We have investigated several 1,3-dipolar cycloadditions of a chiral nitrone prepared from L-erythrulose. While cycloadditions to carbon-carbon multiple bonds of dipolarophiles such as ethyl acrylate, ethyl propiolate, or dimethyl acetylenedicarboxylate were poorly stereoselective, reaction with acrylonitrile provided predominantly one diastereomeric adduct. Furthermore, the regioselectivity exhibited by the two structurally similar dipolarophiles ethyl acrylate and ethyl propiolate was found to be opposite. The molecular mechanisms of these cycloadditions have thus been investigated by means of density functional theory (DFT) methods with the B3LYP functional and the 6-31G and 6-31+G basis sets. A simplified achiral version of nitrone 1 as the dipole, and methyl propiolate or acrylonitrile as the dipolarophiles, were chosen as computational models. The cycloadditions have been shown to take place through one-step pathways in which the C-C and C-O sigma bonds are formed in a nonsynchronous way. For the reaction with methyl propiolate, DFT calculations predict the experimentally observed meta regioselectivity. For the reaction with acrylonitrile, however, the predicted regioselectivity has been found to depend on the computational level used. The calculations further indicate the exo approach to be energetically favored in the case of the latter dipolarophile, in agreement with experimental findings. The main reason for this is the steric repulsion between the nitrile function and one of the methyl groups on the nitrone that progressively develops in the alternative endo approach.

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The additions of various Grignard reagents to a chiral nitrone prepared from L-erythrulose take place with variable diastereoselectivity. The degree and strength of the facial selectivity can be modified if the reaction is performed in the presence of Lewis acidic additives: zinc bromide enhances attack to the si face whereas diethyl aluminum chloride promotes attack to the re side. The obtained adducts can be then efficiently transformed into protected N-hydroxy a,a-disubstituted a-amino acid derivatives as well as into the corresponding a,a-disubstituted a-amino acids.The addition of carbon nucleophiles to C=N bonds 1 is a synthetically important method of preparing many types of biologically relevant nitrogen-containing compounds, among them non-proteinogenic amino acids. These are used, for example, for the synthesis of non-natural peptides. 2 One important class of non-proteinogenic amino acids are a,a-disubstituted a-amino carboxylic acids. 3 Another class, also interesting as synthetic targets, are N-hydroxy amino acids. 4 In relation with these synthetic goals, we described a few years ago the stereoselective additions of organolithium reagents to the C=N bond of chiral E oximes 1 (P, P¢ = protecting groups), 5 prepared from the four-carbon monosaccharide L-erythrulose 6 (Scheme 1). The obtained adducts were then transformed into various a-substituted serine derivatives. As an alternative approach to the same targets, we later reported on the stereoselective additions of lithium and magnesium organometallics to the C=N bond of the chiral keto nitrone 7 2, also prepared from L-erythrulose. 8 Even though the nucleophilic additions to the C=N bond took place in both cases with an excellent diastereoselectivity (diastereomeric ratios, dr, > 95:5 in many cases), the overall efficiency of the process suffered from insatisfactory yields in the preparation of precursors 1 and 2. 9 We thus looked for another chiral nitrone which should be obtained from L-erythrulose with a good yield and show a good diastereoselectivity in its reactions with carbon nucleophiles. After due experimentation, we found that the reaction of a known silylated erythrulose derivative 6 with N-benzyl hydroxyl amine gave rise to nitrone 3 in a good yield (Scheme 2). The compound was an oil and thus not amenable to X-ray diffraction analysis but NOE measurements permitted us to assign the configuration of the C=N bond as Z. 10,11 The results of the reactions of nitrone 3 12 with several Grignard reagents in THF to yield a mixture of the diastereoisomeric adducts 4 and 5 (Scheme 2) are indicated in the Table. 13 Various mechanistic models have been proposed to explain the stereochemical outcome of such additions, which have in most cases been performed on functionalized nitrones derived from aldehydes. 14 For instance, the formation of either 4 or 5 can be rationalized within the mechanistic frame of Cram's a-chelated (® 4) vs. Felkin-Anh's nonchelated (® 5) transition states 5a (MLn = MgBr in Scheme 2). According to our experience w...

Diastereoselective Additions of Organolithium and OrganomagnesiumReagents to the C=N Bond of a Chiral, Cyclic Nitrone Derived from Erythrulose.-Compound (III), whose structure is determined by X-ray analysis, is unreactive towards organometallic reagents either in the presence or absence of Lewis acids. The title nitrone (IV) represents a useful alternative synthon for the preparation of amino acid derivatives and related compounds. -(MARCO, J. A.; CARDA, M.; MURGA, J.; PORTOLES, R.; FALOMIR, E.; LEX, J.; Tetrahedron Lett. 39 (1998) 20, 3237-3240; Dep. Quim. Org.,