A two-step synthesis of 3-(2-chloropyrimidin-4-yl)imidazo[1,2-a]pyridines is presented. The late ... more A two-step synthesis of 3-(2-chloropyrimidin-4-yl)imidazo[1,2-a]pyridines is presented. The late stage elaboration of the imidazopyridine through a cyclocondensation allows a rapid access to a variety of substitution patterns. The intermediate enol ethers were obtained from inexpensive reagents in a ligand-free Heck coupling. This methodology has been extended to the formation of pyrazolo[1,5-a]pyridines via a formal 1,3-dipolar cycloaddition.
ABSTRACT 4-(1,3-Benzothiazol-2-yl)thiophene-2-sulfonamide (4a) was found to be a moderately poten... more ABSTRACT 4-(1,3-Benzothiazol-2-yl)thiophene-2-sulfonamide (4a) was found to be a moderately potent inhibitor of cyclin-dependent kinase 5 (cdk5) from a HTS screen. The synthesis and SAR around this hit is described. The X-ray coordinates of ligand 4a with cdk5 are also reported, showing an unusual binding mode to the hinge region via a water molecule.
O-2,4-Dimethoxybenzyl hydroxylamine and O-2,4-dimethoxybenzyl-N-2,4,6-trimethoxybenzyl hydroxylam... more O-2,4-Dimethoxybenzyl hydroxylamine and O-2,4-dimethoxybenzyl-N-2,4,6-trimethoxybenzyl hydroxylamine have been prepared and used for the preparation of hydroxamic acid based inhibitors of biological interest.
Abstract α-O-t-Butyldiphenylsilyl-(D)-erythronolactone [(+)-25] (a new chiral vector) was esterif... more Abstract α-O-t-Butyldiphenylsilyl-(D)-erythronolactone [(+)-25] (a new chiral vector) was esterified with 4-methoxybenzylidene pyruvic acid (19). Eu(fod)3 catalyzed [4+2] heterocycloaddition of the latter 1-oxabutadiene with 4-methoxystyrene (as the dienophile), afforded high yields of the endo adduct 23c with 95 5 diastereofacial ratio. Five further steps led to enantiomerically pure natural (−)-O-dimethylsugiresinol (−)-2 in 12% overall yield from the acid 19.
Abstract The benzylidenepyruvic esters 6, 10a–d and 11 smoothly reacted with the alkoxystyrenes 1... more Abstract The benzylidenepyruvic esters 6, 10a–d and 11 smoothly reacted with the alkoxystyrenes 12 and 13 in refluxing hexane or toluene and in the presence of catalytic amounts of Eu(fod)3, thus selectively leading to the endo adducts 14–21 in high yields. This represents the first examples of an efficient heterocycloaddition of styrene derivatives without using the high pressure technique. The above adducts are potential intermediates for sugiresinol 7 and related tetrahydropyran neolignans.
4-(1,3-Benzothiazol-2-yl)thiophene-2-sulfonamide (4a) was found to be a moderately potent inhibit... more 4-(1,3-Benzothiazol-2-yl)thiophene-2-sulfonamide (4a) was found to be a moderately potent inhibitor of cyclin-dependent kinase 5 (cdk5) from a HTS screen. The synthesis and SAR around this hit is described. The X-ray coordinates of ligand 4a with cdk5 are also reported, showing an unusual binding mode to the hinge region via a water molecule.
Please cite this article as: Barlaam, B., Cosulich, S., Degorce, S., Ellston, R., Fitzek, M., Gre... more Please cite this article as: Barlaam, B., Cosulich, S., Degorce, S., Ellston, R., Fitzek, M., Green, S., Hancox, U., Lambert-van der Brempt, C., Lohmann, J-J., Maudet, M., Morgentin, R., Plé, P., Ward, L., Warin, N., Discovery of a series of 8-(1-phenylpyrrolidin-2-yl)-6-carboxamide-2-morpholino-4H-chromen-4-one as PI3Kβ/δ inhibitors for the treatment of PTEN-deficient tumours, Bioorganic & Medicinal Chemistry Letters (2017), doi: http:// dx.doi.org/10.1016/j.bmcl.2017.03.027
The synthesis of methyl 2-(5-hydroxy-3-methoxypyridin-2-yl)acetate and alkyl 2-(5-hydroxypyrimidi... more The synthesis of methyl 2-(5-hydroxy-3-methoxypyridin-2-yl)acetate and alkyl 2-(5-hydroxypyrimidin-2-yl)acetate is described. Methodology for an efficient access to 5-hydroxy-pyridin- and pyrimidin-2-yl acetate cores has been developed. Based on the difference in halogen reactivity, 5-bromo-2-chloropyridine and its pyrimidine analogue were functionalized judiciously by SNAr and palladium-catalyzed reactions. The outlined strategy provides a high-yielding route suitable for large-scale synthesis of these compounds as well
A two-step synthesis of 3-(2-chloropyrimidin-4-yl)imidazo[1,2-a]pyridines is presented. The late ... more A two-step synthesis of 3-(2-chloropyrimidin-4-yl)imidazo[1,2-a]pyridines is presented. The late stage elaboration of the imidazopyridine through a cyclocondensation allows a rapid access to a variety of substitution patterns. The intermediate enol ethers were obtained from inexpensive reagents in a ligand-free Heck coupling. This methodology has been extended to the formation of pyrazolo[1,5-a]pyridines via a formal 1,3-dipolar cycloaddition.
