97% ee (Scheme 15)[34]. Analogous rhodium catalysts based on known chiral diphosphines such as BDPP, BINAP, CHIRAPHOS, DIOP, and Ph P-Glup reduced A-benzoylhy-dra/ones with low relative rates and low enantioselectivites (highest 23% ee. 75% conversion over 48 hr with BINAP-Rh). This process provides simple access to a-arylhydrazines (33, R = aromatic or heteroaromatic ring) and a-hydrazino acids (33, R = CO2Me) with high enantiomeric excesses. 

The following section delineates one recent application of the cationic DuPHOS/BPE rhodium catalysts aimed at the rapid generation of collections of chiral building blocks. 

The application of DuPHOS rhodium(I) catalysts for commercial scale asymmetric hydrogenation... 

In order for these rhodium DuPHOS catalysts to achieve the desired reactivity and selectivity, the hydrogenation substrate must contain certain features to facilitate the highly diastereoselective transition state required for the reaction. All the substrates to which rhodium DuPHOS hydrogenation catalysts have been successfully applied thus far possess a donor atom y to the olefin (Fig. 2). Within the constraint of this geometric requirement a wide array of prochiral olefins have been demonstrated as suitable substrates for asymmetric hydrogenation with rhodium DuPHOS catalysts. Examples include enamides 2 [1, 2], vinylacetic acid derivatives 3 [3], and enol acetates 4 [4]. 

A new family of chelating diphosphines, where phosphorus is part of a five-membered ring containing two asymmetric centers, was developed at Du Pont by Burk et al. in 1990 [58a]. These C2-symmetric Hgands (duphos and derivatives) gave excellent rhodium catalysts for asymmetric hydrogenation of many types of imsatuxated systems. 

Most rhodium catalysts for the enantioselective reduction of the C=N group are prepared in situ from a dimeric Rh-diene complex and a chiral diphosphine. Only few of the tested diphosphine ligands exhibit enantioselectivities >70% bdpp, cycphos, and phephos for imines and duphos for acylhydrazones. The activity of most Rh-diphosphine complexes for imine hydrogenation is low and therefore most of them are of limited practical use. Although some catalysts work already at ambient reaction conditions, most Rh-diphosphine complexes show low tof s even at elevated hydrogen pressures (>60 bar). 

Rhodium complexes of the type [(COD)Rh(DuPhos)]+X (X = weakly or noncoordinating anion) have been developed as one of the most general classes of catalyst precursors for efhcient, enantioselective low-pressure hydrogenation of enamides (21) (Scheme 9.22). ° The DuPhos approach overcomes some of the limitations of the DIPAMP system as the substrates may be present as mixtures of E- and Z-geometric isomers. For substrates that possess a single p-substituent (e.g., = H), the Me-DuPhos-Rh and Et-DuPhos-Rh catalysts were found to give enantioselec-... 

DuPHOS Rhodium(I) Catalysts A Comparison of COD Versus NBD Precatalysts Under Conditions of Industrial Application... 

In all enantioselective hydrogenations the ability of the substrate to form a chelate ring with the catalyst is extremely important. For this reason the enantioselective reductive ami-nation of ketones is always particularly difficult, because these compounds usually do not have a structure suitable for the required chelation. Burk et al. circumvent this problem by reversible derivatization. The ketones are converted into A -acetylhydrazones, whose structures resemble those of enamides. [11] The C-N double bond can then be hydrogenated by nPr-DuPHOS-rhodium with ee values almost as high as those for C-C double bonds of enamides. The A-acetylhydrazines obtained thus can either be transformed into... 

Later, in the 1990s a remarkable asymmetric catalyst with the chiral chelating phosphine DuPHOS (3.49) (Figure 3.19) was developed by M. J. Burk at DuPont. This cationic DuPHOS/rhodium complex showed very high ee values of 99% in asymmetric hydrogenation of enamides. As can be seen the choice of chiral phosphine chelating ligand had a dramatic effect on the ee values. 

---