José A. Gálvez

Organocatalyzed enantioselective desymmetrization of diols in the preparation of chiral building blocks.

Desymmetrization of diols is a powerful tool to the synthesis of chiral building blocks. Among the different approaches to perform discrimination between both enantiotopic hydroxyl groups, the organocatalytic approach has gained importance in the last years. A diverse range of organocatalysts has been used to efficiently promote this enantioselective transformation and this Minireview examines the different contributions in this field.

A novel pan-negative-gating modulator of KCa2/3 channels, fluoro-di-benzoate, RA-2, inhibits endothelium-derived hyperpolarization-type relaxation in coronary artery and produces bradycardia in vivo

Small/intermediate conductance KCa channels (KCa2/3) are Ca2+/calmodulin regulated K+ channels that produce membrane hyperpolarization and shape neurologic, epithelial, cardiovascular, and immunologic functions. Moreover, they emerged as therapeutic targets to treat cardiovascular disease, chronic inflammation, and some cancers. Here, we aimed to generate a new pharmacophore for negative-gating modulation of KCa2/3 channels. We synthesized a series of mono- and dibenzoates and identified three dibenzoates [1,3-phenylenebis(methylene) bis(3-fluoro-4-hydroxybenzoate) (RA-2), 1,2-phenylenebis(methylene) bis(3-fluoro-4-hydroxybenzoate), and 1,4-phenylenebis(methylene) bis(3-fluoro-4-hydroxybenzoate)] with inhibitory efficacy as determined by patch clamp. Among them, RA-2 was the most drug-like and inhibited human KCa3.1 with an IC50 of 17 nM and all three human KCa2 subtypes with similar potencies. RA-2 at 100 nM right-shifted the KCa3.1 concentration-response curve for Ca2+ activation. The positive-gating modulator naphtho[1,2-d]thiazol-2-ylamine (SKA-31) reversed channel inhibition at nanomolar RA-2 concentrations. RA-2 had no considerable blocking effects on distantly related large-conductance KCa1.1, Kv1.2/1.3, Kv7.4, hERG, or inwardly rectifying K+ channels. In isometric myography on porcine coronary arteries, RA-2 inhibited bradykinin-induced endothelium-derived hyperpolarization (EDH)–type relaxation in U46619-precontracted rings. Blood pressure telemetry in mice showed that intraperitoneal application of RA-2 (≤100 mg/kg) did not increase blood pressure or cause gross behavioral deficits. However, RA-2 decreased heart rate by ≈145 beats per minute, which was not seen in KCa3.1−/− mice. In conclusion, we identified the KCa2/3–negative-gating modulator, RA-2, as a new pharmacophore with nanomolar potency. RA-2 may be of use to generate structurally new types of negative-gating modulators that could help to define the physiologic and pathomechanistic roles of KCa2/3 in the vasculature, central nervous system, and during inflammation in vivo.

Stereoselective amination of chiral enolates: Synthesis of chiral key intermediates for β-lactam antibiotics

Abstract Stereoselective enolate trapping of lithium ( 1S, 2R, 4R )- 10-dicyclohexylsulfamoylisobornyl-2-cyano-3-phenylpropanoate with O-(diphenylphosphinyl) hydroxylamine followed by appropriate reduction, hydrolysis, and cyclisation processes allows the asymmetric synthesis of ( S )-3-amino-3-benzyl-2-azetidinone.

High-performance liquid chromatographic enantioseparation of unusual amino acid derivatives with axial chirality on polysaccharide-based chiral stationary phases

The successful enantioseparation of axially chiral amino acid derivatives containing a cyclohexylidene moiety on an analytical and semipreparative scale was achieved for the first time by HPLC using polysaccharide-based chiral stationary phases. Racemic methyl N-benzoylamino esters, easily obtained by methanolysis of the corresponding 5(4H)-oxazolones, were subjected to chiral HPLC resolution using chiral stationary phases based on immobilized 3,5-dimethylphenylcarbamate derivatives of amylose (Chiralpak(®) IA column) or cellulose (Chiralpak(®) IB column). The behaviour of both selectors under different elution conditions was evaluated and compared. The amylose column showed better performance than the cellulose column for all enantiomers tested. The semipreparative resolution of axially chiral amino acid derivatives with different side chains has been achieved on a 250mm×20mm ID Chiralpak(®) IA column using the appropriate mixture of n-hexane/chlorofom/ethanol as eluent by successive injections of a solution of the sample in chloroform. Using this protocol up to 120mg of each enantiomer of the corresponding axially chiral amino acid derivative were obtained from 300mg of racemate. [(Sa)-2a, 105mg; (Ra)-2a, 60mg, [(Sa)-2b, 105mg; (Ra)-2b, 90mg, [(Sa)-2c, 120mg; (Ra)-2c, 100mg].

