Peripheral editing of complex molecules via C−H functionalization removes the pervasive retrosynthetic bias toward pre‐functionalization and taps into the innate, often subtle, stereoelectronic ...differences between C−H linkages. Using this approach, bioactive molecules and residues can be modified without being beholden to lengthy sequences, thus allowing biochemical hypotheses to be interrogated on accelerated timelines. Herein, the C−H functionalization paradigm is leveraged to tackle C7 C−H functionalization of the biologically important tryptophan core. The devised process, which was expanded to indolyl (and related) systems, utilizes an N‐bound unsymmetrical “designer” phosphine to direct C−H functionalization to the desired position while maintaining operational ease of directing group installation/removal. Quantum mechanically calculated steric properties and activation free energies suggest that this phosphine is hindered enough for favoring C−H functionalization over deactivation pathways but is still easily cleaved by nucleophiles. In addition, the process enables the direct C−H methylation, cyclopropanation, and arylation of tryptophan to yield unnatural amino acid (UAA) building blocks. As a testament to the versatility of this method, a solid phase peptide synthesis (SPPS)‐ready phosphinated tryptophan was incorporated into a pentapeptide and the C−H functionalization/dephosphination sequence was executed with ease. The utility of “on‐peptide” editing was exhibited through the late‐stage functionalization of several pentapeptides with a diverse set of C7 substituents on‐ and off‐resin.
Late-stage functionalization (LSF) of heteroarenes can dramatically accelerate SAR studies by enabling the installation of functional groups that would otherwise complicate a synthetic sequence. ...Although heteroaryl halides and boronic esters have well-established chemistries for LSF, alternatives that enable site-selective C–H functionalization are highly attractive. Recently, three unrelated cationic groups (phosphonium, pyridinium, and thianthrenium), which can replace C–H bonds late stage, have been identified as precursors to various functional groups. This review will discuss the synthesis and application of these three salts with an emphasis on their use for LSF and application to medicinal chemistry.
A two-carbon homologation of vinyl triflates and bromides for the synthesis of homoallylic nitro products is described. This palladium-catalyzed double coupling of nitromethane exploits the anion ...stabilizing and leaving group properties of nitromethane, generating the homo allyl nitro products via a tandem cross-coupling/π-allylation sequence. The resultant process provides a mild and convenient entry to nitroethylated products, which are versatile precursors to β,γ-unsaturated carbonyls, homoallylic amines, and nitrile oxides.
Endosomal toll-like receptors (TLRs) 7 and 8 recognize viral single-stranded RNAs, a class of imidazoquinoline compounds, 8-oxo-adenosines, 8-aminobenzodiazepines, pyrimidines, and guanosine ...analogues. Substantial evidence is present linking chronic inflammation mediated specifically by TLR7 to the progression of autoimmunity. We identified a new TLR7/8 dual inhibitor (1) and a TLR8-specific inhibitor (2) based on our previous screen targeting TLR8. Compound 1, bearing a benzanilide scaffold, was found to inhibit TLR7 and TLR8 at low micromolar concentrations. We envisioned making modifications on the benzanilide scaffold of 1 resulting in a class of highly specific TLR7 inhibitors. Our efforts led to the discovery of a new TLR8 inhibitor (CU-115) and identification of a TLR7/8 dual inhibitor (CU-72), bearing a distinct diphenyl ether skeleton, with potential for TLR7 selectivity optimization. Given the role of TLR8 in autoimmunity, we also optimized the potency of 2 and developed a new TLR8 inhibitor bearing a 1,3,4-oxadiazole motif.
Aerobic Copper-Catalyzed Organic Reactions Allen, Scott E; Walvoord, Ryan R; Padilla-Salinas, Rosaura ...
Chemical reviews,
08/2013, Letnik:
113, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Information about copper-catalyzed oxidation chemistry that uses aerobic oxygen as an oxidant is presented. Special attention is given to stoichiometric reactions with copper.
