Exploitation of a Multienzymatic Stereoselective Cascade Process in the Synthesis of 2-Methyl-3-Substituted Tetrahydrofuran Precursors

Abstract

Enantiopure 2-methyl-3-substituted tetrahydrofurans are key precursors of several biologically active products (drugs, flavors, and agrochemicals). Thus, a stereocontrolled and efficient methodology for the obtainment of these synthons is highly desirable. We exploited a two-step multienzymatic stereoselective cascade reduction of α-bromo-α,β-unsaturated ketones to give the corresponding bromohydrins in good yields, with high ee and de values. The cascade process is catalyzed by an ene-reductase and an alcohol dehydrogenase. Further manipulations of these bromohydrins, by two diastereodivergent routes, allowed the preparation of the tetrahydrofuran synthons. One route is based on a lipase catalyzed cleavage of the protecting group. The second route is characterized by a camphor sulfonic acid mediated isomerization of a β-hydroxyepoxide to give the tetrahydrofuran-2-ol. Finally, the synthesis of the most odorous and pleasant stereoisomer of the roasted meat aroma, i.e., (2S,3R)-2-methyl-3-thioacetate tetrahydrofuran, is reported as well.

Chemo‐Enzymatic Oxidative Rearrangement of Tertiary Allylic Alcohols: Synthetic Application and Integration into a Cascade Process

“…In the last years, several examples of how different enzymatic activities can be simply integrated either in sequential or cascade multi‐step processes have been reported . Especially, we found very profitable the combination of ene‐reductases (ERs, enzymes that catalyse the asymmetric reduction of electronically activated C=C double bonds) with alcohol dehydrogenases (ADHs, enzymes capable of reducing/oxidising ketones/alcohols) in the stereoselective synthesis of flavours, fragrances, natural products or active pharmaceutical ingredients, starting from α,β‐unsaturated ketones. Therefore, in this regard, the TEMPO/laccase‐catalysed rearrangement of a tertiary allylic alcohols could be an ideal partner of the ER‐ADH catalytic system, allowing the set‐up of a more complex and challenging multi‐step process.…”

Stereodivergent routes in organic synthesis: marine natural products, lactones, other natural products, heterocycles and unnatural compounds

“…In addition, 2,3-disubstituted tetrahydrofurans are used for the preparation of aromas, drugs and agrochemicals. 85 Diastereodivergent routes to cis-and trans-2,3-disubstituted tetrahydrofurans of the roasted meat aroma, have been performed by Gatti and co-workers. 85 Starting from a chiral Obenzylated bromohydrin, its treatment with NaH gave an epoxide, which was debenzylated by hydrogenolysis to give an epoxyalcohol (Scheme 55).…”

“…85 Diastereodivergent routes to cis-and trans-2,3-disubstituted tetrahydrofurans of the roasted meat aroma, have been performed by Gatti and co-workers. 85 Starting from a chiral Obenzylated bromohydrin, its treatment with NaH gave an epoxide, which was debenzylated by hydrogenolysis to give an epoxyalcohol (Scheme 55). After camphorsulfonic acid (CSA)-promoted rearrangement, an inversion of the configuration at the C-3 occurred giving (2S,3R)-tetrahydrofuranol.…”

The Impact of Recent Developments in Technologies which Enable the Increased Use of Biocatalysts

“…This is because the compound with the labile α ‐stereocentre is not isolated when the two enzymes are used together. Workers from the same group also combined four different enzymes, this time in addition to the ADH and ene‐reductase, GDH and a lipase were used in the synthesis of bromodiol 11 , a precursor to the tetrahydrofuran 12 , which is also a fragrance molecule (Scheme ) . The substrate was modified, so that after reaction with the ene‐reductase and alcohol dehydrogenase, it would give a suitable substrate for the lipase, as well as furnishing enantiopure products from the bioreductions.…”