María D. Díaz-de-Villegas

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.

Efficient access to all four stereoisomers of phenylalanine cyclopropane analogues by chiral HPLC

Bonded polysaccharide-derived chiral stationary phases were found to be useful for the preparation of the four stereoisomers of the cyclopropane analogue of phenylalanine (c(3)Phe) as well as for the direct determination of the enantiomeric purity of c(3)Phe derivatives by HPLC. Three chiral stationary phases, consisting of cellulose and amylose derivatives chemically bonded on allylsilica gel, were tested. The mixed 10-undecenoate/3, 5-dimethylphenylcarbamate of cellulose, 10-undecenoate/3, 5-dimethylphenylcarbamate of amylose and 10-undecenoate/p-methylbenzoate of cellulose were the starting polysaccharide derivatives for CSP-1, CSP-2, and CSP-3, respectively. Using mixtures of n-hexane/chloroform/2-propanol as mobile phase on a semi-preparative column (150 mm x 20 mm ID) containing CSP-2, we separated about 1.7 g of racemic cis-methyl 1-tert-butoxycarbonylamino-2-phenylcyclopropanecarboxylate (cis-6) and 1.2 g of racemic trans-methyl-1-tert-butoxycarbonylamino-2-phenylcycloprop-anecarboxyl ate (trans-6) by successive injections. Copyright 1999 Wiley-Liss, Inc.

Synthesis of constrained prolines by Diels–Alder reaction using a chiral unsaturated oxazolone derived from (R)-glyceraldehyde as starting material

Abstract This report describes a new route for the asymmetric synthesis of enantiomerically pure 2-substituted 7-azabicyclo[2.2.1]heptane-1-carboxylic acids, which are new conformationally constrained β-functionalised proline analogues. Our strategy is based on the preparation of a valuable azabicyclic intermediate by a key step that involves the intramolecular cyclisation of a derivative obtained from the transformation of the adducts provided by the asymmetric Diels–Alder reaction of a chiral oxazolone derived from (R)-glyceraldehyde with Danishefskys diene. The application of this procedure to the synthesis of (1S,2R,4R)-7-azabicyclo[2.2.1]heptane-1,2-dicarboxylic acid and (1S,2R,4R)-2-propyl-7-azabicyclo[2.2.1]heptane-1-carboxylic acid hydrochlorides, which can be also considered as l -aspartic acid and l -norleucine analogues respectively, is useful to illustrate the versatility of our methodology.

Diastereoselective Strecker reaction of imines derived from D-glyceraldehyde. A new route to β-hydroxy-α-amino acids

Abstract A diastereoselective Strecker type reaction of imines derived from conveniently protected D-glyceraldehyde has been achieved with good to excellent stereoselectivity through an appropriate choice of the protecting group and reaction conditions

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.

Wittig olefination of methyl (1S, 2R)-1-benzamido-2-formylcyclopropanecarboxylate. A powerful tool for the synthesis of new conformationally constrained cyclopropyl amino acids

Abstract The behaviour of methyl(1S, 2R)-1-benzamido-2-formylcyclopropanecarboxylate with stabilised and semi-stabilised ylids has been tested in order to evaluate its synthetic utility in the synthesis of cyclopropyl amino acids by Wittig olefination. Wittig adducts were further elaborated to obtain the corresponding cyclopropyl amino acids in high yields and enantiomerically pure form. Download : Download full-size image

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.