N-benzyl nitrones

MacMillan s imidazolidinone salts, used successfully in the organocatalysed Diels-Alder reaction (see Section 8.1) also function as effective catalysts in the asymmetric nitrone cycloaddition with simple monodentate dipolarophiles. Thus acrolein (8.63) and crotonaldehyde (8.99) both react with acyclic C-aryl, N-benzyl nitrones and C-aryl N-alkyl nitrones such as (8.198) with high ees ranging from 90 to 99% in the presence of the perchlorate salt of imidazolidinone (8.91). 

On the basis of this successful application of 23d, this catalyst was applied in a series of reactions (Scheme 6.22). For all eight reactions of nitrones 1 and alkenes 19 in which 23d was applied as the catalyst, diastereoselectivities >90% de were observed, and most remarkably >90% ee is obtained for all reactions involving a nitrone with an aromatic substituent whereas reactions with N-benzyl and N-alkyl nitrones led to lower enantioselectivities [65]. 

Scheme 3.7 1,3-dipolar cycloaddition reaction of N-benzyl-C(2-Pyridyl) nitrone and methyl acrylate. 

Bis(oxazolinyl)pyridine-Ce(IV) triflate complex 78 catalyzed the enantioselective 1,3-DC of acyclic nitrones with a, 3-unsaturated 2-acyl imidazoles. For example, C-phenyl 7V-benzyl nitrone reacted with 77 in the presence of 78 to give the adduct 79 with excellent diastereo-and enantioselectivity. Isoxazolidine 79 was then converted into P -hydroxy-P-amino acid derivatives by hydrogenation of the N-0 bond in the presence of Pd(OH)2/C and cleavage of the 2-acyl imidazole with MeOTf in MeCN <06OL3351>. 

The main building block of PEDC (1 -phenyl-2-[(S)-l-aminoethyl] -N,N -di-ethylcyclopropanecarboxamide), a potent NDMA (N -methyl-D-aspartic acid) receptor antagonist of a cyclopropane structure, N -benzyl-C-cyclopropyl nitrone... 

Nucleophilic addition of organometalic reagents occurs when the nitrone form is in equilibrium with the hydroxylamine form, for instance, in the case of N -benzyl-/V-glycosyl hydroxylamines (Scheme 2.130) (213). 

Transformation of chiral nitrones into enantiomer enriched a-chiral N -hydroxylamines and their derivatives, has been successfully employed in the enantioselective synthesis of (+ )-(R)- and (—)-(S)-zileuton (216). An expeditious synthesis of thymine polyoxin C (347), based on the stereocontrolled addition of 2-lithiofuran (a masked carboxylate group) to the A-benzyl nitrone derived from methyl 2,3-O-isopropylidene-dialdo-D-ribofuranoside, is described (Scheme 2.151) (194). 

The reaction of O-methyl-O-tert-butyldimethylsilyl ketene acetal with N-benzyl- and A-methyl-2,3-O-Mopropylidene D-glyceraldehyde nitrones (292), in the presence of boron trifluoride etherate, affords the corresponding isoxazolidine-5-ones in high yields. These compounds were successfully applied as key intermediates in the synthesis of isoxazolidinyl nucleosides of the L-series (Scheme 2.177) (638). 

F. L. Tejero, T. Ready access to enantiopure 5-substituted 3-pyrrolin-2-ones from N-benzyl-2,3-O-isopropylidene-D-glyceraldehyde nitrone. Tetrahedron Asymmetry 1998, 9,1759— 1769. 

A polymer-supported version of MacMillan s catalyst 114 has been developed by anchoring a tyrosine-derived imidazohdin-4 -one via a spacer to the monomethyl ether of PEG (Scheme 3.32) [62]. The reaction of N-benzyl-C-phenyl nitrone 115 with acrolein 116 proceeded in the presence of PEG-supported chiral imidazolidi-none and acid in wet nitromethane to give the isoxazolidine 117. The supported catalysts behaved very similarly to their nonsupported counterparts in terms of enantioselectivity, but were somewhat less efficient in terms of chemical yield. 

Discrimination of diastereotopic groups and faces in intramolecular 13-DC of nitrile oxides and Af-benzyl nitrones were studied. For example nitrile oxides 38 afforded isoxazolines 39 with complete diastereotopic group selection (dr >99 1) and a high degree of n-face discrimination (dr from 10 1 to 26 1) <01JOC3834>. 

Merino P, Castillo E, Franco S, Merchan FL, Tejero T (1998) Nucleophilic Additions of Grignard Reagents to N-benzyl-2,3-0-isopropylidene-D-glyceraldehyde Nitrone (BIGN). Synthesis of (2S,3R) and (2S,3S)-3-phenylisoserine. Tetrahedon 54 12301... 

Chavant and Vallee have demonstrated dialkylzinc-promoted addition of pinacolyl alkenylboronates to nitrones (Equation 15) [85]. The reaction is tolerant of chloro and pivalate ester functionality on the alkenylboronate 85. Nitrones 86 derived from aromatic aldehydes with either N-benzyl or N-alkyl functionality were mainly used, although two examples employing nitrones derived from enolizable aliphatic aldehydes were also reported. The addition protocol is thought to rely on a transmetaUation of the pinacolyl alkenylboronates with dimethylzinc to give alkenylzinc species, which then undergo addition to give products such as 87. The use of diethylzinc resulted in some competitive direct ethylation of the nitrones. and NMR studies... 

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