Improved prediction for a multivariate normal distribution with unknown mean and variance

The prediction problem for a multivariate normal distribution is considered where both mean and variance are unknown. When the Kullback–Leibler loss is used, the Bayesian predictive density based on the right invariant prior, which turns out to be a density of a multivariate t-distribution, is the best invariant and minimax predictive density. In this paper, we introduce an improper shrinkage prior and show that the Bayesian predictive density against the shrinkage prior improves upon the best invariant predictive density when the dimension is greater than or equal to three.     

1,3-Bis(pyren-1-yliminomethyl)calix[4]arene as a selective fluorescent turn-on sensor for mercury(II) ion

A novel calixarene-based diimine, 1,3-bis(pyren-1-yliminomethyl)calix[4]arene (5), serves as a turn-on-type fluorescent sensor, which selectively detects Hg²⁺ in THF/H₂O (99:1, v/v) in the presence of various other metal ions. Such selectivity is not seen with half salen 1 derived from salicylaldehyde and 1-aminopyrene. ¹H NMR analysis reveals that it is a chemodosimetric sensor based on its hydrolysis mediated by Hg²⁺ to release 1-aminopyrene molecules as fluorescent chromophores.     

Effective form of sulfoquinovosyldiacyglycerol (SQDG) vesicles for DNA polymerase inhibition

Sulfoquinovosyldiacyglycerol (SQDG) has a wide range of biological activities that make it an attractive compound for the development of new drugs. Chemically synthesized beta-SQDG-C(18:0) (1,2-di-O-stearoyl-3-O-(6-deoxy-6-sulfo-beta-d-glucopyranosyl)-sn-glycerol), for example, has a potent inhibitory effect on DNA polymerases. We investigated the properties of the vesicle form of beta-SQDG-C(18:0) as the monomer has low solubility in water. The structure of the beta-SQDG-C(18:0) vesicles are highly influenced by NaCl concentration in preparation process. At low NaCl concentrations, the beta-SQDG-C(18:0) vesicles have high surface curvature and form small unilamellar vesicles. Increases in NaCl concentration, resulted in decreased surface curvature and a tendency for beta-SQDG-C(18:0) to form large multilamellar vesicles. The small unilamellar vesicles showed a potent inhibitory effect on DNA polymerase beta, whereas the large multilamellar vesicles had no such effect. We investigated further the relationship between vesicle size and activity by preparing smaller vesicles (262, 99 and 43 nm in diameter) using an extrusion technique. These smaller vesicles had a greater inhibitory effect on DNA polymerase beta activity than non-extruded vesicles. beta-SQDG-C(18:0) vesicles, especially those of small size, were effective in DNA polymerase inhibition and are expected to have high applicability in DNA polymerase study.     

Formal total synthesis of (−)-hamigeran B from a chemo-enzymatically prepared building block with quaternary chiral center

A formal total synthesis of (?)-hamigeran B was achieved in 17 steps from commercially available ethyl 2-oxocyclopentanecarboxylate. Carbonyl reductase-catalyzed asymmetric reduction and the subsequent chemical transformations furnished an enantiomerically pure synthetic intermediate, (R)-5-formyl-2-isopropyl-5-methylcyclopent-1-en-1-yl trifluoromethylsulfonate. Suzuki-Miyaura coupling with Gao's arylboronate [2-(2-formyl-3-methoxy-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane], under PdCl₂(dppf)?CH₂Cl₂ catalysis, and the subsequent cyclization by way of intramolecular reductive SmI₂-mediated 1,2-diol formation provided a tricyclic skeleton with a tetrasubstituted double bond between C-1 and C-9b. Upon hydrogenation of this double bond, the proper stereochemistry of the remaining chiral centers was established. Exclusive addition of the hydrogen atom from the β-face occurred, owing to the shielding of the α-face with a bulky TBS protective group on the C-4 alcohol. The hydrogenation products were transformed into Clive's synthetic precursor for (?)-hamigeran B.     

Photosalient Effect of a Diarylethene with a Perfluorocyclohexene Ring

Crystals of a diarylethene with a perfluorocyclohexene ring exhibit a remarkable photosalient effect upon UV light irradiation that is attributed to the structural changes that occur when going from open‐ to closed‐ring isomers in the crystalline state, together with the existence of two conformers with different photoconversions compared with those of a perfluorocyclopentene derivative. Our current results give a design principle for molecular structures so as to achieve the photosalient effect for photochromic crystals.     

Iron‐Catalyzed Dehydration of Aldoximes to Nitriles Requiring Neither Other Reagents Nor Nitrile Media

The dehydration of aldoximes is an environmentally benign reaction affording the desired nitrile and water as a by‐product. However, most of the reported catalytic dehydration reactions of aldoximes require a solvent containing nitrile to synthesize the corresponding nitrile compounds. Inspired by recent reports on the enzymatic synthesis under nitrile‐free conditions, we here describe that a simple iron salt catalyzes the dehydration of aldoximes requiring neither other reagents nor nitrile media. Our method can be applied to the one‐pot synthesis of nitiriles from aldehydes.     

