Schedler David - Academia.edu (original) (raw)

Papers by Schedler David

Research paper thumbnail of A novel inhibitor of human α-L-fucosidase: Enantioselective synthesis of L-fucoamidrazone

Tetrahedron Letters, 1994

Research paper thumbnail of Synthesis and evaluation of 3-modified 1D-myo-inositols as inhibitors and substrates of phosphatidylinositol synthase and inhibitors of myo-inositol uptake by cells

Journal of Medicinal Chemistry, 1993

A number of 3-substituted ID-myo-inositols were synthesized and evaluated as substrates for phosp... more A number of 3-substituted ID-myo-inositols were synthesized and evaluated as substrates for phosphatidylinositol synthase and uptake by intact cells. lD-3-Amino- ,-3-chloro-, and-3-(acetylthio)-3-deoxy-myo-inositols were all synthesized by nucleophilic displacement of the 6-0-(trifluoromethy1)sdfonyl group of 1~-1,2:3,4-di-O-cyclohexylidene-5-O-methyl-6-O-[(trifluoromethyl)sulfonyl]-chiro-inositol (which was prepared from L-quebrachitol), respectively, by reaction with LiN3, followed by reduction of the azido function, and with LiCl and KSAc to give the 0-protected compounds. 0-Demethylation using BBr3 and concomitant acetal hydrolysis furnished the freehydroxy 3-amino-and 3-chloro-3-deoxy-1D-myo-inositols. The 3-mercapto analogue was obtained by removal of the acetal groups of the acetylthio analogue, followed by acetylation and purification of the peracetate, and subsequent 0-demethylation and deacetylation. The 3-deoxy derivative was synthesized from the 6-O-(imidazol-l-ylthiocarbonyl) compound via Barton-McCombie deoxygenation. The 3-azido derivative was directly synthesized from 1L-1-0-tosyl-chiro-inositol via displacement with azide. The 3-keto analogue was prepared by Pt-catalyzed air oxidation of 1L-chiro-inositol. The compounds were all evaluated as substrates for phosphatidylinositol (PtdIns) synthase from mouse brain. The 3-NH2, 3-F, 3-deoxy, and 3-keto analogues all showed activity as substrates, as measured by liberation of cytidine monophosphate. These compounds also showed inhibition of the reaction of myo-[3H]inositol with PtdIns synthase. These results taken together indicate that these compounds are likely to be incorporated into phospholipids. As a further indication that these compounds might be useful as probes for the PtdIns pathway, it was demonstrated that the 3-"z, 3-F, and 3-deoxy compounds are taken up by intact fibroblast cells as evidenced by their competing with myo-r3H] inositol uptake.

Research paper thumbnail of Drug Discovery: A History (Sneader, Walter)

Journal of Chemical Education, 2006

Research paper thumbnail of Fluorinated cyclitols. An improved synthesis of 5-deoxy-5-fluoro-myo-inositol, its deuterium labeling, and synthesis of a 5,5-gem-difluoro analogue

Carbohydrate Research, 1990

Abstract An improved synthesis of 5-deoxy-5-fluoro- myo -inositol is provided via the reaction of... more Abstract An improved synthesis of 5-deoxy-5-fluoro- myo -inositol is provided via the reaction of diethylaminosulfur trifluoride (DAST) with the versatile intermediate, 1,4,6-tri- O -benzyl-2,3- O -cyclohexylidene- neo -inositol (I), followed by appropriate deprotection reactions. Reaction of DAST with the 5- keto analogue of I gave the gem -difluoro compound, which upon deprotection afforded 5-deoxy-5,5-difluoro- myo -inositol. A 1 H-n.m.r. study of the deuteration of 5-deoxy-5-fluoro- myo -inositol with Raney nickel-deuterium oxide revealed that the equatorial H-2 proton was most rapidly exchanged, followed by the sterically identical H-1 and H-3 protons, which exchanged at a significantly slower rate.

