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Retinoic acid has been previously proposed in the treatment of Alzheimer's disease (AD). Here, five transgenic mouse models expressing AD and frontotemporal dementia risk genes (i.e., PLB2APP, PLB2TAU, PLB1Double, PLB1Triple, and PLB4) were used to investigate if consistent alterations exist in multiple elements of the retinoic acid signaling pathway in these models. Many steps of the retinoic acid signaling pathway including binding proteins and metabolic enzymes decline, while the previously reported increase in RBP4 was only consistent at late (6 months) but not early (3 month) ages. The retinoic acid receptors were exceptional in their consistent decline in mRNA and protein with transcript decline of retinoic acid receptors β and γ by 3 months, before significant pathology, suggesting involvement in early stages of disease. Decline in RBP1 transcript may also be an early but not late marker of disease. The decline in the retinoic acid signaling system may therefore be a therapeutic target for AD and frontotemporal dementia. Thus, novel stable retinoic acid receptor modulators (RAR-Ms) activating multiple genomic and non-genomic pathways were probed for therapeutic control of gene expression in rat primary hippocampal and cortical cultures. RAR-Ms promoted the non-amyloidogenic pathway, repressed lipopolysaccharide induced inflammatory genes and induced genes with neurotrophic action. RAR-Ms had diverse effects on gene expression allowing particular RAR-Ms to be selected for maximal therapeutic effect. Overall the results demonstrated the early decline of retinoic acid signaling in AD and frontotemporal dementia models and the activity of stable and potent alternatives to retinoic acid as potential therapeutics.

Neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by progressive neuronal loss and currently lack effective treatments that block the degenerative process. It has been suggested that retinoids, a class of vitamin A-derived compounds, may hold potential as future therapeutics for these disorders.In this review, we explore the role of retinoids in modulating various signaling pathways in the brain which influence pathologically relevant processes such as cellular differentiation, immune and antioxidant response, neurite outgrowth and neurite regeneration. These actions are predominantly mediated by the retinoic acid receptors and we discuss the developmental history of ligands for these receptors, assessing how refinements in receptor binding specificity and improved pharmacokinetic properties may influence the management of off-target effects.New approaches to understanding retinoid's mechanisms of action, including non-genomic pathways, and how these mechanisms interact may prove vital in the development of future retinoid-based neurodegenerative disease treatments.

Vinyliodide reacts chemoselectively under Heck–Mizoroki conditions with terminal alkenes, including vinylboronate esters, to give dienes. The resulting dienylboronates undergo Suzuki–Miyaura couplings with aryl, heteroaryl and alkenyl halides to access dienes and trienes.

An efficient, photocatalytic chlorination of alkylarene α-H groups using NaCl/HCl as a chlorine source has been developed, which involves a radical mechanism under visible-light (including sunlight) conditions. A chlorine radical is proposed to be formed by an electron transfer from chloride ion to O2 in air through the bandgap hole of the semiconductor AgCl. The chlorination protocol is characterized by its use of natural sunlight or other visible light, mild conditions, cheap source of chlorine, green solvent, and high selectivity. The yield of benzylchloride is 95% with a toluene conversion as high as 40%, which rivals traditional chlorination methods.

The conversion of 3-aryl or 3-alkyl substituted acrolein or methacrolein derivatives to the corresponding imines and subsequent in situ borylation of the latter is extensively studied.

SummaryDaptomycin is a lipopeptide antibiotic produced by a nonribosomal peptide synthetase (NRPS) in Streptomyces roseosporus. The holoenzyme is composed of three subunits, encoded by the dptA, dptBC, and dptD genes, each responsible for incorporating particular amino acids into the peptide. We introduced expression plasmids carrying dptD or NRPS genes encoding subunits from two related lipopeptide biosynthetic pathways into a daptomycin nonproducing strain of S. roseosporus harboring a deletion of dptD. All constructs successfully complemented the deletion in trans, generating three peptide cores related to daptomycin. When these were coupled with incomplete methylation of 1 amino acid and natural variation in the lipid side chain, 18 lipopeptides were generated. Substantial amounts of nine of these compounds were readily obtained by fermentation, and all displayed antibacterial activity against gram-positive pathogens.

An efficient, catalytic, asymmetric route to both (R)-fluoxetine (II) and (S)-duloxetine (IV) through the asymmetric copper-mediated β-borylation of α,β-unsaturated imines is developed.

