Bioinspired Synthesis of Pinoxaden Metabolites Using a Site-Selective C–H Oxidation Strategy

Sameer Tyagi, Bruce P. McKillican, Tolani K. Salvador, Moses G. Gichinga, William J. Eberle, Russell Viner, Katarina J. Makaravage, Trey S. Johnson, C. Adam Russell, and Subho Roy (TCGLS Member)

Publication: J. Org. Chem. 2022, 87, 9, 6202–6211

DOI: https://doi.org/10.1021/acs.joc.2c00440

Abstract: A bioinspired synthesis of Pinoxaden metabolites 2–5 is described herein. A site-selective C–H oxidation strategy validated by density functional theory (DFT) calculations was devised for preparing metabolites 2–4. Oxidation of the benzylic C–H bond in tertiary alcohol 7 using K2S2O8 and catalytic AgNO3 formed the desired metabolite 2 that enabled access to metabolites 3 and 4 in a single step. Unlike most metal/persulfate-catalyzed transformations reported for the C–C and C–O bond formation reactions wherein the metal acts as a catalyst, we propose that Ag(I)/K2S2O8 plays the role of an initiator in the oxidation of intermediate 7 to 2. Metabolite 2 was subjected to a ruthenium tetroxide-mediated C–H oxidation to form metabolites 3 and 4 as a mixture that were purified to isolate pure standards of these metabolites. Metabolite 5 was synthesized from readily available advanced intermediate 9via a House–Meinwald-type rearrangement in one step using a base.