Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters.

Due to their ease of preparation, stability, and diverse reactivity, N-hydroxyphthalimide (NHPI) esters have found many applications as radical precursors. Mechanistically, NHPI esters undergo a reductive decarboxylative fragmentation to provide a substrate radical capable of engaging in diverse transformations. Their reduction via single-electron transfer (SET) can occur under thermal, photochemical, or electrochemical conditions and can be influenced by a number of factors, including the nature of the electron donor, the use of Brønsted and Lewis acids, and the possibility of forming charge-transfer complexes. Such versatility creates many opportunities to influence the reaction conditions, providing a number of parameters with which to control reactivity. In this perspective, we provide an overview of the different mechanisms for radical reactions involving NHPI esters, with an emphasis on recent applications in radical additions, cyclizations and decarboxylative cross-coupling reactions. Within these reaction classes, we discuss the utility of the NHPI esters, with an eye towards their continued development in complexity-generating transformations.

A Bioinspired Synthesis of 1,4-Benzothiazines by Selective Addition of Sulfur Nucleophiles to ortho-Quinones.

Herein, we report a bioinspired approach to the synthesis of 1,4-benzothiazines by drawing inspiration from the biosynthesis of pheomelanin pigments (pheomelanogenesis). In this context, general conditions for the regioselective coupling reaction between ortho-quinones and thiols were developed. The mild conditions proved amenable to a wide scope of both thiol and ortho-quinone coupling partners while simultaneously suppressing redox-exchange. The utility of this methodology was demonstrated by a synthesis of 1,4-benzothiazines, following a biomimetic, oxidative cyclization.

Dearomatization of Biaryls through Polarity Mismatched Radical Spirocyclization.

Dearomatization reactions involving radical cyclizations can facilitate the synthesis of complex polycyclic systems that find applications in medicinal chemistry and natural product synthesis. Here we employ redox-neutral photocatalysis to affect a radical spirocyclization that transforms biaryls into spirocyclic cyclohexadienones under mild reaction conditions. In a departure from previously reported methods, our work demonstrates the polarity mismatched addition of a nucleophilic radical to an electron rich arene, and allows the regioselective synthesis of 2,4- or 2,5-cyclohexadienones with broad functional group tolerance. By transforming biaryls into spirocycles, our methodology accesses underexplored three-dimensional chemical space, and provides an efficient means of creating quaternary spirocenters that we apply to the first synthesis of the cytotoxic plant metabolite denobilone A.

Synthesis of 1,2-Dihydroisoquinolines by a Modified Pomeranz-Fritsch Cyclization.

Isoquinolines (IQs) and their derivatives are present in many natural products and biologically active small molecules. Herein, we report a modified procedure for the classical Pomeranz-Fritsch protocol, which expands the scope of 1,2-dihydroisoquinoline (DHIQ) products. 1,2-DHIQs are an attractive branch point for the synthesis of IQs, but because of their innate reactivity, they have remained difficult to prepare. We demonstrate that the Fujioka/Kita conditions, combining trimethylsiyltriflate (TMSOTf) and an amine base, activate dimethylacetals required for Pomeranz-Fritsch cyclization under sufficiently mild conditions to prepare a broad range of 1,2-DHIQ products. We also demonstrate the synthetic value of these DHIQs by further functionalization to either reduced tetrahydroisoquinoline (THIQ) or fully aromatized IQ natural products.

Recent Applications of Diazirines in Chemical Proteomics.

The elucidation of substrate-protein interactions is an important component of the drug development process. Due to the complexity of native cellular environments, elucidating these fundamental biochemical interactions remains challenging. Photoaffinity labeling (PAL) is a versatile technique that can provide insight into ligand-target interactions. By judicious modification of substrates with a photoreactive group, PAL creates a covalent crosslink between a substrate and its biological target following UV-irradiation. Among the commonly employed photoreactive groups, diazirines have emerged as the gold standard. In this Minireview, recent developments in the field of diazirine-based photoaffinity labeling will be discussed, with emphasis being placed on their applications in chemical proteomic studies.

Selectivity in the Aerobic Dearomatization of Phenols: Total Synthesis of Dehydronornuciferine by Chemo- and Regioselective Oxidation.

We describe a selective aerobic oxidation of meta-biaryl phenols that enables rapid access to functionalized phenanthrenes. Aerobic oxidations attract interest due to their efficiency, but remain underutilized in complex molecule settings due to challenges of selectivity. We discuss these issues in the context of Cu catalysis, and highlight the advantages of confining oxygen activation and substrate oxidation to the catalyst's inner-coordination sphere. This gives rise to predictable selectivity that we use for a concise synthesis of the aporphine dehydronornuciferine.

A Bioinspired Synthesis of Polyfunctional Indoles.

