Stefano Crosignani - Academia.edu (original) (raw)

Papers by Stefano Crosignani

Research paper thumbnail of Polymer-Supported Mukaiyama Reagent: A Useful Coupling Reagent for the Synthesis of Esters and Amides

ChemInform, 2005

Synthesis of Esters and Amides. -A polymer-supported version of the title reagent is found to be ... more Synthesis of Esters and Amides. -A polymer-supported version of the title reagent is found to be an excellent coupling reagent for the synthesis of both amides and esters, in particular when poorly nucleophilic amines are used. The products are obtained in high purity and high yield (to be continued). -(CROSIGNANI, S.; GONZALEZ, J.; SWINNEN*, D.; Org. Lett. 6 (2004) 24, 4579-pp; Serono Pharm. Res. Inst., CH-1228 Geneva, Switz.; Eng.) -Steudel 11-070

Research paper thumbnail of Polymer-Supported Mukaiyama Reagent: A Useful Coupling Reagent for the Synthesis of Esters and Amides

Organic Letters, 2004

Synthesis of Esters and Amides. -A polymer-supported version of the title reagent is found to be ... more Synthesis of Esters and Amides. -A polymer-supported version of the title reagent is found to be an excellent coupling reagent for the synthesis of both amides and esters, in particular when poorly nucleophilic amines are used. The products are obtained in high purity and high yield (to be continued). -(CROSIGNANI, S.; GONZALEZ, J.; SWINNEN*, D.; Org. Lett. 6 (2004) 24, 4579-pp; Serono Pharm. Res. Inst., CH-1228 Geneva, Switz.; Eng.) -Steudel 11-070

Research paper thumbnail of A Straightforward, One-Pot Protocol for the Preparation of Libraries of 2-Oxazolines

Journal of Combinatorial Chemistry, 2005

A practical protocol for the parallel synthesis of 2-oxazolines using polymer-supported reagents ... more A practical protocol for the parallel synthesis of 2-oxazolines using polymer-supported reagents is described. Polymer-supported Mukaiyama reagent is used to couple a carboxylic acid with an amino alcohol, giving a beta-hydroxyamide, which is then cyclized in situ using either polymer-supported sulfonyl chloride resin or polymer-bound 2-fluoropyridinium triflate. Both 2,4-disubstituted and 2,4,5-trisubstituted 2-oxazolines are obtained in high yields and excellent purities after a simple resin filtration and solvent evaporation routine.

Research paper thumbnail of Synthesis of 5-Carboxamide-oxazolines with a Passerini-Zhu/Staudinger-Aza-Wittig Two-Step Protocol

Journal of Combinatorial Chemistry, Sep 13, 2010

... Stefano Crosignani ‡ , Luca Banfi † , Renata Riva † and Andrea Basso* †. ... AB acknowledge M... more ... Stefano Crosignani ‡ , Luca Banfi † , Renata Riva † and Andrea Basso* †. ... AB acknowledge Merck Serono and Fondazione San Paolo for financial support. Supporting Information ... This article references 28 other publications. 1. Banfi, L. and Riva, R. The Passerini reaction. ...

Research paper thumbnail of 6-AMINO-PYRIMIDINE-4-CARBOXAMIDE Derivatives and Related Compounds Which Bind to the Sphingosine 1-PHOSPHATE (S1P) Receptor for the Treatment of Multiple Sclerosis

Research paper thumbnail of A Mild, Phosphine-Free Method for the Conversion of Alcohols into Halides (Cl, Br, I) via the Corresponding O-Alkyl Isoureas

Tetrahedron Letters

A novel procedure for the conversion of primary and secondary alcohols into the corresponding alk... more A novel procedure for the conversion of primary and secondary alcohols into the corresponding alkyl chlorides, bromides and iodides is described. The transformation is high-yielding in the case of chlorides and bromides, tolerates a range of functional groups, and does not rely on the use of phosphines.

