Complementary Reactivity Research Articles

Chemoselective Cleavage of Acylsulfonamides and Sulfonamides by Aluminum Halides.

The chemoselective cleavage of C-N bonds of amides, sulfonamides, and acylsulfonamides by aluminum halides is described. AlCl3 and AlI3 display complementary reactivities toward N-alkyl and N-acyl moieties. N-Alkylacylsulfonamides, secondary N-(tert-butyl)sulfonamides, and tertiary N-(tert-butyl)amides undergo N-dealkylation upon treatments with AlI3 generated in situ from aluminum and iodine in acetonitrile. In contrast, AlCl3 preferentially cleaves N-acyl groups of tertiary and secondary sulfonamides.

Synergistic Catalyst-Mediator Pairings for Electroreductive Cross-Electrophile Coupling Reactions.

Electroreductive cross-electrophile coupling (eXEC) represents an attractive approach for the direct C-C coupling of two electrophiles but generally suffers from limited scope compared to reactions with chemical reductants. This work demonstrates that mediator-assisted electrocatalysis is a general strategy for the enhancement of eXEC reactions. While eXEC reactions catalyzed by a variety of widely available ligand-nickel complexes are low yielding when applied to reductive couplings of challenging substrates, reactions with the same complexes generate products in near-quantitative yield when a redox-matched mediator is included. We identify a library of catalyst-mediator systems that provide complementary reactivity and enable coupling of a range of substrate classes in high yields. These catalyst systems are applicable to both chemical and electrochemical reduction, but some require electroreduction due to the low potentials required for activation. Finally, mechanistic studies offer insights that facilitate catalyst-mediator pairing.

Site-Selective α-C-H Functionalization of Trialkylamines via Reversible Hydrogen Atom Transfer Catalysis.

Trialkylamines are widely found in naturally occurring alkaloids, synthetic agrochemicals, biological probes, and especially pharmaceuticals agents and preclinical candidates. Despite the recent breakthrough of catalytic alkylation of dialkylamines, the selective α-C(sp3)-H bond functionalization of widely available trialkylamine scaffolds holds promise to streamline complex trialkylamine synthesis, accelerate drug discovery, and execute late-stage pharmaceutical modification with complementary reactivity. However, the canonical methods always result in functionalization at the less-crowded site. Herein, we describe a solution to switch the reaction site through fundamentally overcoming the steric control that dominates such processes. By rapidly establishing an equilibrium between α-amino C(sp3)-H bonds and a highly electrophilic thiol radical via reversible hydrogen atom transfer, we leverage a slower radical-trapping step with electron-deficient olefins to selectively forge a C(sp3)-C(sp3) bond with the more-crowded α-amino radical, with the overall selectivity guided by the Curtin-Hammett principle. This subtle reaction profile has unlocked a new strategic concept in direct C-H functionalization arena for forging C-C bonds from a diverse set of trialkylamines with high levels of site selectivity and preparative utility. Simple correlation of site selectivity and 13C NMR shift serves as a qualitative predictive guide. The broad consequences of this dynamic system, together with the ability to forge N-substituted quaternary carbon centers and implement late-stage functionalization techniques, hold potential to streamline complex trialkylamine synthesis and accelerate small-molecule drug discovery.

A relay catalysis strategy for enantioselective nickel-catalyzed migratory hydroarylation forming chiral α-aryl alkylboronates

A relay catalysis strategy for enantioselective nickel-catalyzed migratory hydroarylation forming chiral α-aryl alkylboronates

Chemical proteomic analysis of palmostatin beta-lactone analogs that affect N-Ras palmitoylation

