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Tohru Takayasu - One of the best experts on this subject based on the ideXlab platform.
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azulene annulated tricyclo 4 3 1 01 6 deca 2 4 7 triene derivatives and their anions a novel cycloheptatriene norcaradiene valence isomerization in the azulene annulated tricyclo 4 3 1 01 6 deca 2 4 7 triene ring system
ChemInform, 2010Co-Authors: Makoto Nitta, Tohru TakayasuAbstract:10-Trifluoroacetyl-11,11a-dihydro-4aH-4a,11a-methanoindeno[1,2-a]azulene 18 and methyl {11,11a-dihydro-4aH-4a,11a-methanoindeno[1,2-a]azulen-10-yl}carboxylate 19 are synthesized starting from the azulene-annulation reaction of 2H-cyclohepta[b]furan-2-one with the pyrrolidine enamine derived from tricyclo[4.3.1.01,6]dec-3-en-8-one. The 13C NMR spectra at various temperatures reveal that compound 18 exists in a norcaradiene structure, while compound 19 is in equilibrium between norcaradiene and cycloheptatriene structures. The latter compound is the first example of a cycloheptatriene, which experiences a forced shortening of the C6–C11 distance by a three carbon chain.† The facile valence isomerization of compound 19 is ascribed to the interaction of the lowest unoccupied molecular orbital (LUMO) of the Walsh orbital of cyclopropane and the highest occupied molecular orbital (HOMO) of the methoxycarbonylazulene, and the interaction occurs effectively as to weaken the basal C6–C11 bond of the cyclopropane ring, as compared to that in compound 18 involving an azulene nucleus bearing the more electron-withdrawing Trifluoroacetyl Group. The hydrogen–deuterium exchange reaction of compounds 18 and 19 in MeONa–MeOD occurs stereospecifically to give 12-exo-deuterated products (exo to the bridge methylene), respectively. Marked spectroscopic differences between the anions 30 and 31, which are derived from compounds 18 and 19 by treatment with [2H5]dimsyl sodium in [2H6]DMSO, respectively, are also observed: the anionic charge in the former is not delocalized over the Trifluoroacetylazulene nucleus, while that in the latter is delocalized over the methoxycarbonylazulene nucleus. The thermal rearrangement of the anion generated from compound 19 is also observed to result in the formation of 11-methoxycarbonylazuleno[1,2-a]azulene. Furthermore, the Diels–Alder reaction of the tricyclo[4.3.1.01,6]deca-2,4,7-triene (methanoindeno[1,2-a]azulene) ring system in compounds 18 and 19 has been studied as well.
Nicolaou Ioannis - One of the best experts on this subject based on the ideXlab platform.
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Enhancing activity and selectivity in a series of pyrrol-1-yl-1-hydroxypyrazole-based aldose reductase inhibitors: The case of Trifluoroacetylation
2017Co-Authors: Papastavrou Nikolaos Nikolaos, Chatzopoulou Maria, Ballekova Jana, Cappiello Mario, Moschini Roberta, Balestri Francesco, Patsilinakos Alexandros, Ragno Rino, Stefek Milan, Nicolaou IoannisAbstract:Aldose reductase (ALR2) has been the target of therapeutic intervention for over 40 years; first, for its role in long-term diabetic complications and more recently as a key mediator in inflammation and cancer. However, efforts to prepare small-molecule aldose reductase inhibitors (ARIs) have mostly yielded carboxylic acids with rather poor pharmacokinetics. To address this limitation, the 1-hydroxypyrazole moiety has been previously established as a bioisostere of acetic acid in a Group of aroyl-substituted pyrrolyl derivatives. In the present work, optimization of this new class of ARIs was achieved by the addition of a Trifluoroacetyl Group on the pyrrole ring. Eight novel compounds were synthesized and tested for their inhibitory activity towards ALR2 and selectivity against aldehyde reductase (ALR1). All compounds proved potent and selective inhibitors of ALR2 (IC50/ALR2 = 0.043-0.242 μΜ, Selectivity index = 190-858), whilst retaining a favorable physicochemical profile. The most active (4g) and selective (4d) compounds were further evaluated for their ability to inhibit sorbitol formation in rat lenses ex vivo and to exhibit substrate-specific inhibition.status: publishe
