carmen escolano - Academia.edu (original) (raw)
Papers by carmen escolano
Cell Death & Disease
On glucose restriction, epithelial cells can undergo entosis, a cell-in-cell cannibalistic proces... more On glucose restriction, epithelial cells can undergo entosis, a cell-in-cell cannibalistic process, to allow considerable withstanding to this metabolic stress. Thus, we hypothesized that reduced protein glycosylation might participate in the activation of this cell survival pathway. Glucose deprivation promoted entosis in an MCF7 breast carcinoma model, as evaluated by direct inspection under the microscope, or revealed by a shift to apoptosis + necrosis in cells undergoing entosis treated with a Rho-GTPase kinase inhibitor (ROCKi). In this context, curbing protein glycosylation defects with N-acetyl-glucosamine partially rescued entosis, whereas limiting glycosylation in the presence of glucose with tunicamycin or NGI-1, but not with other unrelated ER-stress inducers such as thapsigargin or amino-acid limitation, stimulated entosis. Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M; PCK2) is upregulated by glucose deprivation, thereby enhancing cell survival. Therefore, we...
Journal of Medicinal Chemistry, 2020
The FASEB Journal, 2018
Imidazoline I2 receptors (I2-IRs) are widely distributed in the brain. I2-IRs are associated with... more Imidazoline I2 receptors (I2-IRs) are widely distributed in the brain. I2-IRs are associated with analgesia and human brain disorders, such as depression and Alzheimer’s disease (AD). Since, a high...
The FASEB Journal, 2021
modulation of I2-IR by bicyclic α-iminophosphonates may open a new therapeutic venue for unmet ne... more modulation of I2-IR by bicyclic α-iminophosphonates may open a new therapeutic venue for unmet neurodegenerative conditions.
British Journal of Pharmacology, 2021
Disease-modifying treatment with I2 imidazoline receptor ligand LSL60101 in an Alzheimer's diseas... more Disease-modifying treatment with I2 imidazoline receptor ligand LSL60101 in an Alzheimer's disease mouse model: A Comparative study with donepezil.
European Journal of Medicinal Chemistry, 2021
Recent findings unveil the pharmacological modulation of imidazoline I2 receptors (I2-IR) as a no... more Recent findings unveil the pharmacological modulation of imidazoline I2 receptors (I2-IR) as a novel strategy to face unmet medical neurodegenerative diseases. In this work, we report the chemical characterization, three-dimensional quantitative structure-activity relationship (3D-QSAR) and ADMET in silico of a family of benzofuranyl-2-imidazoles that exhibit affinity against human brain I2-IR and most of them have been predicted to be brain permeable. Acute treatment in mice with 2-(2-benzofuranyl)-2-imidazole, known as LSL60101 (garsevil), showed non-warning properties in the ADMET studies and an optimal pharmacokinetic profile. Moreover, LSL60101 induced hypothermia in mice while decreased pro-apoptotic FADD protein in the hippocampus. In vivo studies in the familial Alzheimer's disease 5xFAD murine model with the representative compound, revealed significant decreases in the protein expression levels of antioxidant enzymes superoxide dismutase and glutathione peroxidase in hippocampus. Overall, LSL60101 plays a neuroprotective role by reducing apoptosis and modulating oxidative stress.
