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The molecular structure of nanothreads produced by the slow compression of 13C4-furan was studied by advanced solid-state NMR. Spectral editing showed that >95% of carbon atoms were bonded to one hydrogen (C-H) and that there were 2-4% CH2, 0.6% C═O, and

The selective modification of α-amino acids and peptides constitutes a pivotal arena for accessing new peptide-based materials and therapeutics. In recent years, visible light photoredox catalysis has appeared as a powerful platform for the activation of small molecules via single-electron transfer events, allowing previously inaccessible reaction pathways to be explored. This review outlines the recent advances, mechanistic underpinnings, and opportunities of applying photoredox catalysis to the expansion of the synthetic repertoire for the modification of specific amino acid residues.1 Introduction2 Visible-Light-Mediated Functionalization of α-Amino Acids2.1 Decarboxylative Functionalization Involving Redox-Active Esters2.2 Direct Decarboxylative Coupling Strategies2.3 Hypervalent Iodine Reagents2.4 Dual Photoredox and Transition-Metal Catalysis2.5 Amination and Deamination Strategies3 Photoinduced Peptide Diversification3.1 Gese-Type Bioconjugation Methods3.2 Peptide Macrocyclization through Photoredox Catalysis3.3 Biomolecule Conjugation through Arylation3.4 C–H Functionalization Manifolds4 Conclusions and Outlook

We present a modular approach to control the small molecule–mediated degradation of cellular proteins of interest using light., PROTACs (PROteolysis TArgeting Chimeras) are bifunctional molecules that target proteins for ubiquitylation by an E3 ligase complex and subsequent degradation by the proteasome. They have emerged as powerful tools to control the levels of specific cellular proteins. We now introduce photoswitchable PROTACs that can be activated with the spatiotemporal precision that light provides. These trifunctional molecules, which we named PHOTACs (PHOtochemically TArgeting Chimeras), consist of a ligand for an E3 ligase, a photoswitch, and a ligand for a protein of interest. We demonstrate this concept by using PHOTACs that target either BET family proteins (BRD2,3,4) or FKBP12. Our lead compounds display little or no activity in the dark but can be reversibly activated with different wavelengths of light. Our modular approach provides a method for the optical control of protein levels with photopharmacology and could lead to new types of precision therapeutics that avoid undesired systemic toxicity.

Azobenzenes are versatile photoswitches that have found widespread use in a variety of fields, ranging from photo-pharmacology to the material sciences. In addition to regular azobenzenes the cyclic diazocines have recently emerged. Although diazocines have fascinating conformational and photophysical properties, their use has been limited by their synthetic accessibility. Herein, we present a general, high-yielding protocol that relies on the oxidative cyclization of diani-lines. In combination with a modular substrate synthesis, it allows for rapid access to diversely functionalized diazocines on gram scales. Our work systematically explores substituent effects on the photoisomerization and thermal relaxation of diazocines. It will enable their incorporation into a wide variety of functional molecules, unlocking the full potential of these emerging photoswitches. The method can be applied to the synthesis of a new cyclic azobenzene with a nine-membered central ring and distinct properties.

Photopharmacology relies on ligands that change their pharmacodynamics upon photoisomerization. Many of these ligands are azobenzenes that are thermodynamically more stable in their elongated trans-configuration. Often, they are biologically active in this form and lose activity upon irradiation and photoisomerization to their cis-isomer. Recently, cyclic azobenzenes, so-called diazocines, have emerged, which are thermodynamically more stable in their bent cis-form. Incorporation of these switches into a variety of photopharmaceuticals could convert dark-active ligands into dark-inactive ligands, which is preferred in most biological applications. This “pharmacological sign-inversion” is demonstrated for a photochromic blocker of voltage-gated potassium channels, termed CAL, and a photochromic opener of G protein-coupled inwardly rectifying potassium (GIRK) channels, termed CLOGO.

Aplydactone (1) is a brominated ladderane sesquiterpenoid that was isolated from the sea hare Aplysia dactylomela together with the chamigranes dactylone (2) and 10-epi-dactylone (3). Given the habitat of A. dactylomela, it seems likely that 1 is formed from 2 through a photochemical [2 + 2] cycloaddition. Here, we disclose a concise synthesis of 1, 2, and 3 that was guided by excited state theory and relied on several highly stereoselective transformations. Our experiments and calculations confirm the photochemical origin of 1 and explain why it is formed as the sole isomer. Irradiation of 3 with long wavelength UV light resulted in a [2 + 2] cycloaddition that proceeded with opposite regioselectivity. On the basis of this finding, it seems likely that the resulting regioisomer, termed “8-epi-isoaplydactone”, could also be found in A. dactylomela., We report the photochemistry, supported by excited state theory, of the brominated chamigranes dactylone and 10-epi-dactylone in the biomimetic synthesis of aplydactone and its isomer, which we anticipate is a natural product.

