Alternative Approach to Access 5-Hydroxy-1H-pyrrol-2-(5H)-ones from Base-Induced Tandem Intramolecular Cyclization of Sulfur Ylide with Ketones and 1,3-Hydroxy Rearrangement.

An easily adaptable protocol for the preparation of 5-hydroxy-1H-pyrrol-2(5H)-ones from readily available starting materials has been reported. The reaction of sulfur ylides with carbonyl compounds is a common approach to synthesizing epoxides. Alternatively, we have developed a method with mild reaction conditions wherein sulfur ylide underwent an intramolecular cyclization with a ketonic carbonyl group in a highly efficient way and was followed by 1,3-hydroxy rearrangement to produce 5-hydroxy-1H-pyrrol-2(5H)-ones in excellent yields. The present method offers a straightforward approach to synthesize 5-hydroxy-1H-pyrrol-2(5H)-ones from sulfur ylides without the aid of transition metal in one-pot operation, which involves sequential cyclization and rearrangement reaction. The formation of 5-hydroxy-1H-pyrrol-2(5H)-ones is supported by different spectroscopic techniques, including X-ray crystallographic data and 2D NMR studies (COSY, HSQC, HMBC, and DEPT).

Identification of ß-aminopyrrolidine containing peptides as ß-amyloid aggregation inhibitors for Alzheimer's disease.

Alzheimer's disease (AD) is caused by a series of events initiated by the production and aggregation of the amyloid ß-protein (Aß). In the early stages of the disease, Aß is released in a soluble form then progressively forms oligomeric, multimeric, and fibrillar aggregates, triggering neurodegeneration. Thus, development of inhibitors that initiate reverse Aß aggregation is thought to be a logical approach in treating AD. In this context, we developed ß-aminopyrrolidine containing 12 mer peptide 3 which is very potent in inhibiting the Aß aggregation and also reducing Aß(42)-induced cytotoxicity.

A designed three-stranded ß-sheet in an α/ß hybrid peptide.

The incorporation of ß-amino acid residues into the antiparallel ß-strand segments of a multi-stranded ß-sheet peptide is demonstrated for a 19-residue peptide, Boc-LV(ß)FV(D)PGL(ß)FVVL(D)PGLVL(ß)FVV-OMe (BBH19). Two centrally positioned (D)Pro-Gly segments facilitate formation of a stable three-stranded ß-sheet, in which ß-phenylalanine ((ß)Phe) residues occur at facing positions 3, 8 and 17. Structure determination in methanol solution is accomplished by using NMR-derived restraints obtained from NOEs, temperature dependence of amide NH chemical shifts, rates of H/D exchange of amide protons and vicinal coupling constants. The data are consistent with a conformationally well-defined three-stranded ß-sheet structure in solution. Cross-strand interactions between (ß)Phe3/(ß)Phe17 and (ß)Phe3/Val15 residues define orientations of these side-chains. The observation of close contact distances between the side-chains on the N- and C-terminal strands of the three-stranded ß-sheet provides strong support for the designed structure. Evidence is presented for multiple side-chain conformations from an analysis of NOE data. An unusual observation of the disappearance of the Gly NH resonances upon prolonged storage in methanol is rationalised on the basis of a slow aggregation step, resulting in stacking of three-stranded ß-sheet structures, which in turn influences the conformational interconversion between type I' and type II' ß-turns at the two (D)Pro-Gly segments. Experimental evidence for these processes is presented. The decapeptide fragment Boc-LV(ß)FV(D)PGL(ß)FVV-OMe (BBH10), which has been previously characterized as a type I' ß-turn nucleated hairpin, is shown to favour a type II' ß-turn conformation in solution, supporting the occurrence of conformational interconversion at the turn segments in these hairpin and sheet structures.