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A 2-azabicyclo[4.2.0]octa-4,7-diene derivative was unexpectedly isolated from the photochemical irradiation of 2-vinyl-1,2-dihydropyridine. A cascading 6π–8π–4π electrocyclic rearrangement has been proposed as a possible mechanistic pathway. Herein disclosed is the isolation of the 2-azabicyclo[4.2.0]octa-4,7-diene skeleton derived from the photochemical irradiation of 2-vinyl-1,2-dihydropyridine. A cascading 6π–8π–4π electrocyclic rearrangement is proposed as the mechanistic rationale. This is the first observation of this ring system. [ABSTRACT FROM AUTHOR]

Homocubane, a highly strained cage hydrocarbon, contains two very different positions for the introduction of a nitrogen atom into the skeleton, e. g. a position 1 exchange results in a tertiary amine whereas position 9 yields a secondary amine. Herein reported is the synthesis of 9‐azahomocubane along with associated structural characterization, physical property analysis and chemical reactivity. Not only is 9‐azahomocubane readily synthesized, and found to be stable as predicted, the basicity of the secondary amine was observed to be significantly lower than the structurally related azabicyclo[2.2.1]heptane, although similar to 1‐azahomocubane. [ABSTRACT FROM AUTHOR]

Using computational methods and chemical intuition, the proposed structure of janthinolide A is shown to be incorrect. It is further shown that the material described as janthinolide A is highly likely to be janthinolide C. [ABSTRACT FROM AUTHOR]

Natural products continue to be reported at an astonishing rate from a wide range of multidisciplinary research activities in the pursuit of understanding the chemistry of biodiversity. However, the elucidation of chemical structure in the modern era is heavily reliant on the analysis and interpretation of multiple spectroscopic outputs, and in most cases this activity is by no means trivial. Structural errors continue to be described given the inherent complexity of natural products. Computer‐Assisted Structure Elucidation (CASE) continues to provide improved resolving power in this regard, but for enhanced accuracy quantum chemical spectrum prediction methodology is paramount. Reported herein are a range of counterfactual natural products, identified through chemical principal screening, which have been reassigned using a combination of chemical intuition, chemical synthesis, CASE and DU8+ spectrum prediction. [ABSTRACT FROM AUTHOR]

Unusual polyenols that defied chemical principles were reassigned as the nucleosides, adenosine and uridine, using a combination of chemical intuition underpinned by Computer Assisted Structure Elucidation (CASE) and DFT methods. [ABSTRACT FROM AUTHOR]

UbiA prenyltransferase domain‐containing protein‐1 (UBIAD1) is responsible for the biosynthesis of menaquinone‐4 (MK‐4), a cofactor for extrahepatic carboxylation of vitamin K‐dependent (VKD) proteins. Genetic variations of UBIAD1 are mainly associated with Schnyder corneal dystrophy (SCD), a disease characterized by abnormal accumulation of cholesterol in the cornea. Results from in vitro studies demonstrate that SCD‐associated UBIAD1 mutations are defective in MK‐4 biosynthesis. However, SCD patients do not exhibit typical phenotypes associated with defects of MK‐4 or VKD carboxylation. Here, we coupled UBIAD1's biosynthetic activity of MK‐4 with VKD carboxylation in HEK293 cells that stably express a chimeric VKD reporter protein. The endogenous Ubiad1 gene in these cells was knocked out by CRISPR‐Cas9‐mediated genome editing. The effect of UBIAD1 mutations on MK‐4 biosynthesis and VKD carboxylation was evaluated in Ubiad1‐deficient reporter cells by determining the production of MK‐4 or by measuring the efficiency of reporter‐protein carboxylation. Our results show that the hot‐spot mutation N102S has a moderate impact on MK‐4 biosynthesis (retained ˜ 82% activity) but does not affect VKD carboxylation. However, the G186R mutation significantly affected both MK‐4 biosynthesis and VKD carboxylation. Other mutations exhibit varying degrees of effects on MK‐4 biosynthesis and VKD carboxylation. These results are consistent with in vivo results obtained from gene knock‐in mice and SCD patients. Our findings suggest that UBIAD1's MK‐4 biosynthetic activity does not directly correlate with the phenotypes of SCD patients. The established cell‐based assays in this study provide a powerful tool for the functional studies of UBIAD1 in a cellular milieu. [ABSTRACT FROM AUTHOR]

