Support studies toward the hicksoane alkaloids reveal cascade reactions of a (tryptophanamido)methylglycinate.

Herein we report unanticipated results that emerged from a synthetic study targeting the unique triazocane present in the hicksoane alkaloids. An initial strategy focused on the cyclisation-ring expansion of a 3-(tryptophyl)imidazolidin-4-one failed due to the high reactivity of the imide unit; passing a methanolic solution of this compound through a weakly basic ion exchange resin led to methanolysis to form a (tryptophanamido)methylglycinate. Attempted lactamisation of this (tryptophanamido)methylglycinate led to the formation of a (tryptophyl)imidazolidin-4-one, a rare imidazopyrido[3,4-b]indolone and a ß-carboline. Control reactions informed a mechanistic rationale for these cascade processes.

Electrochemical oxidation of 3-substituted indoles.

2-Oxindoles are an abundant heteroaromatic motif in natural products and pharmaceuticals. An appealing method for accessing 2-oxindoles is by oxidation of the corresponding indole, a transformation currently executed using stoichiometric quantities of unsafe chemical oxidants that can also form unwanted side-products. Herein, we report that 3-substituted indoles undergo a logistically straightforward, electrochemical oxidation to the corresponding 2-oxindole in the presence of potassium bromide (>20 examples), with only traces of the oxidative dimer detected. Cyclic voltammetry and control studies infer that the reaction proceeds by electrochemical generation of elemental bromine (Br2) that upon reaction with indole, followed by hydrolysis, delivers the 2-oxindole. This procedure is an appealing alternative to existing methods used to access 2-oxindoles by oxidation of the parent indole.

Solvent-Free, Ambient Temperature and Pressure Destruction of Perfluorosulfonic Acids under Mechanochemical Conditions: Degradation Intermediates and Fluorine Fate.

Perfluorosulfonic acids (PFSAs) are a recalcitrant subclass of per- and polyfluoroalkyl substances (PFASs) linked to numerous negative health effects in humans. Scalable technologies that effectively destroy PFSAs will greatly reduce the future health and ecological impact of these "forever chemicals". Herein, we show that several PFSAs undergo facile mechanochemical destruction (MCD) in the presence of quartz sand (SiO2). This process operates in the absence of solvent, at ambient temperature and pressure, generating a benign solid byproduct. Quantitative analysis of milled samples revealed high destruction efficiencies of 99.95% to 100% for five different PFSAs subjected to MCD conditions in the presence of SiO2 only. Extensive nontargeted analysis showed that, during degradation, other PFASs form and are ultimately destroyed upon extended mechanochemical treatment. Direct polarization (DP) and cross-polarization (CP) solid-state nuclear magnetic resonance (SSNMR) spectroscopy showed abundant silicon-fluorine (Si-F) bond formation post-MCD, indicating that fluorine was secured in a stable reservoir. Collectively, these results identified the degradation profile for an environmentally sound and effective PFSA degradation process that is amenable to scale-up.

Progress toward a biomimetic synthesis of pegaharmaline A.

Efforts towards a biomimetic synthesis of the alkaloid pegaharmaline A began with attempted validation of the putative biosynthesis described in the isolation report. The reaction between vasicinone-derived pyrroloquinazoline 1 and tryptamines 2 and 9 proceeded under aqueous conditions at ambient temperature, forming the 1,6,10-triazaspiro[4.5]dec-7-anes 7 and 8. Alternative pyrroloquinazoline precursors were subsequently investigated; the reaction between dehydrodimethylisovasicinone (10) and tryptamine (9) led to the ring-opened product 13 that could not be converted into pegaharmaline A scaffold under Bischler-Napieralski conditions. The Pictet-Spengler reaction between a model isovasicinone (22) and tryptamine (9) was successful, but the resulting tetrahydro-ß-carboline could not be converted into the natural product. These studies suggest an alternative biosynthetic pathway is potentially operating, while structural revision of the natural product cannot be ruled out at this time. As vasicinones and tryptamines are widely distributed throughout Nature, the novel scaffolds reported herein may be undiscovered natural products.

Haber-independent, asymmetric synthesis of the marine alkaloid epi-leptosphaerin from a chitin-derived chiral pool synthon.

Chitin-derived platforms are emerging as valuable chemical entities for the construction of nitrogenous fine chemicals in processes independent of Haber ammonia. However, much of the work in this area has focused on achiral platforms that limit routine entry into enantiopure, bio-based N-chemical space. Herein, dihydroxyethyl acetamidofuran (Di-HAF), a chiral synthon readily available from chitin, has been transformed into the marine alkaloid epi-leptosphaerin. This work extends the fledgling Haber-independent synthesis concept to enantiopure chemical space not routinely accessible from existing achiral platforms.

