Discovery of BI-9508, a Brain-Penetrant GPR88-Receptor-Agonist Tool Compound for In Vivo Mouse Studies.

Decreased activity and expression of the G-protein coupled receptor GPR88 is linked to many behavior-linked neurological disorders. Published preclinical GPR88 allosteric agonists all have in vivo pharmacokinetic properties that preclude their progression to the clinic, including high lipophilicity and poor brain penetration. Here, we describe our attempts to improve GPR88 agonists' drug-like properties and our analysis of the trade-offs required to successfully target GPR88's allosteric pocket. We discovered two new GPR88 agonists: One that reduced morphine-induced locomotor activity in a murine proof-of-concept study, and the atropoisomeric BI-9508, which is a brain penetrant and has improved pharmacokinetic properties and dosing that recommend it for future in vivo studies in rodents. BI-9508 still suffers from high lipophilicity, and research on this series was halted. Because of its utility as a tool compound, we now offer researchers access to BI-9508 and a negative control free of charge via Boehringer Ingelheim's open innovation portal opnMe.com.

Skeletal rearrangement of 6,8-dioxabicyclo[3.2.1]octan-4-ols promoted by thionyl chloride or Appel conditions.

A skeletal rearrangement of a series of 6,8-dioxabicyclo[3.2.1]octan-4-ols has been developed using SOCl2 in the presence of pyridine. An oxygen migration from C5 to C4 was observed when the C4 alcohols were treated with SOCl2/pyridine, giving a 2-chloro-3,8-dioxabicyclo[3.2.1]octane ring-system via the chlorosulfite intermediate. Analogous allylic alcohols with endocyclic and exocyclic unsaturations underwent chlorination without rearrangement due to formation of allylic cations. The rearrangement was also demonstrated using Appel conditions, which gave similar results via the alkoxytriphenylphosphonium intermediate. Several reactions of the products were investigated to show the utility of the rearrangement.

Oxa-Michael-initiated cascade reactions of levoglucosenone.

The reactions of aromatic aldehydes and levoglucosenone promoted by methoxide gives bridged α,ß-unsaturated ketones, formed by a series of oxa-Michael-initiated cascade reactions in yields of up to 91% (14 examples). A complex series of equilibria operate during the reaction, and the formation of the bridged species is thermodynamically favored, except in the case of 5-methylfurfural and pyrrole-2-carboxaldehyde. This is the first report detailing this type of aldol/Michael cascade involving oxa-Michael initiation.

The Diversity of Volatile Compounds in Australia's Semi-Desert Genus Eremophila (Scrophulariaceae).

Australia's endemic desert shrubs are commonly aromatic, with chemically diverse terpenes and phenylpropanoids in their headspace profiles. Species from the genus Eremophila (Scrophulariaceae ex. Myoporaceae) are the most common, with 215 recognised taxa and many more that have not yet been described, widely spread across the arid parts of the Australian continent. Over the years, our research team has collected multiple specimens as part of a survey to investigate the chemical diversity of the genus and create leads for further scientific enquiry. In the current study, the diversity of volatile compounds is studied using hydrodistilled essential oils and leaf solvent extracts from 30 taxa. Several rare terpenes and iridoids were detected in chemical profiles widely across the genus, and three previously undescribed sesquiterpenes were isolated and are assigned by 2D NMR-E-11(12)-dehydroisodendrolasin, Z-11-hydroxyisodendrolasin and 10-hydroxydihydro-α-humulene acetate. Multiple sampling from Eremophila longifolia, Eremophila arbuscular, Eremophila latrobei, Eremophila deserti, Eremophila sturtii, Eremophila oppositifolia and Eremophila alternifolia coneys that species in Eremophila are highly chemovariable. However, taxa are generally grouped according to the expression of (1) furanosesquiterpenes, (2) iridoids or oxides, (3) mixtures of 1 and 2, (4) phenylpropanoids, (5) non-furanoid terpenes, (6) mixtures of 4 and 5, and less commonly (7) mixtures of 1 and 5. Furthermore, GC-MS analysis of solvent-extracted leaves taken from cultivated specimens conveys that many heavier 'volatiles' with lower vapour pressure are not detected in hydrodistilled essential oils and have therefore been neglected in past chemical studies. Hence, our data reiterate that chemical studies of the genus Eremophila will continue to describe new metabolites and that taxon determination has limited predictive value for the chemical composition.

Biomimetic Synthesis of Mitchellenes B-H from the Abundant Biological Precursor 14-Hydroxy-6,12-muuroloadien-15-oic Acid.

