Synthesis of Hexahydrofuro[2,3-b]furan and Hexahydrofuro[2,3-b]pyran Derivatives Starting from Baylis-Hillman Adducts via the Ueno-Stork Reaction

Abstract

Fused polycyclic acetals are embodied in a wide range of natural products. Among bicyclic acetals, furofuran and furopyran derivatives are of special interest since both aliphatic and benzoannelated compounds of biological and pharmaceutical activity are known. Especially, the hexahydrofurofuran unit is present in many biologically active natural products. Some representative examples are communiol D, lupulin A, and asteltoxin as shown in Figure 1. During the investigation of radical cyclization of the suitably modified Baylis-Hillman adducts, we reasoned that we could synthesize a variety of furofuran and furopyran derivatives by following the Scheme 1. We reasoned that synthesis of bromoacetals from cinnamyl alcohols and 2,3dihydrofuran or 3,4-dihydro-2H-pyran and the following radical cyclization (Ueno-Stork reaction) would give the desired furofuran or furopyran derivatives. The use of cinnamyl alcohol derivative like 1a as the starting material would afford the furofuran or furopyran derivatives having the ester functionality at the 3-position, which could be functionalized for further transformations. The reaction of the cinnamyl alcohol 1a, which was prepared from the Baylis-Hillman adduct of benzaldehyde and methyl acrylate, and 3,4-dihydro-2H-pyran in the presence of NBS (N-bromosuccinimide) in acetonitrile at room temperature gave the desired bromoacetal 2a in moderate yield (74%). As reported, 2a was obtained as a trans isomer via the ring opening reaction of the intermediate bromonium ion. With bromoacetal 2a in our hand we tried radical cyclization (Ueno-Stork reaction) under the typical condition, n-Bu3SnH/AIBN in refluxing benzene. As expected, we could obtain the diastereomeric