Research paper thumbnail of Synthesis of Heterocycles Using Polymer-Supported Reagents under Microwave Irradiation

Research paper thumbnail of Preclinical assessment of a novel small molecule inhibitor of tryptophan 2,3-dioxygenase 2 (TDO2)

Journal for ImmunoTherapy of Cancer, 2014

Research paper thumbnail of A Mild, Phosphine-Free Method for the Conversion of Alcohols into Halides (Cl, Br, I) via the Corresponding O-Alkyl Isoureas

ChemInform, 2004

A novel procedure for the conversion of primary and secondary alcohols into the corresponding alk... more A novel procedure for the conversion of primary and secondary alcohols into the corresponding alkyl chlorides, bromides and iodides is described. The transformation is high-yielding in the case of chlorides and bromides, tolerates a range of functional groups, and does not rely on the use of phosphines.

Research paper thumbnail of ChemInform Abstract: 4-Naphthyl-Substituted Bis(oxazoline): A New, Easily Recoverable and Efficient Chiral Ligand in Asymmetric Catalysis of the Diels-Alder Reaction

Research paper thumbnail of Microwave-assisted ester formation using O-alkylisoureas: a convenient method for the synthesis of esters with inversion of configuration

The Journal of organic chemistry, Jan 3, 2009

The formation of carboxylic esters via reaction of carboxylic acids with O-alkylisoureas proceeds... more The formation of carboxylic esters via reaction of carboxylic acids with O-alkylisoureas proceeds in excellent yields with very short reaction times when conducted in a monomode microwave synthesizer. Efficient processes were developed using preformed or commercially available isoureas derived from primary and secondary alcohols, with a reaction time of only 5 min or less. It was demonstrated that under these microwave conditions, ester formation proceeded in good yields with clean inversion of configuration where appropriate. The process was validated using menthol, a hindered substrate for S(N)2 reactions. In addition, starting from primary alcohols, ester formation was successfully accomplished using an in situ isourea formation procedure. A polymer-assisted solution-phase procedure was also developed by employing preformed solid-supported isoureas and by an efficient "catch and release" ester formation procedure whereby primary alcohols were caught on resin as isoureas...

Research paper thumbnail of Microwaves, supported-reagents and parallel synthesis: Isocyanide and ester synthesis

Molecular Diversity, 2003

The benefits of microwave irradiation are described for a number of important reactions such as a... more The benefits of microwave irradiation are described for a number of important reactions such as amid and ester formation and dehydration of formamide to the corresponding isonitriles. Not only were reaction times dramatically reduced but the transformations were less prone to side reactions and decomposition.

Research paper thumbnail of A Practical Synthesis of a High-Loading Solid-Supported IBX Amide for the Oxidation of Alcohols

ChemInform, 2006

Oxidation O 0212 A Practical Synthesis of a High-Loading Solid-Supported IBX Amide for the Oxidat... more Oxidation O 0212 A Practical Synthesis of a High-Loading Solid-Supported IBX Amide for the Oxidation of Alcohols. -The novel IBX resin can be reoxidized and reused with minimal loss of activity after the second reoxidation. -(LECARPENTIER, P.; CROSIGNANI, S.; LINCLAU*, B.; Mol. Diversity 9 (2005) 4, 341-351; Comb. Cent. Excellence, Univ. Southampton, Southampton SO17 1BJ, UK; Eng.) -Nuesgen 21-043

Research paper thumbnail of Pharmacophore-Based Design of Novel Oxadiazoles as Selective Sphingosine-1-phosphate (S1P) Receptor Agonists with in vivo Efficacy

