A General Synthetic Strategy toward the Truxillate Natural Products via Solid-State Photocycloadditions.

The truxillates constitute a large class of dimeric natural products featuring a central, highly substituted cyclobutane core. In principle, these structures could be efficiently synthesized via [2 + 2] photocycloaddition. However, the difficulty in controlling the high-energy electronically excited reactive intermediates in the solution state can lead to poor regio- and diastereocontrol. This has limited the use of photocycloaddition methodology toward the synthesis of this important class of natural products. Herein, we demonstrate that acid-controlled precipitation of C-acyl imidazoles promotes a highly selective solid-state photocycloaddition, and the products of this reaction can be quickly transformed into truxillate natural products.

Divergent Bimetallic Mechanisms in Copper(II)-Mediated C-C, N-N, and O-O Oxidative Coupling Reactions.

Copper-catalyzed aerobic oxidative coupling of diaryl imines provides a route for conversion of ammonia to hydrazine. The present study uses experimental and density functional theory computational methods to investigate the mechanism of N-N bond formation, and the data support a mechanism involving bimolecular coupling of Cu-coordinated iminyl radicals. Computational analysis is extended to CuII-mediated C-C, N-N, and O-O coupling reactions involved in the formation of cyanogen (NC-CN) from HCN, 1,3-butadiyne from ethyne (i.e., Glaser coupling), hydrazine from ammonia, and hydrogen peroxide from water. The results reveal two different mechanistic pathways. Heteroatom ligands with an uncoordinated lone pair (iminyl, NH2, OH) undergo charge transfer to CuII, generating ligand-centered radicals that undergo facile bimolecular radical-radical coupling. Ligands lacking a lone pair (CN and CCH) form bridged binuclear diamond-core structures that undergo C-C coupling. This mechanistic bifurcation is rationalized by analysis of spin densities in key intermediates and transition states, as well as multiconfigurational calculations. Radical-radical coupling is especially favorable for N-N coupling owing to energetically favorable charge transfer in the intermediate and thermodynamically favorable product formation.

Chemoselective Silver-Catalyzed Nitrene Transfer: Tunable Syntheses of Azepines and Cyclic Carbamimidates.

Azepines and their saturated azepane counterparts are important moieties in bioactive molecules but are under-represented in current drug screening libraries. Herein, we report a mild and efficient azepine formation via silver-catalyzed dearomative nitrene transfer. A 2,2,2-trichloroethoxysulfonyl (Tces)-protected carbamimidate nitrene precursor, coupled with the appropriate ligand for silver, is essential for achieving the unexpected chemoselectivity between arene dearomatization and benzylic C(sp3)-H amination. Potential applications in the late-stage diversification of azepines to complex molecular scaffolds and diastereoselective hydrogenations to sp3-rich derivatives are also highlighted.

Enantioselective Paternò-Büchi Reactions: Strategic Application of a Triplet Rebound Mechanism for Asymmetric Photocatalysis.

The Paternò-Büchi reaction is the [2 + 2] photocycloaddition of a carbonyl with an alkene to afford an oxetane. Enantioselective catalysis of this classical photoreaction, however, has proven to be a long-standing challenge. Many of the best-developed strategies for asymmetric photochemistry are not suitable to address this problem because the interaction of carbonyls with Brønsted or Lewis acidic catalysts can alter the electronic structure of their excited state and divert their reactivity toward alternate photoproducts. We show herein that a triplet rebound strategy enables the stereocontrolled reaction of an excited-state carbonyl compound in its native, unbound state. These studies have resulted in the development of the first highly enantioselective catalytic Paternò-Büchi reaction, catalyzed by a novel hydrogen-bonding chiral Ir photocatalyst.

"Off-Label Use" of the Siderophore Enterobactin Enables Targeted Imaging of Cancer with Radioactive Ti(IV).

The development of inert, biocompatible chelation methods is required to harness the emerging positron emitting radionuclide 45Ti for radiopharmaceutical applications. Herein, we evaluate the Ti(IV)-coordination chemistry of four catechol-based, hexacoordinate chelators using synthetic, structural, computational, and radiochemical approaches. The siderophore enterobactin (Ent) and its synthetic mimic TREN-CAM readily form mononuclear Ti(IV) species in aqueous solution at neutral pH. Radiolabeling studies reveal that Ent and TREN-CAM form mononuclear complexes with the short-lived, positron-emitting radionuclide 45Ti(IV), and do not transchelate to plasma proteins in vitro and exhibit rapid renal clearance in naïve mice. These features guide efforts to target the 45Ti isotope to prostate cancer tissue through the design, synthesis, and evaluation of Ent-DUPA, a small molecule conjugate composed of a prostate specific membrane antigen (PSMA) targeting peptide and a monofunctionalized Ent scaffold. The [45Ti][Ti(Ent-DUPA)]2- complex forms readily at room temperature. In a tumor xenograft model in mice, selective tumor tissue accumulation (8±5 %, n=5), and low off-target uptake in other organs is observed. Overall, this work demonstrates targeted imaging with 45Ti(IV), provides a foundation for advancing the application of 45Ti in nuclear medicine, and reveals that Ent can be repurposed as a 45Ti-complexing cargo for targeted nuclear imaging applications.