S-Palmitoylation is a reversible post-translational lipid modification that regulates protein trafficking and signaling. The enzymatic depalmitoylation of proteins is inhibited by the beta-lactones Palmostatin M and B, which have been found to target several serine hydrolases. In efforts to better understand the mechanism of action of Palmostatin M, we describe herein the synthesis, chemical proteomic analysis, and functional characterization of analogs of this compound. We identify Palmostatin M analogs that maintain inhibitory activity in N-Ras depalmitoylation assays while displaying complementary reactivity across the serine hydrolase class as measured by activity-based protein profiling. Active Palmostatin M analogs inhibit the recently characterized ABHD17 subfamily of depalmitoylating enzymes, while sparing other candidate depalmitoylases such as LYPLA1 and LYPLA2. These findings improve our understanding of the structure–activity relationship of Palmostatin M and refine the set of serine hydrolase targets relevant to the compound’s effects on N-Ras palmitoylation dynamics.

ChemBead Enabled High-Throughput Cross-Electrophile Coupling Reveals a New Complementary Ligand.

High-throughput experimentation (HTE) methods are central to modern medicinal chemistry. While many HTE approaches to C-N and Csp2 -Csp2 bonds are available, options for Csp2 -Csp3 bonds are limited. We report here how the adaptation of nickel-catalyzed cross-electrophile coupling of aryl bromides with alkyl halides to HTE is enabled by AbbVie ChemBeads technology. By using this approach, we were able to quickly map out the reactivity space at a global level with a challenging array of 3×222 micromolar reactions. The observed hit rate (56 %) is competitive with other often-used HTE reactions and the results are scalable. A key to this level of success was the finding that bipyridine 6-carboxamidine (BpyCam), a ligand that had not previously been shown to be optimal in any reaction, is as general as the best-known ligands with complementary reactivity. Such "cryptic" catalysts may be common and modern HTE methods should facilitate the process of finding these catalysts.

Complementary Reactivity in Selective Radical Processes: Electrochemistry of Oxadiazolines to Quinazolinones.

Electrochemistry has recently emerged as a sustainable approach for efficiently generating radical intermediates utilizing eco-friendly electric energy. An electrochemical process was developed to transform 1,2,4-oxadiazolines under mild conditions. The electrochemical N-O bond cleavage at a controlled oxidation potential led to the selective synthesis of quinazolinone derivatives that could not be obtained by photocatalytic radical processes, indicating complementary reactivities in radical processes. The electrochemical reaction pathways were fully revealed by density functional theory-based investigations.

Catalysis of Redox-Neutral Reactions By Electron Exchange between Electrodes and Organic Compounds

To most chemists the term ‘electrocatalysis’ is known as the facilitation of a heterogeneous electron transfer via a chemical interaction between the electrode and a substrate [1]. The opposite case, the utilization of a heterogeneous electron exchange to catalyze a chemical reaction (‘electrochemical catalysis’), is a much less known but yet a very powerful approach in electrosynthesis [2]. Here, the injection (or removal) of an electron into (or from) a substrate triggers a redox-neutral reaction (e.g. a molecular rearrangement) that may otherwise require harsh conditions and/or the use of reagents. Such processes involve the electrogeneration of an ionic or radical ionic species, which after a coupled chemical step either undergoes a backward electron exchange with the electrode (ECEb mechanism) or triggers a chain process in the bulk solution. Under these circumstances, sub-stoichiometric amounts of charge are sufficient to achieve a full conversion and conceptionally, the electrons and holes can be understood as being catalysts.In this contribution, the concept of electrochemical catalysis will be illustrated using the Newman-Kwart rearrangement (NKR) of O-aryl thiocarbamates 2 to the corresponding S-aryl compounds 3 as an example (see scheme below) [3]. Generally, the NKR represents the key-reaction in the three-step synthesis of thiophenols 4 from phenols 1 and proceeds between 200 and 300 °C [3]. Electrochemical catalysis, however, allows for operation at room temperature and provides a complementary reactivity with respect to the arene substitution [3,4]. The results of batch and flow electrolysis will be presented, along with a detailed mechanistic analysis based on cyclic voltammetry studies, control experiments, and quantum chemical calculations.