The one-pot, three-component, coupling reaction of indoles/pyrroles, dimethyl malonate, and acetic acid was performed using Mn(III) acetate as an oxidant. In the presence of Mn(OAc)3, indole-2, and indole-3-carbonyl compounds were alkylated at the 3- and 2- positions, respectively, with subsequent oxidation and nucleophilic capture occurring at the newly formed benzylic carbon. In contrast, oxidation of 2- and 3-indole carboxylic acids afforded the corresponding 2-oxindol-3-ylidenes and 3-oxindol-2-ylidenes. The reaction conditions, scope, and mechanism are discussed herein.

The development of a sustainable, carbon-neutral biorefinery has emerged as a prominent scientific and engineering goal of the 21st century. As petroleum has become less accessible, biomass-based carbon sources have been investigated for utility in fuel production and commodity chemical manufacturing. One underutilized biomaterial is lignin; however, its highly crosslinked and randomly polymerized composition have rendered this biopolymer recalcitrant to existing chemical processing. More recently, insight into lignin's molecular structure has reinvigorated chemists to develop catalytic methods for lignin depolymerization. This review examines the development of transition-metal catalyzed reactions and the insights shared between the homogeneous and heterogeneous catalytic systems towards the ultimate goal of valorizing lignin to produce value-added products.

Catching a break in polyphenol synthesis Chemical synthesis is usually rather different from playing with a modeling kit. If two large fragments of a molecule are not properly oriented, it is not typically possible to break them apart, rotate one, and then paste them back together. Yet that is precisely the trick that Keylor et al. used to synthesize two plant-derived polyphenols. Resveratrol forms a variety of dimers, trimers, and tetramers. When one central carbon-carbon bond links the fragments, it is weak enough to break spontaneously and reversibly at room temperature. The authors leveraged this equilibrium to generate an efficient route to two of the tetramers, nepalensinol B and vateriaphenol C. Science , this issue p. 1260

Lignin valorization has long been recognized as a sustainable solution for the renewable production of aromatic compounds. Two-step oxidation/reduction strategies, whereby the first oxidation step is required to “activate” lignin systems for controlled fragmentation reactions, have recently emerged as viable routes toward this goal. Herein we describe a catalytic protocol for oxidation of lignin model systems by combining photoredox and Pd catalysis. The developed dual catalytic protocol allowed the efficient oxidation of lignin model substrates at room temperature to afford the oxidized products in good to excellent yields.

Since the dawn of the 20th century, the average life expectancy at birth has nearly doubled due to advances in science and medicine. As medical records grew more reliable, it became apparent that, while overall life span was increasing, there were significant epidemiological differences between geographical regions, with people from countries such as Japan, France, and Switzerland enjoying longer life expectancy as compared to other regions of the world. The causative factors for these disparities in both mortality and morbidity have been attributed not only to genetics but also to the contributions of highly variable lifestyle and environmental influences.1 Barring differences in modernization and public health policy, diet is the most significant epidemiological factor cross-culturally and is thought to be a profoundly important contributor to health and overall well-being. Prior to the early 1990s, there was a general consensus in support of the belief that moderate alcohol consumption significantly lowered the risk of coronary heart disease (CHD).2 However, it was not clear whether this was true of all alcoholic beverages or which constituents in the drinks were responsible for these beneficial properties.3 In 1992, Siemann and Creasy4 reported that resveratrol (1) was present in significant concentrations in red wine, drawing attention to the fact that it was also an active principle found in Japanese and Chinese folk medicines used to treat ailments related to the liver, skin, heart, and lipid metabolism.5 The discovery of resveratrol in wine was particularly timely; although the correlation between high fat and cholesterol consumption and coronary heart disease was widely accepted,6 certain populations, namely the French, had a low incidence of CHD mortality despite a diet and lifestyle that exposed these individuals to elevated risk factors.7 The cardioprotective ability of resveratrol, its oligomers, along with other phytochemicals present in wine, appeared to resolve this “French Paradox” and advanced the notion that a chemical constituent of one’s diet could be beneficial to health.8 Although the reality of the French Paradox remains contentious,9,10 research into the health benefits of resveratrol has exploded as a result. The reported biological activities of resveratrol are numerous, including antioxidant,11 anticancer,12 antidiabetic,13,14 cardioprotective,15 and even antiaging properties,16 to name a few. The body of literature regarding the biological activity of resveratrol is expansive and beyond of the scope of this review. We invite the readers to the following resources for background on this exciting and ongoing field of research.17−21 Despite its enormous popularity, resveratrol is but a single compound in a large, structurally diverse class of oligomeric stilbenoids that are present in the wines and foods that we consume.22,23 Until recently, access to these oligomeric natural products was limited to isolation from natural sources, which severely hampered their biological evaluation. The scientific interest in resveratrol has undoubtedly instigated the renewed attention in these compounds by the chemical community. Advances in the characterization, isolation techniques, and synthesis of these natural products have significantly enriched our understanding of their chemistry and biology. Our review seeks to document the history and recent progress in the isolation, chemical synthesis, and biology of this fascinating class of phytochemicals, while providing new insight on the biosynthesis and future prospects for the field as a whole.