Regiochemical and Stereochemical Studies of the Intramolecular Dipolar Cycloaddition of Nitrones Derived from Quaternary Aldehydes

Abstract

Three aldehydes each with a quaternary  carbon stereocentre bearing an alkenyl, a phenyl, and a methyl ester group were treated with N-methylhydroxylamine. In each case bicyclic isoxazolidine products were formed by condensation to give intermediate nitrones that undergo intramolecular dipolar cycloaddition. The stereoselectivity was influenced by the -carbonyl substituent, possibly by a hydrogen bond between CO and a nearby CH of the nitrone in the transition state (supported by DFT and X-ray studies), and the regioselectivity was affected by the length of the tether and by the presence of an ester on the alkene dipolarophile.Key words: Cycloaddition; Diastereoselectivity; Domino reaction; Fused-ring systems; Heterocycles.Intramolecular dipolar cycloaddition reactions of nitrones have been known for more than 50 years. 1 One of the attractions of this chemistry is that it allows the rapid synthesis of cyclic and polycyclic compounds with 1,3-amino-alcohol functionality. The presence of polycyclic amines in alkaloids has prompted a considerable number of studies into intramolecular nitrone cycloadditions, 2 including work in our own research group. 3 Many alkaloids contain not just an amino group but an aromatic ring, often derived from a -arylethylamine precursor. Not surprisingly, therefore, there are reports of the intramolecular cycloadditions of nitrones bearing an aromatic substituent attached  to the nitrogen atom. 4,5 Of these examples, as far as we are aware, only one uses a quaternary aldehyde (compound 1) which was heated with N-methylhydroxylamine hydrochloride salt and pyridine to give the cycloadduct 2 as a single stereoisomer (Scheme 1). 4a We were interested in exploring further examples of this type of reaction of quaternary substituted aldehydes and report here our findings. Scheme 1 Related literature example. 4aIn related synthetic chemistry efforts, we wanted to test nitrone cycloadditions derived from aldehydes with an -quaternary stereocentre bearing an aryl group and an ester group. We therefore prepared the aldehyde 6 by double alkylation of the ester 3 followed by Swern oxidation 6 (Scheme 2). Scheme 2 Cycloaddition with aldehyde 6.Heating the aldehyde 6 with N-methylhydroxylamine hydrochloride salt and diisopropylethylamine in toluene gave a mixture of the cycloadducts 7a and 7b in a 1:1.6 ratio. The structures of both cycloadducts were determined by single crystal X-ray analysis (see Supporting Information, SI). This reaction is a direct comparison with the formation of the cycloadduct 2, where a single stereoisomer was reported. This suggests that, although a phenyl group has a stronger preference for the exo position than a methyl group, there is a preference for a methyl ester, rather than a phenyl group, to be exo. A possible reason for this is evident in the X-ray crystal structure of 7b (Fig. 1), in which the preference for this isomer might arise from a favorable interaction between the ester carbonyl oxygen atom and the proton at the ring junction  to the nitr...