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Jon C Antilla - One of the best experts on this subject based on the ideXlab platform.
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catalytic asymmetric aza darzens reaction with a vaulted biphenanthrol magnesium Phosphate Salt
ChemInform, 2011Co-Authors: Shawn E Larson, Gerald B Rowland, Denise Junge, Rongcai Huang, Lee H Woodcock, Jon C AntillaAbstract:The reaction is applied to a variety of aromatic imines and tolerates functional groups such as halides or methoxy.
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catalytic asymmetric aza darzens reaction with a vaulted biphenanthrol magnesium Phosphate Salt
Organic Letters, 2011Co-Authors: Shawn E Larson, Gerald B Rowland, Denise Junge, Rongcai Huang, Lee H Woodcock, Jon C AntillaAbstract:Conditions for a catalytic asymmetric aza-Darzens aziridine synthesis mediated by a vaulted biphenanthrol (VAPOL) magnesium Phosphate Salt is described. Using simple substrates, this methodology explores the scope and reactivity of a new magnesium catalyst for an aziridination reaction capable of building chirality and complexity simultaneously.
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chiral magnesium binol Phosphate catalyzed phosphination of imines access to enantioenriched α amino phosphine oxides
Organic Letters, 2011Co-Authors: Gajendrasingh K Ingle, Yuxue Liang, Michael G Mormino, Frank R Fronczek, Jon C AntillaAbstract:A new method to synthesize chiral α-amino phosphine oxides is reported. The reaction combines N-substituted imines and diphenylphosphine oxide and is catalyzed by a chiral magnesium Phosphate Salt. A wide variety of aliphatic and aromatic aldimines substituted by electron-neutral benzhydryl or dibenzocycloheptene groups were excellent substrates for the addition reaction. The dibenzocycloheptene protected imines afforded improved enantioselectivity in the resulting products. Substituted diphenylphosphine oxide nucleophiles also showed good reactivity.
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highly enantioselective catalytic benzoyloxylation of 3 aryloxindoles using chiral vapol calcium Phosphate
Angewandte Chemie, 2011Co-Authors: Zuhui Zhang, Wenhua Zheng, Jon C AntillaAbstract:3-Hydroxy-2-oxindoles are structural motifs present in a number of natural products and biologically active compounds.[1, 2] Among these molecules, 3-aryl-3-hydroxyoxindoles represent an important class of molecules that have found broad applications in medicinal chemistry. One such example is SM-130686 (Scheme 1), a compound exhibiting potent activity with respect to growth hormone release.[2a] The absolute configuration of the hydroxy group at the C3 position was shown to further modulate the biological activity.[2c] It is therefore of high importance to introduce asymmetry at the C3 position with high enantiocontrol. To date, only a limited number of approaches have been reported, which outline the preparation of chiral 3-hydroxy-2-oxindoles. One type of approach calls for the asymmetric nucleophilic addition of organometallic reagents[3] or electron-rich reagents[4–6] to isatins. The second approach entails asymmetric hydroxylation of 3-substituted 2-oxindoles.[7] Despite these developments, the available methodologies are often limited and a new methodology is highly desirable, considering the importance of chiral 3-substituted oxindoles. Scheme 1 Structure of SM-130686. Since the independent reports by Akiyama and Terada in 2004,[8] chiral phosphoric acids have proven to be versatile catalysts and have subsequently been applied to a variety of transformations with high stereocontrol.[9] Moreover, the alkali or alkaline earth derived Salts of chiral phosphoric acids have proven to be highly effective catalysts in several recent reports.[10] Benzoyl peroxide (BPO) is a readily available oxylation reagent, which has been known for decades.[11] Nonetheless, asymmetric oxylation using BPO are very rare.[12] Herein, we describe, to the best of our knowledge, the first example of a highly enantioselective benzoyloxylation of an oxindole with BPO catalyzed by a chiral calcium Phosphate (Scheme 2).