This review provides insight into the variety of structures and biological activities found in the non-isoprenoid family of polyene natural products and examines the strategies and synthetic methods applied for the polyenic components in particular by way of examples.

The influence of the chain length in homoboroproline homologues on their catalytic activity in aldol reactions is examined.

In the last few years, multicomponent reactions involving boron substituted 1,3-dienes have emerged as important tools in synthetic organic chemistry. The most significant recent results and developments obtained in this area are reported in this review.

The key feature of this enantioselective route for the one-pot conversion of enals to γ-amino alcohols is an in situ imine formation using a sterically demanding amine to ensure complete selectivity in the subsequent β-boration step.

The direct amidation of amino acid derivatives catalyzed by arylboronic acids has been examined. The reaction was generally slow relative to simple amine-carboxylic acid combinations though proceeded at 65–68 °C generally avoiding racemization. 3,4,5-Trifluorophenylboronic and o-nitrophenylboronic acids were found to be the best catalysts, though for slower dipeptide formations, high catalyst loadings were required and an interesting synergistic catalytic effect between two arylboronic acids was discovered.

An extremely simple and efficient palladium-catalyzed coupling procedure for the synthesis of functionalized styrenes and dienes is utilized to demonstrate how 4,4,6-trimethyl-2-vinyl-1,3,2-dioxaborinane can be employed to selectively undergo Suzuki-Mivaura counline with a range of halide substrates.

A one-pot hetero-Diels–Alder/ring contraction cascade is presented from the reaction of 1-boronodienes and arylnitroso derivatives to derive N-arylpyrroles in moderate to good yields (up to 82%).

An efficient, 4-step, one-pot, highly stereoselective route to γ-amino alcohols has been developed via an in situ α,β-unsaturated imine formation, β-boration, reduction (CN) and oxidation (C–B) sequence and especially for certain water-soluble γ-amino alcohols, a further step can be added to directly access the corresponding 1,3-oxazine derivatives.

A novel one-pot tandem cyclization of electron-deficient aromatic enynes furnishing indenones or 6,5,6-fused tricyclic lactones is developed.

The area of boron conjugate addition via diboration (β-boration) has grown rapidly since the first examples appeared in the late 1990s. This article aims to give a comprehensive review of the current advances in β-boration (of electron deficient alkenes), providing a commentary upon the development of the asymmetric version. To date, many mechanistic models have been put forward to explain the experimental observations and this review surveys some of these key ideas. Recently, the development of organocatalytic methodologies that facilitate β-boration have also been demonstrated and current ideas regarding the mechanisms of such processes are examined.

A scandium-catalyzed dihydropyridine synthesis by a multicomponent cycloaddition reaction is elaborated.

A wide variety of oximes, imines, hydrazones and nitriles is efficiently reduced to the corresponding amines using sodium borohydride in the presence of amorphous nickel as catalyst.

Starting from the α,β-unsaturated ketone (I) or the α,β-unsaturated imines (VI), three-step routes are developed involving boron conjugate addition, reduction, and oxidation to give the syn-1,3-diol (IV) or syn-1,3-amino alcohols, respectively.

A stereoselective synthesis of arylidene N-alkoxydiketopiperazines viaoxime-ether formation and intramolecular acylation is described, followed by an acid-catalysed rearrangement-fragmentation to give novel diketopiperazine hemiaminal derivatives with useful bioactivity against certain tumour cell lines.

Intra- and intermolecular versions are used to prepare a variety of cycloaddition products as oxazines or their bridged analogues.

A review into the aza-Diels–Alder reaction, mainly concentrating on literature examples that form piperidin-4-ones from the reaction of imines and electron rich dienes or enones, either through a Lewis acidic/Bronsted acid approach or through the use of an organocatalyst. This review questions whether the mechanism of the aza-Diels–Alder reaction is step wise as opposed to concerted when using oxygenated dienes.

A series of title compounds of type (VI) and (VIII) are investigated for their antifungal activities.

Deprotonation of β-boronate carbonyl derivatives can be readily achieved using LDA. Reaction of the resulting enolates with aldehydes gives the corresponding Aldol products, with high syn-selectivity for Z-enolates. This result is consistent with chelation enhanced stabilisation of the enolate geometry via the boronate moiety.

