Atli Thorarensen - Academia.edu (original) (raw)
Papers by Atli Thorarensen
ChemMedChem, Jan 18, 2015
There has been significant interest in spleen tyrosine kinase (Syk) owing to its role in a number... more There has been significant interest in spleen tyrosine kinase (Syk) owing to its role in a number of disease states, including autoimmunity, inflammation, and cancer. Ongoing therapeutic programs have resulted in several compounds that are now in clinical use. Herein we report our optimization of the imidazopyrazine core scaffold of Syk inhibitors through the use of empirical and computational approaches. Free-energy perturbation (FEP) methods with MCPRO+ were undertaken to calculate the relative binding free energies for several alternate scaffolds. FEP was first applied retrospectively to determine if there is any predictive value; this resulted in 12 of 13 transformations being predicted in a directionally correct manner. FEP was then applied in a prospective manner to evaluate 17 potential targets, resulting in the realization of imidazotriazine 17 (3-(4-(3,4-dimethoxyphenylamino)imidazo[1,2-f][1,2,4]triazin-2-yl)benzamide), which shows a tenfold improvement in activity relative...
ChemInform, 1998
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform, 1999
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform, 1995
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform, 1998
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform, 1998
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Tetrahedron Letters, 1997
Absbnctz Several new sulfoxide and amide substituted beumquinam have been employed as ligands iu ... more Absbnctz Several new sulfoxide and amide substituted beumquinam have been employed as ligands iu the Pd(II)catalyzed 1,4-oxidation of 2-pheoyl-1,3-cyzlohexadiene (1). Tbe sulfoxide l&and 4 is a supexior ligd io the reachm affordiog high yield in the hmctionalization of this sensitive 1,3diene, and with this ligaad the rransdketate was obtaiued with up to 45% enantiom~c excess. 0 1997 Elsevier Science Ltd. Palladium(II)-catalyzed 1.4oxidation of 13-dienes is a useful reaction in the preparation of highly funtionalized compounds.1 A wide range of nucleophiles is tolerated in the reaction which proceeds with a high degree of stereo-and regioselectivity. Both inter-and intramolecular versions of the reaction are available which have been utilized in natural product synthesis.2 An asymmetric version of this reaction would therefore be highly desirable. Contrary to numerous reports of successful asymmetric Pd(O)-catalyxed reactions3 there are only few reports of asymmetric Pd(II)-catalyzed reactions, especially regarding Pd(II)-catalyzed oxidation.4 An exception to this is the recent elegant work by Hayashi allylphenola4a on asymmetric Wacker-type oxidation of o-Scheme 1 cat. Pd(OAch A cat.L' OAc ?Ac cat. Fe@) 1 atmc40, LiOACVHOAc -@Ph + $Ph OAc AC L' = chilal quinone trztn.92 major cis2 minor
ChemInform, 1995
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform, 1997
Tandem (4 + 2)/(3 + 2) Cycloadditions of Nitroalkenes. Part 11. The Synthesis of (+)-Crotanecine.
Acta crystallographica. Section C, Crystal structure communications, Jan 15, 1996
The structure of the title compound, C31H39NO7Si, was determined and found to be a fused tricycli... more The structure of the title compound, C31H39NO7Si, was determined and found to be a fused tricyclic nitroso acetal. Remarkable features include a twist-boat conformation of the tetrahydro-1,2-oxazine ring and a highly pyramidalized N atom [Sigma (angles) = 310.6(6) degrees]. Three of the contiguous stereocenters in the nitroso acetal are of the same correct relative and absolute configuration as is found in (+)-crotanecine.