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Enhancing activity and selectivity in a series of pyrrol-1-yl-1-hydroxypyrazole-based aldose reductase inhibitors: The case of Trifluoroacetylation
'Elsevier BV', 2017Co-Authors: Papastavrou Nikolaos, Chatzopoulou Maria, Ballekova Jana, Cappiello Mario, Moschini Roberta, Balestri Francesco, Patsilinakos Alexandros, Ragno Rino, Stefek Milan, Nicolaou IoannisAbstract:Aldose reductase (ALR2) has been the target of therapeutic intervention for over 40 years; first, for its role in long-term diabetic complications and more recently as a key mediator in inflammation and cancer. However, efforts to prepare small-molecule aldose reductase inhibitors (ARIs) have mostly yielded carboxylic acids with rather poor pharmacokinetics. To address this limitation, the 1-hydroxypyrazole moiety has been previously established as a bioisostere of acetic acid in a Group of aroyl-substituted pyrrolyl derivatives. In the present work, optimization of this new class of ARIs was achieved by the addition of a Trifluoroacetyl Group on the pyrrole ring. Eight novel compounds were synthesized and tested for their inhibitory activity towards ALR2 and selectivity against aldehyde reductase (ALR1). All compounds proved potent and selective inhibitors of ALR2 (IC50/ALR2 = 0.043−0.242 μΜ, Selectivity index = 190−858), whilst retaining a favorable physicochemical profile. The most active (4g) and selective (4d) compounds were further evaluated for their ability to inhibit sorbitol formation in rat lenses ex vivo and to exhibit substrate-specific inhibition
Makoto Nitta - One of the best experts on this subject based on the ideXlab platform.
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azulene annulated tricyclo 4 3 1 01 6 deca 2 4 7 triene derivatives and their anions a novel cycloheptatriene norcaradiene valence isomerization in the azulene annulated tricyclo 4 3 1 01 6 deca 2 4 7 triene ring system
ChemInform, 2010Co-Authors: Makoto Nitta, Tohru TakayasuAbstract:10-Trifluoroacetyl-11,11a-dihydro-4aH-4a,11a-methanoindeno[1,2-a]azulene 18 and methyl {11,11a-dihydro-4aH-4a,11a-methanoindeno[1,2-a]azulen-10-yl}carboxylate 19 are synthesized starting from the azulene-annulation reaction of 2H-cyclohepta[b]furan-2-one with the pyrrolidine enamine derived from tricyclo[4.3.1.01,6]dec-3-en-8-one. The 13C NMR spectra at various temperatures reveal that compound 18 exists in a norcaradiene structure, while compound 19 is in equilibrium between norcaradiene and cycloheptatriene structures. The latter compound is the first example of a cycloheptatriene, which experiences a forced shortening of the C6–C11 distance by a three carbon chain.† The facile valence isomerization of compound 19 is ascribed to the interaction of the lowest unoccupied molecular orbital (LUMO) of the Walsh orbital of cyclopropane and the highest occupied molecular orbital (HOMO) of the methoxycarbonylazulene, and the interaction occurs effectively as to weaken the basal C6–C11 bond of the cyclopropane ring, as compared to that in compound 18 involving an azulene nucleus bearing the more electron-withdrawing Trifluoroacetyl Group. The hydrogen–deuterium exchange reaction of compounds 18 and 19 in MeONa–MeOD occurs stereospecifically to give 12-exo-deuterated products (exo to the bridge methylene), respectively. Marked spectroscopic differences between the anions 30 and 31, which are derived from compounds 18 and 19 by treatment with [2H5]dimsyl sodium in [2H6]DMSO, respectively, are also observed: the anionic charge in the former is not delocalized over the Trifluoroacetylazulene nucleus, while that in the latter is delocalized over the methoxycarbonylazulene nucleus. The thermal rearrangement of the anion generated from compound 19 is also observed to result in the formation of 11-methoxycarbonylazuleno[1,2-a]azulene. Furthermore, the Diels–Alder reaction of the tricyclo[4.3.1.01,6]deca-2,4,7-triene (methanoindeno[1,2-a]azulene) ring system in compounds 18 and 19 has been studied as well.
