5-Chloro-8-nitro-1-naphthoyl (NNap): A Selective Protective Group for Amines and Amino Acids.

The synthesis of 5-chloro-8-nitro-1-naphthoyl chloride and its use as a protective group for amines is described. Protection is carried out with an auxiliary amine or under mild Schotten-Baumann conditions in high yield (>86%), while deprotection can be achieved easily under gentle reducing conditions due to the large steric tension between C-1 and C-8 naphthalene substituents. The reaction has been successfully tested in dipeptide synthesis and amino alcohols protection, and it has proved selective for the ε-amine group of lysine.

Tryptophan association in water driven by charge-transfer interactions with electron-deficient aromatic haptens.

The ability of a series of electron-deficient aromatic compounds to form charge-transfer complexes with tryptophan in water has been evaluated by X-ray diffraction studies, UV-vis spectra and NMR. As dinitrophenyl (DNP) ligands are well-known to generate antibody-mediated responses and the π-π stacking interactions with tryptophan residues of the antibody Fab fragment have been reported, most of the aromatic receptors studied here are nitro derivatives. Charge-transfer interactions between the rich indole ring of tryptophan and the electron-deficient aromatic receptors have been observed in the solid state, as four crystal structures of the complexes were obtained. The aromatic donor-acceptor interactions in solution were also verified by UV-vis and NMR spectroscopy. The association of the tripeptide Trp-Gly-Trp, a motif found in antigen Ag43, with the electron-deficient aromatic diimide was also studied by UV-vis and NMR spectroscopy. Our results show that these simple electron-deficient molecules could potentially behave as novel haptens and be incorporated in more elaborated drugs targeting protein-protein interactions, due to the synergistic effect of multiple non-covalent interactions.

Transesterification of Non-Activated Esters Promoted by Small Molecules Mimicking the Active Site of Hydrolases.

The synthesis of small molecules able to mimic the active site of hydrolytic enzymes has been largely pursued in recent decades. The high reaction rates and specificity shown by natural hydrolases present an attractive target, and yet the preparation of suitable small-molecule mimics remains challenging, requiring activated substrates to achieve productive outcomes. Here we present small synthetic artificial enzymes which mimic the catalytic site and the oxyanion hole of chymotrypsin and N-terminal hydrolases and are able to perform, for the first time, the transesterification of a non-activated ester such as ethyl acetate with methanol under mild and neutral reaction conditions.

An Adjustable Cleft Based on an 8-Sulfonamide-2-Naphthoic Acid with Oxyanion Hole Geometry.

Cleft type receptors showing the oxyanion hole motif have been prepared in a straightforward synthesis starting from the commercial 3,7-dihidroxy-2-naphthoic acid. The double H-bond donor pattern is achieved by the introduction of a sulfonamide group in the C-8 position of naphthalene and a carboxamide at the C-2 position. This cleft, for which the geometry resembles that of an oxyanion hole, is able to adjust to different guests, as shown by the analysis of the X-ray crystal structures of associates with methanol or acetic acid. Combination of hydrogen bonds and charge-transfer interactions led to further stabilization of the complexes, in which the electron-rich aromatic ring of the receptor was close in space to the electron-deficient dinitroaromatic guests. Modelling studies and bidimensional NMR experiments have been carried out to provide additional information.

Highly Enantioselective Extraction of Phenylglycine by a Chiral Macrocyclic Receptor Based on Supramolecular Interactions.

Using supramolecular interactions, a novel macrocyclic receptor is able to selectively extract zwitterionic phenylglycine from neutral aqueous solutions into chloroform with up to 91.8% ee. Modeling studies, nuclear magnetic resonance experiments, and X-ray diffraction analysis were carried out to explain the high enantioselectivity observed.

A cleft type receptor which combines an oxyanion hole with electrostatic interactions.

A receptor for carboxylic acids which combines an oxyanion-hole structure with electrostatic forces has been prepared. X-ray diffraction studies have been carried out to evaluate the geometry of both the free receptor and its associated species with several carboxylic acids and many different arrangements have been discovered for the H-bond pattern in the associated species.

