Enamide reactions amino acid synthesis

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... 

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). 

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]. 

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). 

Carboxylation. Bredereck s reagent has been used in a simple synthesis of L-y-carboxyglutamic acid (S), an unusual natural amino add present in prothrombin and believed to be involved in elotting. The starting material is the lactam 1 derived from L-glutamic acid and available commercially. It is converted by reaction with this reagent into the enamide 2. Reaction with 2,2,2-trichloroethoxycarbonyl chloride transforms 2 into the trichloroethyl ester 3 in moderate yield. The synthesis of 5 is completed by reaction with benzyl alcohol and triethylamine followed by hy drogenolysis. ... 

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