Allyl Linker Research Articles

Catalytic Chemo- and Regioselective Coupling of 1,3-Dicarbonyls with N-Heterocyclic Nucleophiles.

The development of a decarboxylative palladium-catalyzed coupling of 1,3-dicarbonyl compounds with indole, pyrrole, imidazole, and pyrazole nucleophiles via an allylic linker under neutral conditions is disclosed. This process enables the installation of an all-carbon quaternary center and new C-C and C-N bonds in a single operation. Despite the weakly acidic nature of N-heterocycles, the reactions proceed with good efficiency and complete regio- and chemoselectivity.

ChemInform Abstract: Regioswitchable Palladium‐Catalyzed Decarboxylative Coupling of 1,3‐Dicarbonyl Compounds.

AbstractA palladium catalyzed chemo‐ and regioselective coupling of 1,3‐dicarbonyl compounds via an allylic linker is presented.

Rational design, synthesis and in vitro evaluation of allylidene hydrazinecarboximidamide derivatives as BACE-1 inhibitors.

BACE-1 (β-secretase) is considered to be one of the promising targets for treatment of Alzheimer's disease as it catalyzes the rate limiting step of Aβ-42 production. Herein, we report a novel class of allylidene hydrazinecarboximidamide derivatives as moderately potent BACE-1 inhibitors, having aminoguanidine substitution on allyl linker with two aromatic groups on either side. A library of derivatives was designed based on the docking studies, synthesized and evaluated for BACE-1 inhibition in vitro. The designed ligands displayed interactions with the catalytic aspartate dyad through guanidinium functionality. Further, the aromatic rings placed on either side of the linker occupied S1 and S3 active site regions contributing to the activity. These ligands were also predicted to follow Lipinski rule and cross blood brain barrier. Compound 2.21, having high docking score, was found to be most active with IC50 of 6.423μM indicating good correlation with docking prediction.

Regioswitchable Palladium-Catalyzed Decarboxylative Coupling of 1,3-Dicarbonyl Compounds.

A palladium-catalyzed chemo- and regioselective coupling of 1,3-dicarbonyl compounds via an allylic linker has been developed. This reaction, which displays broad substrate scope, forms two C-C bonds and installs two all-carbon quaternary centers. The regioselectivity of the reaction can be predictably controlled by utilizing an enol carbonate of one of the coupling partners.

Fluorogenic cephalosporin substrates for β-lactamase TEM-1

Cephalosporin was used to synthesize soluble and precipitating fluorogenic β-lactam substrates that demonstrated differential catalytic hydrolysis by three different subtypes of β-lactamase: TEM-1 (class A), p99 (class C), and a Bacillus cereus enzyme sold by Genzyme (class B). The most successful soluble substrate contained difluorofluorescein (Oregon Green 488) ligated to two cephalosporin moieties that, therefore, required two turnovers to produce the fluorescent Oregon Green 488 leaving group. The bis-cephalosporin modification was required so that the final reaction product was the Oregon Green 488 carboxylic acid rather than a less bright phenolic adduct of the dye. Hydrolysis in pH 5.5 Mes and pH 7.2 phosphate-buffered saline (PBS) buffers was similar, but in pH 8.0 Tris the hydrolysis rate nearly doubled. Activity of the β-lactamases on the various substrates was shown to depend highly on the linker between the cephalosporin and the fluorophore, with an allyl linker promoting faster turnover than a phenol ether linker. Measured K m values for dichlorofluorescein and difluorofluorescein cephalosporin substrates were approximately the same as K m values for penicillin G and ampicillin found in the literature (∼30–40 μM).

Solid-phase synthesis of protected α-amino phosphonic acid oligomers

By establishing both a highly efficient phosphonamidate formation and a RuCp-catalyzed cleavage of an allyl linker, the solid-phase synthesis of Fmoc-(GlyP(OBn))(6)-OH/DIEA, a protected form of a new type of unnatural peptide alpha-amino phosphonic acid oligomer (APO), has been realized.

Membrane Receptor Probes: Solid-Phase Synthesis of Biotin-Asp-PEG-arvanil Derivatives

[structure: see text] A modular, flexible solid-phase synthetic route for the preparation of biotinylated cross-linking probes of membrane receptors is described. The route utilizes an orthogonal protection strategy employing a Pd[0] cleavable allyl linker attached to the probe via an aspartate residue. The versatility of the method is illustrated through the synthesis of a number of arvanil-derived cannabinoid receptor ligands displaying either a photoaffinity or a chemical cross-linking group.