Serge L. Beaucage - One of the best experts on this subject based on the ideXlab platform.
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the 4 n methyl n 2 2 2 Trifluoroacetyl amino butyl Group as an alternative to the 2 cyanoethyl Group for phosphate protection in the synthesis of oligodeoxyribonucleotides
Journal of Organic Chemistry, 1999Co-Authors: Andrzej Wilk, Andrzej Grajkowski, And Lawrence R Phillips, Serge L. BeaucageAbstract:The 4-[N-methyl-N-(2,2,2-Trifluoroacetyl)amino]butyl Group for phosphate protection in the synthesis of oligodeoxyribonucleotides has been developed to completely prevent nucleobase alkylation by acrylonitrile that could potentially occur upon deprotection of the traditional 2-cyanoethyl phosphate protecting Group. The properties of this new phosphate protecting Group were evaluated using the model phosphotriester 9. The mechanism of phosphate deprotection was studied by treating 9 with concentrated NH4OH. NMR analysis of the deprotection reaction demonstrated that cleavage of the N-Trifluoroacetyl Group is rate-limiting. The resulting phosphotriester intermediate 13 was also shown to undergo rapid cyclodeesterification to produce O,O-diethyl phosphate 15 and N-methylpyrrolidine 16 (Scheme 2). Given the facile removal of the 4-[N-methyl-N-(2,2,2-Trifluoroacetyl)amino]butyl phosphate protecting Group under mild basic conditions, its utilization in oligonucleotide synthesis began with the preparation of the...
Taeko Tokuda - One of the best experts on this subject based on the ideXlab platform.
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chemoenzymatic synthesis of both enantiomers of 2 tert butyl 2 methyl 1 3 benzodioxole 4 carboxylic tbmb acid
Advanced Synthesis & Catalysis, 2010Co-Authors: Toshinori Higashi, Chika Abe, Keiko Ninomiya, Takuya Machida, Nobuyuki Chishima, Shohei Taketomi, Miyu Furuta, Yoko Komaki, Yoshihiko Senba, Taeko TokudaAbstract:Both enantiomers of 2-tert-butyl-2-methyl-1,3-benzodioxole-4-carboxylic (TBMB) acid, which has a unique quaternary chiral center located on the acetal carbon, were prepared from a racemic ketone in which the carboxy Group was replaced by a Trifluoroacetyl Group. First, reduction with fungi, Geotrichum candidum provided (2S,1′S)- and (2R,1′S)- 1′-(2-tert-butyl-2-methyl-1,3-benzodioxol-4-yl)-2′,2′,2′-trifluoroethanol in a highly enantiofacially selective manner. After acetylation, the resulting diastereomeric mixture was submitted to Candida antarctica lipase B-catalyzed transesterification. The reaction proceeded in a stereoselective manner under the influence of the chiral center at the acetal carbon, even though it was six atoms removed from the ester carbonyl carbon. Although the two substrates had the same absolute configuration at the secondary alcohol, the reaction rate of one stereoisomer was 72 times greater than that of the other isomer. The reason for this differential reactivity was attributed mainly to a large difference in Vmax(app) between the stereoisomers. The products, acetate and alcohol, were easily separated by chromatography, and each was then derivatized to (R)- and (S)-TBMB acid, with >99.2% ee, respectively.
