A-Amino nitrones

N-substituted and N,N-disubstituted chiral a-amino nitrones are also available from the corresponding a-amino aldehydes. In a first study, it was shown that the addition of phenylmagnesium bromide to N-Boc derivatives exclusively gave the syn N-Boc a-aminohydroxylamines with good yields, but... 

Mesylation of a-amino nitrones (253) in dichloromethane gave amidines (254) via a 3,3-sigmatropic rearrangement (Scheme 2.93) (351). 

A similar intermediate is invoked when a-amino nitrones 159 are treated with mesyl chloride in the presence of triethylamine . The corresponding mesyloxyamidines 161 are formed formally by [3,3]-sigmatropic rearrangement of 160 (equation 47). 

Nucleophilic additions to chiral a-alkoxy and a-amino nitrones have been reviewed, focusing on tuning of Lewis acid catalysts and protecting groups so as to exert stereocontrol in producing hydroxylamines and ultimately useful amino acids, amino alcohols, and nucleoside analogues.96... 

A method for the stereoselective synthesis of a-aminophosphonates and their N-hydroxy derivatives by aminophosphonylation of carbohydrate and amino acid derivatives using nitrone- based chemistry has been reported (an example of reactions of N-monoprotected a-amino nitrones, whose progenitors were alanine, phenylalanine and leucine respectively, affording the corresponding N-hydroxy a-aminophosphonates, is given in Scheme 67). ... 

The enantioselective inverse electron-demand 1,3-dipolar cycloaddition reactions of nitrones with alkenes described so far were catalyzed by metal complexes that favor a monodentate coordination of the nitrone, such as boron and aluminum complexes. However, the glyoxylate-derived nitrone 36 favors a bidentate coordination to the catalyst. This nitrone is a very interesting substrate, since the products that are obtained from the reaction with alkenes are masked a-amino acids. One of the characteristics of nitrones such as 36, having an ester moiety in the a position, is the swift E/Z equilibrium at room temperature (Scheme 6.28). In the crystalline form nitrone 36 exists as the pure Z isomer, however, in solution nitrone 36 have been shown to exists as a mixture of the E and Z isomers. This equilibrium could however be shifted to the Z isomer in the presence of a Lewis acid [74]. 

The condensation of nitro compounds and imines, the so-called aza-Henry or nitro-Mannich reaction, has recently emerged as a powerful tool for the enantioselective synthesis of 1,2-diamines through the intermediate /3-amino nitro compounds. The method is based on the addition of a nitronate ion (a-nitro carbanion), generated from nitroalkanes, to an imine. The addition of a nitronate ion to an imine is thermodynamically disfavored, so that the presence of a protic species or a Lewis acid is required, to activate the imine and/or to quench the adduct. The acidic medium is compatible with the existence of the nitronate anion, as acetic acid and nitromethane have comparable acidities. Moreover, the products are often unstable, either for the reversibility of the addition or for the possible /3-elimination of the nitro group, and the crude products are generally reduced, avoiding purification to give the desired 1,2-diamines. Hence, the nitronate ion is an equivalent of an a-amino carbanion. 

This route has been widely exploited because of the availability of a-amino azomethine compoimds from natural (S)-a-amino acids, through the corresponding a-amino aldehydes, which are configurationally stable provided that the amino function is suitably protected. Moreover, some a-amino acids are available with the R configuration and a number of enzymatic and chemical transformations have been described for the preparation of optically active unnatural a-amino acids. Overall, the route suffers from the additional steps required for protection/deprotection of the amino function and, in the case of hydrazones and nitrones, cleavage of the N - N or N - O bond. 

