A Synthetic Strategy toward Eight-Membered Cyclic Amines by Cycloetherification and Claisen Rearrangement.

Eight-membered nitrogen-containing heterocycles were straightforwardly produced by a nickel-catalyzed cycloetherification and subsequent Claisen rearrangement of secondary and tertiary alcohols. In particular, a one-pot transformation was achieved with tertiary alcohols in moderate to good yields. This operationally simple reaction is tolerant of many functional groups and applicable to the synthesis of various medium-sized ring nitrogen-containing heterocycles.

RhII -Catalyzed ß-C(sp2 )-H Alkylation of Enol Ethers, Enamides and Enecarbamates with α-Diazo Dicarbonyl Compounds.

A RhII -catalyzed method for intermolecular alkylation of the ß-C(sp2 )-H bond of enol ethers, enamides, and enecarbamates with α-diazo-1,3-dicarbonyl compounds is reported. The products are formed in up to 99 % yield and can be readily derivatized under a variety of conditions. By utilizing a combination of experimental and computational studies, the presumptive addition-elimination reaction mechanism was investigated and found to proceed under thermodynamic control at higher temperature. The acquired fundamental knowledge was translated into a strategic reaction design and yielded the first example of the ß-C-H functionalizations of acyclic enol ethers using α-diazo-1,3-dicarbonyl compounds.

Catalytic, Cascade Ring-Opening Benzannulations of 2,3-Dihydrofuran O,O- and N,O-Acetals.

An Al(OTf)3 -catalyzed intramolecular cascade ring-opening benzannulation of 2,3-dihydrofuran O,O- and N,O-acetals is described. The cascade sequence involves the dihydrofuran ring-opening by acetal hydrolysis, an intramolecular Prins-type cyclization, and aromatization to generate an array of benzo-fused (hetero)aromatic systems in up to 95 % yield. This method represents the first example of dihydrofuran acetal usage in benzannulation reactions. The approach provides excellent regiocontrol based on the choice of alkenes used to form the requisite dihydrofuran acetals.

Ligands for glaucoma-associated myocilin discovered by a generic binding assay.

Mutations in the olfactomedin domain of myocilin (myoc-OLF) are the strongest link to inherited primary open angle glaucoma. In this recently identified protein misfolding disorder, aggregation-prone disease variants of myocilin hasten glaucoma-associated elevation of intraocular pressure, leading to vision loss. Despite its well-documented pathogenic role, myocilin remains a domain of unknown structure or function. Here we report the first small-molecule ligands that bind to the native state of myoc-OLF. To discover these molecules, we designed a general label-free, mix-and-measure, high throughput chemical assay for restabilization (CARS), which is likely readily adaptable to discover ligands for other proteins. Of the 14 hit molecules identified from screening myoc-OLF against the Sigma-Aldrich Library of Pharmacologically Active Compounds using CARS, surface plasmon resonance binding studies reveal three are stoichiometric ligand scaffolds with low micromolar affinity. Two compounds, GW5074 and apigenin, inhibit myoc-OLF amyloid formation in vitro. Structure-activity relationship-based soluble derivatives reduce aggregation in vitro as well as enhance secretion of full-length mutant myocilin in a cell culture model. Our compounds set the stage for a new chemical probe approach to clarify the biological function of wild-type myocilin and represent lead therapeutic compounds for diminishing intracellular sequestration of toxic mutant myocilin.

Intramolecular donor-acceptor cyclopropane ring-opening cyclizations.

Cyclization reactions of donor-acceptor (D-A) cyclopropanes are recognized as versatile methods for construction of carbocyclic and heterocyclic scaffolds. In the literature, many examples of these polarized cyclopropanes' reactivity with nucleophiles, electrophiles, and radicals are prevalent. Although intermolecular reactivity of donor-acceptor cyclopropanes is widely reported, reviews that center on their intramolecular chemistry are rare. Thereupon, this tutorial review focalizes on new intramolecular transformations of donor-acceptor cyclopropanes for cycloisomerizations, formal cycloadditions, umpolung reactions, rearrangements and ring-opening lactonizations/lactamizations from 2009 to 2013. Furthermore, the role of D-A acceptor cyclopropanes as reactive subunits in natural product synthesis is underscored.

A general intramolecular Friedel-Crafts approach to functionalized pyrrolo[3,2,1-ij]quinolin-4-ones.

An indium(III)-catalyzed intramolecular Friedel-Crafts annulation for the efficient synthesis of pyrrolo[3,2,1-ij]quinolin-4-ones is described. The products are formed in good to excellent yields (51-97%) with diastereoselectivities up to >99 : 1 dr.

Diastereoselective intramolecular Friedel-Crafts cyclizations of substituted methyl 2-(1H-indole-1-carbonyl)acrylates: efficient access to functionalized 1H-pyrrolo[1,2-a]indoles.

A general, catalytic method for the diastereoselective synthesis of functionalized 1H-pyrrolo[1,2-a]indoles via an intramolecular Friedel-Crafts alkylation of N-acyl indoles is reported. Products were obtained in excellent yields (up to 98%) with high diastereoselectivities (up to >25:1 dr).

An efficient synthesis of hydropyrido[1,2-a]indole-6(7H)-ones via an In(III)-catalyzed tandem cyclopropane ring-opening/Friedel-Crafts alkylation sequence.

An efficient Lewis acid-catalyzed cyclopropane ring-opening/Friedel-Crafts alkylation sequence of methyl 1-(1H-indole-carbonyl)-1-cyclopropanecarboxylates is reported. The protocol affords functionalized hydropyrido[1,2-a]indole-6(7H)-ones in up to 99% yield.

A catalytic homo-Nazarov cyclization protocol for the synthesis of heteroaromatic ring-fused cyclohexanones.

A general protocol for the catalytic homo-Nazarov cyclization of cyclopropyl heteroaryl ketones has been developed, which employs indium triflate as the promoter. A range of heteroaromatic ring-fused cyclohexanones was synthesized in 56-91% yield using this protocol. An example of a tandem cyclopropanation/homo-Nazarov cyclization is also reported in which the one-pot yield is greater than the overall yield of the two individual steps.

Amyloid fiber formation and membrane disruption are separate processes localized in two distinct regions of IAPP, the type-2-diabetes-related peptide.

Aggregation of Islet Amyloid Polypeptide (IAPP) has been implicated in the development of type II diabetes. Because IAPP is a highly amyloidogenic peptide, it has been suggested that the formation of IAPP amyloid fibers causes disruption of the cellular membrane and is responsible for the death of beta-cells during type II diabetes. Previous studies have shown that the N-terminal 1-19 region, rather than the amyloidogenic 20-29 region, is primarily responsible for the interaction of the IAPP peptide with membranes. Liposome leakage experiments presented in this study confirm that the pathological membrane disrupting activity of the full-length hIAPP is also shared by hIAPP 1-19. The hIAPP 1-19 fragment at a low concentration of peptide induces membrane disruption to a near identical extent as the full-length peptide. At higher peptide concentrations, the hIAPP 1-19 fragment induces a greater extent of membrane disruption than the full-length peptide. Similar to the full-length peptide, hIAPP 1-19 exhibits a random coil conformation in solution and adopts an alpha-helical conformation upon binding to lipid membranes. However, unlike the full-length peptide, the hIAPP 1-19 fragment did not form amyloid fibers when incubated with POPG vesicles. These results indicate that membrane disruption can occur independently from amyloid formation in IAPP, and the sequences responsible for amyloid formation and membrane disruption are located in different regions of the peptide.