Biomedicine & Pharmacotherapy, 2020
Background: Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the decarboxylation of oxaloaceta... more Background: Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate. The mitochondrial isozyme, PEPCK-M is highly expressed in cancer cells, where it plays a role in nutrient stress response. To date, pharmacological strategies to target this pathway have not been pursued. Methods: A compound embodying a 3-alkyl-1,8-dibenzylxanthine nucleus (iPEPCK-2), was synthesized and successfully probed in silico on a PEPCK-M structural model. Potency and target engagement in vitro and in vivo were evaluated by kinetic and cellular thermal shift assays (CETSA). The compound and its target were validated in tumor growth models in vitro and in murine xenografts. Results: Cross-inhibitory capacity and increased potency as compared to 3-MPA were confirmed in vitro and in vivo. Treatment with iPEPCK-2 inhibited cell growth and survival, especially in poor-nutrient environment, consistent with an impact on colony formation in soft agar. Finally, daily administration of the PEPCK-M inhibitor successfully inhibited tumor growth in two murine xenograft models as compared to vehicle, without weight loss, or any sign of apparent toxicity. Conclusion: We conclude that iPEPCK-2 is a compelling anticancer drug targeting PEPCK-M, a hallmark gene product involved in metabolic adaptations of the tumor. 1. Background Phosphoenolpyruvate carboxykinase (PEPCK) (GTP; EC 4.1.1.32) catalyzes the GTP-dependent conversion of oxaloacetate (OAA) to phosphoenolpyruvate (PEP) from two very similar isozymes localized to the cytosol (PEPCK-C) or the mitochondria (PEPCK-M) [1,2], and
Neurotherapeutics, 2018
As populations increase their life expectancy, age-related neurodegenerative disorders such as Al... more As populations increase their life expectancy, age-related neurodegenerative disorders such as Alzheimer's disease have become more common. I 2-Imidazoline receptors (I 2-IR) are widely distributed in the central nervous system, and dysregulation of I 2-IR in patients with neurodegenerative diseases has been reported, suggesting their implication in cognitive impairment. This evidence indicates that high-affinity selective I 2-IR ligands potentially contribute to the delay of neurodegeneration. In vivo studies in the female senescence accelerated mouse-prone 8 mice have shown that treatment with I 2-IR ligands, MCR5 and MCR9, produce beneficial effects in behavior and cognition. Changes in molecular pathways implicated in oxidative stress, inflammation, synaptic plasticity, and apoptotic cell death were also studied. Furthermore, treatments with these I 2-IR ligands diminished the amyloid precursor protein processing pathway and increased Aβ degrading enzymes in the hippocampus of SAMP8 mice. These results collectively demonstrate the neuroprotective role of these new I 2-IR ligands in a mouse model of brain aging through specific pathways and suggest their potential as therapeutic agents in brain disorders and age-related neurodegenerative diseases.
![Research paper thumbnail of On the configuration of (3R,8aS)-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine](https://attachments.academia-assets.com/116553467/thumbnails/1.jpg)
](Tetrahedron: Asymmetry, 2003
The configuration of (3R,8aS)-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine 2 h... more The configuration of (3R,8aS)-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine 2 has been unambiguously confirmed by X-ray crystallographic analysis. A 1 H NMR-based method for the stereochemical assignment of 3,8a-cis and trans phenylglycinol-derived bicyclic lactams is also proposed.
Tetrahedron: Asymmetry, 2003
The addition of the enolate of methyl 1-methyl-2-indoleacetate 1 and lithium 2-(lithiomethyl)indo... more The addition of the enolate of methyl 1-methyl-2-indoleacetate 1 and lithium 2-(lithiomethyl)indole-1-carboxylate 5 to pyridines and N-alkylpyridinium salts bearing a chiral auxiliary at the 3-position (tolylsulfinyl, acyl iron complexes, bornane-10,2sultam), with subsequent acid cyclization of the resulting dihydropyridines, is investigated.
![Research paper thumbnail of Cyclization of 1-(carbamoyl)dichloromethyl radicals upon activated alkenes. A new entry to 2-azabicyclo[3.3.1]nonanes](https://attachments.academia-assets.com/116553464/thumbnails/1.jpg)
](Tetrahedron Letters, 1997
The synthesis of 2-azabicyclo[3.3.1]nonanes using a radical cyclization process as the piperidine... more The synthesis of 2-azabicyclo[3.3.1]nonanes using a radical cyclization process as the piperidine ring-forming step is described. The reaction involves 1-(carbamoyl)dichloromethyl radicals which react inlramolecularly with simple or activated alkenas, such as enol acetates or silyl enol ethers.
![Research paper thumbnail of Synthesis of 2-azabicyclo[3.3.1]nonanes by means of (carbamoyl)dichloromethyl radical cyclization](https://attachments.academia-assets.com/116553469/thumbnails/1.jpg)
](Tetrahedron, 1997
A new procedure for the synthesis of 2-azabicyclo[3.3.1 ]nonanes by intramolecular carboradical c... more A new procedure for the synthesis of 2-azabicyclo[3.3.1 ]nonanes by intramolecular carboradical cyclization of 4-(trichloroacetamido)cyclohexenes substituted with an electron withdrawing substituent (ester or nitrile) is described. The procedure allows the preparation of synthetically interesting azabicyclos 14 and 15 in nearly 70% yield.