On the other hand, following the same sequences from the differently protected serine-derived nitrone 168, through the formation of hydroxylamines 169, C2 epimers of carboxylic acid and aldehydes are obtained, i.e., (2S,3R)-170 and (2S,3R)-171. Moreover, the syn adducts 164 were exclusively obtained in the addition of Grignard reagents to the nitrone 163, whereas the same reactions on nitrone 168 occurred with a partial loss of diastereoselectivity [80]. Q, j6-Diamino acids (2R,3S)- and (2R,3R)-167 can also be prepared from the a-amino hydroxylamines 164 and 169 by reduction, deprotection and oxidation steps. The diastereoselective addition of acetylide anion to N,N-dibenzyl L-serine phenyhmine has been also described [81]. 

Scheme 27 Addition of nitronates, enolates and silyl ketene acetals to chiral a-amino imines and iminium ions...

Scheme 10.7 1,3-Dipolar cycloadditions of nitrones with 1,1-diethoxypropene catalysed by oxazaborolidines derived A-tosyl-L-a-amino acids.

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... 

X,P-Dehydro-a-amino acids are prepared by elimination of HN02 from P-nitro-a-amino acids, which are prepared by reaction of a-bromoglycine derivatives with alkyl nitronates (see Eq. 7.135).181 This process is a new type of the Michael addition of nitro compounds followed by elimination of HNOz. Such unusual amino acids are interesting as enzyme inhibitors.182... 

Under suitable conditions, oxidation of /V-alkyl-a-amino acids, accompanied by decarboxylation, has made it possible to carry out regioselective syntheses of nitrones which were utilized in the synthesis of 1-azabicyclic alkaloids (Scheme 2.6) (48, 49). 

Similarly, chiral nitrones (61a—c) and (62a—c) were obtained from the corresponding a-amino aldehydes (209, 210), nitrones (63a,b) from p-amino-a-hydroxy aldehydes (211), and chiral nitrones (64) and (65) from IV-fluorenyl-methoxycarbonyl (/V-Fmoc) amino acids and /V-Fmoc-dipeptides (Fig. 2.6) (212). 

Chiral imidazoline nitrone (88) was synthesized by condensation of hydrochloride a-amino oxime (87) with triethyl orthoformate according to Scheme 2.33... 

A strictly dehned region of chemical shifts of C2, C4, and C5 atoms in A-oxides of 4A-imidazoles allows to dehne clearly the position of the A-oxide oxygen atom (102). Chemical shifts of the a-C nitrone group in a-N-, O-, and S-substituted nitrones are located in the region of 137 to 150 ppm (388, 413). On the basis of 13C NMR analysis of 3-imidazoline-3-oxide derivatives, the position of tautomeric equilibria in amino-, hydroxy-, and mercapto- nitrones has been estimated. It is shown that tautomeric equilibria in OH- and SH-derivatives are shifted toward the oxo and thioxo forms (approximately 95%), while amino derivatives remain as amino nitrones (413). In the compounds with an intracyclic amino group, an aminonitrone (A) - A-hydroxyaminoimino (B) tautomeric equilibrium was observed (Scheme 2.76), depending on both, the nature of the solvent and the character of the substituent in position 2 of the heterocycle (414). 

In the series of a-substituted nitrones, the a-methoxy nitrones are the most easily oxidized nitrone derivatives. The study of electrochemical behavior of acyclic a-methoxy-, a-amino-, a-cyano- and a-mercapto-nitrones has shown an irreversible one-electron oxidation of the nitrone group (429). 

Oxidative Animation of Nitrones to a-Amino-Substituted Nitroxyl Radicals Similar to the oxidative methoxylation reaction, oxidative animation of 4H -imidazole TV-oxides, in amine saturated alcohol solutions, give stable nitroxyl (282), nitronyl nitroxyl (283), imino nitroxyl (284) and (285) radicals with the amino group at the a-carbon atom of the nitroxyl group (Scheme 2.107) (520, 521). The observed influence of substituents on the ratio of animation products at C2 and C5 atom is close to the ratio observed in the previously mentioned oxidative methoxylation reaction. It allows us to draw conclusions about the preference of the radical cation reaction route. 

