Tuesday, March 24, 2015
Allylic Arylation of the Unfunctionalized C7 Position of a Steroidal Pregnenolone Using Visible-Light-Mediated Dual Catalysis
Professor David MacMillan of Princeton University delivered the Scynexis Lecture at the University of North Carolina in Chapel Hill last week. He discussed a recently disclosed technology that may be suitable for late-stage diversification of a range structurally complex natural products, including medicinally relevant steroids and triterpenoids. The new reaction uses both photoredox and organic catalysis to accomplish allylic C-H arylation of an unfunctionalized olefinic precursor. The C-C bond forming process accommodates a range of alkene reactants including the unprotected steroidal 5-pregnen-3b-ol-20-one substrate depicted above. Due to its dual catalysis mechanism involving single-electron transfer (SET), the arene coupling partner must be highly electron-deficient and the majority of the transformations reported in the 2015 Princeton manuscript employ either a dicyanobenzene or 4-cyanopyridine.
Mechanistically, the reaction involves two synergistic catalysis cycles (as outlined in the scheme above). Initial photoactivation of a commercially available iridium(III) catalyst with visible light generates an excited state complex that engages the electron-deficient arene in a single-electron reduction. The SET reduction step affords an intermediary ‘persistent’ radical anion, along with an iridium(IV) oxidant species. Next, the resultant oxidant triggers an organocatalytic cycle, wherein a thiol catalyst is converted to a thiyl radical with concomitant regeneration of Ir(III). An allylic hydrogen atom is then abstracted from the olefinic reactant by the newly formed thiyl radical. Finally, radical-radical coupling between the persistent arene radical and the more reactive allylic radical, followed by elimination of cyanide, furnishes the arylation product containing a new C-C bond. While somewhat narrow in scope with regard to the aromatic coupling partner, the new allylic arylation reaction is operationally simple to conduct, requires only commercially available catalysts and proceeds under mild conditions. MacMillan's conceptually novel chemistry should open up new opportunities for late-stage diversification of complex organic molecules, an R & D strategy that is of great interest to the pharmaceutical industry.