We report the regioselective and direct functionalization of rationally designed imidazole derivatives through electrophilic fluorination with N-fluorobenzenesulfonimide enabled via in situ deprotonation with lithium 2,2,6,6-tetramethylpiperidine. Aided by a controlled protecting group switch, we were able to effectively target both the reactive 5- as well as the difficult to target 4-position of these molecules, leading to a series of fluorinated polysubstituted imidazoles in gram scale.

AbstractTitle compounds are obtained in high yields and enantioselectivities in a single step.

An efficient organocatalytic asymmetric [3 + 2] cycloaddition reaction between 3-substituted methylenebenzofuranone derivatives and diverse Morita-Baylis-Hillman carbonates to provide complex polysubstituted spirocyclopentenebenzofuranone scaffolds in a single step is reported. C2-symmetric phospholanes were efficient nucleophilic catalysts of this transformation under mild conditions, providing reaction products comprised of three consecutive stereocenters, including one all-carbon center, with excellent enantioselectivity.

A novel organocatalytic strategy for the synthesis of highly substituted spirocyclopentaneoxindoles was developed employing simple nitrostyrenes and 3-substituted oxindoles as starting materials. Michael-Henry cascade reactions, enabled through cinchona alkaloid organocatalysis, provided products in high yield and excellent enantioselectivity in a single step.

The assembly of complex spirocyclopentaneoxindoles via a novel organocatalytic iminium-enamine cascade process is reported. Reactions between 3-substituted oxindoles and α,β-unsaturated aldehydes catalyzed by second generation prolinol ethers provided the desired products in high yield with excellent levels of enantioselectivity in a single step.

A peptide nucleic acid (PNA) targeting a splice junction of the murine PTEN primary transcript was covalently conjugated to various basic peptides. When systemically administered to healthy mice, the conjugates displayed sequence-specific alteration of PTEN mRNA splicing as well as inhibition of full length PTEN protein expression. Correlating activity with drug concentration in various tissues indicated strong tissue-dependence, with highest levels of activity observed in adipose tissue. While the presence of a peptide carrier was found to be crucial for efficient delivery to tissue, little difference was observed between the various peptides evaluated. A second PNA-conjugate targeting the murine insulin receptor primary transcript showed a similar activity profile, suggesting that short basic peptides can generally be used to effectively deliver peptide nucleic acids to adipose tissue.

A novel organocatalyst was developed that effectively catalyzed the reactions of unprotected or protected dihydroxyacetone with a variety of aldehydes to provide syn-aldol products with good yields and ee values up to >99%. Significantly, this amide catalyst was effective with a variety of nonaromatic aldehyde acceptors that had proven difficult in the presence of other catalysts. Reactions of protected dihydroxyacetone proceeded in aqueous media without addition of organic solvents.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

The development of enantioselective anti-selective Mannich-type reactions of aldehydes and ketones with imines catalyzed by 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives is reported in detail. Both (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid and (R)-3-pyrrolidinecarboxylic acid efficiently catalyzed the reactions of aldehydes with alpha-imino esters under mild conditions and afforded anti-Mannich products with high diastereo- and enantioselectivities (anti/syn up to 99:1, up to >99% ee). For the reactions of ketones with alpha-imino esters, (R)-3-pyrrolidinecarboxylic acid was an efficient catalyst (anti/syn up to >99:1, up to 99% ee). Evaluation of a series of pyrrolidine-based catalysts indicated that the acid group at the beta-position of the pyrrolidine ring of the catalyst played an important role in forwarding the carbon-carbon bond formation and in directing anti-selectivity and enantioselectivity.

Cellular permeation peptides have been used successfully for the delivery of a variety of cargoes across cellular membranes, including large hydrophilic biomolecules such as proteins, oligonucleotides, or plasmid DNA. For the present work, a series of short amphipathic peptides was designed to elucidate the structural requirements for efficient and nontoxic delivery of peptide nucleic acids (PNAs). On the basis of an idealized alpha-helical structure, the helical parameters were modulated systematically to yield peptides within a certain range of hydrophobicity and amphipathicity. The corresponding PNA conjugates were synthesized and characterized in terms of secondary structure, enzymatic stability, and antisense activity. The study revealed correlations between the physicochemical and biophysical properties of the conjugates and their biological activity and led to the development of potent peptide vectors for the cellular delivery of antisense PNAs. Two representative compounds were radiolabeled and evaluated for their biodistribution in healthy mice.

[reaction: see text] Organocatalytic asymmetric Mannich reaction of protected amino ketones with imines in the presence of an L-proline-derived tetrazole catalyst afforded diamines with excellent yields and enantioselectivities of up to 99%. The amino ketone protecting group controlled the regioselectivity of the reaction providing access to chiral 1,2-diamines from azido ketones and 1,4-diamines from phthalimido ketones.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Catalytic enantioselective Michael addition reactions of α-amino functionalized aldehydes to nitroolefins have been developed. The Michael product was obtained in up to 98% ee, but the enantiomeric purity of the Michael product was decreased during isolation of the product.

Improving cellular uptake and biodistribution remains one of the major obstacles for a successful and broad application of peptide nucleic acids (PNAs) as antisense therapeutics. Recently, we reported the identification and functional characterization of an antisense PNA, which redirects splicing of murine CD40 pre-mRNA. In this context, it was discovered that a simple octa(l-lysine) peptide covalently linked to the PNA is capable of promoting free uptake of the conjugate into BCL1 cells as well as primary murine macrophages. On the basis of this peptide motif, the present study aimed at identifying the structural features, which define effective peptide carriers for cellular delivery of PNA. While the structure-activity relationship study revealed some clear correlations, only a few modifications actually led to an overall improvement as compared to the parent octa(l-lysine) conjugate. In a preliminary PK/tissue distribution study in healthy mice, the parent conjugate exhibited relatively broad tissue distribution and only modest elimination via excretion within the time frame of the study.

Cognate recognition between the CD40 receptor and its ligand, CD154, is thought to play a central role in the initiation and propagation of immune responses. We describe the specific down regulation of cell surface associated CD40 protein expression by use of a peptide nucleic acid (PNA) antisense inhibitor, ISIS 208529, that is designed to bind to the 3' end of the exon 6 splice junction within the primary CD40 transcript. Binding of ISIS 208529 was found to alter constitutive splicing, leading to the accumulation of a transcript lacking exon 6. The resulting protein product lacks the transmembrane domain. ISIS 208529-mediated CD40 protein depletion was found to be sequence specific and dose dependent, and was dependent on the length of the PNA oligomer. CD40-dependent induction of IL-12 in primary murine macrophages was attenuated in cells treated with ISIS 208529. Oligolysine conjugation to the PNA inhibitor produced an inhibitor, ISIS 278647, which maintained its specificity and displayed efficacy in BCL1 cells and in primary murine macrophages in the absence of delivery agents. These results demonstrate that PNA oligomers can be effective inhibitors of CD40 expression and hence may be useful as novel immuno-modulatory agents.