Amino acids enamide reactions

Essentially the same results were later obtained with various prochi-ral substrates a-dehydro amino acids, enamides, - P-dehydroamino acid, unsaturated phosphonate, ° and itaconic ester. All studied substrates reacted instantaneously with 28a, b at -100°C yielding high ee s of the hydrogenation products—either equal or comparable to the ee s observed in the corresponding catalytic reactions. - ... 

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... 

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. 

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... 

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... 

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... 

Intermolecular cyclopropanation reactions with ethyl diazoacetate have been employed for the construction of the cyclopropane-containing amino acid 7 (equation 25) Thus, rhodium(II) acetate catalysed decomposition of ethyl diazoacetate in the presence of d-cbz-vinylglycine methyl ester 5 afforded cyclopropyl ester 6 in 85% yield. Removal of the protecting group completed the synthesis of 7. Another example illustrating intermolecular cyclopropanation can be found in Piers and Moss synthesis of ( )-quadrone 8" (equation 26). Intermolecular cyclopropanation of enamide or vinyl ether functions using ethyl diazoacetate has also been used in the synthesis of eburnamonine 9", pentalenolactone E ester 10" and ( )-dicranenone A11" (equations 27-29). 

Rhodium-Catalyzed Asymmetric Hydrogenation of Olefins. MiniPHOS (1) can be used in rhodium-catalyzed asymmetric hydrogenation of olefinic compounds. The complexation with rhodium is carried out by treatment of 1 with [Rh(nbd)2]BF4in THF (eq 2). The hydrogenation of a-(acylamino)acrylic derivatives proceeds at room temperature and an initial H2 pressure of 1 or 6 atm in the presence of the 0.2 mol% MiniPHOS-Rh complex 2. The reactions are complete within 24—48 h to afford almost enantiomerically pure a-amino acids (eq 3). Itaconic acids, enamides, and dehydro-3-ami no acids can also be hydrogenated with excellent enantioselectivity (eq 4—6). 

The most commonly used reactions that employ Rh[(5,5)-Et-DuPHOS](cod) X complexes involve the enantioselective hydrogenation of a-(/V-acyl)enamide carboxylates. a-Amino acids are obtained in quantitative yield with high optical purity (95-99% ee) (eq 3). ... 

Hydrogenation of enamides 17 (X — NR, Y = C, W = R), especially with R] = COOR, is not only the best-known test reaction but also has a very high potential for the production of pesticides or pharmaceuticals. The original motivation for developing this reaction type was the manufacture of a-amino acids but except for small-scale applications such as L-dopa, the preparation of the enamide substrates was too expensive and most amino acids are now produced via bioca-talytic methods [13]. Many different substrates of type 17 can be hydrogenated with ee values between 95 and 99% [11a, 12a] but much less is reported on catalyst activity and productivity. In general, more and larger substituents lead to a decrease in catalyst activity either when directly attached to C=C or when bound to X or W. 

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]. 

The Me-DuPhos-Rh and more electron-rich Me-BPE-Rh catalysts can be used to access -branched amino acids (Scheme 9.22, R, R H). Symmetric and dissymmetric p-substituted enamides were found to hydrogenate with very high enantioselectivities. In the latter case, hydrogenation of E- and Z-enamide isomers in separate reactions allowed the generation of the second, new p-stereogenic center with high selectivity. 

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). 

Davis et al. reported synthetic studies of martefragin A (91) [28]. For the construction of the asymmetric centre next to the oxazole, HWE reaction of the aldehyde and subsequent asymmetric hydrogenation were applied. The HWE reaction of chiral aldehyde 86 with phosphonate 87 in the presence of DBU gave (Z)-enamide ester 88, although epimeriza-tion was observed (75% ee). When the reaction was conducted using TMG (3), epimerization was suppressed (95% ee). Enamide ester was converted to the potential precursor 90 for 91 through the a-amino acid ester 89 via asymmetric hydrogenation (Scheme 7.18). 

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