Amino acids from enamides

Asymmetric hydrogenation has proved extremely successful in the synthesis of amino-acids from enamides, but it is less effective with other substrates. Most, but not all (48) reported work has been carried out with 7-ring chelates, and some results are recorded in Table III. 

Noyori asymmetric hydrogenation Formation of enantio-enriched carboxylic acids, alcohols and amino acids from unsaturated carboxylic acids, allylic alcohols and enamides, respectively. 316... 

Clerici and Porta reported that phenyl, acetyl and methyl radicals add to the Ca atom of the iminium ion, PhN+Me=CHMe, formed in situ by the titanium-catalyzed condensation of /V-methylanilinc with acetaldehyde to give PhNMeCHMePh, PhNMeCHMeAc, and PhNMeCHMe2 in 80% overall yield.83 Recently, Miyabe and co-workers studied the addition of various alkyl radicals to imine derivatives. Alkyl radicals generated from alkyl iodide and triethylborane were added to imine derivatives such as oxime ethers, hydrazones, and nitrones in an aqueous medium.84 The reaction also proceeds on solid support.85 A-sulfonylimines are also effective under such reaction conditions.86 Indium is also effective as the mediator (Eq. 11.49).87 A tandem radical addition-cyclization reaction of oxime ether and hydrazone was also developed (Eq. 11.50).88 Li and co-workers reported the synthesis of a-amino acid derivatives and amines via the addition of simple alkyl halides to imines and enamides mediated by zinc in water (Eq. 11.51).89 The zinc-mediated radical reaction of the hydrazone bearing a chiral camphorsultam provided the corresponding alkylated products with good diastereoselectivities that can be converted into enantiomerically pure a-amino acids (Eq. 11.52).90... 

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. 

Esters of -branched amino acids are obtained by highly enantioselective hydrogenation of a-acylaminoacrylatcs bearing different substituents at the ff-carbon using Rh complexes of Me-DuPHOS (XI) and Me-BPE (XV). The D-a//o-isoleucine derivative 17 with 98.2% ee is obtained from the (Z)-enamide 16, and the D-isoleucine... 

As stated earlier, Knowles and co-workers developed an efficient asymmetric catalyst based on the chiral bisphosphine, R,R-DIPAMP (2), that has chirality at the phosphorus atoms and can form a 5-membered chelate ring with rhodium. (Digital Specialty Chemical has optimized this process, and both antipodes of DIPAMP are available in kilogram quantities.) [Rh(COD)(R,R-DIPAMP)]+BF4 (13) has been used by Monsanto for the production of L-dopa (12), a drug used for the treatment of Parkinson s disease, by an asymmetric reduction of the Z-enamide, 14a, in 96% ee (Scheme 12.1). The pure isomer of the protected amino acid intermediate, 15a, can be obtained on crystallization from the reaction mixture because it is a conglomerate.17... 

An important class of compounds that are frequently used as building blocks in drugs is the P-amino acids. Here, the precursors are made from the P-keto esters by reaction with NH4OAc, followed by acylation with Ac20. These enamides can be made predominantly in either the E-44... 

The favorable effect of the enamide function on asymmetric induction is indicated not only by the result with compound I, but also by later results summarized in Table I, where optical purities in the range of 70 to 80% were generally obtained for various derivatives of alanine, phenylalanine, tyrosine, and 3,4-dihydroxyphenylalanine (DOPA). The Paris group found that the Rh-(-)-DIOP catalyst yielded the unnatural R or d -amino acid derivatives, whereas l-amino acid derivatives could be obtained with a (+)-DIOP catalyst. Since the optical purity of the IV-acylamino acids can often be considerably increased by a single recrystallization (fractionation of pure enantiomer from racemate) and the IV-acetyl group can be removed by acid hydrolysis, this scheme provides an excellent asymmetric synthesis route to several amino acids. 

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. 

As noted above, a stereoselective synthesis of the enamide is important. The azlac-tone method (Fig. 3) results in the preferential formation of the Z-enamide when an aromatic aldehyde is employed. In addition, this isomer usually precipitates from the reaction mixture and this simplifies purification. When an alkyl aldehyde is used, the ratio of enamide isomers is often 1 1 or close to this. In addition, many of these alkyl examples are not crystalline and physical separations such as chromatography have to be employed. This is obviously a limitation of the methodology when compared with catalysts that employ the DuPHOS ligands, and related ligand families where both isomers can be reduced down to the same enantiomer of the desired amino acid [12]. 

Comparing these results with enamide hydrogenation, it is evident that catalysts effecting R amino acid synthesis from enamides direct S-carboxylic acid formation from unsaturated acids. This implies (Scheme 9) that the preferred carboxyl-group configuration is similar in the two series. 

Enamide ester, which is a useful synthetic intermediate for a variety of a-amino acids, can be prepared by means of the HWE reaction in the presence of TMG (3) or DBU [20,21]. In the synthesis of teicoplanin aglycon (80) reported by Evans et al. [22], one of the phenylalanine derivatives 79 was synthesized from the aldehyde 75. HWE reaction of aldehyde 75 with phosphonate 76 using TMG (3) in THF gave (Z)-enamide ester 77 in 99% yield. Asymmetric hydrogenation of 77 catalysed by rhodium(I) complex 78 (1 mol%) gave the phenylalanine ester 79 in 96% with 94% ee (Scheme 7.16). 

Since the above methodology provides easy access to a variety of a-amino acid derivatives, many applications for the synthesis of natural products have been reported [23-25]. The HWE reaction of the stericaUy hindered aldehyde 81 with phosphonate 82 using TMG (3) proceeded to give (Z)-enamide 83 in 80% yield from the alcohol (2-step yield) [26]. The resulting enamide 83 was submitted to the asymmetric hydrogenation reaction using Burk s rhodium(l) catalyst [27] to give 84 in 85% yield as the sole product (Scheme 7.17). The a-amino acid ester 84 was successfully converted to neodysiherbaine A (85). 

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