Computationally Guided Ligand Discovery from Compound Libraries and Discovery of a New Class of Ligands for Ni-Catalyzed Cross-Electrophile Coupling of Challenging Quinoline Halides.

Although screening technology has heavily impacted the fields of metal catalysis and drug discovery, its application to the discovery of new catalyst classes has been limited. The diversity of on- and off-cycle pathways, combined with incomplete mechanistic understanding, means that screens of potential new ligands have thus far been guided by intuitive analysis of the metal binding potential. This has resulted in the discovery of new classes of ligands, but the low hit rates have limited the use of this strategy because large screens require considerable cost and effort. Here, we demonstrate a method to identify promising screening directions via simple and scalable computational and linear regression tools that leads to a substantial improvement in hit rate, enabling the use of smaller screens to find new ligands. The application of this approach to a particular example of Ni-catalyzed cross-electrophile coupling of aryl halides with alkyl halides revealed a previously overlooked trend: reactions with more electron-poor amidine ligands result in a higher yield. Focused screens utilizing this trend were more successful than serendipity-based screening and led to the discovery of two new types of ligands, pyridyl oxadiazoles and pyridyl oximes. These ligands are especially effective for couplings of bromo- and chloroquinolines and isoquinolines, where they are now the state of the art. The simplicity of these models with parameters derived from metal-free ligand structures should make this approach scalable and widely accessible.

Computational Methods Enable the Prediction of Improved Catalysts for Nickel-Catalyzed Cross-Electrophile Coupling.

Cross-electrophile coupling has emerged as an attractive and efficient method for the synthesis of C(sp2)-C(sp3) bonds. These reactions are most often catalyzed by nickel complexes of nitrogenous ligands, especially 2,2'-bipyridines. Precise prediction, selection, and design of optimal ligands remains challenging, despite significant increases in reaction scope and mechanistic understanding. Molecular parameterization and statistical modeling provide a path to the development of improved bipyridine ligands that will enhance the selectivity of existing reactions and broaden the scope of electrophiles that can be coupled. Herein, we describe the generation of a computational ligand library, correlation of observed reaction outcomes with features of the ligands, and the in silico design of improved bipyridine ligands for Ni-catalyzed cross-electrophile coupling. The new nitrogen-substituted ligands display a 5-fold increase in selectivity for product formation versus homodimerization when compared to the current state of the art. This increase in selectivity and yield was general for several cross-electrophile couplings, including the challenging coupling of an aryl chloride with an N-alkylpyridinium salt.

Metal-Free Electrochemical Reduction of Disulfides in an Undivided Cell under Mass Transfer Control.

Electroorganic synthesis is generally considered to be a green alternative to conventional redox reactions. Electrochemical reductions, however, are less advantageous in terms of sustainability, as sacrificial metal anodes are often employed. Divided cell operation avoids contact of the reduction products with the anode and allows for convenient solvent oxidation, enabling metal free greener electrochemical reductions. However, the ion exchange membranes required for divided cell operation on a commercial scale are not amenable to organic solvents, which hinders their applicability. Herein, we demonstrate that electrochemical reduction of oxidatively sensitive compounds can be carried out in an undivided cell without sacrificial metal anodes by controlling the mass transport to a small surface area electrode. The concept is showcased by an electrochemical method for the reductive cleavage of aryl disulfides. Fine tuning of the electrode surface area and current density has enabled the preparation of a wide variety of thiols without formation of any oxidation side products. This strategy is anticipated to encourage further research on greener, metal free electrochemical reductions.

Fast detection of liver fibrosis with collagen-binding single-nanometer iron oxide nanoparticles via T1-weighted MRI.