Organic & Biomolecular Chemistry, 2013
Bicyclic α-iminophosphonates were prepared via the first diastereoselective silver catalyzed [3 +... more Bicyclic α-iminophosphonates were prepared via the first diastereoselective silver catalyzed [3 + 2] cycloaddition reaction of diethyl isocyanomethylphosphonate and diversely N-substituted maleimides. The reduction of the resulting imine by catalytic hydrogenation led to cyclic α-aminophosphonates, which are α-aminoester surrogates. The relative stereochemistry of the adducts was confirmed by X-ray crystallographic analysis of . The diastereoselectivity of the cycloaddition reaction was rationalised by theoretical studies.
The Journal of Organic Chemistry, 2003
Starting from a common lactam, (3R,8aS)-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]py... more Starting from a common lactam, (3R,8aS)-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (1), or its enantiomer, the enantioselective synthesis of 2-alkylpiperidines and cis- and trans-2,6-dialkylpiperidines is reported. The potential of this approach is illustrated by the synthesis of the piperidine alkaloids (R)-coniine, (2R,6S)-dihydropinidine, (2R,6R)-lupetidine, and (2R,6R)-solenopsin A, the indolizidine alkaloids (5R,8aR)-indolizidine 167B and (3R,5S,8aS)-monomorine I, and the nonnatural base (4R,9aS)-4-methylquinolizidine.
The Journal of Organic Chemistry, 2009
The enantioselective construction of the 3-ethylindolo[2,3-a]quinolizidine moiety present in nume... more The enantioselective construction of the 3-ethylindolo[2,3-a]quinolizidine moiety present in numerous indole alkaloids is reported, the key steps being a stereoselective cyclocondensation of (S)-tryptophanol with an appropriate racemic δ-oxoester and a regio-and stereoselective cyclization of the resulting oxazolopiperidones on the lactam carbonyl group. A new procedure for the removal of the hydroxymethyl auxiliary group, involving oxidation to an aldehyde, dehydration of the corresponding oxime, and reductive decyanation of the resulting R-aminonitrile, has been developed. The preparation of indoloquinolizidine 27 represents a formal total synthesis of (+)-dihydrocorynantheine, (-)-dihydrocorynantheol, and other indolo[2,3-a]quinolizidine and oxindole alkaloids bearing the same substitution pattern. † Dedicated to Professor Josep Font on the occasion of his 70th birthday.
The Journal of Organic Chemistry, 2002
The Journal of Organic Chemistry, 2008
The reversal of the π-facial diastereoselectivity observed in the benzyl bromide alkylation of th... more The reversal of the π-facial diastereoselectivity observed in the benzyl bromide alkylation of the enolate of phenylglycinol-derived oxazolopiperidone is examined by means of theoretical calculations and experimental assays. When the angular carbon adopts an R configuration, the endo addition is intrinsically favored due to the lower torsional strain induced in the TS, but for the reaction with benzyl bromide, which affords the exo product. This reversal is attributed to the formation of a C-H • • • π hydrogen bond between the C-H unit of the C8a angular position and the benzene ring of the alkylating reagent. A similar secondary interaction explains the stereochemical reversion observed in the benzyl alkylation of the enolate of oxazolopyrrolidinone. These findings point out that the delicate balance between factors that dictate the diastereoselectivity in the alkylation of chiral byciclic lactams can be unexpectedly altered by weak secondary interactions. The results presented here provide valuable guidelines to tune the selective preparation of enantiopure bioorganic and pharmaceutical compounds.