ABSTRACT 4-(1,3-Benzothiazol-2-yl)thiophene-2-sulfonamide (4a) was found to be a moderately poten... more ABSTRACT 4-(1,3-Benzothiazol-2-yl)thiophene-2-sulfonamide (4a) was found to be a moderately potent inhibitor of cyclin-dependent kinase 5 (cdk5) from a HTS screen. The synthesis and SAR around this hit is described. The X-ray coordinates of ligand 4a with cdk5 are also reported, showing an unusual binding mode to the hinge region via a water molecule.
O-2,4-Dimethoxybenzyl hydroxylamine and O-2,4-dimethoxybenzyl-N-2,4,6-trimethoxybenzyl hydroxylam... more O-2,4-Dimethoxybenzyl hydroxylamine and O-2,4-dimethoxybenzyl-N-2,4,6-trimethoxybenzyl hydroxylamine have been prepared and used for the preparation of hydroxamic acid based inhibitors of biological interest.
Abstract α-O-t-Butyldiphenylsilyl-(D)-erythronolactone [(+)-25] (a new chiral vector) was esterif... more Abstract α-O-t-Butyldiphenylsilyl-(D)-erythronolactone [(+)-25] (a new chiral vector) was esterified with 4-methoxybenzylidene pyruvic acid (19). Eu(fod)3 catalyzed [4+2] heterocycloaddition of the latter 1-oxabutadiene with 4-methoxystyrene (as the dienophile), afforded high yields of the endo adduct 23c with 95 5 diastereofacial ratio. Five further steps led to enantiomerically pure natural (−)-O-dimethylsugiresinol (−)-2 in 12% overall yield from the acid 19.
Abstract The benzylidenepyruvic esters 6, 10a–d and 11 smoothly reacted with the alkoxystyrenes 1... more Abstract The benzylidenepyruvic esters 6, 10a–d and 11 smoothly reacted with the alkoxystyrenes 12 and 13 in refluxing hexane or toluene and in the presence of catalytic amounts of Eu(fod)3, thus selectively leading to the endo adducts 14–21 in high yields. This represents the first examples of an efficient heterocycloaddition of styrene derivatives without using the high pressure technique. The above adducts are potential intermediates for sugiresinol 7 and related tetrahydropyran neolignans.
4-(1,3-Benzothiazol-2-yl)thiophene-2-sulfonamide (4a) was found to be a moderately potent inhibit... more 4-(1,3-Benzothiazol-2-yl)thiophene-2-sulfonamide (4a) was found to be a moderately potent inhibitor of cyclin-dependent kinase 5 (cdk5) from a HTS screen. The synthesis and SAR around this hit is described. The X-ray coordinates of ligand 4a with cdk5 are also reported, showing an unusual binding mode to the hinge region via a water molecule.
Please cite this article as: Barlaam, B., Cosulich, S., Degorce, S., Ellston, R., Fitzek, M., Gre... more Please cite this article as: Barlaam, B., Cosulich, S., Degorce, S., Ellston, R., Fitzek, M., Green, S., Hancox, U., Lambert-van der Brempt, C., Lohmann, J-J., Maudet, M., Morgentin, R., Plé, P., Ward, L., Warin, N., Discovery of a series of 8-(1-phenylpyrrolidin-2-yl)-6-carboxamide-2-morpholino-4H-chromen-4-one as PI3Kβ/δ inhibitors for the treatment of PTEN-deficient tumours, Bioorganic & Medicinal Chemistry Letters (2017), doi: http:// dx.doi.org/10.1016/j.bmcl.2017.03.027
The synthesis of methyl 2-(5-hydroxy-3-methoxypyridin-2-yl)acetate and alkyl 2-(5-hydroxypyrimidi... more The synthesis of methyl 2-(5-hydroxy-3-methoxypyridin-2-yl)acetate and alkyl 2-(5-hydroxypyrimidin-2-yl)acetate is described. Methodology for an efficient access to 5-hydroxy-pyridin- and pyrimidin-2-yl acetate cores has been developed. Based on the difference in halogen reactivity, 5-bromo-2-chloropyridine and its pyrimidine analogue were functionalized judiciously by SNAr and palladium-catalyzed reactions. The outlined strategy provides a high-yielding route suitable for large-scale synthesis of these compounds as well
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