A molecular receptor selective for zwitterionic alanine.

A molecular receptor has been synthesized joining an aza-crown ether with a chiral chromane which mimics the oxyanion hole of the enzymes. With this receptor an apolar host-guest complex with zwitterionic alanine has been achieved through the formation of up to seven H-bonds. This complex allows the extraction of aqueous alanine to a chloroform phase, while other natural amino acids are poorly extracted or are not extracted at all. Due to the chiral nature of the receptor, enantioselective extraction from the aqueous alanine solution to a chloroform phase takes place. X-Ray analysis combined with anisotropic effects, NOE and CD studies revealed the absolute configuration of both strong and weak complexes. Modelling studies also support the proposed structures. The presence of an oxyanion-hole motif in this structure was corroborated by X-ray diffraction studies.

A bio-inspired enantioselective small-molecule artificial receptor for ß adrenergic agonists and antagonists and its application for enantioselective extraction.

Administration of enantiomerically pure ß-adrenergic agonists and antagonists increases their activity and reduces side effects. We report here a small-molecule artificial receptor (SMAR) that, by mimicking the ß-adrenergic receptor, is able to enantioselectively extract commercial ß-adrenergic interacting drugs. The selectivity is justified according to DFT calculations and X-ray diffraction experiments.

A molecular receptor for zwitterionic phenylalanine.

The combination of a 1,3-ketoenol system and two pyridine molecules attached as sulfonamide and carboxamide to a benzofuran skeleton allows the preparation of a novel chiral receptor for zwitterionic phenylalanine association. Interestingly, no crown-ether, urea or guanidinium are necessary to carry out the extraction of amino acids from the aqueous solution, which constitutes a breakthrough in comparison with other receptors for zwitterionic amino acid extraction.

A highly selective receptor for zwitterionic proline.

A chiral chromane receptor has been synthesized which mimics the oxyanion hole of the enzymes. In this receptor H-bonds and cation-π interactions team up to generate an apolar host-guest complex with zwitterionic proline. This complex allows the extraction of only proline to a chloroform phase, while no other natural amino acids are extracted. Due to the chiral nature of the receptor, enantioselective extraction from the aqueous proline solution to a chloroform phase takes place. L-Proline provided an easy method to resolve the receptor racemic mixture, while anisotropic effects, NOE and CD studies revealed the absolute configuration of the receptor. Modelling studies also support the proposed structures. The presence of an oxyanion-hole motif in this structure was corroborated by X-ray diffraction studies.

Chiral recognition with a benzofuran receptor that mimics an oxyanion hole.

A new chiral benzofuran receptor has been synthesized and its properties in the association of amino acid derivatives have been studied. X-ray structures were obtained and these corroborate the presence of an oxyanion-hole motif in these structures.

4,5-Dibromo-2,7-di-tert-butyl-9,9-dimethyl-9H-thioxanthene.

In the title compound, C(23)H(28)Br(2)S, the thioxanthene unit is twisted, showing a dihedral angle of 29.3 (5)° between the benzene rings. When projected along [001], the packing shows two types of channels. The crystal studied was a racemic twin.

Sulfonamide carbazole receptors for anion recognition.

Carbazole-based receptors functionalized with two sulfonamide groups have been synthesized and their properties as anion receptors have been evaluated. The receptor with bis(trifluoromethyl)aniline groups has shown a very high affinity for halide ions, especially remarkable as only two hydrogen bonds are formed in the complexes. (1)H NMR and fluorescence titrations have been carried out and binding constants up to 7.9 × 10(6) M(-1) have been reached. X-ray structures have been obtained and a modelling study has shown the possible reasons for the large affinity of these compounds for halide anions.

Synthesis of monoacylated derivatives of 1,2- cyclohexanediamine. Evaluation of their catalytic activity in the preparation of Wieland-Miescher ketone.

