Methyl Insertion Reactions of Tetrahydropyrans Having a C1’-Mesyloxy Group on the C2-Side Chain with Trimethylaluminum

Abstract

Methyl insertion reactions of tetrahydropyrans having a C1'-mesyloxy group on the C2-side chain, mediated by trimethylaluminum, were investigated.Removal of the mesyloxy group, 1,2-hydride shift and/or ring-expansion, and methyl insertion took place concertedly, depending on the stereostructure of the substrate, to give 2-methylated tetrahydropyran and/or 2-or 3-methylated oxepane.Since brevetoxin B was isolated as a red tide toxin, many marine polycyclic ethers have been reported. 1ey have a unique trans-fused polycyclic ether ring system and exhibit potent biological activities, such as neurotoxicity, cytotoxicity, and antiviral and antifungal activities.The marine natural products often contain cyclic ethers having a C2-methyl group as an angular methyl group, such as 2-methyl-tetrahydropyran.In connection with synthetic studies on marine polycyclic ethers, we have recently developed a new synthetic method for 2,3-trans-2-methyl-tetrahydropyran-3-ol and oxepan-3-ol derivatives through a unique methyl insertion reaction of cyclic ethers (1) having mesylate on the C2-side chain. 2,3Thus, upon treatment of cyclic ethers (1) having a C1'-mesyloxy (OMs) group with trimethylaluminum (Me 3 Al), methyl insertion took place to give the C2-methylated compound (2) as the sole product (Figure 1).The present reaction is considered to take place concertedly via removal of the mesyloxy group, 1,2-hydride shift, and methyl insertion into the resulting oxonium ion.We now report further studies on the present reaction using the four possible stereoisomers of 2-(1'-mesyloxy)ethyl-5-hexyl-tetrahydropyrans (3-6) (Figure 2). 4,5