Polyfunctional indoles bearing substituents at C5 and C6 are prevalent in natural products, pharmaceuticals, agrochemicals, and materials. Owing to the remoteness of the C5 and C6 positions, indoles of this family can be difficult to prepare, and often require multistep syntheses. Herein, we describe a concise process that converts simple derivatives of tyrosine into 5,6-difunctionalized indoles by direct oxidation of C-H, N-H, and O-H bonds. Our work draws inspiration from the biosynthetic polymerization of tyrosine to make melanin pigments, but makes an important departure to provide well-defined indole heterocycles.

Synthesis of ortho-Azophenols by Formal Dehydrogenative Coupling of Phenols and Hydrazines or Hydrazides.

Azophenols are important chromophores and reagents in organic synthesis, with applications as pigments and molecular switches. Here, we describe a catalytic aerobic process that couples phenols and hydrazines or hydrazides for their synthesis. The key aromatic C-N bond is formed by condensation between the hydrazine or hydrazide and an ortho-quinone, which triggers a redox-isomerization to install the azo-functionality. Notable features include rapid access to highly functionalized azophenols with a range of electronic configurations, including "push-pull" systems, conditions that employ simple, unactivated substrates, occurrence at room temperature using an earth-abundant and commercially available copper catalyst, and production of water as the only stoichiometric byproduct.

Stopping Aerobic Oxidation in Its Tracks: Chemoselective Synthesis of Benzaldehydes from Methylarenes.

A practical and elegant solution to the long-standing challenge of methylarene partial oxidation has recently been provided by Pappo and co-workers who devised a catalytic aerobic route to benzaldehydes. The solution hinges on the unique hydrogen-bonding capacity of hexafluoroisopropanol, which prevents overoxidation of the aldehyde to the carboxylic acid.

Synthesis of a 1,3-Bridged Macrobicyclic Enyne via Chemoselective Cycloisomerization Using Palladium-Catalyzed Alkyne-Alkyne Coupling.

A unique intramolecular Pd-catalyzed alkyne-alkyne coupling is presented. This transformation generates a strained, 1,3-bridged, macrocyclic enyne. The process was readily executed on gram scale, and the structure of the product was elucidated via X-ray crystallographic analysis. A mechanistic rationale for the observed chemoselectivity is provided.

A Catalyst-Controlled Aerobic Coupling of ortho-Quinones and Phenols Applied to the Synthesis of Aryl Ethers.

ortho-Quinones are underutilized six-carbon-atom building blocks. We herein describe an approach for controlling their reactivity with copper that gives rise to a catalytic aerobic cross-coupling with phenols. The resulting aryl ethers are generated in high yield across a broad substrate scope under mild conditions. This method represents a unique example where the covalent modification of an ortho-quinone is catalyzed by a transition metal, creating new opportunities for their utilization in synthesis.

Simple Copper Catalysts for the Aerobic Oxidation of Amines: Selectivity Control by the Counterion.

We describe the use of simple copper-salt catalysts in the selective aerobic oxidation of amines to nitriles or imines. These catalysts are marked by their exceptional efficiency, operate at ambient temperature and pressure, and allow the oxidation of amines without expensive ligands or additives. This study highlights the significant role counterions can play in controlling selectivity in catalytic aerobic oxidations.

A Biomimetic Mechanism for the Copper-Catalyzed Aerobic Oxygenation of 4-tert-Butylphenol.

Controlling product selectivity during the catalytic aerobic oxidation of phenols remains a significant challenge that hinders reaction development. This work provides a mechanistic picture of a Cu-catalyzed, aerobic functionalization of phenols that is selective for phenoxy-coupled ortho-quinones. We show that the immediate product of the reaction is a Cu(II)-semiquinone radical complex and reveal that ortho-oxygenation precedes oxidative coupling. This complex is the resting state of the Cu catalyst during turnover at room temperature. A mechanistic study of the formation of this complex at low temperatures demonstrates that the oxygenation pathway mimics the dinuclear Cu enzyme tyrosinase by involving a dinuclear side-on peroxodicopper(II) oxidant. Unlike the enzyme, however, the rate-limiting step of the ortho-oxygenation reaction is the self-assembly of the oxidant from Cu(I) and O2. We provide details for all steps in the cycle and demonstrate that turnover is contingent upon proton-transfer events that are mediated by a slight excess of ligand. Finally, our knowledge of the reaction mechanism can be leveraged to diversify the reaction outcome. Thus, uncoupled ortho-quinones are favored in polar, coordinating media, highlighting unusually high levels of chemoselectivity for a catalytic aerobic oxidation of a phenol.

A bio-inspired total synthesis of tetrahydrofuran lignans.

Lignan natural products comprise a broad spectrum of biologically active secondary metabolites. Their structural diversity belies a common biosynthesis, which involves regio- and chemoselective oxidative coupling of propenyl phenols. Attempts to replicate this oxidative coupling have revealed significant challenges for controlling selectivity, and these challenges have thus far prevented the development of a unified biomimetic route to compounds of the lignan family. A practical solution is presented that hinges on oxidative ring opening of a diarylcyclobutane to intercept a putative biosynthetic intermediate. The effectiveness of this approach is demonstrated by the first total synthesis of tanegool in 4 steps starting from ferulic acid, as well as a concise synthesis of the prototypical furanolignan pinoresinol.