Ureas, carbamoyl derivatives, amides, and sulfonamides can be easily prepared from the strained (R,R)-cylohexanediamine urea (1) in high yield, leaving a free amino group that shows good catalytic activity in intramolecular aldol condensations. The preparation of Wieland-Miescher ketone has been studied with these catalysts.

Synthesis of a chiral artificial receptor with catalytic activity in Michael additions and its chiral resolution by a new methodology.

Xanthone derivatives were tested as organocatalysts for the Michael addition of pyrrolidine to an alpha,beta-unsaturated lactam. The receptors combine a double H-bond donor pattern that resembles the oxyanion hole in natural enzymes, with a sulfone or sulfoxide that acts as a proton-transfer group. Since these compounds cannot be obtained enantiomerically pure from natural sources, chiral resolution was necessary to study their enantioselectivity. For the most promising receptor, this was accomplished using a new methodology that exploits its supramolecular interactions with a chiral guest and that is inspired in dynamic combinatorial chemistry. The success in the resolution of the racemic mixture indicates that this new method offers an alternative to kinetic resolution.

Imidazolidinone intermediates in prolinamide-catalyzed aldol reactions.

The reaction between acetone and 4-nitrobenzaldehyde catalyzed by aniline prolinamide 1 was studied in depth. Working in different solvents with equimolar amounts of reagents and monitoring the reaction by 1H NMR, we detected and identified several imidazolidinones, such as those of the acetone 4, the aldol products 5a and 5b, and aldehydes 10a and 10b. According to our results, these compounds could influence the reaction rate and diminish product enantioselectivity. Furthermore, acetone imidazolidinone 4 was seen to react with 4-nitrobenzaldehyde to furnish the aldol product 3. This reaction can be catalyzed by different nucleophiles and acids. In fact, strong acids such as camphorsulfonic or trifluoroacetic acid, convert imidazolidinones into iminium salts and afford more enantioselective aldol reactions when different aromatic prolinamides are used. Enantiomeric excesses of ca. 82% are reached.

A Fluorescent Sensor for Dinitrobenzoic Acid Based on a Cyanuric Acid and Xanthene Skeleton.

A new fluorescent sensor based on a dimethylxanthene skeleton has beensynthesized. Because of its oxyanion hole structure, this receptor includes a suitablecavity for the association of carboxylic acids. The receptor's fluorescence is quenchedupon addition of dinitrobenzoic acid.

Macrocyclic chiral receptors toward enantioselective recognition of naproxen.

[structure: see text] A macrocyclic receptor based on a bischromenylurea and an alpha,alpha'-(o,o'-dialkyl)diphenyl-p-xylylenediamine spacer provides a C(2) chiral cavity to associate carboxylates by H-bonds. The extent of the selectivity obtained for the racemic receptor 2 and enantiomerically pure (S)-naproxen is 7.2:1. Steric repulsions close to the cavity are decisive for the chiral selectivity.

Chromogenic charge transfer cleft-type tetrahydrobenzoxanthene enantioselective receptors for dinitrobenzoylamino acids.

A combination of a benzoxanthene cleft-type receptor with an electron-rich aromatic ring capable of establishing charge-tranfer interactions provides enantioselective receptors for dinitrobenzoylamino acids. Racemic mixtures of the receptor can be resolved with TLCs impregnated with the guest. The structure of the complexes has been established in an X-ray study. Enantiomeric amino acids provide complexes with different colors.

Aminopyridine-benzoxanthene enantioselective receptor for sulfonylamino acids.

Combination of a cis-tetrahydrobenzoxanthene skeleton with a benzoxazole and an amidopyridine provides an enantioselective receptor for sulfonylamino acids with chiral recognitions of up to 18. The structure of the complex between receptor 1 and the leucine triflate is known by X-ray analysis. The receptor racemic mixture can be suitably resolved through crystalization in the presence of leucine triflate as guest. Receptor 1 can be used for the enantioselective extraction of sulfonylamino acids from aqueous solutions of their salts.