A step-economic biomimetic synthesis of mitchellenes B-H found in Eremophila sturtii has been achieved. Starting from the putative muurolane biological precursor, redox isomerization of the allylic alcohol gave an epimeric mixture of aldehydes, which could be used as a handle for cyclization onto the C6 position, using Bu3SnH-mediated radical cyclization or NHC-catalyzed Stetter reaction. The NHC-mediated approach was superior as the epimeric mixture underwent a dynamic kinetic resolution during the reaction, and reduction of the mixture with NaBH4 selectively formed the mitchellene ring system in 56% yield for the three steps. In the campaign to obtain the acid-starting material, two new natural products, mitchellene H and a muurolane aldehyde, were isolated. Synthetic procedures to access this family of natural products will enable further studies on their biological properties.

Asymmetric Carboxycyanation of Aldehydes by Cooperative AlF/Onium Salt Catalysts: from Cyanoformate to KCN as Cyanide Source.

Asymmetric 1,2-additions of cyanide yield enantioenriched cyanohydrins as versatile chiral building blocks. Next to HCN, volatile organic cyanide sources are usually used. Among them, cyanoformates are more attractive on technical scale than TMSCN for cost reasons, but catalytic productivity is usually lower. Here, the development of a new strategy for cyanations is described, in which this activity disadvantage is overcome. A Lewis acidic Al center cooperates with an aprotic onium moiety within a remarkably robust bifunctional Al-F-salen complex. This allowed for unprecedented turnover numbers of up to 104 . DFT studies suggest an unexpected unique trimolecular pathway in which the ammonium bound cyanide attacks the aldehyde, which itself is activated by the carbonyl group of the cyanoformate binding to the Al center. In addition, a novel practical carboxycyanation method was developed that makes use of KCN as the sole cyanide source. The use of a pyrocarbonate as carboxylating reagent provided the best results.

Revision of the Phytochemistry of Eremophila sturtii and E. mitchellii.

Eremophila sturtii and E. mitchellii are found in the arid and temperate regions of Australia and, because of their similar appearances, are often confused. Previous phytochemical investigations have described mitchellene sesquiterpenes (1-5) reported from E. mitchellii but are here demonstrated to be from E. sturtii. A previous study that described serrulatic acids (16 and 17) from a species reported as E. sturtii actually used E. mitchellii. In addition, two new C-15 modified analogues, mitchellenes F (14) and G (15), were isolated from E. sturtii. The absolute configuration of 14 was determined with the first X-ray structure of a compound with the mitchellene skeleton.

An Aluminum Fluoride Complex with an Appended Ammonium Salt as an Exceptionally Active Cooperative Catalyst for the Asymmetric Carboxycyanation of Aldehydes.

Al-F bonds are among the most stable σ bonds known, exhibiting an even higher bond energy than Si-F bonds. Despite a stability advantage and a potentially high Lewis acidity of Al-F complexes, they have not been described as structurally defined catalysts for enantioselective reactions. We show that Al-F salen complexes with appended ammonium moieties give exceptional catalytic activity in asymmetric carboxycyanations. In addition to aromatic aldehydes, enal and aliphatic substrates are well accepted. Turnover numbers up to around 104 were achieved, whereas with previous catalysts 101 -102 turnovers were typically attained. In contrast to Al-Me and Al-Cl salen complexes, the analogous Al-F species are remarkably stable towards air, water, and heat, and can be recovered unchanged after catalysis. They possess a considerably increased Lewis acidity as shown by DFT calculations.

The Iridoid Myodesert-1-ene and Elemol/Eudesmol are found in Distinct Chemotypes of the Australian Aboriginal Medicinal Plant Eremophila dalyana (Scrophulariaceae).

The strongly aromatic Australian desert species Eremophila dalyana is an Aboriginal medicinal plant that continues to be used today in Central Australia in the treatment of respiratory complaints and Sarcoptes scabiei infestation. Using hydrodistillation of aerial parts of the plant, the new natural product myodesert-l- ene was isolated in two disjunct populations at up to 98% of the volatiles present in the hydrodistilled oils. Weak antimicrobial activities were observed for whole oils and myodesert-l-ene. Activities in the hydrodistilled oil were attributed to the antimicrobial sesquiterpenes elemol and eudesmol which showed good activity when isolated and were relatively abundant in the chemotype used medicinally. The biogenesis of myodesert-l-ene from iridodial is proposed.

Modeling of high-order terms in potential energy surface expansions using the reference-geometry Harris-Foulkes method.

The reference-geometry Harris-Foulkes (RGHF) approach has been used to model high-order terms within the expansion of multi-dimensional potential energy surfaces (PES) as needed within the calculation of accurate vibrational frequencies beyond the harmonic approximation. The key step of this method is a localization of the electron density to the atoms of the molecule at a given reference structure and a subsequent transfer of these atom-centered partial densities to the atom positions of distorted structures. This concept has been used to evaluate the 3-mode coupling terms of a multi-mode expansion of the PES as arising in the Watson Hamiltonian. Systematic benchmark calculations for vibrational frequencies obtained from vibrational configuration interaction (VCI) theory have been performed in order to study the effects of this approximation on the fundamental modes of a test suite of 28 molecules.