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These data are the R scripts, environments, output used for analyzing chemoproteomics data. The volcano plot shown in the manuscript is based on the DEP R package. To validate the enrichment output from DEP, the proteomics data was also processed with the proDA package. Filename (7 files) Description combined_protein_Int.txt Output from database search hdac6_dep_submitted.R script used to process data (from DEP package) hdac6_dep_submitted.R.RData workspace environment from DEP package hdac6probecontrol_dep.csv exported list of p-value and fold-change from DEP hdac6probecontrol_proda.csv exported list of p-value and fold-change from proDA hdac6proda_submitted.R proDA script hdac6proda_submitted.RData proDA workspace environment, PXD039880 - the raw data is also uploaded to PRIDE.

Herein we report the first enantioselective total synthesis of 3,5-dimethylorsellinic acid-derived meroterpenoids (-)-berkeleyone A and its five congeners ((-)-preaustinoids A, A1, B, B1, and B2) in 12-15 steps, starting from commercially available 2,4,6-trihydroxybenzoic acid hydrate. Based upon the recognition of latent symmetry within D-ring, our convergent synthesis features two critical reactions: 1) a symmetry-breaking, diastereoselective dearomative alkylation to assemble the entire carbon core, and 2) a Sc(OTf)3 -mediated sequential Krapcho dealkoxycarbonylation/carbonyl α-tert-alkylation to forge the intricate bicyclo[3.3.1]nonane framework. We also conducted our preliminary biomimetic investigations and uncovered a series of rearrangements (α-ketol, α-hydroxyl-β-diketone, etc.) responsible for the biomimetic diversification of (-)-berkeleyone A into its five preaustinoid congeners.

The outstanding impact of fluorine atom in drug discovery cannot be overestimated. Substantially, the incorporation of the gem-difluoro (CF2) group into organic frameworks is highly sought due to the influence of this unit on physicochemical and pharmacological properties of molecules. Yet, introduction of CF2 moiety into organic structures is a step-intensive preparation, and known approaches are often limited to certain classes of molecules. Development of strategies for a rapid incorporation of gem-difluoro synthon that utilizes inexpensive commercial reagents is highly desirable. In the context of divergency and applicability of such reagents, switchable synthesis can be beneficial to access a wide range of fluorinated compounds. Herein we report a mild and operationally simple protocols to access various gem-difluoro compounds that employs chlorodifloroacetic anhydride (CDFAA) as a low cost and versatile fluoroalkylating reagent. Detailed mechanistic investigations revealed that electron-transfer photocatalysis triggers mesolytic cleavage of a C−Cl bond generating a gem-difluoro carboxy radical. In the presence of alkene molecule, this radical species acts as an efficient and unique bifunctional reagent that, under solvent-controlled reaction conditions, delivers a wide range of gem-difluorinated γ-lactams, γ-lactones, as well as promotes oxy-perfluoroalkylation. These protocols are flow and batch scalable, possess excellent chemo- and regioselectivity, and can be used for the late-stage diversification of biorelevant molecules.

The dearomatization of 2-naphthols represents a simple method for the construction of complex 3D structures from simple planar starting materials. We describe a cyclopropanation of 2-naphthols that proceeds via cyclopropene ring-opening using rhodium and acid catalysis under mild conditions. The vinyl cyclopropane molecules were formed with high chemoselectivity and scalability, which could be further functionalized at different sites. Both computational and experimental evidence were used to elucidate the reaction mechanism.

Capitalizing on the late-stage diversification of an essential 1,3-diene intermediate, we describe herein a 9-step enantioselective total synthesis of (+)-hyperforin and (+)-pyrohyperforin, starting from commercially available allylacetone. Our convergent synthesis features a series of critical reactions: 1) an enantioselective deconjugative α-alkylation of α,β-unsaturated acid using chiral lithium amides as noncovalent stereodirecting auxiliaries; 2) a HfCl

The use of ammonium halide salts as metal hydride precursors in a new Pd-catalyzed cycloisomerization of 1,6-diynes, which affords unexplored silylated 2-azafluorenes, is reported. This cascade process includes the addition of a Pd-hydride species to a π-system, intramolecular carbopalladation, and C(sp2)-H bond activation. A variety of functional groups are tolerated, and the synthetic utility of the resulting products has been demonstrated by a series of derivatizations.

