The highly convergent total synthesis of dimeric diketopiperazine alkaloids (+)-asperazine A and (+)-pestalazine B is described. A critical aspect of our expedient route was the development of a directed regio- and diastereoselective C3-N1' coupling of complex tetracyclic diketopiperazine components. This late-stage heterodimerization reaction was made possible by design of tetracyclic diketopiperazines that allow C3-carbocation coupling of the electrophilic component to the N1' locus of the nucleophilic fragment. The application of this new coupling reaction to the first total synthesis of (+)-asperazine A led to our revision of the sign and magnitude of the optical rotation for the reported structure.

The bis(pyridine)silver (I) permanganate promoted hydroxylation of diketopiperazines has served as a pivotal transformation in the synthesis of complex epipolythiodiketopiperazine alkaloids. This late-stage C–H oxidation chemistry is strategically critical to access N-acyl iminium ion intermediates necessary for nucleophilic thiolation of advanced diketopiperazines en route to potent epipolythiodiketopiperazine anticancer compounds. In this study, we develop an informative mathematical model using hydantoin derivatives as a training set of substrates by relating the relative rates of oxidation to various calculated molecular descriptors. The model prioritizes Hammett values and percent buried volume as key contributing factors in the hydantoin series while correctly predicting the experimentally observed oxidation sites in various complex diketopiperazine case studies. Thus, a method is presented by which to use simplified training molecules and resulting correlations to explain and predict reaction behavior for more complex substrates.

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-butyl ammonium (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 CH oxidation is 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.

A series of dinuclear organophosphorus‐bridged vanadium(IV) complexes with the Kläui ligand, [CpPOMeCo]–, have been synthesized to model the catalytic activity of industrially used vanadium phosphate oxidation catalysts. Dimeric species of the general formula [(CpPOMeCo)V(O)(μ‐O2PR′R″)]2 (R′,R″ = H, OH, Me, Ph, or 4‐OPh‐NO2), [(CpPOMeCo)V(O)]2(μ‐oxalate), and [(CpPOMeCo)V(Cl)]2(μ‐oxalate) are reported. These complexes have been characterized via spectral and magnetic analyses. The synthesis, characterization, and X‐ray structures of the mononuclear vanadium(IV) complexes (CpPOMeCo)V(O)Cl(OH2) and(CpPOMeCo)V(O)(acac) are also presented here. [CpPOMeCo]–= η5‐cyclopentadienyltris(dimethylphosphito‐κ1P)cobaltate(III); acac = acetylacetonate.