ChemInform, 2001
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ACS Chemical Biology, 2014
Kinases constitute an important class of therapeutic targets being explored by both academia and ... more Kinases constitute an important class of therapeutic targets being explored by both academia and the pharmaceutical industry. The major focus of this effort has been directed towards the identification of ATP-competitive inhibitors. Although it has long been recognized that the intracellular concentration of ATP is very different from the concentrations utilized in biochemical enzyme assays, little thought has been devoted to incorporating this discrepancy into our understanding of translation from enzyme inhibition to cellular function. Significant work has been dedicated to the discovery of JAK kinase inhibitors; however, a disconnect between enzyme and cellular function is prominently displayed in the literature for this class of inhibitors. Herein we demonstrate utilizing the four JAK family members that the difference in the ATP K M of each individual kinase has a significant impact on the enzyme to cell inhibition translation. We evaluated a large number of JAK inhibitors in enzymatic assays utilizing either 1 mM ATP or K M ATP for the four isoforms as well as in primary cell assays. This dataset provided the opportunity to examine individual kinase contribution to the heterodimeric kinase complexes mediating cellular signaling. In contrast to a recent study, we demonstrate that for IL-15 cytokine signaling it is sufficient to inhibit either JAK1 or JAK3 to fully inhibit downstream STAT5 phosphorylation. This additional data thus provides a critical piece of information explaining why JAK1 has incorrectly been thought as having a dominant role over JAK3. Beyond enabling a deeper understanding of JAK signaling, conducting similar analyses for other kinases by taking into account potency at high ATP rather than K M ATP may provide crucial insights into a compound's activity and selectivity in cellular contexts.
ChemInform, 2002
amines amines (naphthalene compounds) Q 0810
Synlett, 2010
A regioselective and efficient procedure for the N-alkylation of 3-iodoindazole with chlorodifluo... more A regioselective and efficient procedure for the N-alkylation of 3-iodoindazole with chlorodifluoromethane is described. The reaction was extensively optimized with regard to combinations of base, solvent, addition order as well as stoichiometry. A key reaction parameter was the ...
Pure and Applied Chemistry, 2000
Bbstract; Nitroalkenes have proven to be extremely versatile 4x-components in heterodiene [4+2]-c... more Bbstract; Nitroalkenes have proven to be extremely versatile 4x-components in heterodiene [4+2]-cycloadditions. Our efforts in this area have been intensively methodological with focus on the reaction scope, mechanism, stereoselectivity and transformations of the cycloadducts. The three modes of tandem inter [4+2]/ intra [3+2] cycloaddition, fused, spiro and bridged have been documented. An efficient and highly selective synthesis of (-)-hastanwine has been completed.
Journal of the American Chemical Society, 1997
Journal of the American Chemical Society, 1996
ABSTRACT (−)-Rosmarinecine (2) is the necine base portion of the pyrrolizidine alkaloid (−)-rosma... more ABSTRACT (−)-Rosmarinecine (2) is the necine base portion of the pyrrolizidine alkaloid (−)-rosmarinine. (−)-Rosmarinecine is a representative of the group of pyrrolizidines that show a cis relationship between adjacent stereocenters C(1), C(7), and C(7a), in addition to a highly oxygenated skeleton. (−)-Rosmarinecine (2) has been synthesized in eight steps and 14.8% overall yield, as an illustration of a general approach for the construction of pyrrolizidines having this stereochemical feature. The key step in the asymmetric synthesis is a Lewis acid-promoted, tandem inter-[4 + 2]/intra-[3 + 2] cycloaddition between a fumaroyloxy nitroalkene and a chiral vinyl ether.
The Journal of Organic Chemistry, 1995
ABSTRACT Chiral enol ethers derived from (R)-(-)-2,2-diphenylcyclopentanol ((-)-3) have been foun... more ABSTRACT Chiral enol ethers derived from (R)-(-)-2,2-diphenylcyclopentanol ((-)-3) have been found to provide high levels of asymmetric induction in tandem inter [4 + 2]/intra [3 + 2] nitroalkene cycloadditions. The chiral auxiliary (>97% ee) is readily prepared in three steps from diphenylacetonitrile employing an asymmetric oxazaborolidine-catalyzed borane reduction. Either enantiomeric series of tandem cycloaddition/hydrogenolysis product 7 is available from the chiral auxiliary of a single absolute configuration by judicious selection of the Lewis acid promoter, Ti(O-i-Pr)(2)Cl-2 (98% ee, (-)-7) or MAPh (93% ee, (+)-7). Propenyl ethers derived from (-)-3 undergo endo selective [4 + 2] cycloadditions (2.3/1 - 8.2/1) in the presence Ti(O-i-Pr)(2)Cl-2; however, exo selective [4 + 2] cycloadditions (10.2/1 - 54.8/1) are observed in the presence of MAPh.
