The two-alkyne annulations of a variety of chromium and tungsten carbene complexes are examined i... more The two-alkyne annulations of a variety of chromium and tungsten carbene complexes are examined in which both of the alkynes are tethered to the carbene complex. The reactions of complexes in which the two alkynes and the first alkyne and the carbene carbon are connected by methylene groups were investigated for their potential in the construction of tricyclic phenols. This methodology was screened for a number of different ring sizes, and it was found that the efficiency of phenol formation depended on the nature of the metal, the solvent, and the sizes of the rings produced. In the reactions of chromium complexes, for certain ring sizes an unprecedented lactone product was also observed which resulted from the incorporation of the two alkynes as well as two carbon monoxide ligands from the metal. A new strategy for entry to the tetracyclic ring system of steroids is developed that involves a tandem coupling of a Diels-Alder reaction of carbene complexes with the double-intramolecular two-alkyne annulation. In a model system where the A and C rings are aromatic, the feasibility of this strategy was demonstrated in a reaction where all four rings of the steroid ring system can be generated in a one-pot reaction. In a second generation of this strategy, it was demonstrated that the tandem coupling of these reactions can also lead to the generation of nonaromatic steroidal ring systems.
... Arnold L. Rheingold Department of Chemistry University of Delaware, Newark, Delaware 1971 6 R... more ... Arnold L. Rheingold Department of Chemistry University of Delaware, Newark, Delaware 1971 6 Received January 25, 1993 ... Ordering information is given on any current masthead. (25) (a) Corey, E. J.; Loh, TP; Roper, TD; Azimioara, M. D.; Lee, M. C. J. Am. Chem. SOC. ...
ABSTRACT Catalysts prepared from the vaulted biaryls 2 and 3 and bromoborane dimethylsulfide were... more ABSTRACT Catalysts prepared from the vaulted biaryls 2 and 3 and bromoborane dimethylsulfide were compared with that generated from the linear biaryl 1 for their ability to provide enantioselective induction in the Diels-Alder reaction of cyclopentadiene and methacrolein. The fact that the S-enantiomers of 2 and 3 give opposite induction than the S-enantiomer of 1 and the fact that effective catalysts can not be generated from 1 and phenylboron dichloride suggests that the catalysts from 2 and 3 do not have the same structure as the C3-symmetrical catalyst 4 produced from 1.
Pentacyclic triterpenoid natural product correolide (1) was converted to ketone 2 via ozonolysis.... more Pentacyclic triterpenoid natural product correolide (1) was converted to ketone 2 via ozonolysis. An unusual fragmentation reaction of ketone 2 with LiCl was discovered. This reaction is general among several similar substrates examined and appears to be specific for the correolidetype E-ring structure (ketone). A mechanism involving a retroaldol reaction, a nucleophilic opening of the epoxide, and a subsequent acetoxy elimination reaction was proposed.
... (c) Wulff, WD In Aduances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press Inc.:... more ... (c) Wulff, WD In Aduances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press Inc.: Greenwich, CT, 1989; Vol. 1. (d) Wulff, WD In Comprehensiue Organic Synthesis; Trost, BM, Fleming, I., Eds.; Per-gamon Press: New York, 1991; Vol. ...
The two-alkyne annulations of a variety of chromium and tungsten carbene complexes are examined i... more The two-alkyne annulations of a variety of chromium and tungsten carbene complexes are examined in which both of the alkynes are tethered to the carbene complex. The reactions of complexes in which the two alkynes and the first alkyne and the carbene carbon are connected by methylene groups were investigated for their potential in the construction of tricyclic phenols. This methodology was screened for a number of different ring sizes, and it was found that the efficiency of phenol formation depended on the nature of the metal, the solvent, and the sizes of the rings produced. In the reactions of chromium complexes, for certain ring sizes an unprecedented lactone product was also observed which resulted from the incorporation of the two alkynes as well as two carbon monoxide ligands from the metal. A new strategy for entry to the tetracyclic ring system of steroids is developed that involves a tandem coupling of a Diels-Alder reaction of carbene complexes with the double-intramolecular two-alkyne annulation. In a model system where the A and C rings are aromatic, the feasibility of this strategy was demonstrated in a reaction where all four rings of the steroid ring system can be generated in a one-pot reaction. In a second generation of this strategy, it was demonstrated that the tandem coupling of these reactions can also lead to the generation of nonaromatic steroidal ring systems.
