Asymmetric synthesis of (1R,5S)-2-methyl-6,7-benzomorphan via Aza-Prins reaction.

(1R,5S)-2-Methyl-6,7-benzomorphan has been synthesised from (R)-(benzyloxy)(phenyl)acetaldehyde. On a 2-mmol scale Bi (OTf)3 promoted Aza-Prins reaction with N-tosylhomoallylamine afforded an 88/12 mixture of 6-oxa-2-azabicyclo[3.2.1]octanes. Major diastereoisomer was converted to enantiomerically pure (2S,4S)-2-benzyl-1- methylpiperidin-4-ol via a high-yielding sequence hydrogenolysis/N-detosylation/N-methylation. Acid-catalysed intramolecular Friedel-Crafts cyclisation of the piperidinol afforded (1R,5S)-2-methyl-6,7-benzomorphan in five steps with a yield of 25%.

Debenzylative Cycloetherification as a Synthetic Tool in the Diastereoselective Synthesis of 3,6-Disubstituted Hexahydro-2H-furo[3,2-b]pyrroles, PDE1 Enzyme Inhibitors with an Antiproliferative Effect on Melanoma Cells.

Two series of novel chiral hexahydro-2H-furo[3,2-b]pyrroles, 4-(7,8-dimethoxyquinazolin-4-yl) series A and 4-(6,7- dimethoxyquinazolin-4-yl) series B, were synthesized in enantiomerically pure form and evaluated for their inhibitory effects on phosphodiesterase 1 (PDE1) and phosphodiesterase 4 (PDE4) as well as for their inhibitory activity on cell proliferation in A375 melanoma and 3T3 fibroblast cells in vitro. Key steps of synthesis were (i) diastereoselective nucleophilic addition of vinylmagnesium bromide to N-allylimine derived from conveniently protected d-glyceraldehyde, (ii) ring-closing metathesis, (iii) debenzylative cycloetherification, and (iv) aromatic nucleophilic substitution. Some of the obtained compounds were proven to be active as inhibitors of PDE1 isoforms, with IC50 values in the high nanomolar/low micromolar concentration range, and showed antiproliferative activity on A375 melanoma cells.

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

Synthesis of new pyrrolidine-based organocatalysts and study of their use in the asymmetric Michael addition of aldehydes to nitroolefins.

New pyrrolidine-based organocatalysts with a bulky substituent at C2 were synthesized from chiral imines derived from (R)-glyceraldehyde acetonide by diastereoselective allylation followed by a sequential hydrozirconation/iodination reaction. The new compounds were found to be effective organocatalysts for the Michael addition of aldehydes to nitroolefins and enantioselectivities up to 85% ee were achieved.

Vascular Reactivity Profile of Novel KCa 3.1-Selective Positive-Gating Modulators in the Coronary Vascular Bed.

Opening of intermediate-conductance calcium-activated potassium channels (KC a 3.1) produces membrane hyperpolarization in the vascular endothelium. Here, we studied the ability of two new KC a 3.1-selective positive-gating modulators, SKA-111 and SKA-121, to (1) evoke porcine endothelial cell KC a 3.1 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), KC a 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 KC a 3.1 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 KC a 3.1 inhibition. In Langendorff-perfused rat hearts, SKA-111 potentiated coronary vasodilation elicited by BK. In conclusion, our data show that positive-gating modulation of KC a 3.1 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 KC a 3.1 could be therapeutically useful to improve coronary blood flow and counteract impaired coronary endothelial dysfunction in cardiovascular disease.

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 Ca(2+)/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 Ca(2+) 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.

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.

Stereoselective synthesis and biological evaluation of D-fagomine, D-3-epi-fagomine and D-3,4-epi-fagomine analogs from D-glyceraldehyde acetonide as a common building block.

The stereoselective synthesis of D-fagomine, D-3-epi-fagomine, and D-3-epi-fagomine analogs starting from readily available D-glyceraldehyde acetonide has been achieved. The synthesis involves diastereoselective anti-vinylation of its homoallylimine, ring-closing metathesis, and stereoselective epoxidation followed by regioselective ring-opening or stereoselective dihydroxylation. The lack of a strong activity as glycosidase inhibitors of these compounds could be advantageous for their therapeutic use as chaperones.

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.

Switch in regioselectivity of epoxide ring-opening by changing the organometallic reagent.

The regio- and stereoselective ring-opening of a 2-(2'-oxiranyl)-1,2,3,6-tetrahydropyridine using organometallic reagents is reported. The choice of the organometallic reagent determines the formation of either 2-[(R)-1-hydroxyalkyl]- or 2-[(S)-2-hydroxy-1-alkyl]-1,2,3,6-tetrahydropyridines. The formation of 2-[(S)-2-hydroxy-1-alkyl]-1,2,3,6-tetrahydropyridines is a rare example of epoxide ring-opening with retention of configuration. The process has been applied to the asymmetric synthesis of ß-(+)-conhydrine and to the formal synthesis of (2S,2'R)-erythro-methylphenidate from a common precursor. Extension of the structural diversity of the process has allowed the synthesis of several ß-(+)-conhydrine analogs.