[13] By comparison to published reports, this work provides access to 3-hydroxyoxindole derivatives with the highest stereoselectivity to date. Scheme 2 Enantioselective benzoyloxylation of oxindoles. We began our investigation with 3-phenyloxindole 1a and BPO as substrates, and toluene as the solvent, as a starting point for optimization studies. Chiral phosphoric acids purified by silica gel column chromatography, were then screened. Catalysts H[P1], H[P4], and H[P6] (Table 1, entries 1, 4, and 6) imparted meagre stereoselectivity. H[P6], a VAPOL-derived phosphoric acid, proved to be the best catalyst when TBME was the solvent (Table 1, entries 7– 9). The reverse selectivity was observed in DCM (Table 1, entry 10).[14] To our delight, an upgrade to 99% ee was obtained using diethyl ether (Table 1, entry 11). Interestingly, H[P6] washed with 6N HCl exhibited poor catalytic efficiency and enantioselectivity under the same conditions (Table 1, entry 12). Correlation of this result to that of a recent report by Ishihara and co-workers,[10a] showing a high abundance of chiral Phosphate Salts in the absence of a final HCl wash of the chiral phosphoric acid/Salt mixture obtained by silica gel purification, directed us to propose the active catalytic species to be that of a chiral Phosphate Salt.[15] To identify the metal counterion, several variants of P6 were prepared and evaluated. Na[P6] and K[P6] afforded the product with no selectivity (Table 1, entries 13 and 14). Ca[P6]2 and Sr[P6]2 both induced remarkably high selectivity (>99%) (Table 1, entries 15 and 16). Ba[P6]2 allowed for a significantly lower enantioselectivity (7 %) (Table 1, entry 17). Mg[P6]2 furnished the product with 60% ee, but with the opposite configuration (Table 1, entry 18), presumably due to a difference on coordination spheres compared to calcium.[16] To our delight, excellent enantioselectivity (95%) is still observed with Ca[P6]2, even when the catalyst loading is reduced to 0.10 mol% (Table 1, entry 22). Table 1 Screening of catalysts and solvents.[a] With the optimized reaction conditions in hand, we turned our attention to the scope of the asymmetric benzoyloxylation of 3-aryloxindoles with Ca[P6]2. As shown in Table 2, introduction of either electron-donating or electron-withdrawing groups on the 3-aryl ring or the arene ring of the oxindole have little effect on the enantioselectivity (2a–2m). The majority of products were obtained with 99% ee and good yield. It is worthy of note that 3-aryloxindoles bearing a heteroatom can provide the desired product with excellent enantioselectivity (2n). Unfortunately, no product was detected using 3-benzyloxindole due to lower reactivity. Table 2 Substrate scope for the asymmetric benzoyloxylation of oxindoles.[a] Determination of the absolute configuration of the products, as well as potential synthetic utility of this methodology is shown in Scheme 3. Boc-deprotection followed by reduction of the benzoyl group of 2a yielded known compound 4a in two steps with good overall yield and excellent retention of chirality.[17] Scheme 3 Transformation of 2 a to known hydroxyoxindole 4 a. TFA = trifluoroacetic acid, DIBAL-H = diisobutylaluminum hydride. While a detailed mechanism for this novel transformation is unknown, we propose that the bifunctional nature of the chiral calcium Phosphate Salt allows for activation of both the nucleophile and the electrophile, as shown in Scheme 4. Two characteristics of calcium were considered in developing this plausible transition state. First, the low electronegativity of calcium should lead to a significant increase in the Bronsted basicity of the chiral Phosphate counteranion. Second, calcium’s various coordination sites presumably allow for a greater number of favorable electrostatic interactions.[18] The coordination between calcium and the carbonyl oxygens of both BPO and the Boc-group of the oxindole serve not only to activate the electrophile but also force the two substrates to be in closer proximity to one another, in the chiral environment. These interactions coupled with the hydrogen-bonding interactions between the hydroxy group of the oxindole tautomer and the P=O moiety of the catalyst can be used to rationalize the unprecedented enantioselectivity observed. Scheme 4 Proposed transition state for the Ca[P6]2-catalyzed benzoyloxylation of oxindole 1 a. In conclusion, we report a novel asymmetric benzoyloxylation of 3-aryl-2-oxindoles catalyzed by a chiral VAPOL calcium Phosphate Salt. This transformation utilizes readily available benzoyl peroxide as a benzoyloxylation reagent. A series of 3-aryl-3-benzoyloxindoles are obtained with good yields and excellent enantioselectivities. Further studies of the benzoyloxylation of additional nucleophiles are currently under investigation in our laboratory and will be reported in due course.