SNIO-CBP, a single-nanometer iron oxide (SNIO) nanoparticle functionalized with a type I collagen-binding peptide (CBP), was developed as a T1-weighted MRI contrast agent with only endogenous elements for fast and noninvasive detection of liver fibrosis. SNIO-CBP exhibits 6.7-fold higher relaxivity compared to a molecular gadolinium-based collagen-binding contrast agent CM-101 on a per CBP basis at 4.7 T. Unlike most iron oxide nanoparticles, SNIO-CBP exhibits fast elimination from the bloodstream with a 5.7 min half-life, high renal clearance, and low, transient liver enhancement in healthy mice. We show that a dose of SNIO-CBP that is 2.5-fold lower than that for CM-101 has comparable imaging efficacy in rapid (within 15 min following intravenous injection) detection of hepatotoxin-induced liver fibrosis using T1-weighted MRI in a carbon tetrachloride-induced mouse liver injury model. We further demonstrate the applicability of SNIO-CBP in detecting liver fibrosis in choline-deficient L-amino acid-defined high-fat diet mouse model of nonalcoholic steatohepatitis. These results provide a platform with potential for the development of high relaxivity, gadolinium-free molecular MRI probes for characterizing chronic liver disease.

Enabling Suzuki-Miyaura coupling of Lewis-basic arylboronic esters with a nonprecious metal catalyst.

The high cost and negative environmental impact of precious metal catalysts has led to increased demand for nonprecious alternatives for widely practiced reactions such as the Suzuki-Miyaura coupling (SMC). Ni-catalyzed versions of this reaction have failed to achieve high reactivity with Lewis-basic arylboron nucleophiles, especially pinacolboron esters. We describe the development of (PPh2Me)2NiCl2 as an inexpensive and air-stable precatalyst that addresses this challenge. Under activation by n-BuMgCl, this complex can catalyze the coupling of synthetically important heteroaryl pinacolborons with heteroaryl halides. Mildly basic conditions (aqueous K3PO4) allow the reaction to tolerate sensitive functional groups that were incompatible with other Ni-SMC methods. Experimental and computational studies suggest that catalyst inhibition by substitution of PPh2Me from Ni(ii) intermediates by Lewis basic reactants and products is disfavored relative to more commonly employed ligands in the Ni-SMC, which allows it to operate efficiently in the presence of Lewis bases such as unhindered pyridines.

Zinc-Free, Scalable Reductive Cross-Electrophile Coupling Driven by Electrochemistry in an Undivided Cell.

Nickel-catalyzed reductive cross-electrophile coupling reactions are becoming increasingly important in organic synthesis, but application at scale is limited by three interconnected challenges: a reliance on amide solvents (complicated workup, regulated), the generation of stoichiometric Zn salts (complicated isolation, waste disposal issue), and mixing/activation challenges of zinc powder. We show here an electrochemical approach that addresses these three issues: the reaction works in acetonitrile with diisopropylethylamine as the terminal reductant in a simple undivided cell (graphite(+)/nickel foam(-)). The reaction utilizes a combination of two ligands, 4,4'-di-tert-butyl-2,2'-bipyridine and 4,4',4''-tri-tert-butyl-2,2':6',2''-terpyridine. Studies show that, alone, the bipyridine nickel catalyst predominantly forms protodehalogenated aryl and aryl dimer, whereas the terpyridine nickel catalyst predominantly forms bialkyl and product. By combining these two unselective catalysts, a tunable, general system results because excess radical formed by the terpyridine catalyst can be converted to product by the bipyridine catalyst. As the aryl bromide becomes more electron rich, the optimal ratio shifts to have more of the bipyridine nickel catalyst. Lastly, examination of a variety of flow-cell configurations establishes that batch recirculation can achieve higher productivity (mmol product/time/electrode area) than single-pass, that high flow rates are essential to maximizing current, and that two flow cells in parallel can nearly halve the reaction time. The resulting reaction is demonstrated on gram scale and should be scalable to kilogram scale.

Single-nanometer iron oxide nanoparticles as tissue-permeable MRI contrast agents.

