Unified Chemoenzymatic Approach to 16α-Methyl Glucocorticoids: Stereocontrolled Synthesis of (+)-Dexamethasone, (+)-Mometasone, (+)-Flumethasone, (+)-Halometasone, and (+)-Vamorolone

High Resolution Image Download MS PowerPoint Slide 16α-Methyl glucocorticoids are a renowned family of steroid molecules with diverse important pharmaceutical applications, and development of innovative, practical, and divergent synthetic routes toward these steroids is highly desirable. Herein, we report a unified stereocontrolled synthesis of five 16α-methyl glucocorticoid pharmaceuticals, namely, (+)-dexamethasone, (+)-mometasone, (+)-flumethasone, (+)-halometasone, and (+)-vamorolone, in 9.9–26.8% overall yields starting from commercially available 9α-hydroxyandrost-4-ene-3,17-dione (9α-OH-AD), featuring a telescoped in-flow synthesis consisting of an acidic resin-mediated dehydration and an enzyme-catalyzed C1,2-dehydrogenation, an Au(I)-catalyzed hydration of enyne to enone, and a conjugate addition–dihydroxylation sequence-enabled construction of the chiral C16α-methyl and C17α,21-dihydroxyacetone moieties. This established chemoenzymatic platform provides a versatile and generic access to other valuable 16α-methyl glucocorticoids.