The reactions of l-(4-hexynyl)methoxymethylenepentacarbonyl complexes 11 of the group 6 metals wi... more The reactions of l-(4-hexynyl)methoxymethylenepentacarbonyl complexes 11 of the group 6 metals with alkynes lead to phenol and cyclopentenedione products, both of which are the result of cyclization with one molecule of the external alkyne and the internal alkyne in the carbene complex. All four of the possible phenol products of this reaction were independently synthesized, and the product distribution among the four isomers and the cyclopentenedione was investigated as a function of solvent, concentration, and the nature of the metal. The results of these experiments suggest that the phenol 13 arises from a vinyl carbene complexed intermediate and that the phenol 16 and cyclopentenedione 12 arise from a vinyl ketene complexed intermediate. This was confirmed by a series of methanol trapping experiments and by the isolation, characterization, and study of the chemistry of the proposed vinyl ketene complex.
... Arnold L. Rheingold Department of Chemistry University of Delaware, Newark, Delaware 1971 6 R... more ... Arnold L. Rheingold Department of Chemistry University of Delaware, Newark, Delaware 1971 6 Received January 25, 1993 ... Ordering information is given on any current masthead. (25) (a) Corey, E. J.; Loh, TP; Roper, TD; Azimioara, M. D.; Lee, M. C. J. Am. Chem. SOC. ...
Two methods for the synthesis of vaulted biaryls were developed involving the reactions of carben... more Two methods for the synthesis of vaulted biaryls were developed involving the reactions of carbene complexes with alkynes and the [2+ 2] cycloaddition of ketenes. The final step in the synthesis of 3, 3'-diphenyl-[2, 2'-binaphthalene]-1, 1'-diol (39) and 2, 2'-diphenyl-[3, 3'- ...
The first examples of the reactions of Fischer carbene complexes with 1, 3-butadiynes are reporte... more The first examples of the reactions of Fischer carbene complexes with 1, 3-butadiynes are reported. These reactions are of interest since they provide new methods for the synthesis of acetylenic substituted arenes and also for the synthesis of biaryls. The reactions of the ...
The formation of cyclic sulfates (4) from syn,syn-3-[N-(benzyloxycarbonyl)amino] 1,2-diols provid... more The formation of cyclic sulfates (4) from syn,syn-3-[N-(benzyloxycarbonyl)amino] 1,2-diols provides a common intermediate to access other diastereomers via two inversion procedures. Thermolysis of the cyclic sulfates in acetonitrile normally leads to inversion of the distal hydroxyl group to form a 1,3-oxazin-2-one (6). Catalytic hydrogenation of the cyclic sulfates under basic conditions (NEt(3)) results in inversion at the proximal hydroxyl group to form a 1,3-oxazolidin-2-one (5).
Hydroisoindoline 2 has been previously identified as a potent, brain-penetrant NK1 receptor antag... more Hydroisoindoline 2 has been previously identified as a potent, brain-penetrant NK1 receptor antagonist with a long duration of action and improved profile of CYP3A4 inhibition and induction compared to aprepitant. However, compound 2 is predicted, based on data in preclinical species, to have a human half-life longer than 40 h and likely to have drug-drug-interactions (DDI), as 2 is a victim of CYP3A4 inhibition caused by its exclusive clearance pathway via CYP3A4 oxidation in humans. We now report 2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one (3) as a next generation NK1 antagonist that possesses an additional clearance pathway through glucuronidation in addition to that via CYP3A4 oxidation. Compound 3 has a much lower propensity for drug-drug interactions and a reduced estimated human half-life consistent with once daily dosing. In preclinical species, compound 3 has demonstrated potency, brain penetration, and a safety profile similar to 2, as well as excellent pharmacokinetics.
