1,3-Dipolar Cycloaddition Reactions of trans-2-Methylene-1,3-dithiolane 1,3-Dioxide with Nitrones

Abstract

The 1,3-dipolar cycloaddition reaction between a nitrone and an olefinic dipolarophile is an efficient method for the synthesis of the isoxazolidine ring system (Figure 1).1 Furthermore, the cycloadducts have found numerous applications in synthesis through reductive cleavage of the N-O bond to give γ-amino alcohols.1 Asymmetric induction in nitrone-olefin cycloadditions has been achieved through incorporation of chirality in both the dipole and dipolarophile.2,3 More recently, advances have been made in the use of metals to influence the rate, regioselectivity, stereoselectivity, and enantioselectivity of the reaction through suitable combinations of metal/ dipole/dipolarophile, effectively overcoming the tendency of nitrones to form inactive dipole/Lewis acid complexes.4 In comparison to the Diels-Alder reaction, the 1,3dipolar cycloaddition of nitrones with olefins generally exhibits lower levels of regioand stereocontrol (exo/endo selectivity), a consequence of significant contributions by both LUMO (dipole)-HOMO (dipolarophile) and HOMO (dipole)-LUMO (dipolarophile) interactions, further complicated by the possibility of interconversion of the nitrone geometry in the case of acyclic nitrones.1 Therefore, despite the advances outlined above, there still remains a need to develop general systems that give predictably high levels of regioand stereocontrol with a range of nitrones. Herein we describe one potential solution to this problem. We have recently reported an asymmetric synthesis of the C2-symmetric cyclic alkenyl sulfoxide (1R,3R)-2methylene-1,3-dithiolane 1,3-dioxide 1 (Figure 2).5 The presence of a C2 symmetry element in 1 means that the exo/endo approaches of 1 to a diene are symmetry related and therefore identical, thereby reducing the number of competing transition states in the reaction. Indeed, 1 showed very high reactivity and stereoselectivity in Diels-Alder reactions with a range of dienes, and after hydrolysis of the bis-sulfoxide moiety of the cyclopentadiene adduct 2, enantiomerically pure norbornenone 3 was obtained. Thus, we were able to demonstrate 1 to be an effective chiral ketene equivalent.5 To the best of our knowledge the potential advantage of using a C2symmetric dipolarophile to overcome the exo/endo issue in 1,3-dipolar cycloaddition chemistry has not been exploited. We report herein our results of the cycloaddition of 1 with some acyclic and cyclic nitrones.