Maurizio Raiteri - One of the best experts on this subject based on the ideXlab platform.
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somatostatin induced activation and up regulation of n methyl d aspartate receptor function mediation through calmodulin dependent protein kinase ii phospholipase c protein kinase c and tyrosine kinase in hippocampal noradrenergic nerve endings
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Anna Pittaluga, Marco Feligioni, Fabio Longordo, Marica Arvigo, Maurizio RaiteriAbstract:Somatostatin receptors and glutamate N-methyl-d-aspartate (NMDA) receptors coexist on hippocampal noradrenergic axon terminals. Activation of somatostatin receptors was previously found to positively influence the function of NMDA receptors regulating norepinephrine release. The somatostatin receptors involved were pharmacologically characterized as sst5 type in experiments in Mg2+-free solutions. Here, we first confirm the pharmacology of these receptors using selective sst5 ligands in Mg2+-containing solutions. Moreover, we show by Western blot that the sst5 protein exists on purified hippocampal synaptosomal membranes. We then investigated the pathways connecting the two receptors using as a functional response the release of norepinephrine from rat hippocampal synaptosomes in superfusion. The release of norepinephrine evoked by somatostatin-14 plus NMDA/glycine was partly prevented by the protein kinase C inhibitor GF109203X [dihydrochloride3-[1-[3-(dimethylamino)propyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione] and by the nonreceptor tyrosine kinase (Src) inhibitors PP2 [3-(4-chlorophenyl)1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine] and lavendustin A; it was largely and almost totally abolished by the phospholipase C inhibitor U73122 [1-(6-[([17β]-3-methoxyextra-1,3,5[10]-trien-17-yl)amino]hexyl)-1H-pyrrole-2,5-dione] and by the Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN93 [N-(2-[N-[4-chlorocinnamyl]-N-methyl-amino-methyl]phenyl)-N-(2-hydroxyethyl)-4-methoxy-benzene-sulfonamide-Phosphate Salt], respectively; and it was unaffected by the protein kinase A inhibitor H89 [N-(2-[p-bromocinnamylamino]ethyl)5-isoquinolinesulfonamide hydrochloride]. The norepinephrine release evoked by somatostatin-14/NMDA/glycine was inhibited when anti-phosphotyrosine antibodies had been entrapped into synaptosomes. Entrapping the recombinant activated tyrosine kinase pp60c-Src strongly potentiated the release of norepinephrine elicited by NMDA/glycine in Mg2+-free medium but failed to permit NMDA receptor activation in presence of external Mg2+ ions. The results suggest the involvement of CaMKII in the sst5 receptor-mediated activation of NMDA receptors in presence of Mg2+ and of the PLC/PKC/Src pathway in the up-regulation of the ongoing NMDA receptor activity.