Probing the discriminating power of chiral crown hosts by CD spectroscopy.

The discriminating efficiency of pyridino- (1), pyridono- and thiopyridono- (2), phenazino- (3), and acridino- (4) 18-crown-6 hosts as well as pyridino- (1) and phenazino- (3) 18-crown-6 hosts with allylic moieties attached either to the macrocyclic ring [X=CH-CH(2)-CH=CH(2) or C(CH(2)-CH=CH(2))(2)] or to the heterocyclic subunit was probed by circular dichroism (CD) spectroscopy using enantiomers of alpha-(1-naphthyl)- ethylamine hydrogen perchlorate (1-NEA). The CD spectra of the diastereomeric complexes as well as the difference and sum of the spectra were analyzed. Titration experiments were also performed monitored by CD or UV spectroscopy. The CD- and (1)H NMR-based enantiomeric preferences were compared. CD spectroscopy showed that the relative stability of heterochiral [(R,R)-host/(S)-guest or (S,S)-host/(R)-guest] complexes generally exceeds that of homochiral [(R,R)/(R)-or (S,S)/(S)] complexes. Bulkier substituents (R=iBu, sBu or tBu) decrease complex stability but increase the discriminating power of the host. According to (1)H NMR titration, attachment of one allylic linker group in position X of the macro ring [(S,S)-1b, (S,S)-1e] changes the discriminating preference (from heterochiral to homochiral) of the parent hosts (S,S)-1a and (S,S)-1d. This change of discriminating preference was not reflected in the CD spectra. Host (S,S)-1g with an allyloxy linker group in position gamma of the pyridine ring gives CD spectra which clearly reflect the high discriminating power and enantiomeric preference of the host. The exciton-coupled circular dichroism (ECCD) spectra of the 1-NEA complexes of phenazino and acridino hosts allow reliable determination of the enantiomeric preference by comparing the A values of the exciton couplets. An allylic group appended to the macrocyclic ring or the N-containing heterocyclic subunit allows for the attachment of the chiral discriminator to the solid matrix of a chromatographic sorbent and also serves as a spectroscopic label of the host. CD spectroscopy is a simple and rapid method, providing qualitative information on enantiomeric discrimination. It can be of great help in designing and testing new host molecules.

RNA synthesis using a universal, base-stable allyl linker.

The application of a universal allyl linker, 9-O-(4,4'-dimethoxytrityl)-10-undecenoic acid, to the solid phase synthesis of RNA molecules is described. Use of this linker simplifies significantly the isolation and purification steps in RNA synthesis. The linker is universal in that it does not contain a nucleoside. The 3'terminal nucleoside is instead attached to the support in the first coupling step. The resultant RNA fragment is then obtained as the 3'-phosphate. The linker is base-stable, and thus all reagents used during deprotection can simply be washed away, leaving the RNA attached. Further, tritylated short fragments resulting from chain cleavage for any reason are also washed away before separation from the support. This linker is compatible with any current synthetic methodology and any amino functionalized support. Of course, silica supports would not be compatible with fluoride reagents. It could also be used to advantage for other applications. Because it is cleaved under conditions orthogonal to those used during many common reactions, the range of post-synthetic manipulations that can be carried out without cleavage from the support is extended significantly.

A universal allyl linker for solid-phase synthesis

We report synthesis of a universal allyl linker for solid-phase synthesis, 9- O-(4,4′-Dimethoxytrityl)-10-undecenoic ( 3), that has a reactive terminal double bond. Since allyl cleavage occurs under conditions orthogonal to those used during the solid-phase synthesis and deprotection of DNA or RNA fragments, this linker extends the range of post-synthetic manipulations that can be carried out without cleavage from the support, and means that this linkage could be used to construct affinity columns. Alternatively, it should be possible also to cleave fully protected molecules from the support if so desired.

Solid-phase synthesis of peptide aminoalkylamides using an allyl linker

The synthesis of an allylic linker is presented to which primary and secondary amino groups can be anchored on solid phase. By acylating MBHA resin with allyl linker HOCH 2CHCHCH 2OCH 2COOH followed by treatment with 4-nitrophenyl chloroformate a mixed carbonate linker is obtained to which amino groups can be attached. The allyl carbamate linkage is stable to both bases and anhydrous acids and can be cleaved by palladium-catalysed allyl transfer under mild reaction conditions.