Research paper thumbnail of Reduction of Secondary Carboxamides to Imines

The Journal of Organic Chemistry, 1996

This article reports in detail on the discovery that zirconium(IV) salts of secondary amides and ... more This article reports in detail on the discovery that zirconium(IV) salts of secondary amides and lactams are transformed by Cp(2)ZrHCl to N-substituted imines in one step. The method represents the first controlled reduction of amides and lactams to the corresponding imines, a transformation that is otherwise very difficult to achieve because imines are reduced more rapidly than carboxamides by most metal hydride reagents. No products of reductive cleavage of the carboxamides are observed. Efforts to replace 2 mol equiv of Cp(2)ZrHCl with simpler, less costly alternatives led to the finding that a diisobutylaluminum enolate can be substituted for the initial zirconium enolate. Such aluminum amides are smoothly reduced to the corresponding imine using Cp(2)ZrHCl in good yield. Moreover, aluminum amides are also reduced to imines using either low-valent titanium species or triethylsilane. In these alternative procedures, use of Cp(2)ZrHCl is eliminated altogether in the title transformation.

Research paper thumbnail of Job$ in the Drug Industry: A Career Guide for Chemists (Friary, Richard)

Journal of Chemical Education, 2000

Research paper thumbnail of Drugs and the Human Body: With Implications for Society, 6th Edition (Liska, Ken)

Journal of Chemical Education, 2002

Research paper thumbnail of Fluorinated cyclitols as useful biological probes of phosphatidylinositol metabolism

Carbohydrate Research, 2004

A number of deoxyfluoro cyclitols have been synthesized and evaluated as probes of the phosphatid... more A number of deoxyfluoro cyclitols have been synthesized and evaluated as probes of the phosphatidylinositol pathway (PtdIns pathway), most notably 5-deoxy-5-fluoro-myo-inositol, which is incorporated into the pathway at about 25% the level of myo-inositol itself. Unfortunately, none of the cyclitols have proved effective in limiting cell proliferation, as the cells are able to 'synthesize around' the fraudulent cyclitols using natural myo-inositol as substrate. Inhibitors for 3-phosphatidylinositol kinase, which has importance in a number of pathological conditions, including cancer, have been intensively investigated. 3-Deoxy-3-fluoro-myo-inositol is incorporated into the PtdIns pathway; however, only related phosphatidyl derivatives, for example, a methyl ether derivative of the 3-deoxy inositol, showed significant antiproliferative activity. Synthesis of the deoxyfluoro analogues most often has been accomplished by DAST fluoro-de-hydroxylation of the appropriate cyclitol, generally leading to products of inversion.

Research paper thumbnail of A novel inhibitor of human α-L-fucosidase: Enantioselective synthesis of L-fucoamidrazone

Tetrahedron Letters, 1994

Research paper thumbnail of Synthesis and evaluation of 3-modified 1D-myo-inositols as inhibitors and substrates of phosphatidylinositol synthase and inhibitors of myo-inositol uptake by cells

Journal of Medicinal Chemistry, 1993

A number of 3-substituted ID-myo-inositols were synthesized and evaluated as substrates for phosp... more A number of 3-substituted ID-myo-inositols were synthesized and evaluated as substrates for phosphatidylinositol synthase and uptake by intact cells. lD-3-Amino- ,-3-chloro-, and-3-(acetylthio)-3-deoxy-myo-inositols were all synthesized by nucleophilic displacement of the 6-0-(trifluoromethy1)sdfonyl group of 1~-1,2:3,4-di-O-cyclohexylidene-5-O-methyl-6-O-[(trifluoromethyl)sulfonyl]-chiro-inositol (which was prepared from L-quebrachitol), respectively, by reaction with LiN3, followed by reduction of the azido function, and with LiCl and KSAc to give the 0-protected compounds. 0-Demethylation using BBr3 and concomitant acetal hydrolysis furnished the freehydroxy 3-amino-and 3-chloro-3-deoxy-1D-myo-inositols. The 3-mercapto analogue was obtained by removal of the acetal groups of the acetylthio analogue, followed by acetylation and purification of the peracetate, and subsequent 0-demethylation and deacetylation. The 3-deoxy derivative was synthesized from the 6-O-(imidazol-l-ylthiocarbonyl) compound via Barton-McCombie deoxygenation. The 3-azido derivative was directly synthesized from 1L-1-0-tosyl-chiro-inositol via displacement with azide. The 3-keto analogue was prepared by Pt-catalyzed air oxidation of 1L-chiro-inositol. The compounds were all evaluated as substrates for phosphatidylinositol (PtdIns) synthase from mouse brain. The 3-NH2, 3-F, 3-deoxy, and 3-keto analogues all showed activity as substrates, as measured by liberation of cytidine monophosphate. These compounds also showed inhibition of the reaction of myo-[3H]inositol with PtdIns synthase. These results taken together indicate that these compounds are likely to be incorporated into phospholipids. As a further indication that these compounds might be useful as probes for the PtdIns pathway, it was demonstrated that the 3-"z, 3-F, and 3-deoxy compounds are taken up by intact fibroblast cells as evidenced by their competing with myo-r3H] inositol uptake.