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somatostatin induced activation and up regulation of n methyl d aspartate receptor function mediation through calmodulin dependent protein kinase ii phospholipase c protein kinase c and tyrosine kinase in hippocampal noradrenergic nerve endings
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Anna Pittaluga, Marco Feligioni, Fabio Longordo, Marica Arvigo, Maurizio RaiteriAbstract:Somatostatin receptors and glutamate N-methyl-D-aspartate (NMDA) receptors coexist on hippocampal noradrenergic axon terminals. Activation of somatostatin receptors was previously found to positively influence the function of NMDA receptors regulating norepinephrine release. The somatostatin receptors involved were pharmacologically characterized as sst5 type in experiments in Mg2+-free solutions. Here, we first confirm the pharmacology of these receptors using selective sst5 ligands in Mg2+-containing solutions. Moreover, we show by Western blot that the sst5 protein exists on purified hippocampal synaptosomal membranes. We then investigated the pathways connecting the two receptors using as a functional response the release of norepinephrine from rat hippocampal synaptosomes in superfusion. The release of norepinephrine evoked by somatostatin-14 plus NMDA/glycine was partly prevented by the protein kinase C inhibitor GF109203X [dihydrochloride3-[1-[3-(dimethylamino)propyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione] and by the nonreceptor tyrosine kinase (Src) inhibitors PP2 [3-(4-chlorophenyl)1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-D]pyrimidin-4-amine] and lavendustin A; it was largely and almost totally abolished by the phospholipase C inhibitor U73122 [1-(6-[([17beta]-3-methoxyextra-1,3,5[10]-trien-17-yl)amino]hexyl)-1H-pyrrole-2,5-dione] and by the Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN93 [N-(2-[N-[4-chlorocinnamyl]-N-methyl-amino-methyl]phenyl)-N-(2-hydroxyethyl)-4-methoxy-benzene-sulfonamide-Phosphate Salt], respectively; and it was unaffected by the protein kinase A inhibitor H89 [N-(2-[p-bromocinnamylamino]ethyl)5-isoquinolinesulfonamide hydrochloride]. The norepinephrine release evoked by somatostatin-14/NMDA/glycine was inhibited when anti-phosphotyrosine antibodies had been entrapped into synaptosomes. Entrapping the recombinant activated tyrosine kinase pp60(c-Src) strongly potentiated the release of norepinephrine elicited by NMDA/glycine in Mg2+-free medium but failed to permit NMDA receptor activation in presence of external Mg2+ ions. The results suggest the involvement of CaMKII in the sst5 receptor-mediated activation of NMDA receptors in presence of Mg2+ and of the PLC/PKC/Src pathway in the up-regulation of the ongoing NMDA receptor activity.
Anna Pittaluga - One of the best experts on this subject based on the ideXlab platform.
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somatostatin induced activation and up regulation of n methyl d aspartate receptor function mediation through calmodulin dependent protein kinase ii phospholipase c protein kinase c and tyrosine kinase in hippocampal noradrenergic nerve endings
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Anna Pittaluga, Marco Feligioni, Fabio Longordo, Marica Arvigo, Maurizio RaiteriAbstract:Somatostatin receptors and glutamate N-methyl-d-aspartate (NMDA) receptors coexist on hippocampal noradrenergic axon terminals. Activation of somatostatin receptors was previously found to positively influence the function of NMDA receptors regulating norepinephrine release. The somatostatin receptors involved were pharmacologically characterized as sst5 type in experiments in Mg2+-free solutions. Here, we first confirm the pharmacology of these receptors using selective sst5 ligands in Mg2+-containing solutions. Moreover, we show by Western blot that the sst5 protein exists on purified hippocampal synaptosomal membranes. We then investigated the pathways connecting the two receptors using as a functional response the release of norepinephrine from rat hippocampal synaptosomes in superfusion. The release of norepinephrine evoked by somatostatin-14 plus NMDA/glycine was partly prevented by the protein kinase C inhibitor GF109203X [dihydrochloride3-[1-[3-(dimethylamino)propyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione] and by the nonreceptor tyrosine kinase (Src) inhibitors PP2 [3-(4-chlorophenyl)1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine] and lavendustin A; it was largely and almost totally abolished by the phospholipase C inhibitor U73122 [1-(6-[([17β]-3-methoxyextra-1,3,5[10]-trien-17-yl)amino]hexyl)-1H-pyrrole-2,5-dione] and by the Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN93 [N-(2-[N-[4-chlorocinnamyl]-N-methyl-amino-methyl]phenyl)-N-(2-hydroxyethyl)-4-methoxy-benzene-sulfonamide-Phosphate Salt], respectively; and it was unaffected by the protein kinase A inhibitor H89 [N-(2-[p-bromocinnamylamino]ethyl)5-isoquinolinesulfonamide hydrochloride]. The norepinephrine release evoked by somatostatin-14/NMDA/glycine was inhibited when anti-phosphotyrosine antibodies had been entrapped into synaptosomes. Entrapping the recombinant activated tyrosine kinase pp60c-Src strongly potentiated the release of norepinephrine elicited by NMDA/glycine in Mg2+-free medium but failed to permit NMDA receptor activation in presence of external Mg2+ ions. The results suggest the involvement of CaMKII in the sst5 receptor-mediated activation of NMDA receptors in presence of Mg2+ and of the PLC/PKC/Src pathway in the up-regulation of the ongoing NMDA receptor activity.
