Stereoselective Synthesis of Fully Protected (<i>S</i>)‐1,7‐Dioxaspiro[5,5]undec‐4‐ene Derivatives of Sugars

Caputo, Romualdo; Ciriello, Umberto; Festa, Pasquale; Guaragna, Annalisa; Palumbo, Giovanni; Pedatella, Silvana

doi:10.1002/ejoc.200300025

Cited by 17 publications

(15 citation statements)

References 11 publications

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“…1‐Benzoyloxy‐4,4‐difluorobutane (41) : To a solution of 4‐benzoyloxybutanal ( 38 ) (4.15 g, 21.6 mmol, 1.00 equiv) stirring in 54 mL CH 2 Cl 2 at 0 °C under an N 2 atmosphere was dropwise added DAST (5.40 mL, 38.9 mmol, 1.80 equiv). After 10 min the reaction mixture was allowed to warm to room temperature and stirred for another 50 min.…”

Section: Methodsmentioning

confidence: 99%

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Effect of Partially Fluorinated N‐Alkyl‐Substituted Piperidine‐2‐carboxamides on Pharmacologically Relevant Properties

et al. 2016

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The modulation of pharmacologically relevant properties of N-alkyl-piperidine-2-carboxamides was studied by selective introduction of 1-3 fluorine atoms into the n-propyl and n-butyl side chains of the local anesthetics ropivacaine and levobupivacaine. The basicity modulation by nearby fluorine substituents is essentially additive and exhibits an exponential attenuation as a function of topological distance between fluorine and the basic center. The intrinsic lipophilicity of the neutral piperidine derivatives displays the characteristic response noted for partially fluorinated alkyl groups attached to neutral heteroaryl systems. However, basicity decrease by nearby fluorine substituents affects lipophilicities at neutral pH, so that all partially fluorinated derivatives are of similar or higher lipophilicity than their non-fluorinated parents. Aqueous solubilities were found to correlate inversely with lipophilicity with a significant contribution from crystal packing energies, as indicated by variations in melting point temperatures. All fluorinated derivatives were found to be somewhat more readily oxidized in human liver microsomes, the rates of degradation correlating with increasing lipophilicity. Because the piperidine-2-carboxamide core is chiral, pairs with enantiomeric N-alkyl groups are diastereomeric. While little response to such stereoisomerism was observed for basicity or lipophilicity, more pronounced variations were observed for melting point temperatures and oxidative degradation.

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Section: Methodsmentioning

confidence: 99%

“…For diol 28 a benzoyl protecting group proved to be stable under the conditions needed for fluorination, while for diol 27 only triphenylmethyl seemed to tolerate DAST. After protection the alcohols were oxidized to aldehydes 37 and 38 with pyridinium chlorochromate (PCC) (Scheme ).…”

Section: Introductionmentioning

confidence: 99%

Effect of Partially Fluorinated N‐Alkyl‐Substituted Piperidine‐2‐carboxamides on Pharmacologically Relevant Properties

et al. 2016

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“…In this context, De Fenza et al explored the inhibition potential of L-glucoconfigured N-alkyl-deoxyiminosugars, ent- (4,14,16,91,92) (Figure 22) against NLGase, thereby studying the effect of chirality on the anti-inflammatory treatment of CF [179]. The synthesis of L-DNJ derivatives was achieved exploiting a de novo methodology [180][181][182] that relied on the use of a homologating agent 93 [183][184][185]. Coupling reaction of this agent with the L-enantiomer of Garner aldehyde (94) led to alcohol 95, whose further elaboration allowed the obtainment of oxirane 96.…”

Section: Exploring the Role Of The Chirality In The Anti-inflamatory mentioning

confidence: 99%

“…L-NBDNJ (ent-4), the non-superimposable mirror image of NBDNJ, was obtained by standard Nalkylation reaction conditions of ent-2, while preparation of ent- (14,16,91,92) was performed by Nalkylation of L-DNJ with reactive alkyl and alkoxyalkyl iodides (98b and 100), in turn prepared by polymer supported triphenylphosphine (PSS-TPP)-mediated iodination reactions (Scheme 12) [187,188]. The synthesis of l-DNJ derivatives was achieved exploiting a de novo methodology [180][181][182] that relied on the use of a homologating agent 93 [183][184][185]. Coupling reaction of this agent with the l-enantiomer of Garner aldehyde (94) led to alcohol 95, whose further elaboration allowed the obtainment of oxirane 96.…”

