Chemoenzymatic Synthesis of the Intermediates in the Peppermint Monoterpenoid Biosynthetic Pathway

A chemoenzymatic approach providing access to all four intermediates in the peppermint biosynthetic pathway between limonene and menthone/isomenthone, including noncommercially available intermediates (−)-trans-isopiperitenol (2), (−)-isopiperitenone (3), and (+)-cis-isopulegone (4), is described. Oxidation of (+)-isopulegol (13) followed by enolate selenation and oxidative elimination steps provides (−)-isopiperitenone (3). A chemical reduction and separation route from (3) provides both native (−)-trans-isopiperitenol (2) and isomer (−)-cis-isopiperitenol (18), while enzymatic conjugate reduction of (−)-isopiperitenone (3) with IPR [(−)-isopiperitenone reductase)] provides (+)-cis-isopulegone (4). This undergoes facile base-mediated chemical epimerization to (+)-pulegone (5), which is subsequently shown to be a substrate for NtDBR (Nicotiana tabacum double-bond reductase) to afford (−)-menthone (7) and (+)-isomenthone (8).