ChemMedChem, 2015

Sphingosine-1-phosphate (S1P) receptor agonists have shown promise as therapeutic agents for mult... more Sphingosine-1-phosphate (S1P) receptor agonists have shown promise as therapeutic agents for multiple sclerosis (MS) due to their regulatory roles within the immune, central nervous system, and cardiovascular system. Here, the design and optimization of novel [1,2,4]oxadiazole derivatives as selective S1P receptor agonists are described. The structure-activity relationship exploration was carried out on the three dominant segments of the series: modification of the polar head group (P), replacement of the oxadiazole linker (L) with different five-membered heterocycles, and the use of diverse 2,2'-disubstituted biphenyl moieties as the hydrophobic tail (H). All three segments have a significant impact on potency, S1P receptor subtype selectivity, physicochemical properties, and in vitro absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of the compounds. From these optimization studies, a selective S1P1 agonist, N-methyl-N-(4-{5-[2-methyl-2'-(trifluoromethyl)biphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzyl)glycine (45), and a dual S1P1,5 agonist, N-methyl-N-(3-{5-[2'-methyl-2-(trifluoromethyl)biphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzyl)glycine (49), emerged as frontrunners. These compounds distribute predominantly in lymph nodes and brain over plasma and induce long lasting decreases in lymphocyte count after oral administration. When evaluated head-to-head in an experimental autoimmune encephalomyelitis mouse model, together with the marketed drug fingolimod, a pan-S1P receptor agonist, S1P1,5 agonist 49 demonstrated comparable efficacy while S1P1 -selective agonist 45 was less potent. Compound 49 is not a prodrug, and its improved property profile should translate into a safer treatment of relapsing forms of MS.

Research paper thumbnail of ChemInform Abstract: Novel Application of α-Azido Aldehydes in Multicomponent Reactions: Synthesis of Triazolo-Fused Dihydrooxazinones via a Passerini Reaction-Dipolar Cycloaddition Strategy

Research paper thumbnail of Synthesis of 2-oxazolines mediated by N,N′-diisopropylcarbodiimide

Tetrahedron Letters, 2004

It is known that amides do not react with isoureas. Nevertheless, as amides have a similar acidit... more It is known that amides do not react with isoureas. Nevertheless, as amides have a similar acidity to ketones, we envisioned that intra-or intermolecular activation of isoureas 2 would be possible, and that the cyclisation to form 2-oxazolines 3 as depicted in Scheme 2 would ...

Research paper thumbnail of ChemInform Abstract: Microwave-Assisted Ester Formation Using O-Alkylisoureas: A Convenient Method for the Synthesis of Esters with Inversion of Configuration

Research paper thumbnail of Polymer-Supported O -Methylisourea: A New Reagent for the O -Methylation of Carboxylic Acids

Organic Letters, 2002

[reaction: see text] A solid-supported O-methylisourea reagent has been prepared in one step star... more [reaction: see text] A solid-supported O-methylisourea reagent has been prepared in one step starting from commercially available solid-supported carbodiimide. The isourea reagent has been successfully used for the preparation of methyl esters from the corresponding carboxylic acids. The crude products obtained after resin filtration and solvent evaporation are generally obtained in >98% purity.

Research paper thumbnail of Chiral amplification in Diels-Alder and 1,3-dipolar cycloadditions catalyzed by bis(oxazoline)-Zn(II)-based chiral complexes

Tetrahedron Letters, 1999

A Zn(II)-bis(oxazoline) chiral complex catalyzes the cycloaddition reactions of alkenoyloxazolidi... more A Zn(II)-bis(oxazoline) chiral complex catalyzes the cycloaddition reactions of alkenoyloxazolidinones with both cyclopentadiene and diphenyl nitrone. The 1,3-dipolar cycloaddition becomes exo selective with an ee of up to 86%. While the Mg(II)-based catalysts give a linear relationship between the ligand's optical purity and the ee of the reaction product, a remarkable positive nonlinear effect was observed in both cycloadditions by using Zn(II) as the cationic core of the catalyst. The result may be rationalized by the formation of a stable, insoluble, and catalytically inactive heterochiral complex.

Research paper thumbnail of A mild, phosphine-free method for the conversion of alcohols into halides (Cl, Br, I) via the corresponding O-alkyl isoureas

Tetrahedron Letters, 2003

A novel procedure for the conversion of primary and secondary alcohols into the corresponding alk... more A novel procedure for the conversion of primary and secondary alcohols into the corresponding alkyl chlorides, bromides and iodides is described. The transformation is high-yielding in the case of chlorides and bromides, tolerates a range of functional groups, and does not rely on the use of phosphines.

