Synthesis of Cyclic Peroxides via Enyne-RCM/Diels-Alder Reaction Sequence

Abstract

The sequence of an enyne ring-closing metathesis (enyneRCM) followed by a Diels-Alder reaction has been applied widely in organic synthesis for the expeditious generation of molecular complexity. Although several dienophiles have been employed to date in Diels-Alder reactions of the cyclic conjugated dienes generated from enyne-RCM, singlet oxygen has not been one of them. The conjugated dienes 5, which are readily obtained by enyne-RCM, could be reacted with singlet oxygen to generate the corresponding cyclic peroxides 6, as shown in Scheme 1. The cyclic peroxide unit is a component of many biologically important structures; furthermore, it can be transformed into several other valuable skeletons. For example, reductive cleavage of the O−O bond could generate allylic diols. Baseor transition metal-catalyzed O−O bond cleavage, followed by dehydration, is a well-known reaction strategy to synthesize furans. We have recently reported the synthesis of 1,2oxaza and 1,2-diaza heterocycles, having a diverse range of scaffolds, by ring-closing metathesis. Herein, we report our recent results on the synthesis of cyclic peroxides by Diels-Alder reactions between singlet oxygen and enyneRCM adducts. The substituted enyne substrates 3 were prepared from the secondary alcohols 2 and N-Boc-protected alkynyl hydroxylamines 1 under the Mitsunobu conditions (Scheme 1). The enynes 3 were treated with Grubbs' catalyst 4a according to our previously reported procedure to give the enyne-RCM adducts 5 in moderate to good yields (Table 1). For substrates 3e and 3g, more reactive second generation Grubbs' catalyst 4b was used for the metathesis reactions (Table 1, entries 5 and 7). The substituted conjugated dienes 5 and previously synthesized ones were utilized in the cycloaddition reaction with singlet oxygen. Acetonitrile solutions of the dienes and a catalytic amount of rose Bengal sensitizer were irradiated using a 400-W tungsten lamp while a steady flow of oxygen was passed though the solution. The reaction flask was cooled in an ice-bath during this procedure. Table 2 summarizes the results of these cycloaddition reactions. The formation of 6a from the corresponding enyne-RCM adduct was complete after 7 h; this product was isolated in 73% yield (Table 2, entry 1). The analogous peroxide 6b was obtained in 82% yield (Table 2, entry 2). The homologues with adjacent 7and 8-membered 1,2-oxaza rings were also