A rapid synthetic route to conformationally restricted [5,5]-bicyclic nucleoside-amino acid conjugates.

A concise synthetic route to a novel class of conformationally rigid 3',4'-cis-fused bicyclic nucleoside derivatives has been developed. The synthetic strategy and approach involves initial synthesis of a key [5,5]-bicyclic 6-aminofurofuran-2-one scaffold, employing an L-serine derived aminobutenolide as a strategically functionalized chiral template. Subsequent utilization of the carbonyl functionality of the above bicyclic lactone toward nucleobase incorporation, and linking of the resident amine functionality with appropriately protected amino acids completed the syntheses of the target bicyclic nucleoside-amino acid conjugates. Following the above route, and utilizing a combination of easily available nucleobases (4) and amino acids (4) as the two diversity elements, combinatorial synthesis of a 16-member demonstration library of the title amino acid-linked nucleosides has been accomplished.

Comparative study of ezrin phosphorylation among different tissues: more is good; too much is bad.

In a comparison of three different tissues, the membrane cytoskeleton linker protein ezrin was found to assume high levels of phosphorylation on threonine-567 (T567) in the brush border membranes of renal proximal tubule cells and small intestine enterocytes, in contrast to the apical canalicular membrane of gastric parietal cells. Together with an earlier observation that increased T567 phosphorylation is associated with more elaborate microvilli in parietal cells, this comparative study suggested a higher phosphorylation level requirement for the denser and more uniform distribution of microvilli at brush border surfaces. Using a kinase inhibitor, staurosporin, and metabolic inhibitor, sodium azide, relatively high turnover of ezrin T567 phosphorylation was observed in all three epithelia. Aiming to understand the role of phosphorylation turnover in these tissues, detergent extraction analysis of gastric glands and proximal tubules revealed that an increased phosphorylation on ezrin T567 greatly enhanced its association with F-actin, while ezrin-membrane interaction persisted regardless of the changes of phosphorylation level on ezrin T567. Finally, expression of Thr567Asp mutant ezrin, which mimics the phospho-ezrin state but does not allow turnover, caused aberrant growth of membrane projections in cultured proximal tubule cells, consistent with what had previously been observed in several cell lines and gastric parietal cells. These results fit into a model of surface plasticity, which posits that the turnover of phosphorylation on T567 empowers ezrin to relax and reposition membrane to the underlying cytoskeleton under varying conditions of filament growth or rapid membrane expansion (or depletion).

De novo synthetic route to a combinatorial library of peptidyl nucleosides.

A stereoselective synthetic route has been developed for the combinatorial synthesis of a structurally unique class of C-4' side chain modified peptide-linked nucleosides. The synthetic strategy and approach involves initial synthesis of a strategically functionalized amino butenolide template, utilizing L-serine as a chiral starting material. Subsequent transformation of the above lactone to C4' aminoalkyl substituted nucleosides, followed by the peptidic coupling of the C4' side chain amine with various amino acids completed the syntheses of the target peptidyl nucleosides. Employing the above route, and utilizing a combination of easily available nucleobases (4) and amino acids (6) as the two diversity elements, synthesis of a 24-member combinatorial library of the title peptide-linked nucleosides has been accomplished.

Trimethylsilyl trifluoromethanesulfonate (TMSOTf) assisted facile deprotection of N,O-acetonides.

Employing TMSOTf as an easily available reagent, we have developed a mild and efficient method for the deprotection of both terminal and internal N,0-acetonide functionalities. Various regularly used protecting groups and common organic functional moieties were found to be unaffected by the described reaction conditions. In a few representative examples, the present method was also extended to deprotect acetonides obtained from 1,2-, and 1,3-terminal diols. The acetonide deprotection protocol described herein is expected to be a useful addition to the presently available methods for performing the above transformation.

Synthesis of +-dihydro-epi-deoxyarteannuin B.

The synthesis of (+)-dihydro-epi-deoxyarteannuin B (3) from (-)-isopulegol is described. Difficulties in the alkylation of menthone derivatives (e.g., 4a --> 6a) were overcome by using Noyori's zincate enolate method. Related problems with nucleophilic addition to the hindered menthone core of 6a were resolved by using either organocerium or acetylide nucleophiles. Finally, two alternative olefin metathesis approaches are reported for the final cyclization. This study provides insight into the reactivity and synthetic processing of the artemisinin sesquiterpenes.

Mix-and-heat benzylation of alcohols using a bench-stable pyridinium salt.

2-Benzyloxy-1-methylpyridinium triflate (1) is a stable, neutral organic salt that converts alcohols into benzyl ethers upon warming. The synthesis and reactivity of 1 are described herein. Benzylation of a wide range of alcohols occurs in good to excellent yield.

p-Siletanylbenzylidene acetal: oxidizable protecting group for diols.

[reactions: see text] Hydrogen peroxide oxidation of benzylidene acetals (and derivative benzyl ethers) that incorporate a siletane ring at the para position creates a deprotection pathway without affecting other important chemical properties of the benzylidene acetal, such as regioselective reductive ring opening.