Enamides substituent effect

The rhodium-catalyzed asymmetric hydrogenation of prochiral enamides was investigated by Feldgus and Landis [691, 692]. They demonstrated that computational methods reproduce the ot-substituent effect in enamide hydrogenation catalysis and probe how the interaction of the enamide C=C bond and the catalyst varies with the structure of the substrate. The picture that emerges emphasizes the complex interaction of both electronic (i.e. those effects that do not depend on the size of the model system) and steric effects in controlling the stereochemistry of enamide hydrogenation reactions [691, 692]. 

Ninomiya, 1., Kiguchi, T, Yamamoto, O., and Naito, T., Photocyclisation of enamides. Part 13. Substituent effects in the photocyKsation of N-benzoylenamides, /. Chem. Soc., Perkin 1,1723-1728,1979. Couture, A., Grandclaudon, R, and Hooijer, S.O., Photocyclization in an alcohol solution containing dissolved base. A New development in enamide photochemistry, /. Org. Chem., 56, 4977-4980,1991. 

Although understanding the effect of the a-substituent on relative alkyl hydride stabilities is straightforward, understanding the effect on the catalyst-enamide diastereomers is not. To clarify this matter we performed a series of calculations on a variety of substituted enamides [78], To eliminate the effect of the amide oxygen, we examined frontier orbitals of the [Rh(PH3)2(formamide)]+ fragment (15) and those of model enamides (16). 

The enantioselectivity depends also on the structure of the enamide substrate, especially the a-substituent, as was already reported by Knowles. In a few substrates the enantioselectivity even reverses These exceptions to the general rule have found explanation in electronic effects [12], Knowles reported that an electron withdrawing substituent at the a-position was important in order to obtain a high enantioselectivity, see Figure 4.12 [13],... 

Rh complexes of ferrocene-based ligands are very effective for the hydrogenation of several types of dehydroamino (2,3,29,41,42,44) and itaconic acid derivatives (4,5,28) as well as for enamide 45, enol acetate 26, and a tetrasubstituted C = C-COOH 21. Of particular interest are substrates that have unusual substituents (41,42,44) at the C = C moiety or are more sterically hindered than the usual model compounds (21,42). Table 15.10 lists typical examples with very high ee s and often respectable TONs and TOFs. Several industrial applications have already been reported using Rh-Josiphos and Ru-Josiphos (see Figure 15.7) as well as Rh-Walphos (Scheme 15.8). 

Preliminary investigations revealed that cationic rhodium complexes [(COD)Rh(-DuPHOS)] OTf bearing the Et-DuPHOS or Pr-DuPHOS ligands [2,5-substitu-ents on phospholanes (1) R = Et or Pr, respectively] were effective catalyst precursors for highly enantioselective hydrogenation of a broad range of A-acetyl a-enamide esters and acids (5 R = Me) (Scheme 2) [4]. 

This idea clearly was inspired by the successful L-dopa process of Monsanto [4]. At that time, little was known about the effects of the substituents at the C=C bond and the amide nitrogen. A selective synthesis of one of the three possible enamide isomers depicted in Fig. 3 looked difficult. 

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). 

In the AITE of styrenyl enamides, the a-directing effect of the phenyl group is overridden by the amide group. Aryl substituents and syngas pressure have a strong influence on enantioselectivity (Scheme 4.72, a) and regioselectivity (Scheme 4.72, b). Obviously, enhancement of pressure between 30 and 60 psi has a particularly positive effect on both parameters. 

Feldgus S, Landis CR (2001) Origin of enantioreversal in the rhodium-catalyzed asymmetric hydrogenation of prochiral enamides and the effect of the alpha-substituent. Organometallics 20 2374-2386... 

Nucleophilicity parameters N and % for electrophile-nucleophile combination based on the Mayr equation log k=+E) were reported for fluorides in protic solvents, enamines derived from imidazolidinones, trimethylsilyl enol ethers with perfluori-nated substituents at the a-carbon, O-methylated Breslow intermediates, anions of nucleobases and their subunits, enamides, symmetrical and unsymmetrical hydrazines, and heteroarylboron compounds. Of note, replacement of CH3 with CF3 and C6H5 with CgF5 in the trimethylsilyl enol ethers reduces the nucleophilicity by 8 and 4.5 orders of magnitude, respectively. Hydrazines have very similar nucle-ophilicities to alkyl amines in other words, there is no evidence of an a-effect. With NH2NMC2, there is a fast reversible reaction corresponding to addition of the tertiary amine, followed by a slow irreversible reaction for addition at the primary amine, with a 3000-fold difference in nucleophilicity between the two sites. ... 

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