Tandem oxidative-dehydrogenation of primary alcohols to give α,β-unsaturated aldehydes in one pot are rare transformations in organic synthesis, with only two methods currently available. Reported herein is a novel method using the bench-stable salt methyltriphenylphosphonium perruthenate (MTP3), and a new co-oxidant NEMO·PF6 (NEMO = N -ethyl- N -hydroxymorpholinium) which provides unsaturated aldehydes in low to moderate yields. The Ley-Griffith oxidation of (hetero)arylated primary alcohols with N -oxide co-oxidants NMO (NMO = N -methylmorpholine N -oxide)/NEMO, is expanded by addition of the N -oxide salt NEMO·PF6 to convert the intermediate saturated aldehyde into its unsaturated counterpart. The discovery, method development, reaction scope, and associated challenges of this method are highlighted. The conceptual value of late-stage dehydrogenation in natural product synthesis is demonstrated via the synthesis of a polyene scaffold related to auxarconjugatin B. A novel method is described, using perruthenate salts, for performing the rarely reported dehydrogenation of primary alcohols to afford unsaturated aldehydes in low to moderate yields. The discovery, method development, reaction scope, and associated challenges of this method are presented in detail. [ABSTRACT FROM AUTHOR]

Cubane, a hexahedral hydrocarbon, can be converted into an asymmetric molecule with a minimum of three substituents. The resulting chiral cubane can be used as a pharmacophore or a chiral ligand. Starting from the cubane carboxamide, the 1,2,3‐substituted compound was synthesized by sequential ortho‐metalation. The 1,3,5‐substituted compound was synthesized by combining site‐selective halogenation and halogen‐metal exchange and the resulting racemate was subjected to enantiomeric resolution by HPLC. [ABSTRACT FROM AUTHOR]

Tyrosinase (TYR) is a key enzyme that catalyzes the synthesis of melanin in plants, microorganisms and mammalian cells. Kojic acid (KA) is a well-known TYR inhibitor widely used as a popular cosmetic skin-lightening ingredient. However, KA is reported to have poor inhibitory activity against pigmentation within intact melanocytes or in clinical assays. In this study, a series of dihydropyrano[3,2-b] chromenedione (DHPC) (1a, 2a, 3a, 4a, 5a, 6a and 7a) and 1,8-dioxooctahydroxanthene (DOHX) (1b, 2b, 3b and 4b) derivatives were evaluated using a DPPH radical-scavenging assay. These results showed that 7a exhibited the most potent radical-scavenging activity. Compound 7a was characterised by X-ray crystallographic studies. Molecular docking was carried out to shed light on the mode of action and types of interaction between the compounds and the target. A metal-binding study suggested that these synthetic heterocyclic compounds may behave as competitive inhibitors for the L-DOPA binding site of the TYR. Finally, molecular modeling provided important insight into the mechanism of binding interactions with the TYR copper active site. [ABSTRACT FROM AUTHOR]

the proposed structure of arneroma B has been revised from a cyclopentadienone to a 2,4-disubstituted furan. The reassignment has been confirmed by total synthesis of the revised structure. [Display omitted] • Molecular formula reassigned by MS. • Structure reassignment by NMR. • Confirmed by synthesis. [ABSTRACT FROM AUTHOR]

[Display omitted] Multiple sclerosis-associated central neuropathic pain (MS-CNP) is difficult to alleviate with clinically used pain-killers and so there is a large unmet medical need for novel treatments for alleviating MS-CNP. Although (R)-alpha lipoic acid (ALA) evoked significant pain relief efficacy in a mouse model of multiple sclerosis-associated central neuropathic pain (MS-CNP), this dietary supplement has poor oral bioavailability due to low gastric stability. Eight ester prodrugs of the R enantiomer of ALA [(R)-ALA] were designed encompassing a range of biocompatible hydrophobic and hydrophilic features and synthesized in an effort to identify a prodrug candidate that was stable at gastric and upper gastrointestinal tract (GIT) pH, and that could be released (hydrolyzed by esterases) in the blood to (R)-ALA immediately after absorption into the portal vein (i.e., highly desirable features for pain relief development). These biocompatible hydrophobic and hydrophilic (R)-ALA pro-dugs underwent comprehensive preliminary screening to reveal PD-ALA4 HCl salt (10) as a promising candidate and PD-ALA 7 (8) could be a viable substitute, utilizing enzyme-free gastric and intestinal stability assessments, LogP evaluations, in vitro plasma stability and caco-2 cell monolayer permeability. [ABSTRACT FROM AUTHOR]