Chiral iminoesters derived from d-glyceraldehyde in [3+2] cycloaddition reactions. Asymmetric synthesis of a key intermediate in the synthesis of neuramidinase inhibitors

Silver-catalyzed endo-selective and copper-catalyzed exo-selective asymmetric [3 + 2] cycloadditions of acrylates to chiral iminoesters derived from D-glyceraldehyde have been investigated. The reaction diastereoselectively provides highly functionalized pyrrolidines. This approach was used to develop the first asymmetric synthesis of a key intermediate in the synthesis of pyrrolidine influenza neuramidinase inhibitors.

Asymmetric Homologation of Ketones. A New Entry to Orthogonally Protected (2R,4R)-Piperidine-2,4-dicarboxylic Acid

A new conformationally constrained analogue of glutamic acid has been synthesized efficiently in seven steps from a chiral 2-alkyl-4-piperidone. The synthesis is based on (a) the unprecedented asymmetric one-carbon homologation of the ketone controlled by the size of the N-substituent and (b) the appropriate manipulation of substituents at positions 2 and 4 of the piperidine ring, a step that involves two independent oxidation processes.

Vascular reactivity profile of novel KCa3.1‐selective positive‐gating modulators in the coronary vascular bed

Opening of intermediate‐conductance calcium‐activated potassium channels (KCa3.1) produces membrane hyperpolarization in the vascular endothelium. Here, we studied the ability of two new KCa3.1‐selective positive‐gating modulators, SKA‐111 and SKA‐121, to (1) evoke porcine endothelial cell KCa3.1 membrane hyperpolarization, (2) induce endothelium‐dependent and, particularly, endothelium‐derived hyperpolarization (EDH)‐type relaxation in porcine coronary arteries (PCA) and (3) influence coronary artery tone in isolated rat hearts. In whole‐cell patch‐clamp experiments on endothelial cells of PCA (PCAEC), KCa currents evoked by bradykinin (BK) were potentiated ≈7‐fold by either SKA‐111 or SKA‐121 (both at 1 μM) and were blocked by a KCa3.1 blocker, TRAM‐34. In membrane potential measurements, SKA‐111 and SKA‐121 augmented bradykinin‐induced hyperpolarization. Isometric tension measurements in large‐ and small‐calibre PCA showed that SKA‐111 and SKA‐121 potentiated endothelium‐dependent relaxation with intact NO synthesis and EDH‐type relaxation to BK by ≈2‐fold. Potentiation of the BK response was prevented by KCa3.1 inhibition. In Langendorff‐perfused rat hearts, SKA‐111 potentiated coronary vasodilation elicited by BK. In conclusion, our data show that positive‐gating modulation of KCa3.1 channels improves BK‐induced membrane hyperpolarization and endothelium‐dependent relaxation in small and large PCA as well as in the coronary circulation of rats. Positive‐gating modulators of KCa3.1 could be therapeutically useful to improve coronary blood flow and counteract impaired coronary endothelial dysfunction in cardiovascular disease.

STRUCTURE OF 4-UNDECYLPYRAZOLE IN THE SOLID STATE: A 13C AND 15N CPMAS NMR SPECTROSCOPY STUDY

INTRODUCTION We have used a combination of crystallography and high-resolution solid-state NMR (C and N) to determine the structure of Λ/Η-pyrazoles in the solid state (1-6). However, in some cases monocrystals cannot be obtained and the structure must be deduced from NMR spectroscopy alone; this is the case with 4-undecylpyrazole 1. This compound owing to the aliphatic chain at position 4 has not only a low melting point but also a plastic character which prevents its crystallisation in good conditions. Although the compound has not the expected mesogenic properties it has, nevertheless, some physical properties which are rather peculiar. EXPERIMENTAL 1. Chemistry The compound was prepared according to Theoreil et al. (7) in a four-step procedure (these authors have prepared I to test it as an inhibitor of alcohol dehydrogenase). The compound, an oil wich solidifies, melt at 63-64°C (lit., m.p. 62.5-63.5°C) (6). 1 H NMR: in CDCI3, the terminal methyl group appears at 0.86 ppm (triplet), the CH2 at position 1 at 2.46 ppm (triplet), the CH2 at position 2 at 1.54 ppm (quintet), the remaining CH2 at 1.24 ppm (multiplet), pyrazole protons at C(3) and C(5) at 7.38 ppm (singlet).

Diastereoselective Construction of the 6-Oxa-2-azabicyclo[3.2.1]octane Scaffold from Chiral α-Hydroxyaldehyde Derivatives by Aza-Prins Reaction

(R)-2,3-Di-O-benzylglyceraldehyde and N-tosyl homoallylamine undergo aza-Prins cyclization to afford (1R,5S,7S)-7-[(benzyloxy)methyl]-2-tosyl-6-oxa-2-azabicyclo[3.2.1]octane in a highly diastereoselective manner through an unexpected intramolecular nucleophilic attack. Our work has opened a new route toward the asymmetric synthesis of 7-(alkyl or aryl)-6-oxa-2-azabicyclo[3.2.1]octane derivatives from chiral α-hydroxyaldehyde derivatives in one step.