Enamides prochiral

Several S/N ligands have also been investigated for the asymmetric hydrogenation of prochiral olefins. Thus, asymmetric enamide hydrogenations have been performed in the presence of S/N ligands and rhodium or ruthenium catalysts by Lemaire et al., giving enantioselectivities of up to 70% ee. Two... 

In this reaction, a rhodium atom complexed to a chiral diphosphine ligand ( P—P ) catalyzes the hydrogenation of a prochiral enamide, with essentially complete enan-tioselectivity and limiting kinetic rates exceeding hundreds of catalyst turnovers per second. While precious metals such as Ru, Rh, and Ir are notably effective for catalysis of hydrogenation reactions, many other transition-metal and lanthanide complexes exhibit similar potency. 

A crucial achievement significantly stimulated the development of the investigation in the field of homogeneous enantioselective catalysis. The Knowles group established a method for the industrial synthesis of I-DOPA, a drug used for the treatment of Parkinson s disease. The key step of the process is the enantiomeric hydrogenation of a prochiral enamide, and this reaction is efficiently catalyzed by the air-stable rhodium complex [Rh(COD)((PP)-CAMP)2]BF4 (Scheme 1.12). 

When an appropriate chiral phosphine ligand and proper reaction conditions are chosen, high enantioselectivity is achievable. If a diphosphine ligand with C2 symmetry is used, two diastereomers for the enamide-coordinated complex can be formed because the olefin can interact with the metal from either the Re- or Sf-face. Therefore, enantioselectivity is determined by the relative concentrations and reactivities of the diastereomeric substrate-Rh complexes. It should be mentioned that in most cases it is not the preferred mode of initial binding of the prochiral olefinic substrate to the catalyst that dictates the final stereoselectivity of these catalyst systems. The determining factor is the differ-... 

Homogeneous enantioselective hydrogenation constitutes one of the most versatile and effective methods to convert prochiral substrates to valuable optically active products. Recent progress makes it possible to synthesize a variety of chiral compounds with outstanding levels of efficiency and enantioselectivity through the reduction of the C=C, C=N, and C=0 bonds. The asymmetric hydrogenation of functionalized C=C bonds, such as enamide substrates, provides access to various valuable products such as amino acids, pharmaceuticals, and... 

When the diphosphine is chiral, binding of a prochiral alkene creates diastereomeric catalyst-alkene adducts. (Diastereomers result because binding of a prochiral alkene to a metal center generates a stereogenic center at the site of unsaturation.) Through a powerful combination of3lP and l3C NMR methods, Brown and Chaloner first demonstrated the presence of two diastereomeric catalyst-enamide adducts with bidentate coordination of the substrate to the metal (Figure 1) [19]. 

Addressing the origins of enantioselectivity requires a chiral model. We chose [Rh((/ ,/ )-Me-DuPHOS)]+ (12) for the model system because of its relative simplicity and high selectivity. As in the previous study, we used the simplified substrate, a-formamidoacrylonitrile (13). Since the double bond in 13 is prochiral, there are two different catalyst-enamide diastereomers as shown in Figure 1. 

The same soluble MPEG-resin was used for the immobihzation of (3R,4R)-3,4-bis(diphenylphosphino)-pyrrolidine ligand (56) (Scheme 4.34). The rhodium(I) catalyst was generated in situ from ligand (56) and [Rh(COD)2] BF4 and was found to be active in the asymmetric hydrogenation of prochiral enamides [126]. 

In asymmetric hydrogenation of olefins, the overwhelming majority of the papers and patents deal with hydrogenation of enamides or other appropriately substituted prochiral olefins. The reason is very simple hydrogenation of olefins with no coordination ability other than provided by the C=C double bond, usually gives racemic products. This is a common observation both in non-aqueous and aqueous systems. The most frequently used substrates are shown in Scheme 3.6. These are the same compounds which are used for similar studies in organic solvents salts and esters of Z-a-acetamido-cinnamic, a-acetamidoacrylic and itaconic (methylenesuccinic) acids, and related prochiral substrates. The free acids and the methyl esters usually show appreciable solubility in water only at higher temperatures, while in most cases the alkali metal salts are well soluble. 

In the presence of a cationic Rh[((/ )-binap)(cod)] complex, geranyl or neryl amides isomerize slowly to give a mixture of the corresponding enamide and dienamide (Scheme 20) (2). The optical purity of the chiral enamide is high, but the chemical yield is low. Certain cyclic allylic amides give the enamide isomers in a high ee. With a DIOP-Rh catalyst, prochiral allylic alcohols are converted to optically active aldehydes with low ee (31). 

When one turns to other prochiral unsaturates not related to enamides, optimizing by varying ligand structure has been only marginally productive, and the 90-95% ee so easily obtained with enamides has remained well out of reach for the most part. In several cases these low results persist in spite of having been the subject of a considerable research effort. 

