The gas-phase cyclopropanation and apparent metathesis reactivity of ligand-supported gold arylidenes with electron-rich olefins is explained by quantum-chemical calculations. A deep potential minimum corresponding to a metal-bound cyclopropane adduct is in agreement with the measured absolute energies of the cyclopropanation and metathesis channels and is also consistent with previously reported electronic effects of arylidenes and supporting phosphorus ylid ligands on the product ratios. In the gas phase, the rate-determining step for the cyclopropanation is dissociation of the Lewis-acidic metal fragment, whereas the metathesis pathway features several rate-limiting transition states that are close in energy to the final product dissociation and hence contribute to the overall reaction rate. Importantly, the presented potential energy surface also accounts for the recently reported gold-catalyzed solution-phase retro-cyclopropanation reactivity.

We report experimental and computational evidence that cationic N-heterocyclic carbene gold complexes with electron-rich cyclopropanes rearrange to produce Fischer gold carbene complexes in the gas phase, in analogy to long-known condensed-phase rearrangements of protonated cyclopropanes. Our results help to generalize the relationship between Lewis-acidic metal complexes of cyclopropanes, metallacyclobutanes and metal carbenes.

Metal-coordinated nitrenes are recognized to be reactive intermediates in aziridination and insertion reactions.[1] Among other metals, the coinage metal triad (Cu, Ag, Au) was demonstrated to be active in catalyzing these important transformations. In particular, He and co-workers recently showed that nitrene transfer could efficiently be accomplished relying on gold.[2] While copper nitrene intermediates have been structurally characterized, [3] we are not aware of any reports on monometallic gold analogues.Having successfully applied a phosphorus ylid-based strategy for the preparation of transient gold(I) benzylidene carbenes inside a modified Finnigan MAT TSQ-700 mass spectrometer, [4] we were motivated to implement a similar approach to the gas-phase synthesis of a metal-bound nitrene species.The triflate salt of IMes-supported (IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene) phosphazene gold adduct 1-OTf was prepared as an air-and moisture-stable solid in 72 % yield (Scheme 1). Upon electrospray, the thermalized parent ion current (m/z 821) was directed into the argon-filled chamber for the collision-induced dissociation (CID) event (Figure 1). Detachment of the labile PPh 3 group proceeds smoothly as the only reaction channel to afford a signal with 559 m/z ratio, which we ascribe to the singlet (vide infra) gold aminonitrene 2s.[5]Energy-resolved reactive cross-section measurements under near-single-collision conditions were conducted for this process in order to quantitatively determine the NÀP bond strength (Figure 2).[6] The L-CID algorithm for the cross-section data fitting requires an input assumption about the properties of the transition state.[7] It generally holds true that simple dissociation, without prior rearrangement, of a neutral fragment from an ion occurs via a loose transition state, that is, with no reverse activation barrier. [8] Standard L-CID treatment [7, 8a-b, 4a] of the process 1!2s + 3 gave a value of 45.0 AE 2.7 kcal mol À1 assuming a loose transition state. We subsequently modeled the PPh 3 detachment at the DFT level of theory (see Computational Section and Supporting Information for details) to confirm the assignment of the daughter ion channel to 2s and to rule out possible rearrangements and spin isomerism. A priori a number of events could precede nitrene formation (Scheme 2). One may speculate that a 1,2-triphenylphosphine shift connects 1 and 4s and formation of 2s could then be accomplished via PPh 3 dissociation from the tricoordinate gold species. However, 1,1-dimethylnitrene 6s is only weakly bound to the gold atom in 4s with an AuÀN distance of 2.867 and thus is predisposed to dissociation producing 5. Since species 5 is not observed experimen-

Expanding the chemical space and simultaneously ensuring synthetic accessibility is of upmost importance, not only for the discovery of effective binders for novel protein classes but, more importantly, for the development of compounds against hard-to-drug proteins. Here, we present AutoCouple, a de novo approach to computational ligand design focused on the diversity-oriented generation of chemical entities via virtual couplings. In a benchmark application, chemically diverse compounds with low-nanomolar potency for the CBP bromodomain and high selectivity against the BRD4(1) bromodomain were achieved by the synthesis of about 50 derivatives of the original fragment. The binding mode was confirmed by X-ray crystallography, target engagement in cells was demonstrated, and antiproliferative activity was showcased in three cancer cell lines. These results reveal AutoCouple as a useful in silico coupling method to expand the chemical space in hit optimization campaigns resulting in potent, selective, and cell permeable bromodomain ligands.

N-heterocyclic carbene (NHC) supported coinage metal cations proved to react in the gas phase with the electron-rich cis-1,2-dimethoxycyclopropane. Upon Collision Induced Dissociation (CID), several spectrometric fragment-ion signals were observed, one corresponding to the recovery of the bare cation IMes-M(+) (IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene) and the second to the methoxymethylidene metal complex IMes-M-[HCOCH3](+). The gold and copper complexes appear to stabilize the carbene sufficiently enough to promote the latter channel. On the contrary, the silver complex binds weakly to the methoxymethylidene moiety as observed by the predominance of the bare cation IMes-M(+) channel. Density Functional Theory (DFT) investigations of the Potential Energy Surface and Bond Energy Decomposition Analyses provided results that correlate well with the experimental data. In the case of the bare cation channel, two distinct reaction pathways were found: a straightforward decoordination of the cyclopropane and a cationic rearrangement of the three-membered ring into a dimethoxypropylene isomer before dissociation. However, for the abstraction of the methoxymethylidene moiety by the metal cation, only one pathway was found. In analogy to earlier studies by other groups, we found the trend Au> Cu > Ag for the metal-carbene bond strength.

Small molecule ligand binding to the ATAD2 bromodomain is investigated here through the synergistic combination of molecular dynamics and protein crystallography. A previously unexplored conformation of the binding pocket upon rearrangement of the gatekeeper residue Ile1074 has been found. Further, our investigations reveal how minor structural differences in the ligands result in binding with different plasticity of the ZA loop for this difficult-to-drug bromodomain.

We analyze 20 crystal structures of complexes between the CBP bromodomain and small-molecule ligands that belong to eight different chemotypes identified by docking. The binding motif of the moiety that mimics the natural ligand (acetylated side chain of lysine) at the bottom of the binding pocket is conserved. In stark contrast, the rest of the ligands form different interactions with different side chains and backbone polar groups on the outer rim of the binding pocket. Hydrogen bonds are direct or water-bridged. van der Waals contacts are optimized by rotations of hydrophobic side chains and a slight inward displacement of the ZA loop. Rare types of interactions are observed for some of the ligands.

BAZ2A is an epigenetic regulator affecting transcription of ribosomal RNA. It is overexpressed in aggressive and recurrent prostate cancer, promoting cellular migration. Its bromodomain is characterized by a shallow and difficult-to-drug pocket. Here, we describe a structure-based fragment-growing campaign for the identification of ligands of the BAZ2A bromodomain. By combining docking, competition binding assays, and protein crystallography, we have extensively explored the interactions of the ligands with the rim of the binding pocket, and in particular ionic interactions with the side chain of Glu1820, which is unique to BAZ2A. We present 23 high-resolution crystal structures of the holo BAZ2A bromodomain and analyze common bromodomain/ligand motifs and favorable intraligand interactions. Binding of some of the compounds is enantiospecific, with affinity in the low micromolar range. The most potent ligand has an equilibrium dissociation constant of 7 μM and a good selectivity over the paralog BAZ2B bromodomain.