Enamides asymmetric

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... 

Scheme 9.15 Proposed asymmetric enamide reduction to generate taranabant.

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]. 

Asymmetric cyclization using chiral ligands has been studied. After early attempts[142-144], satisfactory optical yields have been obtained. The hexahy-dropyrrolo[2,3-6]indole 176 has been constructed by the intramolecular Heck reaction and hydroaryiation[145]. The asymmetric cyclization of the enamide 174 using (S j-BINAP affords predominantly (98 2) the ( )-enoxysilane stereoisomer of the oxindole product, hydrolysis of which provides the ( l-oxindole aldehyde 175 in 84% yield and 95% ec. and total synthesis of (-)-physostig-mine (176) has been achieved[146]. 

Scheme 24. Examples of Rh-catalyzed asymmetric hydrogenation reactions of enamide derivatives...

In 2006, Berens et al. reported the synthesis of novel benzothiophene-based DuPHOS analogues, which gave excellent levels of enantioselectivity when applied as the ligands to the asymmetric rhodium-catalysed hydrogenation of various olefins, such as dehydroamino acid derivatives, enamides and itaco-nates (Scheme 8.10). ... 

The results clearly show that these novel ligands are able to form a suitable asymmetric enviromnent around the metal resulting in high asymmetric induction. Their catalytic potential has been demonstrated in the highly enantioselective Rh-catalyzed hydrogenation of itaconates and a-enamides and Ru-catalyzed hydrogenation of p-functionalized ketone. 

Asymmetric hydrogenation of a cyclic enamide (Approach B) had very sparse literature precedents [7]. It should also be noted that preparation of these cyclic imines and enamides is not straightforward. The best method for the synthesis of cyclic imines involves C-acylation of the inexpensive N-vinylpyrrolidin-2-one followed by a relatively harsh treatment with refluxing 6M aqueous HC1, which accomplishes deprotection of the vinyl group, hydrolysis of the amide, and decarboxylation (Scheme 8.6) [8]. 

The asymmetric reduction of enamides using hydrogenation conditions is a well documented reaction with a number of groups reporting excellent results [14]. Syn delivery of hydrogen from the same face of the molecule ensures that the enamide geometry defines the relative stereochemistry obtained, and a range of chiral catalysts have been developed to control the absolute stereochemistry. However, a... 

It initially appeared that it should be feasible to carry out the asymmetric hydrogenation using bromo-enamide 39 and to introduce the nitrile group as the final chemical transformation (Scheme 9.29). 

With all other pieces of the synthesis in place our attention now focused on the final piece in the jigsaw-the asymmetric hydrogenation of the amide enamide 42. Screening of hydrogenation conditions rapidly led to identification of a number of conditions which allowed the desired hydrogenation to proceed at low catalyst loadings and in non-chlorinated solvents (Table 9.9). 

The asymmetric hydrogenation oftetrasubstituted enamides remains a challenging goal in synthetic organic chemistry. In particular, reduction of an acylic enamide bearingfourdistinctgroups (as in enamides 22 and 42) has yet to be demonstrated by another group at the time of writing. In this section a brief outline of currently documented reductions of tetrasubstitued enamides is presented. 

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

Enamides, in addition to the acrylates shown above, are also asymmetrically hydrogenated with many of the same systems that prove useful for the acetamidoacrylate reductions. The Rh(I)/BICP (2(/J)-2/(i)-bis(dipenylphosphino)-1(R),] (R)-dicyclopenlane) 132 and Rh(I)/DuPHOS systems work well (>90% ee) for the asymmetric hydrogenation of /3-acctamidovinyl methoxymethyl ethers... 

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