Asymmetric Total Synthesis of (+)‐Ryanodol and (+)‐Ryanodine

(+)‐Ryanodine ( 1 ) is the ester derivative of 1H‐pyrrole‐2‐carboxylic acid and the complex terpenoid (+)‐ryanodol ( 2 ), which possesses eleven contiguous stereogenic centers on the ABCDE‐ring system. Compound 1 is known to be a potent modulator of intracellular calcium release channels, whereas the activity of 2 is significantly weaker. To chemically construct 1 , the multiple oxygen functional groups must be installed on the fused pentacycle in stereoselective fashions and the extremely hindered C3‐hydroxy group must be acylated in a site‐selective manner. First, the total synthesis of 2 was accomplished by introducing the five stereocenters from the previously prepared enantiopure ABDE‐ring 7 . Stereoselective construction of the C3‐secondary, C2‐ and C6‐tertiary alcohols was achieved by three nucleophilic reactions. The C9‐ and C10‐trisubstituted carbon centers were regio‐ and stereoselectively introduced by hydroboration/oxidation of the six‐membered C‐ring, which was formed by the ring‐closing metathesis reaction. Direct esterification of the C3‐alcohol with pyrrole‐2‐carboxylic acid proved unsuccessful; therefore, we developed a new, two‐step protocol for attachment of the pyrrole moiety. The C3‐hydroxy group was first converted into the less sterically cumbersome glycine ester, which was then transformed into the pyrrole ring through condensation with 1,3‐bis(dimethylamino)allylium tetrafluoroborate. This procedure resulted in the first total synthesis of 1 .     

Analgesic Characteristics of NanoBEO Released by an Airless Dispenser for the Control of Agitation in Severe Dementia

Chronic pain is one of the most common causes of the need for clinical evaluation, acquiring more importance in the elderly with cognitive impairment. Reduced self-reporting capabilities cause unrelieved pain contributing to the development of agitation. Safe and effective pain treatment can afford the management of agitation without the serious increase in death risk associated with neuroleptics. To this aim, the essential oil of bergamot (BEO), proven by rigorous evidence to have strong preclinical anti-nociceptive and anti-allodynic properties, has been engineered (NanoBEO, patent EP 4003294) to allow randomized, double-blind, placebo-controlled trials (BRAINAID, {"type":"clinical-trial","attrs":{"text":"NCT04321889","term_id":"NCT04321889"}}NCT04321889). The present study: (1) assesses the analgesic effects of a single therapeutic dose of NanoBEO, as supplied by an airless dispenser for clinical translation, in models of inflammatory, neuropathic, and sensitization types of pain relevant to clinic; (2) provides a dose–response analysis of the efficacy of NanoBEO on scratching behavior, a typical behavioral disturbance occurring in dementia. A single therapeutic dose of NanoBEO confirms efficacy following thirty minutes pre-treatment with capsaicin and on the central sensitization phase induced by formalin. Moreover, it has an ID50 of 0.6312 mg and it is efficacious on static and dynamic mechanical allodynia. Altogether, the gathered results strengthen the potential of NanoBEO for clinical management of pain and agitation.     

Symmetry‐Driven Strategy for the Assembly of the Core Tetracycle of (+)‐Ryanodine: Synthetic Utility of a Cobalt‐Catalyzed Olefin Oxidation and α‐Alkoxy Bridgehead Radical Reaction

Ryanodine ( 1 ) is a potent modulator of intracellular calcium release channels, designated as ryanodine receptors. The exceptionally complex molecular architecture of 1 comprises a highly oxygenated pentacyclic system with eleven contiguous stereogenic centers, which makes it a formidable target for organic synthesis. We identified the embedded C₂‐symmetric tricyclic substructure within 1 . This specific recognition permitted us to design a concise synthetic route to enantiopure tricycle 9 by utilizing a series of pairwise functionalizations. The four tetrasubstituted carbon centers of 9 were effectively constructed by three key reactions, a dearomatizing Diels–Alder reaction, the kinetic resolution of the obtained racemic 14 through asymmetric methanolysis, and the transannular aldol reaction of the eight‐membered diketone 10 . A new combination of cobalt‐catalyzed hydroperoxidation and NfF‐promoted elimination enabled conversion of the hindered olefin of 9 into the corresponding ketone, thus realizing the desymmetrization. Finally, the tetrasubstituted carbon was stereospecifically installed by utilizing the α‐alkoxy bridgehead radical to deliver the core tetracycle 7 with the six contiguous tetrasubstituted carbon centers. Consequently, the present work not only accomplishes efficient assembly of four out of the five fused rings of 1 , but also develops two new powerful methodologies: two‐step ketone formation and bridgehead radical reaction.