European Journal of Organic Chemistry, 2011
A cooperative multicatalytic cascade sequence involving isocyanoacetates and α,β‐unsaturated keto... more A cooperative multicatalytic cascade sequence involving isocyanoacetates and α,β‐unsaturated ketones is described for the enantioselective synthesis of 2,3‐dihydropyrroles. The key to promoting the multistep asymmetric reaction is the combination of cinchona alkaloid derived organocatalysts with silver nitrate. Merging both organic and metal catalytic cycles enables the formation of two C–C bonds and the generation of a stereogenic center in a single process. The study has also shown that the bifunctional role of the organocatalyst is crucial for the asymmetric version of the cycloaddition reaction.
European Journal of Lipid Science and Technology, 2012
Triheptanoin‐enriched diets have been successfully used in the experimental treatment of various ... more Triheptanoin‐enriched diets have been successfully used in the experimental treatment of various metabolic disorders. Maximal therapeutic effect is achieved in the context of a ketogenic diet where triheptanoin oil provides 30–40% of the daily caloric intake. However, pre‐clinical studies using triheptanoin‐rich diets are hindered by the difficulty of administering to laboratory animals as a solid foodstuff. In the present study, we successfully synthesized triheptanoin to the highest standards of purity from glycerol and heptanoic acid, using sulfonated charcoal as a catalyst. Triheptanoin oil was then formulated as a solid, stable and palatable preparation using a ketogenic base and a combination of four commercially available formulation agents: hydrophilic fumed silica, hydrophobic fumed silica, microcrystalline cellulose, and talc. Diet compliance and safety was tested on C57Bl/6 mice over a 15‐week period, comparing overall status and body weight change.Practical applications:...
Chemistry – A European Journal, 2006
Phenylglycinol‐derived oxazolopiperidone lactams are exceptionally versatile building blocks for ... more Phenylglycinol‐derived oxazolopiperidone lactams are exceptionally versatile building blocks for the enantioselective construction of structurally diverse piperidine‐containing natural products and bioactive compounds. These lactams are readily available in both enantiomeric series by cyclocondensation of the chiral amino alcohol with a δ‐oxo acid derivative and allow the substituents to be introduced at the different ring positions in a regio‐ and stereocontrolled manner, providing access to enantiopure polysubstituted piperidines bearing virtually any type of substitution pattern, and also quinolizidines, indolizidines, perhydroquinolines, hydroisoquinolines, as well as complex indole alkaloids. Of particular interest are cyclocondensation reactions with racemic or prochiral δ‐oxo (di)acid derivatives in processes involving dynamic kinetic resolution and/or differentiation of enantiotopic or diastereotopic ester groups, as they directly lead to lactams that already incorporate the...
Cell Death & Disease
On glucose restriction, epithelial cells can undergo entosis, a cell-in-cell cannibalistic proces... more On glucose restriction, epithelial cells can undergo entosis, a cell-in-cell cannibalistic process, to allow considerable withstanding to this metabolic stress. Thus, we hypothesized that reduced protein glycosylation might participate in the activation of this cell survival pathway. Glucose deprivation promoted entosis in an MCF7 breast carcinoma model, as evaluated by direct inspection under the microscope, or revealed by a shift to apoptosis + necrosis in cells undergoing entosis treated with a Rho-GTPase kinase inhibitor (ROCKi). In this context, curbing protein glycosylation defects with N-acetyl-glucosamine partially rescued entosis, whereas limiting glycosylation in the presence of glucose with tunicamycin or NGI-1, but not with other unrelated ER-stress inducers such as thapsigargin or amino-acid limitation, stimulated entosis. Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M; PCK2) is upregulated by glucose deprivation, thereby enhancing cell survival. Therefore, we...
Journal of Medicinal Chemistry, 2020
The FASEB Journal, 2018
Imidazoline I2 receptors (I2-IRs) are widely distributed in the brain. I2-IRs are associated with... more Imidazoline I2 receptors (I2-IRs) are widely distributed in the brain. I2-IRs are associated with analgesia and human brain disorders, such as depression and Alzheimer’s disease (AD). Since, a high...
The FASEB Journal, 2021
modulation of I2-IR by bicyclic α-iminophosphonates may open a new therapeutic venue for unmet ne... more modulation of I2-IR by bicyclic α-iminophosphonates may open a new therapeutic venue for unmet neurodegenerative conditions.