Isolation and biological activity of azocine and azocane alkaloids.

Thousands of known alkaloids contain a nitrogen (N) heterocycle. While five-, six- and seven-membered N-heterocycles (ie: pyrroles, imidazoles, indoles, pyridines and azepines and their saturated variants) are common, those with an eight-membered N-heterocycle are comparatively rare. This review discusses the structure and bioactivity of alkaloids that contain an azocine (or saturated azocane) ring, and the array of sources whence they originate.

Synthetic Studies toward Bisindigotin: Polyheteroaromatic Scaffolds via Skeletal Rearrangements of a Diacetoxytetraindole.

The deacetylation of a diacetoxytetraindole formed the basis of a first-generation synthetic route toward the alkaloid bisindigotin. However, this conceptually straightforward plan led to unexpected results. Acid-mediated hydrolysis initiated skeletal rearrangement processes that resulted in the formation of two novel heteroaromatic scaffolds, both of which contain nine rings. Upon treating the same diacetoxytetraindole with base followed by a silica-mediated autoxidation, a distinct cascade process occurred, generating another novel scaffold also comprising nine rings. A mechanistic rationale for these observations is provided.

Octacycles and Nonacycles from 3-Hydroxy-2,2'-bisindole.

3-Hydroxy-2,2'-bisindole undergoes acid- and base-mediated dimerization-skeletal rearrangement processes, generating polyheterocyclic ring systems containing up to nine rings. The mechanistic rationale for these reactions is provided, which infers some overlap with the previously reported reactivity of 3',3″-dihydroxytetraindole under analogous reaction conditions.

Bioinspired Synthesis of the Furopyrazine Alkaloid Hyrtioseragamine A.

A biosynthetic hypothesis proposed herein was used to guide the total synthesis of the marine-derived alkaloid hyrtioseragamine A. In the key biomimetic step, an enedione underwent acid-mediated isomerization-cyclodehydration to form the rare furopyrazine core of the natural product. The spectroscopic data for the synthetic sample is in full agreement with that described in the isolation report.

Synthesis of 3-nitroindoles by sequential paired electrolysis.

3-Nitroindoles are synthetically versatile intermediates but current methods for the preparation hinder their widespread application. Herein, we report that nitroenamines undergo electrochemical cyclisation to 3-nitroindoles in the presence of potassium iodide. Detailed control experiments and cyclic voltammogram studies infer the reaction proceeds via a sequential paired electrolysis process, beginning with anodic oxidation of iodide (I-) to the iodine radical (I˙), which facilitates cyclisation of the nitroenamine to give a 3-nitroindolinyl radical. Cathodic reduction and protonation generates a 3-nitroindoline that upon oxidation forms the 3-nitroindole.

Synthetic studies toward inducamide C.

The alkaloid inducamide C is proposed to contain a very rare benzoxazepine ring. Herein, we report that the benzoxazepine ring in inducamide C is unstable and prone to rearrangement, indicating that structural revision of the natural product may be necessary. In a first-generation synthetic approach, attempts to assemble the benzoxazepine by cyclization of 4-hydroxyinducamide A led to the regioisomeric oxepanoindole, a result of the 4-hydroxyindole (C4-OH) undergoing preferential cyclization instead of the desired chlorosalicylic acid C15-OH. A second-generation approach involved dealkylation of O-isopropylinducamide C, but the same oxepanoindole formed via rearrangement of the proposed inducamide C structure. Computational studies validate preferential formation of the oxepanoindole and the lactone in O-isopropylinducamide C is susceptible to nucleophilic attack. Thus, inducamide C is either highly unstable or in need of structural revision.

Synthesis of bio-based 2-thiothiophenes.

While the synthesis of bio-based compounds containing carbon, oxygen and (to a lesser extent) nitrogen is well studied, the production of organosulfur compounds from biomass has received virtually no attention, despite their widespread application throughout the chemical industry. Herein, we demonstrate that a range of bio-based 2-thiothiophenes are available from the biopolymer cellulose, proving that functionally diverse small-molecule organosulfurs can be prepared independent of fossil carbon. This article is part of the theme issue 'Bio-derived and bioinspired sustainable advanced materials for emerging technologies (part 2)'.

The curious yellow colouring matter of the Iceland poppy.