Recent advances in enantioselective organocatalyzed anhydride desymmetrization and its application to the synthesis of valuable enantiopure compounds.

Recent years have witnessed increasing interest in the field of asymmetric organocatalysis. In particular, efforts in this field have been devoted to the use of small organic molecules in asymmetric processes based on enantiotopic face discrimination and, only recently, efforts have also been devoted to asymmetric organocatalytic desymmetrization of prochiral substrates-a process based on enantiotopic group discrimination. This critical review documents the advances in the use of organocatalysis for the enantioselective desymmetrization of achiral and meso anhydrides and its application to the synthesis of valuable compounds as reported until 2010 (134 references).

Stereocontrolled synthesis of orthogonally protected 2-substituted 4-aminopiperidines.

Expedient and highly stereoselective routes to orthogonally protected chiral 2-substituted 4-aminopiperidines have been developed. Diastereoselective nucleophilic substitution of the hydroxy group of (2R,4S)-2-[(S)-1,2-dibenzyloxyethyl]-4-hydroxy-1-[(S)-1-phenylethyl]piperidine using sodium azide afforded the corresponding azido derivative, which could be reduced and selectively protected to give (2R,4R)-1-tert-butoxycarbonyl-2-[(S)-1,2-dibenzyloxyethyl]-4-acetylaminopiperidine. This compound was easily converted into optically active 2-substituted 4-aminopiperidines using different synthetic methodologies such as epoxide nucleophilic ring opening reactions and Wittig olefination reactions among others.

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.

Base-controlled diastereodivergent synthesis of (R)- and (S)-2-substituted-4-alkylidenepiperidines by the Wadsworth-Emmons reaction.

Significant base and reaction time effects have been observed in the Wadsworth-Emmons reaction between a chiral 2-substituted-4-oxopiperidine and phosphonates. In the reactions carried out using a large excess of DBU as the base and prolonged reaction times, the initially formed 2R products epimerized into thermodynamically more stable products through a retro-conjugate/conjugate addition sequence and 2-substituted-4-alkylidenepiperidines of 2S configuration were selectively synthesized. In contrast, when the reaction was carried out using LDA as the base, epimerization did not occur and 2-substituted-4-alkylidenepiperidines of 2R configuration were obtained with excellent yields.

Unexpected epimerization at C2 in the Horner-Wadsworth-Emmons reaction of chiral 2-substituted-4-oxopiperidines.

The observed epimerization at C2 in the Horner-Wadsworth-Emmons (HWE) reaction of chiral 2-substituted-4-oxopiperidines has been investigated and, on the basis of the experimental results, a mechanism for this unexpected process has been proposed.

On the mechanism of the copper-catalyzed enantioselective 1,4-addition of grignard reagents to alpha,beta-unsaturated carbonyl compounds.

The mechanism of the enantioselective 1,4-addition of Grignard reagents to alpha,beta-unsaturated carbonyl compounds promoted by copper complexes of chiral ferrocenyl diphosphines is explored through kinetic, spectroscopic, and electrochemical analysis. On the basis of these studies, a structure of the active catalyst is proposed. The roles of the solvent, copper halide, and the Grignard reagent have been examined. Kinetic studies support a reductive elimination as the rate-limiting step in which the chiral catalyst, the substrate, and the Grignard reagent are involved. The thermodynamic activation parameters were determined from the temperature dependence of the reaction rate. The putative active species and the catalytic cycle of the reaction are discussed.

Highly diastereoselective cyanation of methyl ketimines obtained from (R)-glyceraldehyde.

[reaction: see text] Addition of trimethylsilyl cyanide to ketimines derived from (R)-2,2-dimethyl-1,3-dioxolan-4-yl methyl ketone to generate a quaternary stereocenter has been achieved with high yields and excellent diastereoselectivity. The stereoselectivity was found to be temperature and solvent dependent. The beta-hydroxy-alpha-amino nitrile of syn configuration was the major compound in kinetically controlled reactions, whereas the anti stereoisomer was obtained in excess in thermodynamically controlled reactions. Double stereodifferentiation under kinetic control conditions was successful, and the cyanation reaction occurred with complete syn diastereoselectivity using the matched pair. The versatility of the resulting amino nitrile as a synthetic intermediate was tested by performing the synthesis of orthogonally protected (R)-(2-aminomethyl)alanine.

Copper-catalyzed asymmetric conjugate addition of Grignard reagents to cyclic enones.

It is no longer necessary to use dialkylzinc reagents to obtain enantioselectivities >95% in the copper-catalyzed asymmetric conjugate addition of organometallic compounds to cyclic enones. We now report how this can be accomplished by using inexpensive and readily available Grignard reagents. Screening of bidentate ligands provided outstanding results with copper complexes of commercially available chiral ferrocenyl-based diphosphines, in particular TaniaPhos and JosiPhos derivatives. These catalysts tolerate a range of Grignard reagents and different cyclic enones as substrates, leading to high regioselectivities and unprecedented enantioselectivities. Moreover, the reactions are successful with moderate catalyst loading (5 mol %) under mild conditions and in the absence of additives.