Phosphines enantioselective hydrogenation

The fundamental concepts of enantioselective hydrogenation were introduced in Section 2.5.1 of Part A, and examples of reactions of acrylic acids and the important case of a-acetamido acrylate esters were discussed. The chirality of enantioselective hydrogenation catalysts is usually derived from phosphine ligands. A number of chiral phosphines have been explored in the development of enantioselective hydrogenation catalysts,21 and it has been found that some of the most successful catalysts are derived from chiral 1, l -binaphthyldiphosphines, such as BINAP.22... 

Tocopherol can be produced as the pure 2R,4 R,8 R stereoisomer from natural vegetable oils. This is the most biologically active of the stereoisomers. The correct side-chain stereochemistry can be obtained using a process that involves two successive enantioselective hydrogenations.28 The optimum catalyst contains a 6, 6 -dimethoxybiphenyl phosphine ligand. This reaction has not yet been applied to the enantioselective synthesis of a-tocopherol because the cyclization step with the phenol is not enantiospecific. 

Togni and co-workers have used the convergent methodology to link phosphine-containing chiral ferrocene ligands on the cyclophosphazene core to obtain dendrimeric structures of the type 37 (Fig. 21) (201). The reaction with the cyclophosphazene end occurs by the replacement of the P-Cl bond and by the formation of the P-0 bond. The dendrimers contain twelve and sixteen ferrocene moieties respectively. The phosphine units present can coordinate to Rh(I) to afford metallic dendrimers, which have been shown to be excellent catalysts for the enantioselective hydrogenation of dimethyl itaconate. The product... 

The effect of surfactant on enantioselective hydrogenation has been thoroughly investigated. Rhodium complexes of phosphinated glucopyranosides were used for hydrogenation of prochiral dehydroaminoacid derivatives in aqueous systems in the presence of sodium dodecylsulfate (SDS)... 

Another important use for Wilkinson s catalyst is in the production of materials that are optically active (by what is known as enantioselective hydrogenation). When the phosphine ligand is a chiral molecule and the alkene is one that can complex to the metal to form a structure that has R or S chirality, the two possible complexes will represent two different energy states. One will be more reactive than the other, so hydrogenation will lead to a product that contains predominantly only one of the diastereomers. 

Before 1968, attempts to perform enantioselective hydrogenations had either used a chiral auxiliary attached to the substrate [1] or a heterogeneous catalyst that was on a chiral support, usually derived from Nature [2]. Since the disclosure of chiral phosphine ligands to bring about enantioselective induction in a hydrogenation, many systems have been developed, as evidenced in this book. The evolution of these transition-metal catalysts has been discussed in a number of reviews [3-12]. 

Secondary phosphine oxides are known to be excellent ligands in palladium-catalyzed coupling reactions and platinum-catalyzed nitrile hydrolysis. A series of chiral enantiopure secondary phosphine oxides 49 and 50 has been prepared and studied in the iridium-catalyzed enantioselective hydrogenation of imines [48] and in the rhodium- and iridium-catalyzed hydrogenation functionalized olefins [86]. Especially in benzyl substituted imine-hydrogenation, 49a ranks among the best ligands available in terms of ex. 

Table28.8 Enantioselective hydrogenation of/l-keto esters using monodentate phosphine ligands.

Initially, research focused on the use of C2-symmetric rhodium and ruthenium-phosphine and phosphinite complexes a rhodium-phosphine complex 3 (Fig. 30.2) was used in the first reported enantioselective hydrogenation of substrate 1 (Table 30.1, entry 1) [1],... 

The mechanistic basis of iridium-complex-catalyzed enantioselective hydrogenation is less secure than in the rhodium case. It is well known that square-planar iridium complexes exhibit a stronger affinity for dihydrogen than their rhodium counterparts. In earlier studies, Crabtree et al. investigated the addition of H2 to their complex and observed two stereoisomeric intermediate dihydrides in the hydrogenation of the coordinated cycloocta-1,5-diene. The observations were in contrast to the course of H2 addition to Ms-phosphine iridium complexes [69]. 

Enantioselective hydrogenation of simple ketones catalyzed by BINAP/chiral diamine-Ru complexes is applied to the synthesis of biologically active compounds and a chiral phosphine ligand. Some examples are shown in Figure 32.44 [85 a, 87, 102, 128, 130, 135],... 

When the peptide synthesis was complete, the phosphines were deprotected by sequential treatment with MeOTf and HMPT (Scheme 36.9). Addition of the rhodium precursor then created the catalyst library, which was screened, on the pin in the enantioselective hydrogenation of methyl-2-acetamidoacrylate (see Scheme 36.10). Unfortunately, this beautiful concept was poorly rewarded with rather low enantioselectivities. 

The effect of a range of additives on enantioselective hydrogenation of the cinnamic acid precursor is shown in Scheme 36.15. One trend that emerges from this screen is the positive effect of the monodentate phosphines, in particular, tri-p-tolylphosphine. 

The polymer-supported chiral phosphine obtained (Fig. 42.15) was treated with an Rh precursor and used for the enantioselective hydrogenation of dehydroamino acid derivatives. The obtained catalyst gave up to 82% ee, albeit with still low activity. Stille has developed this immobilization technique further by even more careful tuning of the polarity of the support with that of the reaction medium. For example, he introduced DIOP to a monomer vinylbenzalde-hyde in reactions analogous to those shown for the polymer in Figure 42.11. 

Scheme 44.10 Phosphine-phosphite ligand in enantioselective hydrogenation.

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