Section: Exploring the Role Of The Chirality In The Anti-inflamatory mentioning

confidence: 99%

Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis

Esposito

D’Alonzo

Fenza

et al. 2020

IJMS

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Iminosugars are sugar analogues endowed with a high pharmacological potential. The wide range of biological activities exhibited by these glycomimetics associated with their excellent drug profile make them attractive therapeutic candidates for several medical interventions. The ability of iminosugars to act as inhibitors or enhancers of carbohydrate-processing enzymes suggests their potential use as therapeutics for the treatment of cystic fibrosis (CF). Herein we review the most relevant advances in the field, paying attention to both the chemical synthesis of the iminosugars and their biological evaluations, resulting from in vitro and in vivo assays. Starting from the example of the marketed drug NBDNJ (N-butyl deoxynojirimycin), a variety of iminosugars have exhibited the capacity to rescue the trafficking of F508del-CFTR (deletion of F508 residue in the CF transmembrane conductance regulator), either alone or in combination with other correctors. Interesting results have also been obtained when iminosugars were considered as anti-inflammatory agents in CF lung disease. The data herein reported demonstrate that iminosugars hold considerable potential to be applied for both therapeutic purposes.

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“…The development of new routes for the synthesis of these frameworks has attracted considerable attention and several distinct approaches have been reported for the preparation of heterocyclic spiranes. These include palladiumpromoted spiroannulations onto carbocyclic or heterocyclic substrates (Møller & Undheim, 2003), spirocyclizations mediated by BF 3 -Et 2 O (Caputo et al, 2003), spiroannulation of carboxylic acids (Rahimizadeh et al, 2007), and oxidative rearrangement sequences and intramolecular Mannich reactions (Marti & Carreira, 2003).…”

Section: Commentmentioning

confidence: 99%

FourN⁷-benzyl-substituted 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-5-spiro-1′-cyclohexane-2′,6′-diones as ethanol hemisolvates: similar molecular constitutions but different crystal structures

et al. 2008

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3-tert-Butyl-7-(4-chlorobenzyl)-4',4'-dimethyl-1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-5-spiro-1'-cyclohexane-2',6'-dione ethanol hemisolvate, C(30)H(34)ClN(3)O(2) x 0.5C(2)H(6)O, (I), its 7-(4-bromobenzyl)- analogue, C(30)H(34)BrN(3)O(2) x 0.5C(2)H(6)O, (II), and its 7-(4-methylbenzyl)- analogue, C(31)H(37)N(3)O(2) x 0.5C(2)H(6)O, (III), are isomorphous, with the ethanol component disordered across a twofold rotation axis in the space group C2/c. In the corresponding 7-[4-(trifluoromethyl)benzyl]- compound, C(31)H(34)F(3)N(3)O(2) x 0.5C(2)H(6)O, (IV), the ethanol component is disordered across a centre of inversion in the space group P\overline{1}. In each of (I)-(IV), the reduced pyridine ring adopts a half-chair conformation. The heterocyclic components in (I)-(III) are linked into centrosymmetric dimers by a single C-H...pi interaction, with the half-occupancy ethanol component linked to the dimer by a combination of C-H...O and O-H...pi(arene) hydrogen bonds. The heterocyclic molecules in (IV) are linked into chains of centrosymmetric rings by C-H...O and C-H...pi hydrogen bonds, again with the half-occupancy ethanol component pendent from the chain. The significance of this study lies in the isomorphism of the related derivatives (I)-(III), in the stoichiometric hemisolvation by ethanol, where the disordered solvent molecule is linked to the heterocyclic component by a two-point linkage, and in the differences between the crystal structures of (I)-(III) and that of (IV).

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Stereoselective Synthesis of Fully Protected (S)‐1,7‐Dioxaspiro[5,5]undec‐4‐ene Derivatives of Sugars

Cited by 17 publications

References 11 publications

Effect of Partially Fluorinated N‐Alkyl‐Substituted Piperidine‐2‐carboxamides on Pharmacologically Relevant Properties

Effect of Partially Fluorinated N‐Alkyl‐Substituted Piperidine‐2‐carboxamides on Pharmacologically Relevant Properties

Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis

FourN⁷-benzyl-substituted 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-5-spiro-1′-cyclohexane-2′,6′-diones as ethanol hemisolvates: similar molecular constitutions but different crystal structures

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Stereoselective Synthesis of Fully Protected (S)‐1,7‐Dioxaspiro[5,5]undec‐4‐ene Derivatives of Sugars

Cited by 17 publications

References 11 publications

Effect of Partially Fluorinated N‐Alkyl‐Substituted Piperidine‐2‐carboxamides on Pharmacologically Relevant Properties

Effect of Partially Fluorinated N‐Alkyl‐Substituted Piperidine‐2‐carboxamides on Pharmacologically Relevant Properties

Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis

FourN7-benzyl-substituted 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-5-spiro-1′-cyclohexane-2′,6′-diones as ethanol hemisolvates: similar molecular constitutions but different crystal structures

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FourN⁷-benzyl-substituted 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridine-5-spiro-1′-cyclohexane-2′,6′-diones as ethanol hemisolvates: similar molecular constitutions but different crystal structures