British Journal of Pharmacology, 2021
Disease-modifying treatment with I2 imidazoline receptor ligand LSL60101 in an Alzheimer's diseas... more Disease-modifying treatment with I2 imidazoline receptor ligand LSL60101 in an Alzheimer's disease mouse model: A Comparative study with donepezil.
European Journal of Medicinal Chemistry, 2021
Recent findings unveil the pharmacological modulation of imidazoline I2 receptors (I2-IR) as a no... more Recent findings unveil the pharmacological modulation of imidazoline I2 receptors (I2-IR) as a novel strategy to face unmet medical neurodegenerative diseases. In this work, we report the chemical characterization, three-dimensional quantitative structure-activity relationship (3D-QSAR) and ADMET in silico of a family of benzofuranyl-2-imidazoles that exhibit affinity against human brain I2-IR and most of them have been predicted to be brain permeable. Acute treatment in mice with 2-(2-benzofuranyl)-2-imidazole, known as LSL60101 (garsevil), showed non-warning properties in the ADMET studies and an optimal pharmacokinetic profile. Moreover, LSL60101 induced hypothermia in mice while decreased pro-apoptotic FADD protein in the hippocampus. In vivo studies in the familial Alzheimer's disease 5xFAD murine model with the representative compound, revealed significant decreases in the protein expression levels of antioxidant enzymes superoxide dismutase and glutathione peroxidase in hippocampus. Overall, LSL60101 plays a neuroprotective role by reducing apoptosis and modulating oxidative stress.
Biomedicine & Pharmacotherapy, 2020
Background: Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the decarboxylation of oxaloaceta... more Background: Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate. The mitochondrial isozyme, PEPCK-M is highly expressed in cancer cells, where it plays a role in nutrient stress response. To date, pharmacological strategies to target this pathway have not been pursued. Methods: A compound embodying a 3-alkyl-1,8-dibenzylxanthine nucleus (iPEPCK-2), was synthesized and successfully probed in silico on a PEPCK-M structural model. Potency and target engagement in vitro and in vivo were evaluated by kinetic and cellular thermal shift assays (CETSA). The compound and its target were validated in tumor growth models in vitro and in murine xenografts. Results: Cross-inhibitory capacity and increased potency as compared to 3-MPA were confirmed in vitro and in vivo. Treatment with iPEPCK-2 inhibited cell growth and survival, especially in poor-nutrient environment, consistent with an impact on colony formation in soft agar. Finally, daily administration of the PEPCK-M inhibitor successfully inhibited tumor growth in two murine xenograft models as compared to vehicle, without weight loss, or any sign of apparent toxicity. Conclusion: We conclude that iPEPCK-2 is a compelling anticancer drug targeting PEPCK-M, a hallmark gene product involved in metabolic adaptations of the tumor. 1. Background Phosphoenolpyruvate carboxykinase (PEPCK) (GTP; EC 4.1.1.32) catalyzes the GTP-dependent conversion of oxaloacetate (OAA) to phosphoenolpyruvate (PEP) from two very similar isozymes localized to the cytosol (PEPCK-C) or the mitochondria (PEPCK-M) [1,2], and
Neurotherapeutics, 2018
As populations increase their life expectancy, age-related neurodegenerative disorders such as Al... more As populations increase their life expectancy, age-related neurodegenerative disorders such as Alzheimer's disease have become more common. I 2-Imidazoline receptors (I 2-IR) are widely distributed in the central nervous system, and dysregulation of I 2-IR in patients with neurodegenerative diseases has been reported, suggesting their implication in cognitive impairment. This evidence indicates that high-affinity selective I 2-IR ligands potentially contribute to the delay of neurodegeneration. In vivo studies in the female senescence accelerated mouse-prone 8 mice have shown that treatment with I 2-IR ligands, MCR5 and MCR9, produce beneficial effects in behavior and cognition. Changes in molecular pathways implicated in oxidative stress, inflammation, synaptic plasticity, and apoptotic cell death were also studied. Furthermore, treatments with these I 2-IR ligands diminished the amyloid precursor protein processing pathway and increased Aβ degrading enzymes in the hippocampus of SAMP8 mice. These results collectively demonstrate the neuroprotective role of these new I 2-IR ligands in a mouse model of brain aging through specific pathways and suggest their potential as therapeutic agents in brain disorders and age-related neurodegenerative diseases.