The voltage-gated potassium channel, Kv1.3, is specifically expressed on human lymphocytes, where... more The voltage-gated potassium channel, Kv1.3, is specifically expressed on human lymphocytes, where it controls membrane potential and calcium influx. Blockade of Kv1.3 channels by margatoxin was previously shown to prevent T cell activation and attenuate immune responses in vivo. In the present study, a triterpene natural product, correolide, was found to block Kv1.3 channels in human and miniswine T cells by electrophysiological characterization. T cell activation events, such as anti-CD3-induced calcium elevation, IL-2 production, and proliferation were inhibited by correolide in a dose-dependent manner. More potent analogs were evaluated for pharmacokinetic profiles and subsequently tested in a delayed-type hypersensitivity (DTH) response to tuberculin in the miniswine. Two compounds were dosed orally, iv, or im, and both compounds suppressed DTH responses, demonstrating that small molecule blockers of Kv1.3 channels can act as immunosuppressive agents in vivo. These studies establish correolide and its derivatives as novel immunosuppressants.
Quinolinones and naphthyridinones with C7 N-t-butyl piperidine substituents were found to be pote... more Quinolinones and naphthyridinones with C7 N-t-butyl piperidine substituents were found to be potent p38 MAP kinase inhibitors. These compounds significantly suppress TNF-a release in both cellular and LPS-stimulated whole blood assays. They also displayed excellent PK profiles across three animal species. Quinolinone 4f at 10 mpk showed comparable oral efficacy to that of dexamethasone at 1 mpk in a murine collagen-induced arthritis model.
The two-alkyne annulations of a variety of chromium and tungsten carbene complexes are examined i... more The two-alkyne annulations of a variety of chromium and tungsten carbene complexes are examined in which both of the alkynes are tethered to the carbene complex. The reactions of complexes in which the two alkynes and the first alkyne and the carbene carbon are connected by methylene groups were investigated for their potential in the construction of tricyclic phenols. This methodology was screened for a number of different ring sizes, and it was found that the efficiency of phenol formation depended on the nature of the metal, the solvent, and the sizes of the rings produced. In the reactions of chromium complexes, for certain ring sizes an unprecedented lactone product was also observed which resulted from the incorporation of the two alkynes as well as two carbon monoxide ligands from the metal. A new strategy for entry to the tetracyclic ring system of steroids is developed that involves a tandem coupling of a Diels-Alder reaction of carbene complexes with the double-intramolecular two-alkyne annulation. In a model system where the A and C rings are aromatic, the feasibility of this strategy was demonstrated in a reaction where all four rings of the steroid ring system can be generated in a one-pot reaction. In a second generation of this strategy, it was demonstrated that the tandem coupling of these reactions can also lead to the generation of nonaromatic steroidal ring systems.
... Arnold L. Rheingold Department of Chemistry University of Delaware, Newark, Delaware 1971 6 R... more ... Arnold L. Rheingold Department of Chemistry University of Delaware, Newark, Delaware 1971 6 Received January 25, 1993 ... Ordering information is given on any current masthead. (25) (a) Corey, E. J.; Loh, TP; Roper, TD; Azimioara, M. D.; Lee, M. C. J. Am. Chem. SOC. ...