Research paper thumbnail of Polymer-Supported Mukaiyama Reagent: A Useful Coupling Reagent for the Synthesis of Esters and Amides

ChemInform, 2005

Synthesis of Esters and Amides. -A polymer-supported version of the title reagent is found to be ... more Synthesis of Esters and Amides. -A polymer-supported version of the title reagent is found to be an excellent coupling reagent for the synthesis of both amides and esters, in particular when poorly nucleophilic amines are used. The products are obtained in high purity and high yield (to be continued). -(CROSIGNANI, S.; GONZALEZ, J.; SWINNEN*, D.; Org. Lett. 6 (2004) 24, 4579-pp; Serono Pharm. Res. Inst., CH-1228 Geneva, Switz.; Eng.) -Steudel 11-070

Research paper thumbnail of Polymer-Supported Mukaiyama Reagent: A Useful Coupling Reagent for the Synthesis of Esters and Amides

Organic Letters, 2004

Synthesis of Esters and Amides. -A polymer-supported version of the title reagent is found to be ... more Synthesis of Esters and Amides. -A polymer-supported version of the title reagent is found to be an excellent coupling reagent for the synthesis of both amides and esters, in particular when poorly nucleophilic amines are used. The products are obtained in high purity and high yield (to be continued). -(CROSIGNANI, S.; GONZALEZ, J.; SWINNEN*, D.; Org. Lett. 6 (2004) 24, 4579-pp; Serono Pharm. Res. Inst., CH-1228 Geneva, Switz.; Eng.) -Steudel 11-070

Research paper thumbnail of A Straightforward, One-Pot Protocol for the Preparation of Libraries of 2-Oxazolines

Journal of Combinatorial Chemistry, 2005

A practical protocol for the parallel synthesis of 2-oxazolines using polymer-supported reagents ... more A practical protocol for the parallel synthesis of 2-oxazolines using polymer-supported reagents is described. Polymer-supported Mukaiyama reagent is used to couple a carboxylic acid with an amino alcohol, giving a beta-hydroxyamide, which is then cyclized in situ using either polymer-supported sulfonyl chloride resin or polymer-bound 2-fluoropyridinium triflate. Both 2,4-disubstituted and 2,4,5-trisubstituted 2-oxazolines are obtained in high yields and excellent purities after a simple resin filtration and solvent evaporation routine.

Research paper thumbnail of Synthesis of 5-Carboxamide-oxazolines with a Passerini-Zhu/Staudinger-Aza-Wittig Two-Step Protocol

Journal of Combinatorial Chemistry, Sep 13, 2010

... Stefano Crosignani ‡ , Luca Banfi † , Renata Riva † and Andrea Basso* †. ... AB acknowledge M... more ... Stefano Crosignani ‡ , Luca Banfi † , Renata Riva † and Andrea Basso* †. ... AB acknowledge Merck Serono and Fondazione San Paolo for financial support. Supporting Information ... This article references 28 other publications. 1. Banfi, L. and Riva, R. The Passerini reaction. ...

Research paper thumbnail of 6-AMINO-PYRIMIDINE-4-CARBOXAMIDE Derivatives and Related Compounds Which Bind to the Sphingosine 1-PHOSPHATE (S1P) Receptor for the Treatment of Multiple Sclerosis

Research paper thumbnail of A Mild, Phosphine-Free Method for the Conversion of Alcohols into Halides (Cl, Br, I) via the Corresponding O-Alkyl Isoureas

Tetrahedron Letters

A novel procedure for the conversion of primary and secondary alcohols into the corresponding alk... more A novel procedure for the conversion of primary and secondary alcohols into the corresponding alkyl chlorides, bromides and iodides is described. The transformation is high-yielding in the case of chlorides and bromides, tolerates a range of functional groups, and does not rely on the use of phosphines.