Tetrahedron: Asymmetry, 2003
The configuration of (3R,8aS)-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine 2 h... more The configuration of (3R,8aS)-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine 2 has been unambiguously confirmed by X-ray crystallographic analysis. A 1 H NMR-based method for the stereochemical assignment of 3,8a-cis and trans phenylglycinol-derived bicyclic lactams is also proposed.
Tetrahedron: Asymmetry, 2003
The addition of the enolate of methyl 1-methyl-2-indoleacetate 1 and lithium 2-(lithiomethyl)indo... more The addition of the enolate of methyl 1-methyl-2-indoleacetate 1 and lithium 2-(lithiomethyl)indole-1-carboxylate 5 to pyridines and N-alkylpyridinium salts bearing a chiral auxiliary at the 3-position (tolylsulfinyl, acyl iron complexes, bornane-10,2sultam), with subsequent acid cyclization of the resulting dihydropyridines, is investigated.
Tetrahedron Letters, 1997
The synthesis of 2-azabicyclo[3.3.1]nonanes using a radical cyclization process as the piperidine... more The synthesis of 2-azabicyclo[3.3.1]nonanes using a radical cyclization process as the piperidine ring-forming step is described. The reaction involves 1-(carbamoyl)dichloromethyl radicals which react inlramolecularly with simple or activated alkenas, such as enol acetates or silyl enol ethers.
Tetrahedron, 1997
A new procedure for the synthesis of 2-azabicyclo[3.3.1 ]nonanes by intramolecular carboradical c... more A new procedure for the synthesis of 2-azabicyclo[3.3.1 ]nonanes by intramolecular carboradical cyclization of 4-(trichloroacetamido)cyclohexenes substituted with an electron withdrawing substituent (ester or nitrile) is described. The procedure allows the preparation of synthetically interesting azabicyclos 14 and 15 in nearly 70% yield.
Organic & Biomolecular Chemistry, 2013
Bicyclic α-iminophosphonates were prepared via the first diastereoselective silver catalyzed [3 +... more Bicyclic α-iminophosphonates were prepared via the first diastereoselective silver catalyzed [3 + 2] cycloaddition reaction of diethyl isocyanomethylphosphonate and diversely N-substituted maleimides. The reduction of the resulting imine by catalytic hydrogenation led to cyclic α-aminophosphonates, which are α-aminoester surrogates. The relative stereochemistry of the adducts was confirmed by X-ray crystallographic analysis of . The diastereoselectivity of the cycloaddition reaction was rationalised by theoretical studies.
The Journal of Organic Chemistry, 2003
Starting from a common lactam, (3R,8aS)-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]py... more Starting from a common lactam, (3R,8aS)-5-oxo-3-phenyl-2,3,6,7,8,8a-hexahydro-5H-oxazolo[3,2-a]pyridine (1), or its enantiomer, the enantioselective synthesis of 2-alkylpiperidines and cis- and trans-2,6-dialkylpiperidines is reported. The potential of this approach is illustrated by the synthesis of the piperidine alkaloids (R)-coniine, (2R,6S)-dihydropinidine, (2R,6R)-lupetidine, and (2R,6R)-solenopsin A, the indolizidine alkaloids (5R,8aR)-indolizidine 167B and (3R,5S,8aS)-monomorine I, and the nonnatural base (4R,9aS)-4-methylquinolizidine.
The Journal of Organic Chemistry, 2009
The enantioselective construction of the 3-ethylindolo[2,3-a]quinolizidine moiety present in nume... more The enantioselective construction of the 3-ethylindolo[2,3-a]quinolizidine moiety present in numerous indole alkaloids is reported, the key steps being a stereoselective cyclocondensation of (S)-tryptophanol with an appropriate racemic δ-oxoester and a regio-and stereoselective cyclization of the resulting oxazolopiperidones on the lactam carbonyl group. A new procedure for the removal of the hydroxymethyl auxiliary group, involving oxidation to an aldehyde, dehydration of the corresponding oxime, and reductive decyanation of the resulting R-aminonitrile, has been developed. The preparation of indoloquinolizidine 27 represents a formal total synthesis of (+)-dihydrocorynantheine, (-)-dihydrocorynantheol, and other indolo[2,3-a]quinolizidine and oxindole alkaloids bearing the same substitution pattern. † Dedicated to Professor Josep Font on the occasion of his 70th birthday.
