摘要：

With the aim of preparing novel beta-functionalized tryptophan derivatives, the reaction of (1S,4S,5R)- N-acetyl-4-(methoxymethyl)-3-oxa-6-azabicyclo[3.1.0]hexan-2-one (4), a newly developed rigid analogue of the synthetically useful aziridine-2-carboxylic esters of type 1, with N-methylindole (6) was studied under acidic (Lewis acid) conditions. N-Methylindole reacted exclusively at C-2 of 4 to give 3-acetamido-2,3-dideoxy-2-C-[3-(1-methylindolyl)]-5-O-methyl-D-xylonolactone (7) in contrast to this nucleophile's known reactivity with aziridine-2-carboxylic esters 1 at C-3 under the same conditions. The desired beta-substituted tryptophan derivative 12 was instead obtained by reacting 6 with the tert-butyldimethylsilyl furanoside precursor of 4 (i.e., 9) followed by desilylation and oxidation of the anomeric hydroxyl function with TPAP. The regioselectivity of aziridine ring opening by 6 was rationalized by comparison of the LUMO coefficients and atomic charge distributions for the reactive centers of the aziridine-2-lactone 4, the aziridine-2-carboxylic ester 16, and the aziridine furanoside 9 in both their ground states and protonated states as determined using MNDO calculations. It was found that (1) protonation of both 4 and 16 causes a large increase in the LUMO coefficients at C-2 and C-3, thereby directing attack by N-methylindole (6), a soft nucleophile, toward these centers via orbital control, as has been experimentally observed; (2) of C-2 and C-3, the higher LUMO coefficient was found at the former position for the N-protonated forms of both 4 and 16, suggesting that C-2 is the preferred site of attack by 6 in both cases. Though this was verified experimentally in the case of lactone 4, the fact that aziridine-2-carboxylic esters (e.g. 16) always react with indoles at C-3 under acidic conditions indicates that in these compounds, steric and/or electrostatic effects rather than orbital considerations determine the course of the reaction; (3) in the case of the N-protonated aziridino furanoside 9, C-3 was calculated to have a higher LUMO coefficient than C-2, in accord with the exclusive attack of 6 at the former position. MNDO calculations thus appear to be a useful tool for the prediction of the reactivity patterns of rigid aziridine structures such as 4 and 9, but are less satisfactory in the case of flexible aziridine-2-carboxylates in which other factors may predominate.

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