Research paper thumbnail of Synthesis of Heterocycles Using Polymer-Supported Reagents under Microwave Irradiation

Research paper thumbnail of Preclinical assessment of a novel small molecule inhibitor of tryptophan 2,3-dioxygenase 2 (TDO2)

Journal for ImmunoTherapy of Cancer, 2014

Research paper thumbnail of A Mild, Phosphine-Free Method for the Conversion of Alcohols into Halides (Cl, Br, I) via the Corresponding O-Alkyl Isoureas

ChemInform, 2004

A novel procedure for the conversion of primary and secondary alcohols into the corresponding alk... more A novel procedure for the conversion of primary and secondary alcohols into the corresponding alkyl chlorides, bromides and iodides is described. The transformation is high-yielding in the case of chlorides and bromides, tolerates a range of functional groups, and does not rely on the use of phosphines.

Research paper thumbnail of ChemInform Abstract: 4-Naphthyl-Substituted Bis(oxazoline): A New, Easily Recoverable and Efficient Chiral Ligand in Asymmetric Catalysis of the Diels-Alder Reaction

Research paper thumbnail of Microwave-assisted ester formation using O-alkylisoureas: a convenient method for the synthesis of esters with inversion of configuration

The Journal of organic chemistry, Jan 3, 2009

The formation of carboxylic esters via reaction of carboxylic acids with O-alkylisoureas proceeds... more The formation of carboxylic esters via reaction of carboxylic acids with O-alkylisoureas proceeds in excellent yields with very short reaction times when conducted in a monomode microwave synthesizer. Efficient processes were developed using preformed or commercially available isoureas derived from primary and secondary alcohols, with a reaction time of only 5 min or less. It was demonstrated that under these microwave conditions, ester formation proceeded in good yields with clean inversion of configuration where appropriate. The process was validated using menthol, a hindered substrate for S(N)2 reactions. In addition, starting from primary alcohols, ester formation was successfully accomplished using an in situ isourea formation procedure. A polymer-assisted solution-phase procedure was also developed by employing preformed solid-supported isoureas and by an efficient "catch and release" ester formation procedure whereby primary alcohols were caught on resin as isoureas...

Research paper thumbnail of Microwaves, supported-reagents and parallel synthesis: Isocyanide and ester synthesis

Molecular Diversity, 2003

The benefits of microwave irradiation are described for a number of important reactions such as a... more The benefits of microwave irradiation are described for a number of important reactions such as amid and ester formation and dehydration of formamide to the corresponding isonitriles. Not only were reaction times dramatically reduced but the transformations were less prone to side reactions and decomposition.

Research paper thumbnail of A Practical Synthesis of a High-Loading Solid-Supported IBX Amide for the Oxidation of Alcohols

ChemInform, 2006

Oxidation O 0212 A Practical Synthesis of a High-Loading Solid-Supported IBX Amide for the Oxidat... more Oxidation O 0212 A Practical Synthesis of a High-Loading Solid-Supported IBX Amide for the Oxidation of Alcohols. -The novel IBX resin can be reoxidized and reused with minimal loss of activity after the second reoxidation. -(LECARPENTIER, P.; CROSIGNANI, S.; LINCLAU*, B.; Mol. Diversity 9 (2005) 4, 341-351; Comb. Cent. Excellence, Univ. Southampton, Southampton SO17 1BJ, UK; Eng.) -Nuesgen 21-043

Research paper thumbnail of Pharmacophore-Based Design of Novel Oxadiazoles as Selective Sphingosine-1-phosphate (S1P) Receptor Agonists with in vivo Efficacy