At this point mechanistic studies have reached an impasse. All of the observable intermediates have been characterized in solution, and enamide complexes derived from diphos and chiraphos have been defined by X-ray structure analysis. Based on limited NMR and X-ray evidence it appears that the preferred configuration of an enamide complex has the olefin face bonded to rhodium that is opposite to the one to which hydrogen is transferred. There are now four crystal structures of chiral biphosphine rhodium diolefin complexes, and consideration of these leads to a prediction of the direction of hydrogenation. The crux of the argument is that nonbonded interactions between pairs of prochiral phenyl rings and the substrate determine the optical yield and that X-ray structures reveal a systematic relationship between P-phenyl orientation and product configuration. 

Although the Rh-catalyzed asymmetric hydrogenations of prochiral enamides have been extensively studied and excellent results have been frequently achieved, the catalytic asymmetric hydrogenations of 2-arylacrylic acids have been less successful. Until recently most catalyst systems gave only moderate optical yields for the 2-arylpropionic acid products (77). An important breakthrough in the study of these reactions was reported by Noyori et al. By using Ru(BINAP)(OAc)2 as a catalyst precursor, these researchers obtained excellent optical yields in the asymmetric hydrogenation of 2-(6 -methoxy-2 -naphthyl)acrylic acid (72). 

VIolecular Mechanics and NOE Investigations of the Solution Structure of Intermediates m the [Rh(chiral bisphosphine)] -Catalyzed Hydrogenation of Prochiral Enamides. 

BINAP was first introduced by Noyori [80]. It has been particularly explored for reduction with ruthenium catalysts. BINAP is an atropisomeric ligand because rotation aroimd the central C-C bond is blocked. Accordingly BINAP exists in two enantiomers. Complexes of Ru(II) with BINAP are extremely powerful catalysts for enantioselective hydrogenations of prochiral a,p- and P,Y-unsaturated carboxylic acids, enamides, allylic and homoallylic alcohols, imines etc. [83]. In many cases, the hydrogenation is quantitative with enantiomeric excesses of over 95%. A wide variety of vitamins, terpenes, P-lactam antibiotics, etc. are accessible by the use of catalysts containing the BINAP stereogenic element. An example for 3-oxo carboxylic esters is shown in reaction (1) of Fig. 6.32. 

The accessibility of prochiral precursors is a key factor to a successful hydrogenation process from a practical point. There are several common and efficient methods for the formation of various enamides. An example is the preparation of N acyl a arylenamides as illustrated in Scheme 9.2. 

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]. 

Systematic studies on the isomerization of W-allylamides 24 and -imides to aliphatic enamides 25 were carried out with iron, rhodium, and ruthenium complexes as catalysts, Eq. (8). Regrettably, no prochiral substrate was applied for the rhodium catalyst bearing polymer-anchored DIOP [33]. In the framework of a study on the conjugative interaction in the isomerization of 1-azabicyc-lo[3.2.2]non-2-ene 26 to orthogonal enamine 27, catalyzed by either f-BuOK or RuH(NO)(PPh3)3, the enamine formation was calculated to be favored by 4 kcal mob, Eq. (9) [34]. Recently, the palladium-catalyzed isomerization of the N-acyl-2,5-dihydropyrroles 28 to N-formyl-2,3-dihydropyrroles 29 was reported, Eq. (10) [35]. 

It was subsequently demonstrated that enamides displace solvent from this adduct, giving new species which are air-sensitive and highly reactive towards hydrogen. These enamide complexes have been characterized spectroscopically (15), and one of the more informative experiments was carried out with the asymmetric ligand DIPAMP and methyl Z-a-benzamidocinnamate (Figure 1). This shows that two diastereomeric enamide complexes are formed in a ratio of 10 1 at room temperature. The two species are related by binding of opposite prochiral faces of... 

The geometry of a chiral 6-membered chelate ring is not conducive to effective asymmetric catalysis. Consider square-planar complexes of d[, l-2,3-diphenyl-l,3 bis (diphenylphosphino) propane (24), which are presumed to exist in chair conformation (Scheme 6) with rapid ring inversion. The close approximation to a-symmetry in the environment of the metal suggests that there will be little discrimination between the diastereomeric modes of binding of a prochiral bidentate ligand, since substituents on the olefin experience similar steric interactions in both isomers. The expectation of low selectivity is borne out in practice, for in some cases enamide complexes derived from this phosphine exist in two diastereomeric forms (Figure 3). 

Two ruthenium complexes, binap 3.43-Ru(OCOR)2(R = Me,CF3) [892] and binap 3.43-RuX2 (X = Cl, Br, I) [893, 894], are quite useful. The acetate and trifluoroacetate complexes of 3.43 induce selective asymmetric hydrogenations of classes of prochiral olefins that are poorly selective with rhodium complexes. These classes include a,(3- or fcy-unsaturated acids and esters, ally alcohols, j3-acylaminoacrylates and enamide precursors of isoquinoline alkaloids [752, 853, 859, 881, 883, 895]. 

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