Mechanism of Permanganate-Promoted Dihydroxylation of Complex Diketopiperazines: Critical Roles of Counter-cation and Ion-Pairing

The mechanism of
permanganate-mediated dual C–H
oxidation of complex diketo­piperazines has been examined with
density functional theory computations. The products of these oxidations
are enabling intermediates in the synthesis of structurally diverse
ETP natural products. We evaluated, for the first time, the impact
of ion-pairing and aggregation states of the permanganate ion and
counter-cations, such as bis­(pyridine)-silver­(I) (Ag+)
and tetra-n-butyl­ammonium (TBA+),
on the C–H oxidation mechanism. The C–H abstraction
occurs through an open shell singlet species, as noted previously,
followed by O-rebound and a competing OH-rebound pathway. The second
C–H oxidation proceeds with a second equivalent of oxidant
with lower free energy barriers than the first C–H oxidation
due to directing effects and the generation of a more reactive oxidant
species after the first C–H oxidation. The success and efficiency
of the second C−H oxidation are found to be critically dependent
on the presence of an ion-paired oxidant. We used the developed mechanistic
knowledge to rationalize an experimentally observed oxidation pattern
for C3-indole-substituted diketo­piperazine (+)-5 under optimal oxidation conditions: namely, the formation
of diol (−)-6 as a single diastereomer and lack
of the ketone products. We proposed two factors that may impede the
ketone formation: (i) the conformational flexibility of the diketo­piperazine
ring, and (ii) hindrance of this site, making it less accessible to
the ion-paired oxidant species.