I. Addition of C-Radicals to Nitrones Recently (525), the addition of alkyl radicals to chiral nitrones as a new method of asymmetrical synthesis of a-amino acids has been described. Addition of ethyl radicals to glycosyl nitrone (286) using Et3B as a source of ethyl radicals appears to proceed with a high stereo-control rate. 

Addition of various organometalic reagents to chiral nitrones, derived from L-erythrulose, proceeds with variable diastereoselectivity, depending on Lewis acids as additives. ZnBr2 facilitates the attack at the Si face of the C=N bond, whereas Et2AlCl makes the attack at the Re face more preferable. The obtained adducts can be transformed into derivatives of /V - h y d r o x y - u. u - d i s u b s t i t u t e d -a-amino acids, with their further conversion into a,a-disubstituted a-amino acids (193, 202). 

As in all cases already mentioned, diastereoselective addition of Grignard reagents to j3-amino nitrones (a-aminoalkyl nitrones) is a key step in the stereo-controlled syntheses of O.,j3-diamino acids (Scheme 2.141) (565, 566), of unsym-metrical a-amino hydroxylamines and 1,2-diamines (Scheme 2.142) (209, 567). 

Stereocontrolled influence of precomplexing additives was used in the synthesis of (2R,3S)- and (2S, 3 S)-2-amino-l,3,4-butanetrioles resulting from a stereo-divergent hydroxymethylation of D-glyceraldehyde nitrones (Fig. 2.24). The obtained syn- and anti-adducts were further converted into C-4 building blocks and to (i-hydroxy-a-amino acids (570). 

Addition of CN Anion Stereoselective addition of the CN-group to nitrones has received considerable attention for the synthesis of optically active a-hydroxyamino nitriles which can be further transformed into a-hydroxyamino acids and a-amino acids. Me SiCN (TMSCN), Et2AlCN, BU4NCN, and LiCN... 

Reactions of Vmylation and Ethynylation Vinylation and ethynyla-tion of nitrones using vinyl (137, 202, 563, 564) and ethynyl (199, 213, 219) organometalic reagents is a convenient method for synthesizing various nitrogen-containing compounds such as a-amino aldehydes, a-amino acids, amino... 

Addition of (trimethylsilyl)acetylides to chiral a-aminoalkyl- (413) and a-alkoxyalkyl-(BIGN) (292) nitrones proceeds stereoselectively. Successive desi-lylation (BU4NF, THF) and transformation of the ethynyl group into carboxyl (RuCl3-NaIC>4) led to the synthesis of diastereomerically pure /V-hydroxy-a-amino acids (414) and a-amino acids (415) (Scheme 2.185) (199, 202, 652, 660). 

Addition of diethyl phosphites to aldo nitrones derived from chiral a-alkoxy (Scheme 2.202) and A-Boc-a-amino (Scheme 2.203) aldehydes can be achieved... 

Chiral oxazinone-derived nitrone (16), being of particular interest as a prototype for the synthesis of y-oxygenated a-amino acids, reacts with alkenes (D2) efficiently and with high stereoselectivity, to give cycloadducts (489) (Scheme 2.239) (73). 

The tandem transesterification/[3 + 2]-cycloaddition methodology is be a powerful synthetic tool, since it guarantees high diastereoselectivity even under thermal conditions. It has been successfully apphed to synthetic work of the N-terminal amino acid component of Nikkomycin Bz (Scheme 11.53) (173). Thus, the sugar-based oxime is condensed with a glyoxylate hemiacetal to produce a chiral nitrone ester, which is then reacted with ( )-p-niethoxycinnamyl alcohol in the presence of a catalytic amount of TiCU at 100 °C. After the intramolecular cycloaddition, the... 

The use of N-acylated-a-amino nitriles, nitrones, or a-amino amides as starting compounds have also been reported. N-Acylated-a-amino nitriles were converted into 5(477)-oxazolones 101 in the presence of ethyl chlorooxoacetate (Scheme 1.21). ... 

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