Magnetic nanoparticles are robust contrast agents for MRI and often produce particularly strong signal changes per particle. Leveraging these effects to probe cellular- and molecular-level phenomena in tissue can, however, be hindered by the large sizes of typical nanoparticle contrast agents. To address this limitation, we introduce single-nanometer iron oxide (SNIO) particles that exhibit superparamagnetic properties in conjunction with hydrodynamic diameters comparable to small, highly diffusible imaging agents. These particles efficiently brighten the signal in T1-weighted MRI, producing per-molecule longitudinal relaxation enhancements over 10 times greater than conventional gadolinium-based contrast agents. We show that SNIOs permeate biological tissue effectively following injection into brain parenchyma or cerebrospinal fluid. We also demonstrate that SNIOs readily enter the brain following ultrasound-induced blood-brain barrier disruption, emulating the performance of a gadolinium agent and providing a basis for future biomedical applications. These results thus demonstrate a platform for MRI probe development that combines advantages of small-molecule imaging agents with the potency of nanoscale materials.

Scalable Synthesis of InAs Quantum Dots Mediated through Indium Redox Chemistry.

Next-generation optoelectronic applications centered in the near-infrared (NIR) and short-wave infrared (SWIR) wavelength regimes require high-quality materials. Among these materials, colloidal InAs quantum dots (QDs) stand out as an infrared-active candidate material for biological imaging, lighting, and sensing applications. Despite significant development of their optical properties, the synthesis of InAs QDs still routinely relies on hazardous, commercially unavailable precursors. Herein, we describe a straightforward single hot injection procedure revolving around In(I)Cl as the key precursor. Acting as a simultaneous reducing agent and In source, In(I)Cl smoothly reacts with a tris(amino)arsenic precursor to yield colloidal InAs quantitatively and at gram scale. Tuning the reaction temperature produces InAs cores with a first excitonic absorption feature in the range of 700-1400 nm. A dynamic disproportionation equilibrium between In(I), In metal, and In(III) opens up additional flexibility in precursor selection. CdSe shell growth on the produced cores enhances their optical properties, furnishing particles with center emission wavelengths between 1000 and 1500 nm and narrow photoluminescence full-width at half-maximum (FWHM) of about 120 meV throughout. The simplicity, scalability, and tunability of the disclosed precursor platform are anticipated to inspire further research on In-based colloidal QDs.

Blue Light Emitting Defective Nanocrystals Composed of Earth-Abundant Elements.

Copper-based ternary (I-III-VI) chalcogenide nanocrystals (NCs) are compositionally-flexible semiconductors that do not contain lead (Pb) or cadmium (Cd). Cu-In-S NCs are the dominantly studied member of this important materials class and have been reported to contain optically-active defect states. However, there are minimal reports of In-free compositions that exhibit efficient photoluminescence (PL). Here, we report a novel solution-phase synthesis of ≈4 nm defective nanocrystals (DNCs) composed of copper, aluminum, zinc, and sulfur with ≈20 % quantum yield and an attractive PL maximum of 450 nm. Extensive spectroscopic characterization suggests the presence of highly localized electronic states resulting in reasonably fast PL decays (≈1 ns), large vibrational energy spacing, small Stokes shift, and temperature-independent PL linewidth and PL lifetime (between room temperature and ≈5 K). Furthermore, density functional theory (DFT) calculations suggest PL transitions arise from defects within a CuAl5 S8 crystal lattice, which supports the experimental observation of highly-localized states. The results reported here provide a new material with unique optoelectronic characteristics that is an important analog to well-explored Cu-In-S NCs.

Development of a quantitative polymerase chain reaction assay and environmental DNA sampling methods for Giant Gartersnake (Thamnophis gigas).