Cyclic guanosine monophosphate–adenosine monophosphate (GMP-AMP) (cGAS), a cytosolic DNA sensor, plays an important role in the type I interferon response. DNA from either invading microbes or ...self-origin triggers the enzymatic activity of cGAS. Aberrant activation of cGAS is associated with various autoimmune disorders. Only one selective probe exists for inhibiting cGAS in cells, while others are limited by their poor cellular activity or specificity, which underscores the urgency for discovering new cGAS inhibitors. Here, we describe the development of new small-molecule human cGAS (hcGAS) inhibitors (80 compounds synthesized) with high binding affinity in vitro and cellular activity. Our studies show CU-32 and CU-76 selectively inhibit the DNA pathway in human cells but have no effect on the RIG-I-MAVS or Toll-like receptor pathways. CU-32 and CU-76 represent a new class of hcGAS inhibitors with activity in cells and provide a new chemical scaffold for designing probes to study cGAS function and development of autoimmune therapeutics.
Late-stage functionalization (LSF) of heteroarenes can dramatically accelerate SAR studies by enabling the installation of functional groups that would otherwise complicate a synthetic sequence. ...Although heteroaryl halides and boronic esters have well-established chemistries for LSF, alternatives that enable site-selective C-H functionalization are highly attractive. Recently, three unrelated cationic groups (phosphonium, pyridinium, and thianthrenium), which can replace C-H bonds late stage, have been identified as precursors to various functional groups. This review will discuss the synthesis and application of these three salts with an emphasis on their use for LSF and application to medicinal chemistry.
Three unrelated cationic groups, which can replace C-H bonds late stage, have been identified as progenitors to various functional groups. This review discusses the chemistry of these salts and their potential application in medicinal chemistry.
Part I of this dissertation focuses on solving the problem of asymmetric hindered C(Aryl)-N(aryl) bond formation to provide a practical route for the synthesis of chiral heterocyclic C–N biaryls. A ...method providing access to chiral C–N atropisomers would have a significant impact for the synthesis of axially chiral heterocyclic ligands and natural products possessing biological activity. A novel copper-catalyzed asymmetric N-arylation reaction between 2-acyl pyrrole, 2-acyl indole, and benzimidazole heterocycles and bis-ortho substituted aryl boronate esters utilizing diamine ligand has been discovered. Bis- and mono-substituted pyrroles with a carbonyl functional group were arylated with moderate to high enantioselectivities (35–95% ee). The N-arylation of a phosphine pyrrole was achieved in 31% yield and 77% ee providing proof of concept that axially chiral heterocylic phosphine oxides, which are precursors for the chiral phosphine ligands, can be accessed using this methodology. Part II of this dissertation focuses on the development of an efficient Pd-catalyzed coupling of vinyl halides and enol triflates with nitromethane to afford homoallylic nitroalkanes. This palladium-catalyzed double coupling of nitromethane exploits the anion stabilizing and leaving group properties of the nitro group, generating the homoallyl nitro products via a tandem cross-coupling/π-allylation sequence. The resultant process provides a mild and convenient entry to nitroethylated products, which are versatile precursors to β,γ-unsaturated carbonyls, homoallylic amines, and nitrile oxides. Part III of this dissertation focuses on solving the problem of ortho-selective C-H arylation of 1,1'-BINOLs for the direct synthesis of 3,3'-diarylated 1,1'-BINOLs in one step. Reported synthetic routes for functionalization of BINOLs require the introduction and subsequent loss of a sacrificial functional group (i.e., halide, boronic acid/ester, or organotin fragment) as well as the protection and de-protection of the hydroxyl functional group. In a collaborative effort with Professor Viresh Rawal at the University of Chicago, parallel microscale high throughput experimentation (HTE) was used to test rapidly the feasibility of an ideal short synthesis of these compounds that led to the rhodium catalyzed ortho-selective C-H arylation of 1,1'-BINOL in 42% yield.
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