Research paper thumbnail of Drug Discovery: A History (Sneader, Walter)

Journal of Chemical Education, 2006

Research paper thumbnail of Fluorinated cyclitols. An improved synthesis of 5-deoxy-5-fluoro-myo-inositol, its deuterium labeling, and synthesis of a 5,5-gem-difluoro analogue

Carbohydrate Research, 1990

Abstract An improved synthesis of 5-deoxy-5-fluoro- myo -inositol is provided via the reaction of... more Abstract An improved synthesis of 5-deoxy-5-fluoro- myo -inositol is provided via the reaction of diethylaminosulfur trifluoride (DAST) with the versatile intermediate, 1,4,6-tri- O -benzyl-2,3- O -cyclohexylidene- neo -inositol (I), followed by appropriate deprotection reactions. Reaction of DAST with the 5- keto analogue of I gave the gem -difluoro compound, which upon deprotection afforded 5-deoxy-5,5-difluoro- myo -inositol. A 1 H-n.m.r. study of the deuteration of 5-deoxy-5-fluoro- myo -inositol with Raney nickel-deuterium oxide revealed that the equatorial H-2 proton was most rapidly exchanged, followed by the sterically identical H-1 and H-3 protons, which exchanged at a significantly slower rate.

Research paper thumbnail of Reduction of Secondary Carboxamides to Imines

The Journal of Organic Chemistry, 1996

This article reports in detail on the discovery that zirconium(IV) salts of secondary amides and ... more This article reports in detail on the discovery that zirconium(IV) salts of secondary amides and lactams are transformed by Cp(2)ZrHCl to N-substituted imines in one step. The method represents the first controlled reduction of amides and lactams to the corresponding imines, a transformation that is otherwise very difficult to achieve because imines are reduced more rapidly than carboxamides by most metal hydride reagents. No products of reductive cleavage of the carboxamides are observed. Efforts to replace 2 mol equiv of Cp(2)ZrHCl with simpler, less costly alternatives led to the finding that a diisobutylaluminum enolate can be substituted for the initial zirconium enolate. Such aluminum amides are smoothly reduced to the corresponding imine using Cp(2)ZrHCl in good yield. Moreover, aluminum amides are also reduced to imines using either low-valent titanium species or triethylsilane. In these alternative procedures, use of Cp(2)ZrHCl is eliminated altogether in the title transformation.

Research paper thumbnail of Job$ in the Drug Industry: A Career Guide for Chemists (Friary, Richard)

Journal of Chemical Education, 2000

Research paper thumbnail of Drugs and the Human Body: With Implications for Society, 6th Edition (Liska, Ken)

Journal of Chemical Education, 2002

Research paper thumbnail of Fluorinated cyclitols as useful biological probes of phosphatidylinositol metabolism

Carbohydrate Research, 2004

A number of deoxyfluoro cyclitols have been synthesized and evaluated as probes of the phosphatid... more A number of deoxyfluoro cyclitols have been synthesized and evaluated as probes of the phosphatidylinositol pathway (PtdIns pathway), most notably 5-deoxy-5-fluoro-myo-inositol, which is incorporated into the pathway at about 25% the level of myo-inositol itself. Unfortunately, none of the cyclitols have proved effective in limiting cell proliferation, as the cells are able to 'synthesize around' the fraudulent cyclitols using natural myo-inositol as substrate. Inhibitors for 3-phosphatidylinositol kinase, which has importance in a number of pathological conditions, including cancer, have been intensively investigated. 3-Deoxy-3-fluoro-myo-inositol is incorporated into the PtdIns pathway; however, only related phosphatidyl derivatives, for example, a methyl ether derivative of the 3-deoxy inositol, showed significant antiproliferative activity. Synthesis of the deoxyfluoro analogues most often has been accomplished by DAST fluoro-de-hydroxylation of the appropriate cyclitol, generally leading to products of inversion.