The Giant Gartersnake (Thamnophis gigas) is a low density visually evasive species with a low detection probability based on standard field survey methods (e.g., traps, visual census). Habitat loss has resulted in extirpations or serious declines for T. gigas populations throughout the southern two thirds of its historic range. Uncertainty regarding its current distribution and occupancy present management challenges for the species. Enhancing survey sensitivity through development of environmental DNA sampling (eDNA) methods would improve compliance monitoring under the Endangered Species Act, recovery planning for T. gigas, and evaluation of California's Central Valley tule marsh habitat on which this species depends. To address these needs, we designed and validated diagnostic quantitative Polymerase Chain Reaction (qPCR) assays for identifying portions of the Cytochrome B (CytB) and the Nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit 4 (ND4) genes of the T. gigas mitochondrial genome. The designed ND4 qPCR assay was not specific to T. gigas DNA and amplified DNA from a closely related and spatially co-occurring Thamnophis species (T.s. fitchi). The CytB T. gigas qPCR assay proved specific to a species level with a sensitivity that reliably detected T. gigas DNA at a concentration of 2.0x10-5 ng µL-1. To assess detection range, coordinated field sampling was conducted at aquatic sites with an observed and documented population of T. gigas. The T. gigas qPCR assay reliably detected DNA from samples taken 300m downstream from the known source. We then used environmental eDNA sampling and qPCR analysis to augment unsuccessful trap surveys in the southern range of T. gigas and detected DNA in 28 of the 52 locations sampled, confirming that T. gigas was still present at some sites where physical trapping failed to identify presence. QPCR-based DNA detection coupled with eDNA sampling methods provides an effective means to obtain critical population metrics from this otherwise cryptic, federally protected and hard to study organism, offering great promise for elucidating patterns of occupancy with greater efficiency and at far less cost than trapping methods, particularly where detection probabilities are low.

Zinc Thiolate Enables Bright Cu-Deficient Cu-In-S/ZnS Quantum Dots.

Copper indium sulfide (CIS) colloidal quantum dots (QDs) are a promising candidate for commercially viable QD-based optical applications, for example as colloidal photocatalysts or in luminescent solar concentrators (LSCs). CIS QDs with good photoluminescence quantum yields (PLQYs) and tunable emission wavelength via size and composition control are previously reported. However, developing an understanding and control over the growth of electronically passivating inorganic shells would enable further improvements of the photophysical properties of CIS QDs. To improve the optical properties of CIS QDs, the focus is on the growth of inorganic shells via the popular metal-carboxylate/alkane thiol decomposition reaction. 1) The role of Zn-carboxylate and Zn-thiolate on the formation of ZnS shells on Cu-deficient CIS (CDCIS) QDs is studied, 2) this knowledge is leveraged to yield >90% PLQY CDCIS/ZnS core/shell QDs, and 3) a mechanism for ZnS shells grown from zinc-carboxylate/alkane thiol decomposition is proposed.

Electrochemical Nickel Catalysis for Sp2-Sp3 Cross-Electrophile Coupling Reactions of Unactivated Alkyl Halides.

A constant-current electrochemical method for reducing catalytic nickel complexes in sp2-sp3 cross-electrophile coupling reactions has been developed. The electrochemical reduction provides reliable nickel catalyst activation and turnover and offers a tunable parameter for reaction optimization, in contrast to more standard activated metal powder reductants. The electrochemical reactions give yields (i.e., 51-86%) and selectivities as high or superior to those using metal powder reductants and provide access to a wider substrate scope.

Coupling of Challenging Heteroaryl Halides with Alkyl Halides via Nickel-Catalyzed Cross-Electrophile Coupling.

Despite their importance, the synthesis of alkylated heterocycles from the cross-coupling of Lewis basic nitrogen heteroaryl halides with alkyl halides remains a challenge. We report here a general solution to this challenge enabled by a new collection of ligands based around 2-pyridyl-N-cyanocarboxamidine and 2-pyridylcarboxamidine cores. Both primary and secondary alkyl halides can be coupled with 2-, 3-, and 4-pyridyl halides as well as other more complex heterocycles in generally good yields (41 examples, 69% ave yield).

Exceedingly small iron oxide nanoparticles as positive MRI contrast agents.