Halomethylboronate derivatives from “ate”-complexes with lithium ester enolates, which are relatively stable at room temperature and can be observed by 11B N.M.R. Reaction of an iodomethylboronate derivative with either an ester, ketone or amide enolate provides the corresponding β-boronate carbonyl derivatives in 43–83% yield.

β-Boronate carbonyl derivatives can be readily deprotonated using LDA and reaction of the resulting enolates with aldehydes gives the corresponding aldol products, with high syn -selectivity for Z -enolates with both benzaldehyde and pivaldehyde. Moderate to good syn -selectivity is observed for E -enolates. These results are consistent with chelation enhanced stabilisation of the enolate geometry via the boronate moiety and chelation enhanced locking of the resulting aldolate stereochemistry.

Furan and 2-hydroxymethylfuran were reacted under Lewis acidic oligomeric precursors, for a subsequent Lewis acid catalysed cyclisation to afford the furan based calixarenes, i.e.cyclic tetramer2a, and small quantities of the cyclic pentamer2b, hexamer 2c and octamer2d.

Force field parameters for use in MM2 modelling programs have been developed for the diazoketone function, from a combination of X-ray crystallographic data, IR spectroscopy, and ab initio and semi-empirical calculations. These parameters have been applied to study the accessible conformations and structure of two diazoketone containing molecules, for which X-ray crystallographic data is available. Comparison of X-ray data and calculated geometry was only possible after allowance was made for the effect of crystal packing forces.

Homochiral β-boronate carbonyl derivative 4 directs the asymmetric reduction of the ketone moiety, providing 89 % enantiomeric excess of the (S)-diol 6, using borane-tetrahydrofuran as the reducing agent.

E- and Z-1-alkenyl iodides react with vinylboronate pinacol ester 1 under palladium(0) catalysed, Heck conditions to provide polyenylboronates in moderate yields after purification. The addition of either silver(I) or thallium(I) salts to the reaction mixture is essential. Alkenyl bromides are unreactive under identical reaction conditions.

N-[(1R)-(–)-camphor-10-ylsulfonyl]imine 1b generated in situ from the corresponding brominated glycinate 4b reacts with Danishefsky's diene under thermal conditions to give a high yield of diastereoisomeric Diels–Alder adducts 7b and 6b in a 2.04 : 1 ratio. Under Lewis acid catalysis at –78 °C the diastereoselectivity improves slightly to 2.30 : 1 using titanium tetraisopropoxide. However, the sense of asymmetric induction is reversed when using diethylaluminium chloride as the catalyst. Determination of the absolute stereochemistry of the adducts 6b and 7b was achieved by comparison with pipecolic acid derivatives 10b and 12b and showed that 7b had the (2R)-configuration at the newly formed chiral centre and 6b the (2S)-configuration.

Hydrolysis of the cycloaddition product derived from tosyl cyanide and cyclopentadiene was investigated using 18O label incorporation experiments; thus, sulfonyl imine 2 was transformed into 18O labelled lactam 3 with 18O labelled acetic acid, which is consistent with the intervention of intermediate 6 during the hydrolysis.

N,N-dibenzyl-2-aminopropanal 1a derived from alanine rearranges to the corresponding ketone, N,N-dibenzyl-1-aminopropanone upon exposure to either silica gel or pyridinium acetate. Similar rearrangements do not occur with aldehydes derived from phenylalinine, valine, leucine, proline or phenylglycine. One mechanistic explanation for the rearrangement is a facile 1,2-methyl shift, followed by 1,2-hydrogen shift. © 1997 Elsevier Science Ltd.

New catalytic asymmetric Lewis acids have been developed for the aza-Diels-Alder reaction of a methyl glyoxalate and p-anisidine derived imine with Danishefsky's diene. The catalysts were developed using parallel combinatorial methods, with the highest e.e. being 97 % using (1S, 2S)-1,2-diphenylethylenediamine and magnesium iodide in acetonitrile.

Tosyl cyanide is activated by titanium(IV) chloride to generate a tolylsulfinyl chloride equivalent, which readily stereo- and regio-specifically adds to certain alkenes to provide β-chlorosulfoxides. These chlorides rapidly hydrolyse on silica gel to provide β-hydroxysulfoxides in stereocontrolled manner.