ABSTRACT Catalysts prepared from the vaulted biaryls 2 and 3 and bromoborane dimethylsulfide were... more ABSTRACT Catalysts prepared from the vaulted biaryls 2 and 3 and bromoborane dimethylsulfide were compared with that generated from the linear biaryl 1 for their ability to provide enantioselective induction in the Diels-Alder reaction of cyclopentadiene and methacrolein. The fact that the S-enantiomers of 2 and 3 give opposite induction than the S-enantiomer of 1 and the fact that effective catalysts can not be generated from 1 and phenylboron dichloride suggests that the catalysts from 2 and 3 do not have the same structure as the C3-symmetrical catalyst 4 produced from 1.
Pentacyclic triterpenoid natural product correolide (1) was converted to ketone 2 via ozonolysis.... more Pentacyclic triterpenoid natural product correolide (1) was converted to ketone 2 via ozonolysis. An unusual fragmentation reaction of ketone 2 with LiCl was discovered. This reaction is general among several similar substrates examined and appears to be specific for the correolidetype E-ring structure (ketone). A mechanism involving a retroaldol reaction, a nucleophilic opening of the epoxide, and a subsequent acetoxy elimination reaction was proposed.
... (c) Wulff, WD In Aduances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press Inc.:... more ... (c) Wulff, WD In Aduances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press Inc.: Greenwich, CT, 1989; Vol. 1. (d) Wulff, WD In Comprehensiue Organic Synthesis; Trost, BM, Fleming, I., Eds.; Per-gamon Press: New York, 1991; Vol. ...
The two-alkyne annulations of a variety of chromium and tungsten carbene complexes are examined i... more The two-alkyne annulations of a variety of chromium and tungsten carbene complexes are examined in which both of the alkynes are tethered to the carbene complex. The reactions of complexes in which the two alkynes and the first alkyne and the carbene carbon are connected by methylene groups were investigated for their potential in the construction of tricyclic phenols. This methodology was screened for a number of different ring sizes, and it was found that the efficiency of phenol formation depended on the nature of the metal, the solvent, and the sizes of the rings produced. In the reactions of chromium complexes, for certain ring sizes an unprecedented lactone product was also observed which resulted from the incorporation of the two alkynes as well as two carbon monoxide ligands from the metal. A new strategy for entry to the tetracyclic ring system of steroids is developed that involves a tandem coupling of a Diels-Alder reaction of carbene complexes with the double-intramolecular two-alkyne annulation. In a model system where the A and C rings are aromatic, the feasibility of this strategy was demonstrated in a reaction where all four rings of the steroid ring system can be generated in a one-pot reaction. In a second generation of this strategy, it was demonstrated that the tandem coupling of these reactions can also lead to the generation of nonaromatic steroidal ring systems.
The reactions of l-(4-hexynyl)methoxymethylenepentacarbonyl complexes 11 of the group 6 metals wi... more The reactions of l-(4-hexynyl)methoxymethylenepentacarbonyl complexes 11 of the group 6 metals with alkynes lead to phenol and cyclopentenedione products, both of which are the result of cyclization with one molecule of the external alkyne and the internal alkyne in the carbene complex. All four of the possible phenol products of this reaction were independently synthesized, and the product distribution among the four isomers and the cyclopentenedione was investigated as a function of solvent, concentration, and the nature of the metal. The results of these experiments suggest that the phenol 13 arises from a vinyl carbene complexed intermediate and that the phenol 16 and cyclopentenedione 12 arise from a vinyl ketene complexed intermediate. This was confirmed by a series of methanol trapping experiments and by the isolation, characterization, and study of the chemistry of the proposed vinyl ketene complex.
... Arnold L. Rheingold Department of Chemistry University of Delaware, Newark, Delaware 1971 6 R... more ... Arnold L. Rheingold Department of Chemistry University of Delaware, Newark, Delaware 1971 6 Received January 25, 1993 ... Ordering information is given on any current masthead. (25) (a) Corey, E. J.; Loh, TP; Roper, TD; Azimioara, M. D.; Lee, M. C. J. Am. Chem. SOC. ...
