Hydrogenation enamide

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. 

R = H or COCH2CI (Sj-NAA or (SJ-nnetolachlor Fig. 4 Enantioselective hydrogenation of methoxyacetone and nucleophilic substitution with an MEA derivative. 

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Enamide hydrogenations have become a routine test reaction for evaluation of the effectiveness of new chiral Hgands [5,11,20,56,59,104]. In addition to being a test reaction, it stands as one of the most powerful and economic methods for the production of enantiomerically pure a-amino acid derivatives. Our group... 

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... 

Table 9.6 Assessment of development targets for the enamide hydrogenation route.

Scheme 9.33 Final enamide hydrogenation route to taranabant.

The team had now demonstrated two alternate asymmetric routes to taranabant namely the DKR and the enamide hydrogenation. Notably each synthesis starts... 

Synthesis attribute DKR route Enamide hydrogenation route... 

Fig. 31.7 Modern presentations of the Quadrant Rule for predicting the course of enamide hydrogenation, following the original work of Knowles.

Emission-control system, 27 312 Emission spectra, 31 113, 115-116 Enamides, hydrogenation of, 25 106 Endopeptidase, 28 326 ENDOR, metalloenzymes, 28 326 Energy activation... 

Figure 1.3 Stable intermediates in the enamide hydrogenation by (S,S)-trans-bis(2,3-diphenylphosphino-butane)rhodium, detected by P NMR. The various multiplicities arise from j Rh, P) and J( P, P).

With the basic (albeit unconventional) tools at hand, we will focus in the following on the detection of key intermediates with standard NMR and the application of the PHIP method to mechanistic studies of enantioselective enamide hydrogenations. 

Figure 9.15 Rhodium monohydrides in enantioselective enamide hydrogenation that were characterized by conventional NMR spectroscopy.

So far, we have demonstrated that two of the three hypothetical intermediates in asymmetric enamide hydrogenation (i. e. the substrate complex and the monohy-... 

With this system, we finally succeeded in characterizing the first rhodium dihydride species in the asymmetric hydrogenation of enamides. Additionally, we succeeded afterwards in the characterization of all the possible catalyst dihydride species [39]. In subsequent work, now knowing what to look for and where to look, all transient complexes in the asymmetric enamide hydrogenation with the Rh(PHA-NEPHOS) catalyst could also be observed with classical NMR techniques [37]. 

FIGURE 13.7 Amines, amino alcohols, and diamines available via DuPhos-Rh-catalyzed enamide hydrogenation. 

For a review comparing DuPhos with different ligands in enamide hydrogenations, see Burk, M. J., Bienewald, F. In Transition Metals for Organic Synthesis and Fine Chemicals, Bolm, C., Beller, M., Eds., VCH Publishers Wienheim, Germany, 1998, Vol. 2, pp. 13-25. 

Various catalyst, pressure, and solvent systems were investigated in an attempt to maximize the stereoselectivity of the enamide hydrogenation. In contrast to the results obtained on the more straightforward derivatives 150 and 151, a mixture of C-4 epimers was obtained under all of the conditions tried. The results obtained are summarized in Scheme 71 and Table 18 below. (Note Solvents/solvent mixtures were chosen with as low a polarity as possible in an attempt to maximize coordination of the substrate to the heterogeneous catalyst.80) Overall yields in all cases where reduction occurred were essentially quantitative. 

An analogous synthesis of acromelic acid B 6 was also attempted using enamide 185. C-2 methyl ester reduction and hydroxyl-directed enamide hydrogenation proceeded smoothly giving a 10 1 mixture of C-4 epimeric catechols, 197 and 198 (Scheme 74). 

Ferrocenyl-based ligands comprise a versatile class of auxiliaries because they can be easily modified at the benzylic position with retention of configuration and can incorporate both central and planar chiralities. The appropriate balance of steric and electronic factors has provided ferrocenyl derivatives featuring chelating P,N properties that proved beneficial in numerous enantioselective transformations [50]. Among more recent applications, they could be utilized very efficiently in Pd-catalyzed hydrosilylation (14 >99% ee) [51] and hydroboration (>94% ee) [52] of olefins, allylic amination (99 % ee) [53], Suzuki cross coupling reactions (Section 2.11) [54], and enamide hydrogenation (>99% ee) [55]. 

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