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.

Mechanochemical destruction of per- and polyfluoroalkyl substances in aqueous film-forming foams and contaminated soil.

Per- and polyfluoroalkyl substances (PFASs) are a class of synthetic chemicals of concern that exhibit extreme persistence within the environment and possess physicochemical properties that are resistant to targeted degradation. Comprising substantial concentrations of PFASs, aqueous film-forming foams (AFFFs) present a major exposure pathway to the environment having been applied to land at firefighting-training sites globally for decades. This has led to significant contamination of environmental media. Herein, we demonstrate that mechanochemical destruction (MCD) is an effective method for the destruction of PFASs in an AFFF concentrate and an authentic sample of PFAS-contaminated soil derived from a decommissioned firefighting training facility. Both targeted analysis and non-targeted analysis were used in this study to evaluate the degradation of PFASs in complex substrates during MCD treatment. Destruction efficiencies of target PFAS subgroups ranged from 99.88% to 100%. The only additive employed for MCD treatment was quartz sand, which was used only for the liquid AFFF sample, with no additives required for the destruction of PFASs in the contaminated soil. This confirms the viability of MCD for both the remediation of PFAS-contaminated land and the destruction of stockpiled AFFFs.

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.

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.

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.

Catalytic deep eutectic solvent for levoglucosenone production by pyrolysis of cellulose.

This work presents the selective production of the versatile bio-based platform levoglucosenone (LGO) using deep eutectic solvents (DESs) as catalysts during cellulose pyrolysis. Among 18 types of DESs examined, those containing p-toluenesulfonic acid as a hydrogen bond donor possessed the requisite thermal stability for use in the pyrolysis of cellulose. When those DESs were combined with cellulose, the pyrolysis temperature could be reduced which led to greater selectivity for LGO, the highest yield being 41.5% on a carbon basis. Because of their thermal stability, the DESs could be recovered from the pyrolysis residue and reused. The DESs recovery reached 97.9% in the pyrolysis at a low temperature with the LGO yield of 14.0%. Thus, DES-assisted cellulose pyrolysis is a promising methodology for LGO production.

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.

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.

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.

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)'.

Itaconate is a covalent inhibitor of the Mycobacterium tuberculosis isocitrate lyase.

Itaconate is a mammalian antimicrobial metabolite that inhibits the isocitrate lyases (ICLs) of Mycobacterium tuberculosis. Herein, we report that ICLs form a covalent adduct with itaconate through their catalytic cysteine residue. These results reveal atomic details of itaconate inhibition and provide insights into the catalytic mechanism of ICLs.

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.

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.

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.

Remediation of poly- and perfluoroalkyl substances (PFAS) contaminated soils - To mobilize or to immobilize or to degrade?

Poly- and perfluoroalkyl substances (PFASs) are synthetic chemicals, which are introduced to the environment through anthropogenic activities. Aqueous film forming foam used in firefighting, wastewater effluent, landfill leachate, and biosolids are major sources of PFAS input to soil and groundwater. Remediation of PFAS contaminated solid and aqueous media is challenging, which is attributed to the chemical and thermal stability of PFAS and the complexity of PFAS mixtures. In this review, remediation of PFAS contaminated soils through manipulation of their bioavailability and destruction is presented. While the mobilizing amendments (e.g., surfactants) enhance the mobility and bioavailability of PFAS, the immobilizing amendments (e.g., activated carbon) decrease their bioavailability and mobility. Mobilizing amendments can be applied to facilitate the removal of PFAS though soil washing, phytoremediation, and complete destruction through thermal and chemical redox reactions. Immobilizing amendments are likely to reduce the transfer of PFAS to food chain through plant and biota (e.g., earthworm) uptake, and leaching to potable water sources. Future studies should focus on quantifying the potential leaching of the mobilized PFAS in the absence of removal by plant and biota uptake or soil washing, and regular monitoring of the long-term stability of the immobilized PFAS.

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.

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.

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.

Structural Revision of Pseudocerosine and Validation of a Biosynthetic Proposal for E-ring Formation in Pyridoacridine Alkaloids.

Pseudocerosine is the pigment responsible for the bright blue color of the rim on the marine flatworm Pseudoceros indicus. Compelling evidence is provided herein that pseudocerosine is actually a pyridoacridine, not an azepinoindole as initially proposed. This study also validates a biosynthesis proposal for E-ring formation in this revered class of alkaloids, and pseudocerosine (along with its intermediates described herein) is a new branch on the pyridoacridine family tree.