Two methods for the synthesis of vaulted biaryls were developed involving the reactions of carben... more Two methods for the synthesis of vaulted biaryls were developed involving the reactions of carbene complexes with alkynes and the [2+ 2] cycloaddition of ketenes. The final step in the synthesis of 3, 3'-diphenyl-[2, 2'-binaphthalene]-1, 1'-diol (39) and 2, 2'-diphenyl-[3, 3'- ...
The first examples of the reactions of Fischer carbene complexes with 1, 3-butadiynes are reporte... more The first examples of the reactions of Fischer carbene complexes with 1, 3-butadiynes are reported. These reactions are of interest since they provide new methods for the synthesis of acetylenic substituted arenes and also for the synthesis of biaryls. The reactions of the ...
The formation of cyclic sulfates (4) from syn,syn-3-[N-(benzyloxycarbonyl)amino] 1,2-diols provid... more The formation of cyclic sulfates (4) from syn,syn-3-[N-(benzyloxycarbonyl)amino] 1,2-diols provides a common intermediate to access other diastereomers via two inversion procedures. Thermolysis of the cyclic sulfates in acetonitrile normally leads to inversion of the distal hydroxyl group to form a 1,3-oxazin-2-one (6). Catalytic hydrogenation of the cyclic sulfates under basic conditions (NEt(3)) results in inversion at the proximal hydroxyl group to form a 1,3-oxazolidin-2-one (5).
Hydroisoindoline 2 has been previously identified as a potent, brain-penetrant NK1 receptor antag... more Hydroisoindoline 2 has been previously identified as a potent, brain-penetrant NK1 receptor antagonist with a long duration of action and improved profile of CYP3A4 inhibition and induction compared to aprepitant. However, compound 2 is predicted, based on data in preclinical species, to have a human half-life longer than 40 h and likely to have drug-drug-interactions (DDI), as 2 is a victim of CYP3A4 inhibition caused by its exclusive clearance pathway via CYP3A4 oxidation in humans. We now report 2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one (3) as a next generation NK1 antagonist that possesses an additional clearance pathway through glucuronidation in addition to that via CYP3A4 oxidation. Compound 3 has a much lower propensity for drug-drug interactions and a reduced estimated human half-life consistent with once daily dosing. In preclinical species, compound 3 has demonstrated potency, brain penetration, and a safety profile similar to 2, as well as excellent pharmacokinetics.
The voltage-gated potassium channel, Kv1.3, is specifically expressed on human lymphocytes, where... more The voltage-gated potassium channel, Kv1.3, is specifically expressed on human lymphocytes, where it controls membrane potential and calcium influx. Blockade of Kv1.3 channels by margatoxin was previously shown to prevent T cell activation and attenuate immune responses in vivo. In the present study, a triterpene natural product, correolide, was found to block Kv1.3 channels in human and miniswine T cells by electrophysiological characterization. T cell activation events, such as anti-CD3-induced calcium elevation, IL-2 production, and proliferation were inhibited by correolide in a dose-dependent manner. More potent analogs were evaluated for pharmacokinetic profiles and subsequently tested in a delayed-type hypersensitivity (DTH) response to tuberculin in the miniswine. Two compounds were dosed orally, iv, or im, and both compounds suppressed DTH responses, demonstrating that small molecule blockers of Kv1.3 channels can act as immunosuppressive agents in vivo. These studies establish correolide and its derivatives as novel immunosuppressants.
Quinolinones and naphthyridinones with C7 N-t-butyl piperidine substituents were found to be pote... more Quinolinones and naphthyridinones with C7 N-t-butyl piperidine substituents were found to be potent p38 MAP kinase inhibitors. These compounds significantly suppress TNF-a release in both cellular and LPS-stimulated whole blood assays. They also displayed excellent PK profiles across three animal species. Quinolinone 4f at 10 mpk showed comparable oral efficacy to that of dexamethasone at 1 mpk in a murine collagen-induced arthritis model.
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