Cyclic Diaryl λ3‐Bromanes as Original Aryne Precursors

Despite the widespread application of hypervalent iodines, the corresponding l 3 -bromanes are less explored. Herein we report a general, safe, and high-yielding strategy to access cyclic diaryl l 3 - bromanes. These unique compounds feature appealing and complementary reactivity to l 3 -iodanes, generating arynes under mild reaction conditions and in a presence of a weak base. Accordingly, formal meta -selective transition metal-free C-O and C-N couplings may be achieved. The mechanistic studies unambiguously support the aryne generation mechanism.

Interactions that shape the complementary reactivities of the flavins of bifurcating electron transfer flavoproteins

Flavin-based electron bifurcation accomplishes the feat of producing highly-reducing electrons at the expense of a less reactive source. By consuming two modestly-reducing electrons from NADH for each one electron transferred to the more reducing ferredoxin acceptor, the process conforms to the laws of thermodynamics. Critical mechanistic ingredients include coupling between two separate electron transfer reactions, a protein conformation change preventing the high-energy electron from exploiting the more exergonic path, and high-efficiency transfer of that electron to the more reducing acceptor instead. All of this is accomplished based on the dynamic structure of the protein, in conjunction with the distinctive electrochemical reactivity of flavins. We are combining QM/MM approaches with site-directed mutagenesis and electrochemistry to clarify how the protein enforces one-electron chemistry at the electron transfer site but bifurcation at the other. Complementary studies seek to identify covalent modifications that accumulate on one of the two flavins, especially at high pH.

Mediator-Enabled Electrocatalysis with Ligandless Copper for Anaerobic Chan-Lam Coupling Reactions.

Simple copper salts serve as catalysts to effect C-X bond-forming reactions in some of the most utilized transformations in synthesis, including the oxidative coupling of aryl boronic acids and amines. However, these Chan-Lam coupling reactions have historically relied on chemical oxidants that limit their applicability beyond small-scale synthesis. Despite the success of replacing strong chemical oxidants with electrochemistry for a variety of metal-catalyzed processes, electrooxidative reactions with ligandless copper catalysts are plagued by slow electron-transfer kinetics, irreversible copper plating, and competitive substrate oxidation. Herein, we report the implementation of substoichiometric quantities of redox mediators to address limitations to Cu-catalyzed electrosynthesis. Mechanistic studies reveal that mediators serve multiple roles by (i) rapidly oxidizing low-valent Cu intermediates, (ii) stripping Cu metal from the cathode to regenerate the catalyst and reveal the active Pt surface for proton reduction, and (iii) providing anodic overcharge protection to prevent substrate oxidation. This strategy is applied to Chan-Lam coupling of aryl-, heteroaryl-, and alkylamines with arylboronic acids in the absence of chemical oxidants. Couplings under these electrochemical conditions occur with higher yields and shorter reaction times than conventional reactions in air and provide complementary substrate reactivity.

Operando Fourier-transform infrared-mass spectrometry reactor cell setup for heterogeneous catalysis with glovebox transfer process to surface-chemical characterization.

We describe a new type of operando Fourier transform infrared (FTIR)-mass spectrometry setup for surface-chemical and reactivity characterization of heterogeneous catalysts. On the basis of a sophisticated all-quartz FTIR reactor cell, capable of operating between room temperature and 1000 °C in reactive gas atmospheres, the setup offers a unique opportunity to simultaneously collect and accordingly correlate FTIR surface-chemical adsorption data of the active catalyst state and FTIR gas phase data with complementary reactivity data obtained via mass spectrometry in situ. The full set of catalytic operation modes (recirculating static and flow reactor conditions) is accessible and can be complemented with a variety of temperature-programmed reaction modes or thermal desorption. Due to the unique transfer process involving a home-built portable glovebox to avoid air exposure, a variety of complementary quasi in situ characterization methods for the pre- and post-reaction catalyst states become accessible. We exemplify the capabilities for additional x-ray photoelectron spectroscopy characterization of surface-chemical states, highlighting the unique strength of combining adsorption, electronic structure, and reactivity data to gain detailed insight into the reactive state of a Cu/ZrO2 heterogeneous catalyst during methanol steam reforming operation.

