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.

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.

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.

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.

Total Synthesis of (S)-Cularine via Nucleophilic Substitution on a Catechol.

Catechols are part of many essential chemicals and are valuable, typically nucleophilic intermediates used in synthesis. Here we describe an unexpected transformation in which they play the role of the electrophile in a formal nucleophilic aromatic substitution. We made this discovery while studying a seven-membered dioxepin ring formation during a synthesis of the benzyltetrahydroisoquinoline (S)-cularine. We suggest a chain mechanism for this new transformation that is triggered by molecular oxygen and that propagates an electrophilic ortho-quinone.

Mimicking oxidative radical cyclizations of lignan biosynthesis using redox-neutral photocatalysis.

Oxidative cyclizations create many unique chemical structures that are characteristic of biologically active natural products. Many of these reactions are catalysed by 'non-canonical' or 'thwarted' iron oxygenases and appear to involve long-lived radicals. Mimicking these biosynthetic transformations with chemical equivalents has been a long-standing goal of synthetic chemists but the fleeting nature of radicals, particularly under oxidizing conditions, makes this challenging. Here we use redox-neutral photocatalysis to generate radicals that are likely to be involved in the biosynthesis of lignan natural products. We present the total syntheses of highly oxidized dibenzocyclooctadienes, which feature densely fused, polycyclic frameworks that originate from a common radical progenitor. We show that multiple factors control the fate of the proposed biosynthetic radicals, as they select between 5- or 11-membered ring cyclizations and a number of different terminating events. Our syntheses create new opportunities to explore the medicinal properties of these natural products, while shedding light on their biosynthetic origin.

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.

Total Synthesis of (S,S)-Tetramethylmagnolamine via Aerobic Desymmetrization.

We describe a concise synthesis of the pseudodimeric tetrahydroisoqunoline alkaloid (S,S)-tetramethylmagnolamine by a catalytic aerobic desymmetrization of phenols. Desymmetrization reactions increase molecular complexity with high levels of efficiency, but those that do so by aerobic oxidation are uncommon. Our conditions employ molecular oxygen as an oxygen atom transfer agent and a formal acceptor of hydrogen, enabling two mechanistically distinct aromatic C-H oxygenation reactions with high degrees of selectivity.

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.

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.

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.

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.

A chlorine-free protocol for processing germanium.

Replacing molecular chlorine and hydrochloric acid with less energy- and risk-intensive reagents would markedly improve the environmental impact of metal manufacturing at a time when demand for metals is rapidly increasing. We describe a recyclable quinone/catechol redox platform that provides an innovative replacement for elemental chlorine and hydrochloric acid in the conversion of either germanium metal or germanium dioxide to a germanium tetrachloride substitute. Germanium is classified as a "critical" element based on its high dispersion in the environment, growing demand, and lack of suitable substitutes. Our approach replaces the oxidizing capacity of chlorine with molecular oxygen and replaces germanium tetrachloride with an air- and moisture-stable Ge(IV)-catecholate that is kinetically competent for conversion to high-purity germanes.

Second-Order Biomimicry: In Situ Oxidative Self-Processing Converts Copper(I)/Diamine Precursor into a Highly Active Aerobic Oxidation Catalyst.

A homogeneous Cu-based catalyst system consisting of [Cu(MeCN)4]PF6, N,N'-di-tert-butylethylenediamine (DBED), and p-(N,N-dimethylamino)pyridine (DMAP) mediates efficient aerobic oxidation of alcohols. Mechanistic study of this reaction shows that the catalyst undergoes an in situ oxidative self-processing step, resulting in conversion of DBED into a nitroxyl that serves as an efficient cocatalyst for aerobic alcohol oxidation. Insights into this behavior are gained from kinetic studies, which reveal an induction period at the beginning of the reaction that correlates with the oxidative self-processing step, EPR spectroscopic analysis of the catalytic reaction mixture, which shows the buildup of the organic nitroxyl species during steady state turnover, and independent synthesis of oxygenated DBED derivatives, which are shown to serve as effective cocatalysts and eliminate the induction period in the reaction. The overall mechanism bears considerable resemblance to enzymatic reactivity. Most notable is the "oxygenase"-type self-processing step that mirrors generation of catalytic cofactors in enzymes via post-translational modification of amino acid side chains. This higher-order function within a synthetic catalyst system presents new opportunities for the discovery and development of biomimetic catalysts.

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.

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.

Asymmetric synthesis of chiral ß-alkynyl carbonyl and sulfonyl derivatives via sequential palladium and copper catalysis.

We present a full account detailing the development of a sequential catalysis strategy for the synthesis of chiral ß-alkynyl carbonyl and sulfonyl derivatives. A palladium-catalyzed cross coupling of terminal alkyne donors with acetylenic ester, ketone, and sulfone acceptors generates stereodefined enynes in high yield. These compounds are engaged in an unprecedented, regio- and enantioselective copper-catalyzed conjugate reduction. The process exhibits a high functional group tolerance, and this enables the synthesis of a broad range of chiral products from simple, readily available alkyne precursors. The utility of the method is demonstrated through the elaboration of the chiral ß-alkynyl products into a variety of different molecular scaffolds. Its value in complex molecule synthesis is further validated through a concise, enantioselective synthesis of AMG 837, a potent GPR40 receptor agonist.

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.