Medical imaging is routine in the diagnosis and staging of a wide range of medical conditions. In particular, magnetic resonance imaging (MRI) is critical for visualizing soft tissue and organs, with over 60 million MRI procedures performed each year worldwide. About one-third of these procedures are contrast-enhanced MRI, and gadolinium-based contrast agents (GBCAs) are the mainstream MRI contrast agents used in the clinic. GBCAs have shown efficacy and are safe to use with most patients; however, some GBCAs have a small risk of adverse effects, including nephrogenic systemic fibrosis (NSF), the untreatable condition recently linked to gadolinium (Gd) exposure during MRI with contrast. In addition, Gd deposition in the human brain has been reported following contrast, and this is now under investigation by the US Food and Drug Administration (FDA). To address a perceived need for a Gd-free contrast agent with pharmacokinetic and imaging properties comparable to GBCAs, we have designed and developed zwitterion-coated exceedingly small superparamagnetic iron oxide nanoparticles (ZES-SPIONs) consisting of ∼3-nm inorganic cores and ∼1-nm ultrathin hydrophilic shell. These ZES-SPIONs are free of Gd and show a high T1 contrast power. We demonstrate the potential of ZES-SPIONs in preclinical MRI and magnetic resonance angiography.

New ligands for nickel catalysis from diverse pharmaceutical heterocycle libraries.

Ligands are essential for controlling the reactivity and selectivity of reactions catalysed by transition metals. Access to large phosphine ligand libraries has become an essential tool for the application of metal-catalysed reactions industrially, but these existing libraries are not well suited to new catalytic methods based on non-precious metals (for example, Ni, Cu and Fe). The development of the requisite nitrogen- and oxygen-based ligand libraries lags far behind that of the phosphines and the development of new libraries is anticipated to be time consuming. Here we show that this process can be dramatically accelerated by mining for new ligands in a typical pharmaceutical compound library that is rich in heterocycles. Using this approach, we were able to screen a structurally diverse set of compounds with minimal synthetic effort and identify several new ligand classes for nickel-catalysed cross-electrophile coupling. These new ligands gave improved yields for challenging cross-couplings of pharmaceutically relevant substrates compared with those of those of previously published ligands.

Development of a concise, asymmetric synthesis of a smoothened receptor (SMO) inhibitor: enzymatic transamination of a 4-piperidinone with dynamic kinetic resolution.

A concise, asymmetric synthesis of a smoothened receptor inhibitor (1) is described. The synthesis features an enzymatic transamination with concurrent dynamic kinetic resolution (DKR) of a 4-piperidone (4) to establish the two stereogenic centers required in a single step. This efficient reaction affords the desired anti amine (3) in >10:1 dr and >99% ee. The title compound is prepared in only five steps with 40% overall yield.

Photochemical synthesis of 3-alkynals from 1-alkynoxy-9,10-anthraquinones.

Photolysis of 1-(3-alkynoxy)-9,10-anthraquinones in deoxygenated methanol leads to moderate yields (35-45%) of 3-alkynals along with the unexpected formation of diacetals. Reaction of these 3-alkynals with Grignard and Wittig reagents occurs nearly quantitatively without rearrangement to their 2,3-dienal isomers.

Search for solutions to the reactivity and selectivity problems in enyne metathesis.

Enyne metathesis is a powerful carbon-carbon bond-forming reaction to generate 1,3-dienes from an alkyne and an alkene. Different from the diene and diyne metathesis, the enyne metathesis suffers from both regio- and stereoselectivity problems, yet there is no general solution to these problems. This Account briefly describes the evolution of various new strategies and substrate platforms from these laboratories to address the reactivity and selectivity issues in the enyne metathesis processes.

Regiochemical control in the metal-catalyzed transposition of allylic silyl ethers.

A novel mode of regiochemical control over the allylic [1,3]-transposition of silyloxy groups catalyzed by Re2O7 has been developed. This strategy relies on a cis-oriented vinyl boronate, generated from the Alder-ene reaction of homoallylic silyl ethers and alkynyl boronates, to trap out the allylic hydroxyl group. The resulting cyclic boronic acids are excellent partners for cross-coupling reactions. High chirality transfer is observed for the rearrangement of enantioenriched allylic silyl ethers.