Surfactant-mediated thioglycosylation of 1-hydroxy sugars in water.

Thioglycosides are an important class of sugars, since they can be used as non-ionic biosurfactants, biomimetic glycosides, and building blocks for carbohydrate synthesis. Previously, Brønsted- or Lewis-acid-catalyzed dehydrative glycosylations between a 1-hydroxy sugar and a thiol have been reported to yield open-chain dithioacetal sugars as the major products instead of the desired thioglycosides. These dithioacetal sugars are by-products derived from the endocyclic bond cleavage of the thioglycosides. Herein, we report dehydrative glycosylation in water mediated by a Brønsted acid-surfactant combined catalyst (BASC). Glycosylations between 1-hydroxy furanosyl/pyranosyl sugars and primary, secondary, and tertiary aliphatic/aromatic thiols in the presence of dodecyl benzenesulfonic acid (DBSA) provided the thioglycoside products in moderate to good yields. Microwave irradiation led to improvements in the yields and a shortening of the reaction time. Remarkably, open-chain dithioacetal sugars were not detected in the DBSA-mediated glycosylations in water. This method is a simple, convenient, and rapid approach to produce a library of thioglycosides without the requirement of anhydrous conditions. Moreover, this work also provides an excellent example of complementary reactivity profiles of glycosylation in organic solvents and water.

Synthesis of the hyper-branched core tetrasaccharide motif of chloroviruses.

Chemical synthesis of complex oligosaccharides, especially those possessing hyper-branched structures with one or multiple 1,2-cis glycosidic bonds, is a challenging task. Complementary reactivity of glycosyl donors and acceptors and proper tuning of the solvent/temperature/activator coupled with compromised glycosylation yields for sterically congested glycosyl acceptors are among several factors that make such syntheses daunting. Herein, we report the synthesis of a semi-conserved hyper-branched core tetrasaccharide motif from chloroviruses which are associated with reduced cognitive function in humans as well as in mouse models. The target tetrasaccharide contains four different sugar residues in which l-fucose is connected to d-xylose and l-rhamnose via a 1,2-trans glycosidic bond, whereas with the d-galactose residue is connected through a 1,2-cis glycosidic bond. A thorough and comprehensive study of various accountable factors enabled us to install a 1,2-cis galactopyranosidic linkage in a stereoselective fashion under [Au]/[Ag]-catalyzed glycosidation conditions en route to the target tetrasaccharide motif in 14 steps.

Unifying Conceptual Density Functional and Valence Bond Theory: The Hardness-Softness Conundrum Associated with Protonation Reactions and Uncovering Complementary Reactivity Modes.

In this study, we address the long-standing issue—arising prominently from conceptual density functional theory (CDFT)—of the relative importance of electrostatic, i.e., “hard–hard”, versus spin-pairing, i.e., “soft–soft”, interactions in determining regiochemical preferences. We do so from a valence bond (VB) perspective and demonstrate that VB theory readily enables a clear-cut resolution of both of these contributions to the bond formation/breaking process. Our calculations indicate that appropriate local reactivity descriptors can be used to gauge the magnitude of both interactions individually, e.g., Fukui functions or HOMO/LUMO orbitals for the spin-pairing/(frontier) orbital interactions and molecular electrostatic potentials (and/or partial charges) for the electrostatic interactions. In contrast to previous reports, we find that protonation reactions cannot generally be classified as either charge- or frontier orbital-controlled; instead, our results indicate that these two bonding contributions generally interplay in more subtle patterns, only giving the impression of a clear-cut dichotomy. Finally, we demonstrate that important covalent, i.e., spin pairing, reactivity modes can be missed when only a single spin-pairing/orbital interaction descriptor is considered. This study constitutes an important step in the unification of CDFT and VB theory.