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somatostatin induced activation and up regulation of n methyl d aspartate receptor function mediation through calmodulin dependent protein kinase ii phospholipase c protein kinase c and tyrosine kinase in hippocampal noradrenergic nerve endings
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Anna Pittaluga, Marco Feligioni, Fabio Longordo, Marica Arvigo, Maurizio RaiteriAbstract:Somatostatin receptors and glutamate N-methyl-D-aspartate (NMDA) receptors coexist on hippocampal noradrenergic axon terminals. Activation of somatostatin receptors was previously found to positively influence the function of NMDA receptors regulating norepinephrine release. The somatostatin receptors involved were pharmacologically characterized as sst5 type in experiments in Mg2+-free solutions. Here, we first confirm the pharmacology of these receptors using selective sst5 ligands in Mg2+-containing solutions. Moreover, we show by Western blot that the sst5 protein exists on purified hippocampal synaptosomal membranes. We then investigated the pathways connecting the two receptors using as a functional response the release of norepinephrine from rat hippocampal synaptosomes in superfusion. The release of norepinephrine evoked by somatostatin-14 plus NMDA/glycine was partly prevented by the protein kinase C inhibitor GF109203X [dihydrochloride3-[1-[3-(dimethylamino)propyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione] and by the nonreceptor tyrosine kinase (Src) inhibitors PP2 [3-(4-chlorophenyl)1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-D]pyrimidin-4-amine] and lavendustin A; it was largely and almost totally abolished by the phospholipase C inhibitor U73122 [1-(6-[([17beta]-3-methoxyextra-1,3,5[10]-trien-17-yl)amino]hexyl)-1H-pyrrole-2,5-dione] and by the Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN93 [N-(2-[N-[4-chlorocinnamyl]-N-methyl-amino-methyl]phenyl)-N-(2-hydroxyethyl)-4-methoxy-benzene-sulfonamide-Phosphate Salt], respectively; and it was unaffected by the protein kinase A inhibitor H89 [N-(2-[p-bromocinnamylamino]ethyl)5-isoquinolinesulfonamide hydrochloride]. The norepinephrine release evoked by somatostatin-14/NMDA/glycine was inhibited when anti-phosphotyrosine antibodies had been entrapped into synaptosomes. Entrapping the recombinant activated tyrosine kinase pp60(c-Src) strongly potentiated the release of norepinephrine elicited by NMDA/glycine in Mg2+-free medium but failed to permit NMDA receptor activation in presence of external Mg2+ ions. The results suggest the involvement of CaMKII in the sst5 receptor-mediated activation of NMDA receptors in presence of Mg2+ and of the PLC/PKC/Src pathway in the up-regulation of the ongoing NMDA receptor activity.
Z B Johnson - One of the best experts on this subject based on the ideXlab platform.