A TEMPO-free copper-catalyzed aerobic oxidation of alcohols.

The copper-catalyzed aerobic oxidation of primary and secondary alcohols without an external N-oxide co-oxidant is described. The catalyst system is composed of a Cu/diamine complex inspired by the enzyme tyrosinase, along with dimethylaminopyridine (DMAP) or N-methylimidazole (NMI). The Cu catalyst system works without 2,2,6,6-tetramethyl-l-piperidinoxyl (TEMPO) at ambient pressure and temperature, and displays activity for un-activated secondary alcohols, which remain a challenging substrate for catalytic aerobic systems. Our work underscores the importance of finding alternative mechanistic pathways for alcohol oxidation, which complement Cu/TEMPO systems, and demonstrate, in this case, a preference for the oxidation of activated secondary over primary alcohols.

Controlling the catalytic aerobic oxidation of phenols.

The oxidation of phenols is the subject of extensive investigation, but there are few catalytic aerobic examples that are chemo- and regioselective. Here we describe conditions for the ortho-oxygenation or oxidative coupling of phenols under copper (Cu)-catalyzed aerobic conditions that give rise to ortho-quinones, biphenols or benzoxepines. We demonstrate that each product class can be accessed selectively by the appropriate choice of Cu(I) salt, amine ligand, desiccant and reaction temperature. In addition, we evaluate the effects of substituents on the phenol and demonstrate their influence on selectivity between ortho-oxygenation and oxidative coupling pathways. These results create an important precedent of catalyst control in the catalytic aerobic oxidation of phenols and set the stage for future development of catalytic systems and mechanistic investigations.

A biomimetic catalytic aerobic functionalization of phenols.

The importance of aromatic C-O, C-N, and C-S bonds necessitates increasingly efficient strategies for their formation. Herein, we report a biomimetic approach that converts phenolic C-H bonds into C-O, C-N, and C-S bonds at the sole expense of reducing dioxygen (O2) to water (H2O). Our method hinges on a regio- and chemoselective copper-catalyzed aerobic oxygenation to provide ortho-quinones. ortho-Quinones are versatile intermediates, whose direct catalytic aerobic synthesis from phenols enables a mild and efficient means of synthesizing polyfunctional aromatic rings.

A para- to meta-isomerization of phenols.

Phenols and their derivatives are ubiquitous in nature and critically important industrial chemicals. Their properties are intimately linked to the relative substitution pattern of the aromatic ring, reflecting well-known electronic effects of the OH group. Because of these ortho-, para-directing effects, meta-substituted phenols have historically been more difficult to synthesize. Here we describe a procedure to transpose phenols that hinges on a regioselective diazotization of the corresponding ortho-quinone. The procedure affords the meta-substituted phenol directly from its more common and accessible para-substituted isomer, and demonstrates good chemoselectivity that enables its application in late-stage settings. By changing the electronic effect of the OH group and its trajectory of hydrogen bonding, our transposition can be used to diversify natural products and existing chemical libraries, and potentially shorten the length and cost of producing underrepresented arene isomers.

Indole-5,6-quinones display hallmark properties of eumelanin.

Melanins are ubiquitous biopolymers produced from phenols and catechols by oxidation. They provide photoprotection, pigmentation and redox activity to most life forms, and inspire synthetic materials with desirable optical, electronic and mechanical properties. The chemical structures of melanins remain elusive, however, creating uncertainty about their roles, and preventing the design of synthetic mimics with tailored properties. Indole-5,6-quinone (IQ) has been implicated as a biosynthetic intermediate and structural subunit of mammalian eumelanin pigments, but its instability has prevented its isolation and unambiguous characterization. Here we use steric shielding to stabilize IQ and show that 'blocked' derivatives exhibit eumelanin's characteristic ultrafast nonradiative decay and its ability to absorb light from the ultraviolet to the near-infrared. These new compounds are also redox-active and a source of paramagnetism, emulating eumelanin's unique electronic properties, which include persistent radicals. Blocked IQs are atomistically precise and tailorable molecules that can offer a bottom-up understanding of emergent properties in eumelanin and have the potential to advance the rational design of melanin-inspired materials.

Total synthesis of exiguamines A and B inspired by catecholamine chemistry.

The evolution of a total synthesis of the exiguamines, two structurally unusual natural products that are highly active inhibitors of indolamine-2,3-dioxygenase (IDO), is described. The ultimately successful strategy involves advanced cross-coupling methodology and features a potentially biosynthetic tautomerization/electrocyclization cascade reaction that forms two heterocycles and installs a quaternary ammonium ion in a single synthetic operation.