Dual Nickel- and Photoredox-Catalyzed Reductive Cross-Coupling of Aryl Halides with Dichloromethane via a Radical Process.

The first catalytic strategy to harness a new chloromethane radical from dichloromethane under dual Ni/photoredox catalytic conditions has been developed. Compared with traditional two-electron reductive process associated with metallic reductants, this method via a single-electron approach can proceed under exceptionally mild conditions (visible light, ambient temperature, no strong base) and exhibits complementary reactivity patterns. It affords a broad scope of many functional groups, including alkenyl, which suffers cyclopropanation in previous routes. The diarylmethane-d2 compounds can be readily available with this transformation.

Abstract 6245: SQ3370 enhances the safety and therapeutic index of cytotoxic agents via local activation therapy with improved local and systemic immune response

Abstract With systemic chemotherapy, only 1-2% of the administered dose reaches a localized tumor, while the remaining leads to adverse off-target toxicities, including immunosuppression. Hence, there is a critical need to locally deliver cytotoxics directly to the tumor. Our patented approach (SQ3370) consists of: 1. SQL70 - a drug-activating biomaterial carrying no payload 2. SQP33 - a chemically-modified prodrug of doxorubicin (Dox) with attenuated activity. SQL70 is injected at the tumor site followed by SQP33 administered systemically. The prodrug is first captured by the biomaterial due to their complementary chemical reactivities. The active drug is then spontaneously released, providing local delivery directly to the tumor region while reducing systemic side effects. Previously, we have shown that the greater safety of SQP33 allows it to be given at over 38 times the dose of standard Dox in SQL70-injected mice. Pharmacokinetic and biodistribution studies in SQ3370-treated rodents and dogs show highly efficient capture and activation of the prodrug, likely due to the rapid reaction of SQP33 with SQL70. Without SQL70, SQP33 shows minimal spontaneous conversion to activated Dox. Additionally, after SQL70 injection, increased dosing of SQP33 led to higher active drug levels at the injection site but not to other tissues. These studies indicate that a single injection of SQL70 can selectively activate multiple doses of SQP33 at the target site, maximizing the local therapeutic index. Recent studies demonstrate that SQ3370 treatment enhances therapeutic response and survival in tumor-bearing mice: In a syngeneic MC38 colorectal cancer model, SQ3370 treatment showed significantly improved anti-tumor response and overall survival compared to conventional Dox therapy. In mice bearing two tumors, we observed that SQL70 injection at one tumor site followed by systemic SQP33 treatment induced an anti-tumor response in both the injected and non-injected tumors. Furthermore, we found that SQ3370 increased CD4 and CD8 TILs and decreased regulatory T-cells in both injected and non-injected tumors. These findings suggest that SQ3370 is capable of inducing an immune-mediated anti-tumor effect, thus expanding potential treatment options in the clinic and highlighting the advantages of immune-sparing cytotoxic therapy. Collectively, our results demonstrate that SQ3370 enables delivery of cytotoxic drugs to a target site while limiting exposure in off-target tissues in small and large animals, leading to improvements in both safety and efficacy. Citation Format: Nathan Yee, Sangeetha Srinivasan, Amir Mahmoodi, Michael Zakharian, Maksim Royzen, Jose Mejia Oneto. SQ3370 enhances the safety and therapeutic index of cytotoxic agents via local activation therapy with improved local and systemic immune response [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6245.

Cobalt-Catalyzed Cross-Couplings between Alkyl Halides and Grignard Reagents.

