REACTIVITY OF 2,3-AZIRIDINO-2,3-DIDEOXY-D-LYXONO-GAMMA-LACTONE DERIVATIVES, RIGID ANALOGS OF AZIRIDINE-2-CARBOXYLIC ESTERS, TOWARD SOFT ANDHARD NUCLEOPHILES - CONTROL OF LACTONE VS AZIRIDINE RING-OPENING AND C-2 VS C-3 REGIOSELECTIVITY

The reactivities of ethoxymethyl)-3-oxa-6-azabicyclo[3.1.0]hexan-2-one (2) and its N-Cbz analogue 12 toward soft nucleophiles (thiols, aceti c acid, bromide) and hard nucleophiles (alcohols, benzylamine) were st udied and compared to the reported reactivities of aziridine-2-carboxy lic esters (1) with the same nucleophiles. Both 2 and 12 reacted with soft nucleophiles in the presence of a Lewis acid to give the products of aziridine ring opening at C-2. This regioselectivity is in distinc t contrast to the known reactions of 1 with these nucleophiles wherein aziridine ring opening at C-3 is almost always observed. The Lewis ac id-catalyzed reaction of 2 with alcohols (methanol or benzyl alcohol) gave products arising from initial attack of the lactone ring yielding the corresponding methyl or benzyl esters, respectively. These interm ediates further reacted to give, in the case of methanol, exclusively the product of N-deacetylation, that is, aziridine-2-carboxylic methyl ester 20 or, in the case of benzyl alcohol, a mixture of the N-deacet ylated aziridine-2-carboxylic benzyl esters 17 and 18, the results of both lactone ring opening and aziridine ring opening at C-3. The latte r compound spontaneously cyclized to its lactone form 19 during the co urse of its purification. N-Deacetylation by alcohols could be suppres sed by using the N-Cbz aziridine derivative 12 as starting material. T hus, 12 reacted with methanol or benzyl alcohol in the presence of a L ewis acid to give lactones 21 and 22, respectively, the products of az iridine ring opening at C-3. The intermediacy of an aziridine-2-carbox ylic ester derivative in these reactions, via initial opening of the l actone ring by the alcohol, was demonstrated by the isolation of the i sopropyl ester 24 when 12 was treated with isopropyl alcohol. The reac tions of 2 and 12 with benzylamine in the absence of Lewis acid cataly sis paralleled those with alcohols. Thus, 2 gave aziridine-2-carboxami de 25, the product of lactone ring opening and N-deacetylation while t he N-Cbz aziridine 12 yielded only the product of lactone ring opening , benzylamide 27. As predicted by perturbational and HSAB (hard and so ft acids and bases) theories, the regioselectivity of attack of 2 and 12 by soft nucleophiles is directed toward the center having the highe st LUMO coefficient (C-2) (determined using MNDO calculations) while h ard nucleophiles react with centers having the highest charge (C-1, C- 1'). The synthetic potential of 2,3-aziridino gamma-lactones of types 2 and 12, as compared to the classical aziridine-2-carboxylic esters, is discussed in terms of these results.