Enantioselective Synthesis of Pyrroloindolines via Noncovalent Stabilization of Indole Radical Cations and Applications to the Synthesis of Alkaloid Natural Products

While
interest in the synthetic chemistry of radical cations continues
to grow, controlling enantioselectivity in the reactions of these
intermediates remains a challenge. Based on recent insights into the
oxidation of tryptophan in enzymatic systems, we report a photocatalytic
method for the generation of indole radical cations as hydrogen-bonded
adducts with chiral phosphate anions. These noncovalent open-shell
complexes can be intercepted by the stable nitroxyl radical TEMPO·
to form alkoxyamine-substituted pyrroloindolines with high levels
of enantioselectivity. Further elaboration of these optically enriched
adducts can be achieved via a catalytic single-electron oxidation/mesolytic
cleavage sequence to furnish transient carbocation intermediates that
may be intercepted by a wide range of nucleophiles. Taken together,
this two-step sequence provides a simple catalytic method to access
a wide range of substituted pyrroloindolines in enantioenriched form
via a standard experimental protocol from a common synthetic intermediate.
The design, development, mechanistic study, and scope of this process
are presented, as are applications of this method to the synthesis
of several dimeric pyrroloindoline natural products.