Studies of stereoselective reactions between 2-(trimethylsiloxy)- furan and imines

Abstract

A new, general method for the preparation of 5-aminoalkyl-furan-2(5H)-ones has been developed, and the details of the reaction have been studied. 5-Aminoalkylfuran-2(5H)-ones, which contain two chiral centers, were synthesized from 2- (trimethylsiloxy)-furan and C = N synthons, which were derived from aldehydes and aryl amines or from α-amidoalkylating agents. The main emphasis of the study was to examine the factors controlling diastereoselectivity and the possible mechanistic pathway which leads to the diastereomers. Results of the study show that the main controlling aspect of the newly developed reaction is the structure of the aldehydes used. Aldehydes which are secondary or tertiary at C2, such as isovaleraldehyde and trimethyl acetaldehyde, displayed the largest diastereoselectivity (94 % de). The anti isomer is preferred in these reactions, and the reaction is rationalized by consideration of possible transition state geometries. The study revealed that the diastereoselectivity of the reactions was dependent on solvent. Reaction in THF produced poor diastereoselectivity and even syn isomer as major product. The solvent effect on diastereoselectivity was discussed. The substituent group at the exposition of the aryl amines had a large effect on the diastereoselectivity of the reaction. The diastereoselectivity decreased as the size of the substituent groups increased. With increase of substituent group size at the o-position, the favored transition state, which gave anti product, was repressed and the diastereoselectivity was lowered. Methoxy, nitro, and methyl ester substituents at the o-position produced the greatest reductions in diastereoselectivity. The diastereoselectivity using aniline was 85 : 15 and the diastereoselectivities using o-anisidine, o-nitroaniline, and methyl anthranilate were 59 : 41, 50 : 50 and 40 : 60, respectively. The α-amidoalkylation reaction with 2-(trimethylsilyoxy)-furan was studied, and the use of trifluoroacetic anhydride produced higher yield (67 - 86 %) than the previously used BF3 *OEt2 (34 - 72 %). A 100% de was obtained using 1-hydroxy-1- carbomethoxy carbamate as the A-acyliminiurn ion source, and the use of chiral auxiliary gave only one isomer. 1H-NMR was used to examine the reaction mechanism. Examination of chemical shifts of the initially formed product showed no evidence for a Diels-Alder reaction as the reaction pathway.