USP5 disassembles unanchored polyubiquitin chains to recycle free monoubiquitin, and is one of the 12 ubiquitin specific proteases featuring a zinc finger ubiquitin-binding domain (ZnF-UBD). This distinct structural module has been associated with substrate positioning or allosteric modulation of catalytic activity, but its cellular function remains unclear. We screened a chemical library focused on the ZnF-UBD of USP5, crystallized hits in complex with the protein, and generated a preliminary structure-activity relationship, which enables the development of more potent and selective compounds. This work serves as a framework for the discovery of a chemical probe to delineate the function of USP5 ZnF-UBD in proteasomal degradation and other ubiquitin signaling pathways in health and disease.

USP5 disassembles unanchored polyubiquitin chains to recycle free mono-ubiquitin, and is one of twelve ubiquitin-specific proteases featuring a zinc finger ubiquitin-binding domain (ZnF-UBD). This distinct structural module has been associated with substrate positioning or allosteric modulation of catalytic activity, but its cellular function remains unclear. We screened a chemical library focused on the ZnF-UBD of USP5, crystallized hits in complex with the protein, and generated a preliminary structure-activity relationship which enables the development of more potent and selective compounds. This work serves as a framework for the discovery of a chemical probe to delineate the function of USP5 ZnF-UBD in proteasomal degradation and other ubiquitin signalling pathways in health and disease.

We report here a proof of concept for the cleavage of unstrained remote Csp3–Csp3 bonds at room temperature assisted by a directing group, opening up new possibilities to use aliphatic carboxylic acids as suitable alkenyl coupling partners. This strategy involves the Pd-mediated Csp3–H activation directed by a tethered 8-aminoquinoline group, followed by a concerted asynchronous carbene insertion into the Pd–C bond, and an unexpected β-carbon-carbon bond splitting. The insertion of a coupling partner into a Pd–C bond is a novel route to promote C–C bond cleavage, which, in contrast to most common methodologies, does not rely on the use of strained carbocycles.

A simple trifluoromethoxylation method enables non-directed functionalization of C-H bonds on a range of substrates, providing access to aryl trifluoromethyl ethers. This light-driven process is distinctly different from conventional procedures and occurs through an OCF3 radical mechanism mediated by a photoredox catalyst, which triggers an N-O bond fragmentation. The pyridinium-based trifluoromethoxylation reagent is bench-stable and provides access to synthetic diversity in lead compounds in an operationally simple manner.

An enantioconvergent C(sp3)–C(sp3) coupling between racemic allenylic electrophiles and alkylzinc reagents has been developed. An Ir/(phosphoramidite,olefin) catalyst provides access to highly enantioenriched allenylic substitution products (93–99% ee) with complete regiocontrol (>50:1 rr in all cases) over the corresponding 1,3-diene isomers which are obtained predominantly when other metal catalysts are emplyed. The synthetic utility of the products obtained was highlighted in a variety of stereoselective transition metal-catalyzed difunctionalization reactions. Furthermore, a combination of experimental and theoretical studies provide support for a putative reaction mechanism wherein enantiodetermining C–C coupling occurs via nucleophilic attack on a highly planarized aryl butadienylium π-system that is coordinated to the Ir center in an η2-fashion.

HDAC6 plays a central role in the recruitment of protein aggregates for lysosomal degradation, and is a promising target for combination therapy with proteasome inhibitors in multiple myeloma. Pharmacologically displacing ubiquitin from the zinc-finger ubiquitin-binding domain (ZnF-UBD) of HDAC6 is an underexplored alternative to catalytic inhibition. Here, we present the discovery of a HDAC6 ZnF-UBD-focused chemical series and its progression from virtual screening hits to low micromolar inhibitors. A carboxylate mimicking the C-terminal extremity of ubiquitin, and an extended aromatic system stacking with W1182 and R1155 are necessary for activity. One of the compounds induced a conformational remodeling of the binding site where the primary binding pocket opens-up onto a ligand-able secondary pocket that may be exploited to increase potency. The preliminary structure-activity relationship accompanied by nine crystal structures should enable further optimization into a chemical probe to investigate the merit of targeting the ZnF-UBD of HDAC6 in multiple myeloma and other diseases.