Metal-catalyzed cross-couplings have emerged as essential tools for the construction of C-C bonds. The identification of efficient catalytic systems as well as large substrate scope made these cross-couplings key reactions to access valuable molecules ranging from materials, agrochemicals to active pharmaceutical ingredients. They have been increasingly integrated in retrosynthetic plans, allowing shorter and original route development. Palladium-catalyzed cross-couplings still largely rule the field, with the most popular reactions in industrial processes being the Suzuki and Sonogashira couplings. However, the extensive use of palladium complexes raises several problems such as limited resources, high cost, environmental impact, and frequent need for sophisticated ligands. As a consequence, the use of nonprecious and cheap metal catalysts has appeared as a new horizon in cross-coupling development. Over the last three decades, a growing interest has thus been devoted to Fe-, Co-, Cu-, or Ni-catalyzed cross-couplings. Their natural abundance makes them cost-effective, allowing the conception of more sustainable and less expensive chemical processes, especially for large-scale production of active molecules. In addition to these economical and environmental considerations, the 3d metal catalysts also exhibit complementary reactivity with palladium complexes, facilitating the use of alkyl halide partners due to the decrease of β-elimination side reactions. In particular, by using cobalt catalysts, numerous cross-couplings between alkyl halides and organometallics have been described. However, cobalt catalysis still stays far behind palladium catalysis in terms of popularity and applications, and the expansion of the substrate scope as well as the development of simple and robust catalytic systems remains an important challenge.In 2012, our group entered the cobalt catalysis field by developing a cobalt-catalyzed cross-coupling between C-bromo glycosides and Grignard reagents. The generality of the coupling allowed the preparation of a range of valuable C-aryl and C-vinyl glycoside building blocks. We then focused on the functionalization of saturated N-heterocycles, and a variety of halo-azetidines, -pyrrolidines, and -piperidines were successfully reacted with aryl and alkenyl Grignard reagents under cobalt catalysis. With the objective of preparing valuable α-aryl amides, a cobalt-catalyzed cross-coupling applied to α-bromo amides was studied and then extended to α-bromo lactams. Recently, we also reported an efficient and general cross-coupling involving cyclopropyl- and cyclobutyl-magnesium bromides. This method allows the alkylation of functionalized small strained rings by a range of primary and secondary alkyl halides.

Ligand-Controlled Regiodivergent Palladium-Catalyzed Hydrogermylation of Ynamides.

Ynamides are fascinating small molecules with complementary reactivities under radical, ionic, and metal-catalyzed conditions. We report herein synthetic and DFT investigations of palladium-catalyzed ligand-controlled regiodivergent hydrometalation reactions of ynamides. Germylated and stannylated enamides are obtained with excellent α,E- or β,E-selectivities and a broad functional group tolerance. Such a regiodivergent palladium-catalyzed process is unique in ynamide chemistry and allows for the elaboration of metalated enamides that are useful building blocks for cross-coupling reactions or heterocyclic chemistry. DFT calculations fully support the experimental data and demonstrate the crucial roles of the trans-geometry of the [H-Pd(L)-Ge] complex, as well as of the steric requirements of the phosphine ligand. In addition, these calculations support the prevalence of a hydro-palladation pathway over a metal palladation of the π system of the ynamide.

Specialized Olefin Metathesis Catalysts Featuring Unsymmetrical N-Heterocyclic Carbene Ligands Bearing N-(Fluoren-9-yl) Arm

Beneficial structural motifs from two known state-of-the-art olefin metathesis catalysts types, bearing unsymmetrical N-heterocyclic carbenes (uNHCs), were combined into a new hybridized design thereby translating the complementary beneficial reactivity demonstrated by their ‘parent’ complexes to the new N-fluorene derived olefin metathesis catalysts. Two chelating 2-iso-propoxy-benzylidene (Hoveyda-type) and two 3-phenyl-1H-inden-1-ylidene (indenylidene-type) complexes were successfully prepared by in situ generation of either the N′-mesityl (Mes) or N′-diisopropylphenyl (Dipp) derived uNHCs taking advantage of the thermal decomposition of the corresponding 2-(penta-fluorophenyl)-imidazolidines (NHC adducts). The new fluorene-derived catalysts mediate challenging olefin metathesis processes, such as α-olefin self-metathesis, with high selectivity and conversion.