Reduction of enamides

The reduction of enamides (62-73) has been applied primarily to the synthesis of cyclic enamines (74-76), but also to acyclic enamines (77). 

An enamine was obtained in the synthesis of coronaridine (648) by aluminum hydride reduction of a bridged lactam, followed by dehydration on alumina. Additional examples of enamine formation by reduction of enamides (649) and thioenamides (650) were reported. 

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... 

Mention should also be made of the DuPhos-type hybrid 10 that works well for the reductions of itaconic acids [62]. A recent addition to the general class is trichickenfootphos (11) this has been developed for the reduction of enamides, dehydroamino acids and a,/ -unsaturated nitriles [63, 64]. (Throughout this chapter, R in generic structures denotes an alkyl group unless otherwise stated.)... 

The system can also be made rigid by modification of the ketal portion, as illustrated by 14 and SK-Phos (15). These ligands provided high stereoselection for reductions of enamides and MOM-protected yS-hydroxy enamides [81]. 

The chemistry of Rh(DIPAMP) and mechanism has been reviewed.914 1617 2 28 Marginally higher catalyst efficiencies are observed with higher alcohols compared to methanol, whereas the presence of water can result in the reduction of slurries. Filtration of the product can improve the % ee while the catalyst and D,L-product remain in the mother liquor. The catalyst stereoselectivities decrease as hydrogen pressure increases. [Rh(COD)(R,W-DIPAMP) +BF4 (13) affords the. S -con-figuration of amino acids on reduction of the enamide substrate. Reduction of enamides in the presence of base eliminates the pressure variances on the stereoselectivities, but the rate of reaction under these conditions is slow.17... 

Rhodium complexes that contain these ligands have demonstrated moderate to high enantio-selectivities (24-96%) in the reduction of enamides to protected amino acids (cf Scheme 12.1).7-70 Despite the moderate degree of asymmetric induction, ANIC S.p.A. (EniChem) developed an industrial process with this catalyst system for the production of (S)-phenylalanine for the synthesis of aspartame.1145 The process uses cationic Rh-7a for the reduction of 14b at 28 psig H2 and 22°C for 3 hours (S/C = 15,000) to give 15b in 83.3% ee that is enriched to 98.3% by recrystallization.72... 

Rhodium complexes that contain (2S,4.S )-PPM ligands efficiently catalyze the asymmetric reduction of enamides to form protected amino acids with the -configuration.95 97 However, no... 

Several new ligands that possess chirality at the phosphorus center have been developed and shown to be excellent catalysts for the asymmetric reduction of enamides to amino acids and chiral amines and P-enamides to P-amino esters. One ligand that shows great promise to be used at the manufacture scale is Trichickenfootphos, which has demonstrated high activity and enantioselectivity in the production of a chiral intermediate for Pregabalin. 

Palladium black gave the highest yield (81%) in the reduction of enamide 88 with complete stereoselectivity for C-4 epimer 102. Proof that the selectivity observed was a steric effect associated with the bulk of the C-2 tert-butyl ester was obtained by repeating the reduction with methyl ester 89. Using palladium black as a catalyst under identical conditions to those used in the reduction of 88, a 70% overall yield of products 106 and 107 in a ratio of 1 13 (isolated yield/ratio after chromatographic purification) was obtained (Scheme 45). 

The first step required was the stereoselective reduction of enamide 184 to give the necessary C-3/C-4 cis stereochemistry. To enable the use of the hydroxyl group directed hydrogenation described in the section on Hydroxyl-Group-Directed Enamide Reduction, enamide 184 was... 

The asymmetric reduction of enamides to produce chiral amine derivatives has also been examined by the Paris Group (52). Subsequent unpublished studies (53) have shown that the degree of asymmetric synthesis is much higher in benzene than it is in ethanol for such systems up to 92% enantiomeric excess was achieved in one case. 

Rhodium complexes that contain (2S, 4S)-PPM ligands efficiently catalyze the asymmetric reduction of enamides to form protected amino acids with the -configuration [75,77], However, no large-scale process has been realized to date, although the potential exists as high substrate to catalyst ratios of 100,000 have been obtained in the hydrogenation of 59 (Scheme 19) [8.78]. 

The literature has many examples of ligands that have been developed to effect asymmetric hydrogenations of a variety of functional groups [4—8]. The reductions of enamides to provide a-amino acids derivatives has been of importance since the pioneering work of Knowles and his colleagues at Monsanto [9, 10]. This approach has been used by Monsanto, Searle and now Egis for the production of L-dopa (Fig. 1) [4]. The chemistry related to L-dopa is discussed in more detail in Chapter I 1, by W.S. Knowles. 

Initial research in this area focussed on the development of enantiomerically pure bidenate bisphosphines, often possessing C2-symmetry, as ligands in the hydrogenation of alkenes, and the a-(acylamino)acrylic acids have remained popular substrates. Many of these ligands have provided high enantioselectivity in the reduction of enamides, and a representative set of such structures (2.04-2.15) is shown, all of which have given over 90% ee (often higher). ... 

Rh(BINAP) ] CIO4 was amongst the first catalysts for the asymmetric reduction of enamides, and is still one of the best catalysts available. The geometry of the enamide has been shown to be important. While the (Z)-alkene substrate (2.30) is converted into the a -amidoacid (2.31) with the (R)-enantiomer predominating. 

Bridged flavinium organocatalysts (150-152) displayed efficiency in diimide-mediated reduction of enamides in aqueous conditions. This was, perhaps, the first diimide reduction of an electron-rich alkene and offered a clean alternative to the use of alkylating agents forAf-alkylation. °... 

Scheme 14.5 Rh-catalysed reduction of enamide 8 using mondentate ligand 11. ...

Scheme 2.13 Enantioselective reduction of enamides using an achiral Br0nsted acid cocatalyst...

Fukuyama showcased the selective reduction of enamide 14, which transpires from the more accessible exo face of the diazabicyclononane ring system (Scheme 8.3) [34]. After installation of the N-methyl group, product 16 was obtained in 75 % yield and was subsequently converted into the antibiotic and antitumor agent saframycin B (17). 

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