Synthesis of Iodoenol Lactone Derivatives from the Baylis-Hillman Adducts Using Iodolactonization Protocol

Abstract

Recently, we have reported the preparation of benzocycloheptene derivatives from the intramolecular Friedel-Crafts reaction of triple bond-tethered methyl cinnamates. In the reaction, we could not obtain any lactone derivatives, which could be formed via the intramolecular attack of the oxygen atom of ester moiety to the activated triple bond by the acid catalyst (Scheme 1). We think that there may be a certain competition between arene moiety and ester group as nucleophiles toward the activated triple bond. From the previous results we concluded that the arene moiety is more nucleophilic than the oxygen atom of ester toward the in-situ generated vinyl cation. In order to increase the nucleophilicity of the oxygen atom of ester group we decided to hydrolyze the ester into acid and to examine the feasibility of iodolactonization in the presence of NaHCO3 as shown in Scheme 1. From the reaction, we could expect the formation of two types of lactones, 5-membered iodoenol lactone or 6membered α-pyrone. Iodoenol lactone derivatives have been studied extensively due to their usefulness as synthetic intermediates and their biological activities. Low molecular weight αpyrones have been shown to be potent HIV-1 protease inhibitors. Recently, Larock and Rossi have reported an elegant synthesis of isocoumarins and α-pyrones via electrophilic cyclization. We were stimulated by their works and envisioned that we could synthesize suitably substituted α-pyrones or iodoenol lactone derivatives starting from the Baylis-Hillman adducts as mentioned in Scheme 1. The starting material 1 was prepared from Baylis-Hillman acetate according to our previous paper. Base hydrolysis of 1 was carried out using LiOH in aqueous THF at room temperature to give 2 in 53-69% yields. The use of KOH or NaOH was less efficient. With 2 in our hands, we initially examined the reaction with iodine in the presence of NaHCO3 in CH3CN, which is a typical condition for the iodolactonization. Unfortunately, complex mixtures were observed on TLC. Among the various conditions, we finally found that the use of THF as solvent afforded the desired iodoenol lactones 3 in moderate to good yields (56-90%). The formation of 3 can be explained as iodolactonization involving iodonium intermediate (I) via 5-exo-dig manner as shown in Scheme 2. We could not find nor isolate the corresponding six-membered α-pyrones, which can be formed via 6-endo-dig fashion. As the other electrophile source we examined H2SO4 and N-bromosuccinimide (NBS) in order to check the possibility for the synthesis of protonor bromine-attached enol lactones. Fortunately, desired compounds were synthesized in moderate yields. As shown in Scheme 3, bromolactonization of 2a (THF, NBS, NaHCO3) gave the bromoenol lactone 4 in 72% yield. Sulfuric acid-mediated cyclization of 2c in acetonitrile afforded enol lactone 5 in 53% yield at