Self-assembled amyloid fibrils with controllable conformational heterogeneity

Amyloid fibrils are a hallmark of neurodegenerative diseases and exhibit a conformational diversity that governs their pathological functions. Despite recent findings concerning the pathological role of their conformational diversity, the way in which the heterogeneous conformations of amyloid fibrils can be formed has remained elusive. Here, we show that microwave-assisted chemistry affects the self-assembly process of amyloid fibril formation, which results in their conformational heterogeneity. In particular, microwave-assisted chemistry allows for delicate control of the thermodynamics of the self-assembly process, which enabled us to tune the molecular structure of ??-lactoglobulin amyloid fibrils. The heterogeneous conformations of amyloid fibrils, which can be tuned with microwave-assisted chemistry, are attributed to the microwave-driven thermal energy affecting the electrostatic interaction during the self-assembly process. Our study demonstrates how microwave-assisted chemistry can be used to gain insight into the origin of conformational heterogeneity of amyloid fibrils as well as the design principles showing how the molecular structures of amyloid fibrils can be controlledopen0

Regio- and stereoselective microwave-assisted synthesis of 5-alkyl-4-alkenyl-4-phenyl-1,3-oxazolidin-2-ones

Chiral symmetrical alk-2-yne-1,4-diols have been stereoselectively transformed into 5-alkyl-4-alkenyl-4-phenyl-1,3-oxazolidin- 2-ones, which are precursors of quaternary α-amino β-hydroxy acids. The key step was the cyclization of the bis(tosylcarbamates) of 2- phenylalk-2-yne-1,4-diols, easily obtained from the starting chiral diols. These cyclizations were accomplished with complete regioselectivity and up to 92:8 dr in the presence of catalytic amounts of Ni(0) or Pd (II) derivatives under microwave heating

AN IMPROVED SYNTHESIS OF 5-ALKYL-2,3-DIHYDRO-FURAN-2,3-DIONES

The synthesis of 5-tert-butyl-2,3-dihydrofuran-2,3-dione (2a) from ethenyloxysilane (3) and oxalyl chloride is reinvestigated. Apart from 2a, two other reaction products, namely furan-3-yl oxalate (6) and difuran-3-yl oxalate (7) are isolated, explaining the low yield of 2a in this process. An improved method for the preparation of 2a, and its 5-methyl analog (2b) by cyclization of acylpyruvic acids (8a,b) is described

[2+4] CYCLOADDITION REACTIONS OF NEAT DIPIVALOYLKETENE

Various [2 + 4] hetero-Diels-Alder cycloaddition reactions of dipivaloylketene (2) with polarized multiple bond systems are described. Aldehydes and ketones react with 2 to furnish 1,3-dioxin-4-ones 7, imines and heterocumulenes (X = C=N) form 1,3-oxazin-4-ones 9 and 11, respectively. Analogous reactions of 2 with ethyl vinyl ether, ethoxyacetylene, diethylcyanamide, and adamantanethione leading to [2 + 4] adducts 12,14,15 and 16 are also reported. All these cycloadditions proceed in high yield at very mild reaction conditions

A Nitroketene to Nitrile Oxide Transformation

2,3-Dihydropyrrole-2,3-diones 1 thermally extrude CO, giving imidoylketenes 2, which cyclise efficiently to 4-quinolones 3; however, the analogous nitro(imidoyl)ketene 5 eliminates CO2 and rearranges to the 3-oximino-3H-indole 9, presumably via an imidoylnitrile oxide 7

Synthesis and Flash Vacuum Pyrolysis of Isoxazolo[5,4-D]Pyrimidines and Isothiazolo[5,4-D]Pyrimidines

The multi-step synthesis of isothiazolo[5,4-d]pyrimidines (1c,d) and isoxazolo[5,4-d]pyrimidine (1b) is described. Flash vacuum pyrolysis of lb leads to phenyliminopropadienone, Ph-N=C=C=C=O, which was identified by Ar matrix infrared spectroscopy

Matrix-Isolation and Infrared-Spectrum of Thioformyl Cyanide

The elusive molecule thioformyl cyanide, S=CH-CN (2), was generated by flash vacuum pyrolysis of allyl cyanomethyl sulfide (1) and characterized by argon matrix infrared spectroscopy. The observed infrared absorptions (2221, 1320, 1103, 889, and 824 cm-1) are in good agreement with ab initio molecular orbital calculations at the MP2/6-31G* level