Coordination variety of phenyltetrazolato and dimethylamido ligands in dimeric Ti, Zr, and Ta complexes.

Three structurally diverse 5-phenyltetrazolato (Tz) Ti, Zr, and Ta complexes, namely, (C2H8N)[Ti2(C7H5N4)5(C2H6N)4]·1.45C6H6 or (Me2NH2)[Ti2(NMe2)4(2,3-µ-Tz)3(2-η1-Tz)2]·1.45C6H6, (1·1.45C6H6), [Zr2(C7H5N4)6(C2H6N)2(C2H7N)2]·1.12C6H6·0.382CH2Cl2 or [Zr2(Me2NH)2(NMe2)2(2,3-µ-Tz)3(2-η1-Tz)2(1,2-η2-Tz)]·1.12C6H6·0.38CH2Cl2 (2·1.12C6H6·0.38CH2Cl2), and (C2H8N)2[Ta2(C7H5N4)8(C2H6N)2O]·0.25C7H8 or (Me2NH2)2[Ta2(NMe2)2(2,3-µ-Tz)2(2-η1-Tz)6O]·0.25C7H8 (3·0.25C7H8), where TzH is 5-phenyl-1H-tetrazole, have been synthesized and structurally characterized. All three complexes are dinuclear; the Ti center in 1 is six-coordinate, whereas the Zr and Ta atoms in 2 and 3 are seven-coordinate. The coordination environments of the Ti centers in 1 are similar, and so are the ligations of the Ta centers in 3. In contrast, the two Zr centers in 2 bear a different number of ligands, one of which is a bidentate η2-5-phenyltetrazolato ligand that has not been observed previously for d-block elements. The dimethylamido ligand, present in the starting materials, remained unchanged, or was converted to dimethylamine and dimethylammonium during the synthesis. Dimethylamine coordinates as a neutral ligand, whereas dimethylammonium is retained as a hydrogen-bonded entity bridging Tz ligands.

Iron-Catalyzed Site- and Regioselective 1,2-Azidoamidations of 1,3-Dienes.

The direct 1,2-azidoamidation of unsaturated precursors represents an advantageous approach for the facile synthesis of ß-functionalized azides from readily available starting materials. In this paper, we describe a convenient and mild iron-catalyzed 1,2-azidoamidation of 1,3-dienes that shows excellent functional group compatibility to furnish versatile precursors to 1,2-diamine products with high levels of site, regio-, and stereoselectivity. The reaction is proposed to proceed via a single electron transfer/radical addition/C-N bond formation relay process.

Crystal structure and characterization of a new one-dimensional copper(II) coordination polymer containing a 4-amino-benzoic acid ligand.

A CuII coordination polymer, catena-poly[[[aqua-copper(II)]-bis-(µ-4-amino-benz-o-ato)-κ2 N:O;κ2 O:N] monohydrate], {[Cu(pABA)2(H2O)]·H2O}n (pABA = p-amino-benzoate, C7H4NO2 -), was synthesized and characterized. It exhibits a one-dimensional chain structure extended into a three-dimensional supra-molecular assembly through hydrogen bonds and π-π inter-actions. While the twinned crystal shows a metrically ortho-rhom-bic lattice and an apparent space group Pbcm, the true symmetry is monoclinic (space group P2/c), with disordered Cu atoms and mixed roles of water mol-ecules (aqua ligand/crystallization water). The luminescence spectrum of the complex shows an emission at 345 nm, cf. 349 nm for pABAH.

Occupational modulation in the (3+1)-dimensional incommensurate structure of (2S,3S)-2-amino-3-hydroxy-3-methyl-4-phenoxybutanoic acid dihydrate.

The incommensurately modulated structure of (2S,3S)-2-amino-3-hydroxy-3-methyl-4-phenoxybutanoic acid dihydrate (C11H15NO4·2H2O or I·2H2O) is described in the (3+1)-dimensional superspace group P212121(0ß0)000 (ß = 0.357). The loss of the three-dimensional periodicity is ascribed to the occupational modulation of one positionally disordered solvent water molecule, where the two positions are related by a small translation [ca 0.666 (9) Å] and ∼168 (5)° rotation about one of its O-H bonds, with an average 0.624 (3):0.376 (3) occupancy ratio. The occupational modulation of this molecule arises due to the competition between the different hydrogen-bonding motifs associated with each position. The structure can be very well refined in the average approximation (all satellite reflections disregarded) in the space group P212121, with the water molecule refined as disordered over two positions in a 0.625 (16):0.375 (16) ratio. The refinement in the commensurate threefold supercell approximation in the space group P1121 is also of high quality, with the six corresponding water molecules exhibiting three different occupancy ratios averaging 0.635:0.365.