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effects of sodium chloride Phosphate type and concentration and pump rate on beef biceps femoris quality and sensory characteristics
Meat Science, 2005Co-Authors: R.t. Baublits, F W Pohlman, A H Brown, Z B JohnsonAbstract:Abstract Beef biceps femoris muscles ( n = 45) were used to evaluate the effect of enhancement with solutions comprising 2.0% sodium chloride and either sodium hexametaPhosphate (SHMP), sodium tripolyPhosphate (STPP), or tetrasodium pyroPhosphate (TSPP) at either 0.2% or 0.4% of product weight. All solutions were injected into muscle samples at either 112% (12% pump) or 118% (18% pump) of raw product weight. Muscles treated with all three Phosphate types had decreased ( P P P > 0.05) from CNT. Disregarding Phosphate type, steaks with 0.4% Phosphate inclusion bound more ( P P P > 0.05) from CNT. Steaks injected at 18% pump had greater ( P P > 0.05) in free water, water binding, or cooking losses from steaks injected at 12% pump. Although there were no differences ( P > 0.05) in Warner–Bratzler shear force in this study, steaks with SHMP, STPP, and TSPP all were rated more tender, and juicier ( P P biceps femoris muscles with STPP or TSPP can improve water retention, yield, and palatability characteristics. Additionally, enhancement with a Phosphate/Salt solution at an 18% pump rate, compared to a 12% pump rate, can allow for improved sensory tenderness perceptions without decreasing product yields.
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effects of sodium chloride Phosphate type and concentration and pump rate on beef biceps femoris quality and sensory characteristics
Meat Science, 2005Co-Authors: R.t. Baublits, F W Pohlman, A H Brown, Z B JohnsonAbstract:Beef biceps femoris muscles (n=45) were used to evaluate the effect of enhancement with solutions comprising 2.0% sodium chloride and either sodium hexametaPhosphate (SHMP), sodium tripolyPhosphate (STPP), or tetrasodium pyroPhosphate (TSPP) at either 0.2% or 0.4% of product weight. All solutions were injected into muscle samples at either 112% (12% pump) or 118% (18% pump) of raw product weight. Muscles treated with all three Phosphate types had decreased (P 0.05) from CNT. Disregarding Phosphate type, steaks with 0.4% Phosphate inclusion bound more (P 0.05) from CNT. Steaks injected at 18% pump had greater (P 0.05) in free water, water binding, or cooking losses from steaks injected at 12% pump. Although there were no differences (P>0.05) in Warner-Bratzler shear force in this study, steaks with SHMP, STPP, and TSPP all were rated more tender, and juicier (P<0.05) by sensory panelists than CNT steaks or steaks enhanced only with sodium chloride. Regardless of Phosphate type, steaks enhanced with 0.4% Phosphate and those steaks at 18% pump received improved (P<0.05) sensory tenderness ratings compared to 0.2% Phosphate and 12% pump, respectively. These results suggest that enhancing biceps femoris muscles with STPP or TSPP can improve water retention, yield, and palatability characteristics. Additionally, enhancement with a Phosphate/Salt solution at an 18% pump rate, compared to a 12% pump rate, can allow for improved sensory tenderness perceptions without decreasing product yields.
Shawn E Larson - One of the best experts on this subject based on the ideXlab platform.
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catalytic asymmetric aza darzens reaction with a vaulted biphenanthrol magnesium Phosphate Salt
ChemInform, 2011Co-Authors: Shawn E Larson, Gerald B Rowland, Denise Junge, Rongcai Huang, Lee H Woodcock, Jon C AntillaAbstract:The reaction is applied to a variety of aromatic imines and tolerates functional groups such as halides or methoxy.
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catalytic asymmetric aza darzens reaction with a vaulted biphenanthrol magnesium Phosphate Salt
Organic Letters, 2011Co-Authors: Shawn E Larson, Gerald B Rowland, Denise Junge, Rongcai Huang, Lee H Woodcock, Jon C AntillaAbstract:Conditions for a catalytic asymmetric aza-Darzens aziridine synthesis mediated by a vaulted biphenanthrol (VAPOL) magnesium Phosphate Salt is described. Using simple substrates, this methodology explores the scope and reactivity of a new magnesium catalyst for an aziridination reaction capable of building chirality and complexity simultaneously.