Two Complementary Synthetic Approaches to the Enantiomeric Forms of the Chiral Building Block (2,6,6-Trimethyltetrahydro-2H-pyran-2-yl)methanol: Application to the Stereospecific Preparation of the Natural Flavor Linaloyl Oxide

The enantiomeric forms of the alcohol (2,6,6-trimethyltetrahydro-2H-pyran-2-yl)methanol are potential chiral building blocks for the stereoselective synthesis of different natural terpenes. Here, we describe their preparation by means of two different synthetic approaches. The first is based on the stereospecific (+)-10-camphorsulfonic acid (CSA)-catalyzed cyclization of (R)- and (S)-2-methyl-5-(2-methyloxiran-2-yl)pentan-2-ol, which were in turn synthesized from (R)- and (S)-linalool, respectively. The latter monoterpenes are easily available from the chiral pool, with different optical purity. As our synthesis makes use of the intermediate 2,6-dimethyloct-7-ene-2,6-diol, whose enantiopurity can be improved through fractional crystallization, we obtained (2,6,6-trimethyltetrahydro-2H-pyran-2-yl)methanol enantiomers in an almost enantiopure form. The second synthetic approach is based on the lipase-mediated resolution of the aforementioned tetrahydropyranyl alcohol, which was prepared in racemic form starting from the industrial intermediate, dehydrolinalool. In this work, we report a large-scale resolution procedure that exploits the opposite enantioselectivity of Novozym (R) 435 lipase and lipase AK in the acetylation reaction of (2,6,6-trimethyltetrahydro-2H-pyran-2-yl)methanol. The two enantiomeric forms of the latter alcohol were employed for the first stereoselective synthesis of both enantiomers of the flavor, linaloyl oxide (2,2,6-trimethyl-6-vinyltetrahydro-2H-pyran).