The mechanism of the palladium-catalyzed spirocyclization of acrylamides with arynes and alkynes has been computationally and experimentally studied., The mechanism of the palladium-catalyzed spirocyclization of acrylamides has been investigated by density functional theory and experimental studies. The results support a mechanistic pathway that proceeds via oxidative addition, intramolecular carbopalladation, C–H bond activation, and migratory insertion sequence. The M06L/def2-TZVPP//BP86/6-31G(d,p)/LANL2DZ level of theory used and the inclusion of solvent effects provide results in good agreement with the experimental data. The C–H bond activation step proceeds via a concerted outer-sphere metallation deprotonation mechanism that explains the absence of a measurable kinetic isotopic effect. The subsequent intermolecular migratory insertion of arynes is significantly faster than the insertion of internal alkynes. Furthermore, the regioselectivities calculated in the case of unsymmetrical reactants are remarkably close to the experimental values. Evaluation of the potential energy surfaces for specific substrates provides an explanation for the lack of product formation observed experimentally. Finally, the computational and experimental analyses of potential side reactions are also presented and support the initially proposed mechanism.

Inhibitors of HDAC6 have attractive potential in numerous cancers. HDAC6 inhibitors to date target the catalytic domains, but targeting the unique zinc-finger ubiquitin-binding domain (Zf-UBD) of HDAC6 may be an attractive alternative strategy. We developed X-ray crystallography and biophysical assays to identify and characterize small molecules capable of binding to the Zf-UBD and competing with ubiquitin binding. Our results revealed two adjacent ligand-able pockets of HDAC6 Zf-UBD and the first functional ligands for this domain.

Herein we describe a rhodium-catalyzed enantioselective isomerization of meso-oxabicyclic alkenes to 1,2-naphthalene oxides. These potentially useful building blocks can be accessed in moderate to excellent yields with impressive enantioselectivities. Additionally, experimental findings supported by preliminary computations suggest that ring-opening reactions of bridgehead disubstituted oxabicyclic alkenes proceed through the intermediacy of these epoxides and may point to a kinetically and thermodynamically favored reductive elimination as the origin for the observed enantioselectivities.

Difficulties associated with handling H2 and CO in metal-catalyzed processes have led to the development of chemical surrogates to these species. Despite many successful examples using this strategy, the application of convenient hydrogen halide (HX) surrogates in catalysis has lagged behind considerably. We now report the use of ammonium halides as HX surrogates to accomplish a Pd-catalyzed hydrohalogenation of enynes. These safe and practical salts avoid many drawbacks associated with traditional HX sources including toxicity and corrosiveness. Experimental and computational studies support a reaction mechanism involving a crucial E-to-Z vinyl–Pd isomerization and a carbon–halogen bond-forming reductive elimination. Furthermore, rare examples of C(sp3)–Br and −Cl reductive elimination from Pd(II) as well as transfer hydroiodination using 1-iodobutane as an alternate HI surrogate are also presented.

The synthesis of chiral variants of monodentate trialkyl and dialkylbiaryl phosphine ligands elaborated on the binepine scaffold is described. Their application in the Pd-catalyzed intramolecular asymmetric α-arylation of aldehydes and the intermolecular asymmetric γ-arylation of α,β-unsaturated aldehydes provides a mean of validating the design of these ligands. For the first reaction, excellent reactivities have been obtained while only modest enantioselectivities were measured. Aside from enantioselectivity, the second reaction offers additional challenges associated with intramolecularity and regioselectivity. With the formal chiral trialkyl monodentate phosphine ligands, good yield, high olefin stereocontrol, and perfect γ-selectivity were obtained while the enantioselectivity remained in the low but promising range.

The origin of the regio- and stereocontrol in the Pd-catalyzed γ-arylation of α,β-unsaturated aldehydes was theoretically investigated. The reaction proceeds via isomerization of different Pd intermediates followed by reductive elimination. Up to 10 Pd isomers were identified and are in equilibrium controlled by an unprecedented swinging palladium mechanism. The subsequent reductive elimination step showed that the formation of the favored γ-arylated product was achieved by a bending of the aryl moiety. Computational studies also shed light on the mechanism of the arylation reaction and are in good agreement with the experimental observations where only the γ-arylated product was detected. All geometries were optimized by density functional theory using the B3LYP functional with standard double-ζ basis set (LANL2DZ) and effective core potentials for the palladium center and the 6-311G(d,p) basis sets for other atoms. The addition of dispersion forces and solvent corrections were found to play an important role in the description of the system.

Using benzyl methyl carbonates as substrate, a series of α-branched aldehydes is benzylated.

A palladium-catalyzed benzylation of α-branched aldehydes has been developed using benzyl methyl carbonates. The method gives access to congested quaternary centers in the vicinity of one of the most sensitive carbonyl functionalities and displays unprecedented generality with respect to both coupling partners. Evidence for the direct involvement of a Pd-η(3)-benzyl intermediate is provided. Extension of this strategy to the γ-benzylation of α,β-unsaturated aldehydes is further demonstrated.