A-enamides

Scheme 8.1 Hydrogenation of a-enamide ester with thioether-phosphine ligands.

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 catalytic reduction reactions represent one of the most efficient and convenient methods to prepare a wide range of enantiomerically pure compounds (i.e. a-amino acids can be prepared from a-enamides, alcohols from ketones and amines from oximes or imines). The chirality transfer can be accomplished by different types of chiral catalysts metallic catalysts are very efficient for the hydrogenation of olefins, some ketones and oximes, while nonmetallic catalysts provide a complementary method for ketone and oxime hydrogenation. 

Figure 12. Asymmetric hydrogenation of a-enamides catalyzed by chiral Rh complexes in scC02...

Asymmetric hydrogenations have also been carried out in scCOi. a-Enamides have been hydrogenated by using a cationic rhodium complex [19]. Enantiomeric... 

Table 2.4 Asymmetric hydrogenation of dehydroamino acid esters and a-enamides catalyzed hy Rh(I)-f-Bu-QuinoxP (see Figure 2.3)...

Alkyl, Aryl (A/Fdisubstituted a-enamide) r2 = Alkyl, Aryl r2 = Alkyl, H... 

However, the method has not generally been adopted for the preparation of 3-branched-a-amino acids that require simultaneous chirality control of the adjacent asymmetric centers, because the preparation of j3,j3-disubstituted a-enamide... 

Intramolecular cyclization of a, -enamide esters Reaction of the a,(3-en-amide (1) with either trimethylsilyl triflate (1 equiv.) or t-butyldimethylsilyl triflate (1 equiv.) and N(C2H5)3 at 15° results in the benzo[a]quinolizidine 2 in high yield. 

Table 2.2. Asymmetric Hydrogenation of a-Enamides with (R, R)-Et-DuPHOS-RH Catalyst...

Scheme 9 Azaallyl ligands different modes of coordination a = enamide mode (rj1- or cr-azaallyl) and b = azaallyl mode (rj3- or 7r-azaallyl)...

Catalytic asymmetric hydrogenations have also been performed in supercritical carbon dioxide [79-81]. For example, a-enamides were hydrogenated in high enantioselectivities comparable to those observed in conventional solvents, using a cationic rhodium complex of the EtDuPHOS ligand (Fig. 7.24) [79]. More recently, catalytic asymmetric hydrogenations have been performed in scC02 with... 

The first published example of asymmetric hydrogenation was by Burk et al. The enantioselective hydrogenation of a-enamides with cationic rhodium (R,R) Et-DuPHOS l,2-bis(tranj-2,5-diethylphospholano) benzene as a catalyst was investigated. To improve the... 

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]. 

We recently have found that the cationic Et-DuPHOS-Rh and Pr-DuPHOS-Rh catalysts allow the highly enantioselective hydrogenation of a wide range of A-Cbz and A-Boc-a-enamide esters and acids [12,16,17]. Moreover, these catalysts were found to reduce both ( )-and (Z)-A-Boc-P-alkyl-a-enamides (5 R = /-BuO, R" = alkyl) with high enantioselectivites. This finding was crucial as present routes to A-Boc-a-enamides generally afford (A)/(Z)-isomeric mixtures. Since A-Boc-a-enamides that possess ( )-p-aryl substituents were hydrogenated with lower enantioselectivities, we have developed a convenient route to a wide variety of isomerically pure (Z)-A-Boc-P-aryl-a-enamides 6 (Scheme 3) [17,18]. 

Thus, treating readily available (Z)-A-acetyl a-enamides, obtained via Erlenmeyer eondensation, with di-ZezV-butyldicarbonate followed directly by hydrazine or LiOH, affords the corresponding A -Boc a-enamide ester or acid, respectively. Hydrogenation of substrates 3 was found to proceed with enantiose-lectivities of > 98% ee by the use of the Et-DuPHOS-Rh catalyst. Alternatively, A-Boc amino acids may be obtained by initial hydrogenation of the A -acctyl a-enamides, followed by transmutation to the A -Boc derivative as previously outlined [18]. The mild nature of this method is evinced by the absence of detectable racemization in the A-Ac to A -Boc conversion performed after hydrogenation. 

Schmid et al. at Hoffmann-La Roche recently reported similar results that bespeak the pre-eminence of the Me-DuPHOS-Rh catalyst for asymmetric hydrogenation of heterocyclic A-Cbz a-enamides [19]. Table 1 lists enantioseleetivities achieved in the hydrogenation of a diverse range of A-Cbz and A-Boc a-enamides using the DuPHOS-Rh catalysts. 

All hydrogenations performed with cationic Rh catalyst precursors [(COD)R]i-DuPHOS]OTf and with a-enamide methyl ester substrates in MeOH, unless otherwise noted. All results involving. -Cbz substrates were extracted from references 7 and 19. All results involving A-Boc substrates derive from reference 17. 

The enantioselectivities we have achieved in the hydrogenation of p,p-di-substituted a-enamides are significantly higher than any previously reported for this challenging class of substrates. The sterically demanding nature of enamides 12 (tetrasubstituted olefins) has presented difficulties in the past with regard to both rates and enantioselectivities. These results lucidly illustrate the advantage... 

Discovery and optimization of peptide and peptidomimetic therapeutics generally requires ready access to a diverse range of chiral building blocks. The DuPHOS-Rh catalysts provide one of the most convenient routes to novel amino acids, yet individual a-enamides must be prepared for each new amino acid needed. In an effort to enhance the efficiency of our hydrogenation methodology, we have developed a two-step tandem catalysis procedure for preparation of a wide range of aromatic amino acids and peptides (Scheme 7) [16,17,24]. 

Asymmetric hydrogenation of bromo-substituted aromatic a-enamides 14 affords the corresponding bromo-amino acid derivatives 15, which subsequently is subjected to Pd-catalyzed cross-coupling with aryl and vinyl boronic acids. In addition to diverse phenylalanine derivatives 16, a broad array of other novel aromatic and heterocyclic amino acids have been produced rapidly from a small number of bromo-functionalized intermediates [24], This same two-step process may be applied to the production of many other classes of aromatic and heterocyclic chiral building blocks, such as arylalkylamines, amino alcohols, diamines, and directly on peptides as well. 

---