![Research paper thumbnail of Tandem [4 + 2]/[3 + 2] Cycloadditions of Nitroalkenes. 10. trans -2-(1-Methyl-1-phenylethyl)cyclohexanol as a New Auxiliary](https://attachments.academia-assets.com/42752206/thumbnails/1.jpg)
](The Journal of Organic Chemistry, 1996
The asymmetric variant of the tandem [4 + 2]/[3 + 2] cycloaddition of nitroalkenes with chiral vi... more The asymmetric variant of the tandem [4 + 2]/[3 + 2] cycloaddition of nitroalkenes with chiral vinyl ethers has been extensively explored in recent years. 1 To date, the chiral vinyl ethers that have been utilized in the tandem sequence are derived from bornane-2,3-diol, 1, trans-2phenylcyclohexanol, 2, and 2,2-diphenylcyclopentanol, 3, . These auxiliaries have served admirably in many aspects of the cycloaddition process, but some limitations still exist, such as the following: (1) length of synthesis, (2) low selectivity in exo mode cycloadditions or (3) unavailability in both enantiomeric series.
The Journal of Organic Chemistry, 1998
Chiral C 2 -symmetric 2,5-bisamide hydroquinone ligands, with -amino alcohols as chiral building ... more Chiral C 2 -symmetric 2,5-bisamide hydroquinone ligands, with -amino alcohols as chiral building units, were synthesized in excellent overall yields. The ligands gave up to 54.4% ee in the palladiumcatalyzed 1,4-dialkoxylation of 1,3-dienes. These findings demonstrate the potential of asymmetric induction utilizing chiral benzoquinones as ligands in palladium(II) catalysis, albeit with modest enantiomeric excesses. Weakly coordinating hydroxyl groups of the ligand appear to be crucial for the success of the reaction. Mechanistic aspects and the origin of enantioselectivity are also discussed.
ChemMedChem, Jan 18, 2015
There has been significant interest in spleen tyrosine kinase (Syk) owing to its role in a number... more There has been significant interest in spleen tyrosine kinase (Syk) owing to its role in a number of disease states, including autoimmunity, inflammation, and cancer. Ongoing therapeutic programs have resulted in several compounds that are now in clinical use. Herein we report our optimization of the imidazopyrazine core scaffold of Syk inhibitors through the use of empirical and computational approaches. Free-energy perturbation (FEP) methods with MCPRO+ were undertaken to calculate the relative binding free energies for several alternate scaffolds. FEP was first applied retrospectively to determine if there is any predictive value; this resulted in 12 of 13 transformations being predicted in a directionally correct manner. FEP was then applied in a prospective manner to evaluate 17 potential targets, resulting in the realization of imidazotriazine 17 (3-(4-(3,4-dimethoxyphenylamino)imidazo[1,2-f][1,2,4]triazin-2-yl)benzamide), which shows a tenfold improvement in activity relative...