The Journal of Organic Chemistry, 2002
The Journal of Organic Chemistry, 2008
The reversal of the π-facial diastereoselectivity observed in the benzyl bromide alkylation of th... more The reversal of the π-facial diastereoselectivity observed in the benzyl bromide alkylation of the enolate of phenylglycinol-derived oxazolopiperidone is examined by means of theoretical calculations and experimental assays. When the angular carbon adopts an R configuration, the endo addition is intrinsically favored due to the lower torsional strain induced in the TS, but for the reaction with benzyl bromide, which affords the exo product. This reversal is attributed to the formation of a C-H • • • π hydrogen bond between the C-H unit of the C8a angular position and the benzene ring of the alkylating reagent. A similar secondary interaction explains the stereochemical reversion observed in the benzyl alkylation of the enolate of oxazolopyrrolidinone. These findings point out that the delicate balance between factors that dictate the diastereoselectivity in the alkylation of chiral byciclic lactams can be unexpectedly altered by weak secondary interactions. The results presented here provide valuable guidelines to tune the selective preparation of enantiopure bioorganic and pharmaceutical compounds.
European Journal of Organic Chemistry, 2011
A cooperative multicatalytic cascade sequence involving isocyanoacetates and α,β‐unsaturated keto... more A cooperative multicatalytic cascade sequence involving isocyanoacetates and α,β‐unsaturated ketones is described for the enantioselective synthesis of 2,3‐dihydropyrroles. The key to promoting the multistep asymmetric reaction is the combination of cinchona alkaloid derived organocatalysts with silver nitrate. Merging both organic and metal catalytic cycles enables the formation of two C–C bonds and the generation of a stereogenic center in a single process. The study has also shown that the bifunctional role of the organocatalyst is crucial for the asymmetric version of the cycloaddition reaction.
European Journal of Lipid Science and Technology, 2012
Triheptanoin‐enriched diets have been successfully used in the experimental treatment of various ... more Triheptanoin‐enriched diets have been successfully used in the experimental treatment of various metabolic disorders. Maximal therapeutic effect is achieved in the context of a ketogenic diet where triheptanoin oil provides 30–40% of the daily caloric intake. However, pre‐clinical studies using triheptanoin‐rich diets are hindered by the difficulty of administering to laboratory animals as a solid foodstuff. In the present study, we successfully synthesized triheptanoin to the highest standards of purity from glycerol and heptanoic acid, using sulfonated charcoal as a catalyst. Triheptanoin oil was then formulated as a solid, stable and palatable preparation using a ketogenic base and a combination of four commercially available formulation agents: hydrophilic fumed silica, hydrophobic fumed silica, microcrystalline cellulose, and talc. Diet compliance and safety was tested on C57Bl/6 mice over a 15‐week period, comparing overall status and body weight change.Practical applications:...
Chemistry – A European Journal, 2006
Phenylglycinol‐derived oxazolopiperidone lactams are exceptionally versatile building blocks for ... more Phenylglycinol‐derived oxazolopiperidone lactams are exceptionally versatile building blocks for the enantioselective construction of structurally diverse piperidine‐containing natural products and bioactive compounds. These lactams are readily available in both enantiomeric series by cyclocondensation of the chiral amino alcohol with a δ‐oxo acid derivative and allow the substituents to be introduced at the different ring positions in a regio‐ and stereocontrolled manner, providing access to enantiopure polysubstituted piperidines bearing virtually any type of substitution pattern, and also quinolizidines, indolizidines, perhydroquinolines, hydroisoquinolines, as well as complex indole alkaloids. Of particular interest are cyclocondensation reactions with racemic or prochiral δ‐oxo (di)acid derivatives in processes involving dynamic kinetic resolution and/or differentiation of enantiotopic or diastereotopic ester groups, as they directly lead to lactams that already incorporate the...