The pigment responsible for the yellow colour of the Iceland poppy (Papaver nudicaule) has fascinated chemists for decades. Named nudicaulin by Sir Robert Robinson in 1939, this flavoalkaloid has been the subject of several structural elucidation, biosynthesis, total synthesis and chemical ecology investigations. This account provides a chronological overview of the fascinating history of this natural product.

Pyridine alkaloids with activity in the central nervous system.

This review discusses all pyridine alkaloids with CNS activity, their therapeutic potential, and the interesting array of sources whence they originate.

Synthesis of the 1,2,4-Thiadiazole Alkaloid Polyaurine B.

A short synthesis of the natural product polyaurine B is described. The 1,2,4-thiadiazole heterocycle was assembled using a Cu(II)-mediated heterocyclization reaction that forges the N-S bond. The final acylation step to install the methylcarbamate must be conducted under anhydrous, nonbasic conditions to prevent thiadiazole ring opening initiated by attack of hydroxide at C-5.

Synthesis of the Tetracyclic Cores of the Integrastatins, Epicoccolide A and Epicocconigrone A.

The integrastatins, epicoccolide A and epicoccongirone A, are natural products containing a unique [6.6.6.6]-tetracyclic core framework that exhibit a broad spectrum of biological activities. A synthesis of the common core of epicoccolide A and epicocconigrone A has been achieved using an umpolung alkylation-lactonization to assemble an isochromanone from which the bridged 1,3-dioxane was readily assembled. A different strategy was required to access the core on the integrastatins; an initial aryllithium addition to an aldehyde, followed by oxidation and treatment of the masked dihydroxyketone with acid gave the desired core structure.

Cleavage of lignin model compounds and ligninox using aqueous oxalic acid.

Aqueous oxalic acid cleaves oxidised ß-O-4 lignin model compounds by two distinct mechanisms that are dependent on the presence of the hydroxymethyl substituent. Various ß-O-4 phenoxyacetophenones that do not contain the hydroxymethyl substituent undergo oxidative cleavage upon exposure to aqueous oxalic acid in the presence of air, likely through concerted ring opening of a dioxetane intermediate to give the corresponding benzoic acid and phenyl formate. Importantly, detrimental side reactions arising from singlet oxygen and hydroperoxy radicals (from both O2 and oxalic acid) are minimal when the cleavage is run under air compared to neat oxygen. When oxidised ß-O-4 lignin model compounds bearing the hydroxymethyl group are cleaved by aqueous oxalic acid, the resulting diketone and phenol products arise from a redox neutral cleavage that is analogous to the formic acid-sodium formate mediated lignin cleavage process reported by Stahl. Aqueous oxalic acid also cleaves lignin itself, with oxidised milled wood lignin (MWLox) from Pinus radiata giving a 14% yield of ethyl acetate soluble aromatics with good selectivity for vanillin. Aqueous oxalic acid appears to be a promising lignin cleavage system given the benign, bio-based reagents, absence of metals and organic solvents and a simple extraction procedure that enables oxalic acid recycling.

Non-monoterpenoid azepinoindole alkaloids.

Covering: 1969 to 2018 Azepinoindole natural products can be broadly classified as being of monoterpenoid or non-monoterpenoid origin. The non-monoterpenoid azepinoindoles have not received as much attention in the literature as their more revered monoterpenoid counterparts. In this review, an overview of all non-monoterpenoid azepinoindoles is provided. Various biological and chemical aspects are discussed, including their isolation, biosynthesis and the elegant total synthesis studies that have been inspired by these alkaloids.

Photosensitized Cross-Linking of Tryptophan and Tyrosine Derivatives by Rose Bengal in Aqueous Solutions.

Photosensitized cross-linking of N-acetyl derivatives of tryptophan and tyrosine by rose bengal in phosphate buffer saline was studied by steady-state absorption and emission spectroscopy, nanosecond transient absorption spectroscopy, and chemical analyses. These amino acids undergo cross-linking to form dimeric and higher oligomeric products under anoxic conditions with rose bengal as a sacrificial oxidant, whereas they react predominantly with singlet oxygen produced by rose bengal in aerated solutions. This investigation provides a comprehensive view into the first steps of rose bengal photosensitized cross-linking of these two amino acids. The results can be helpful for future applications of rose bengal and related dyes, such as photochemical tissue bonding or visible light photocatalysis.

Biomimetic synthesis of the bisindole framework present in sciodole, an alkaloid from Tricholoma sciodes.

A synthesis of the unique bisindole framework present in the mushroom-derived alkaloid sciodole has been achieved, validating a biosynthesis proposal that the C-N bisindole bond present in the natural product is forged by amination of an azafulvenium.