ChemInform, 1998
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform, 1999
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform, 1995
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform, 1998
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform, 1998
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Tetrahedron Letters, 1997
Absbnctz Several new sulfoxide and amide substituted beumquinam have been employed as ligands iu ... more Absbnctz Several new sulfoxide and amide substituted beumquinam have been employed as ligands iu the Pd(II)catalyzed 1,4-oxidation of 2-pheoyl-1,3-cyzlohexadiene (1). Tbe sulfoxide l&and 4 is a supexior ligd io the reachm affordiog high yield in the hmctionalization of this sensitive 1,3diene, and with this ligaad the rransdketate was obtaiued with up to 45% enantiom~c excess. 0 1997 Elsevier Science Ltd. Palladium(II)-catalyzed 1.4oxidation of 13-dienes is a useful reaction in the preparation of highly funtionalized compounds.1 A wide range of nucleophiles is tolerated in the reaction which proceeds with a high degree of stereo-and regioselectivity. Both inter-and intramolecular versions of the reaction are available which have been utilized in natural product synthesis.2 An asymmetric version of this reaction would therefore be highly desirable. Contrary to numerous reports of successful asymmetric Pd(O)-catalyxed reactions3 there are only few reports of asymmetric Pd(II)-catalyzed reactions, especially regarding Pd(II)-catalyzed oxidation.4 An exception to this is the recent elegant work by Hayashi allylphenola4a on asymmetric Wacker-type oxidation of o-Scheme 1 cat. Pd(OAch A cat.L' OAc ?Ac cat. Fe@) 1 atmc40, LiOACVHOAc -@Ph + $Ph OAc AC L' = chilal quinone trztn.92 major cis2 minor
ChemInform, 1995
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform, 1997
Tandem (4 + 2)/(3 + 2) Cycloadditions of Nitroalkenes. Part 11. The Synthesis of (+)-Crotanecine.
Acta crystallographica. Section C, Crystal structure communications, Jan 15, 1996
The structure of the title compound, C31H39NO7Si, was determined and found to be a fused tricycli... more The structure of the title compound, C31H39NO7Si, was determined and found to be a fused tricyclic nitroso acetal. Remarkable features include a twist-boat conformation of the tetrahydro-1,2-oxazine ring and a highly pyramidalized N atom [Sigma (angles) = 310.6(6) degrees]. Three of the contiguous stereocenters in the nitroso acetal are of the same correct relative and absolute configuration as is found in (+)-crotanecine.
ChemInform, 2001
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ACS Chemical Biology, 2014
Kinases constitute an important class of therapeutic targets being explored by both academia and ... more Kinases constitute an important class of therapeutic targets being explored by both academia and the pharmaceutical industry. The major focus of this effort has been directed towards the identification of ATP-competitive inhibitors. Although it has long been recognized that the intracellular concentration of ATP is very different from the concentrations utilized in biochemical enzyme assays, little thought has been devoted to incorporating this discrepancy into our understanding of translation from enzyme inhibition to cellular function. Significant work has been dedicated to the discovery of JAK kinase inhibitors; however, a disconnect between enzyme and cellular function is prominently displayed in the literature for this class of inhibitors. Herein we demonstrate utilizing the four JAK family members that the difference in the ATP K M of each individual kinase has a significant impact on the enzyme to cell inhibition translation. We evaluated a large number of JAK inhibitors in enzymatic assays utilizing either 1 mM ATP or K M ATP for the four isoforms as well as in primary cell assays. This dataset provided the opportunity to examine individual kinase contribution to the heterodimeric kinase complexes mediating cellular signaling. In contrast to a recent study, we demonstrate that for IL-15 cytokine signaling it is sufficient to inhibit either JAK1 or JAK3 to fully inhibit downstream STAT5 phosphorylation. This additional data thus provides a critical piece of information explaining why JAK1 has incorrectly been thought as having a dominant role over JAK3. Beyond enabling a deeper understanding of JAK signaling, conducting similar analyses for other kinases by taking into account potency at high ATP rather than K M ATP may provide crucial insights into a compound's activity and selectivity in cellular contexts.
ChemInform, 2002
amines amines (naphthalene compounds) Q 0810
Synlett, 2010
A regioselective and efficient procedure for the N-alkylation of 3-iodoindazole with chlorodifluo... more A regioselective and efficient procedure for the N-alkylation of 3-iodoindazole with chlorodifluoromethane is described. The reaction was extensively optimized with regard to combinations of base, solvent, addition order as well as stoichiometry. A key reaction parameter was the ...
Pure and Applied Chemistry, 2000
Bbstract; Nitroalkenes have proven to be extremely versatile 4x-components in heterodiene [4+2]-c... more Bbstract; Nitroalkenes have proven to be extremely versatile 4x-components in heterodiene [4+2]-cycloadditions. Our efforts in this area have been intensively methodological with focus on the reaction scope, mechanism, stereoselectivity and transformations of the cycloadducts. The three modes of tandem inter [4+2]/ intra [3+2] cycloaddition, fused, spiro and bridged have been documented. An efficient and highly selective synthesis of (-)-hastanwine has been completed.
Journal of the American Chemical Society, 1997
Journal of the American Chemical Society, 1996
ABSTRACT (−)-Rosmarinecine (2) is the necine base portion of the pyrrolizidine alkaloid (−)-rosma... more ABSTRACT (−)-Rosmarinecine (2) is the necine base portion of the pyrrolizidine alkaloid (−)-rosmarinine. (−)-Rosmarinecine is a representative of the group of pyrrolizidines that show a cis relationship between adjacent stereocenters C(1), C(7), and C(7a), in addition to a highly oxygenated skeleton. (−)-Rosmarinecine (2) has been synthesized in eight steps and 14.8% overall yield, as an illustration of a general approach for the construction of pyrrolizidines having this stereochemical feature. The key step in the asymmetric synthesis is a Lewis acid-promoted, tandem inter-[4 + 2]/intra-[3 + 2] cycloaddition between a fumaroyloxy nitroalkene and a chiral vinyl ether.
The Journal of Organic Chemistry, 1995
ABSTRACT Chiral enol ethers derived from (R)-(-)-2,2-diphenylcyclopentanol ((-)-3) have been foun... more ABSTRACT Chiral enol ethers derived from (R)-(-)-2,2-diphenylcyclopentanol ((-)-3) have been found to provide high levels of asymmetric induction in tandem inter [4 + 2]/intra [3 + 2] nitroalkene cycloadditions. The chiral auxiliary (>97% ee) is readily prepared in three steps from diphenylacetonitrile employing an asymmetric oxazaborolidine-catalyzed borane reduction. Either enantiomeric series of tandem cycloaddition/hydrogenolysis product 7 is available from the chiral auxiliary of a single absolute configuration by judicious selection of the Lewis acid promoter, Ti(O-i-Pr)(2)Cl-2 (98% ee, (-)-7) or MAPh (93% ee, (+)-7). Propenyl ethers derived from (-)-3 undergo endo selective [4 + 2] cycloadditions (2.3/1 - 8.2/1) in the presence Ti(O-i-Pr)(2)Cl-2; however, exo selective [4 + 2] cycloadditions (10.2/1 - 54.8/1) are observed in the presence of MAPh.
The Journal of Organic Chemistry, 1996
The asymmetric variant of the tandem [4 + 2]/[3 + 2] cycloaddition of nitroalkenes with chiral vi... more The asymmetric variant of the tandem [4 + 2]/[3 + 2] cycloaddition of nitroalkenes with chiral vinyl ethers has been extensively explored in recent years. 1 To date, the chiral vinyl ethers that have been utilized in the tandem sequence are derived from bornane-2,3-diol, 1, trans-2phenylcyclohexanol, 2, and 2,2-diphenylcyclopentanol, 3, . These auxiliaries have served admirably in many aspects of the cycloaddition process, but some limitations still exist, such as the following: (1) length of synthesis, (2) low selectivity in exo mode cycloadditions or (3) unavailability in both enantiomeric series.
The Journal of Organic Chemistry, 1998
Chiral C 2 -symmetric 2,5-bisamide hydroquinone ligands, with -amino alcohols as chiral building ... more Chiral C 2 -symmetric 2,5-bisamide hydroquinone ligands, with -amino alcohols as chiral building units, were synthesized in excellent overall yields. The ligands gave up to 54.4% ee in the palladiumcatalyzed 1,4-dialkoxylation of 1,3-dienes. These findings demonstrate the potential of asymmetric induction utilizing chiral benzoquinones as ligands in palladium(II) catalysis, albeit with modest enantiomeric excesses. Weakly coordinating hydroxyl groups of the ligand appear to be crucial for the success of the reaction. Mechanistic aspects and the origin of enantioselectivity are also discussed.