ChemMedChem, 2015

Sphingosine-1-phosphate (S1P) receptor agonists have shown promise as therapeutic agents for mult... more Sphingosine-1-phosphate (S1P) receptor agonists have shown promise as therapeutic agents for multiple sclerosis (MS) due to their regulatory roles within the immune, central nervous system, and cardiovascular system. Here, the design and optimization of novel [1,2,4]oxadiazole derivatives as selective S1P receptor agonists are described. The structure-activity relationship exploration was carried out on the three dominant segments of the series: modification of the polar head group (P), replacement of the oxadiazole linker (L) with different five-membered heterocycles, and the use of diverse 2,2'-disubstituted biphenyl moieties as the hydrophobic tail (H). All three segments have a significant impact on potency, S1P receptor subtype selectivity, physicochemical properties, and in vitro absorption, distribution, metabolism, excretion and toxicity (ADMET) profile of the compounds. From these optimization studies, a selective S1P1 agonist, N-methyl-N-(4-{5-[2-methyl-2'-(trifluoromethyl)biphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzyl)glycine (45), and a dual S1P1,5 agonist, N-methyl-N-(3-{5-[2'-methyl-2-(trifluoromethyl)biphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzyl)glycine (49), emerged as frontrunners. These compounds distribute predominantly in lymph nodes and brain over plasma and induce long lasting decreases in lymphocyte count after oral administration. When evaluated head-to-head in an experimental autoimmune encephalomyelitis mouse model, together with the marketed drug fingolimod, a pan-S1P receptor agonist, S1P1,5 agonist 49 demonstrated comparable efficacy while S1P1 -selective agonist 45 was less potent. Compound 49 is not a prodrug, and its improved property profile should translate into a safer treatment of relapsing forms of MS.

Research paper thumbnail of ChemInform Abstract: Novel Application of α-Azido Aldehydes in Multicomponent Reactions: Synthesis of Triazolo-Fused Dihydrooxazinones via a Passerini Reaction-Dipolar Cycloaddition Strategy

Research paper thumbnail of Synthesis of 2-oxazolines mediated by N,N′-diisopropylcarbodiimide

Tetrahedron Letters, 2004

It is known that amides do not react with isoureas. Nevertheless, as amides have a similar acidit... more It is known that amides do not react with isoureas. Nevertheless, as amides have a similar acidity to ketones, we envisioned that intra-or intermolecular activation of isoureas 2 would be possible, and that the cyclisation to form 2-oxazolines 3 as depicted in Scheme 2 would ...

Research paper thumbnail of ChemInform Abstract: Microwave-Assisted Ester Formation Using O-Alkylisoureas: A Convenient Method for the Synthesis of Esters with Inversion of Configuration

Research paper thumbnail of Polymer-Supported O -Methylisourea: A New Reagent for the O -Methylation of Carboxylic Acids

Organic Letters, 2002

[reaction: see text] A solid-supported O-methylisourea reagent has been prepared in one step star... more [reaction: see text] A solid-supported O-methylisourea reagent has been prepared in one step starting from commercially available solid-supported carbodiimide. The isourea reagent has been successfully used for the preparation of methyl esters from the corresponding carboxylic acids. The crude products obtained after resin filtration and solvent evaporation are generally obtained in >98% purity.

Research paper thumbnail of Chiral amplification in Diels-Alder and 1,3-dipolar cycloadditions catalyzed by bis(oxazoline)-Zn(II)-based chiral complexes

Tetrahedron Letters, 1999

A Zn(II)-bis(oxazoline) chiral complex catalyzes the cycloaddition reactions of alkenoyloxazolidi... more A Zn(II)-bis(oxazoline) chiral complex catalyzes the cycloaddition reactions of alkenoyloxazolidinones with both cyclopentadiene and diphenyl nitrone. The 1,3-dipolar cycloaddition becomes exo selective with an ee of up to 86%. While the Mg(II)-based catalysts give a linear relationship between the ligand's optical purity and the ee of the reaction product, a remarkable positive nonlinear effect was observed in both cycloadditions by using Zn(II) as the cationic core of the catalyst. The result may be rationalized by the formation of a stable, insoluble, and catalytically inactive heterochiral complex.

Research paper thumbnail of A mild, phosphine-free method for the conversion of alcohols into halides (Cl, Br, I) via the corresponding O-alkyl isoureas

Tetrahedron Letters, 2003

A novel procedure for the conversion of primary and secondary alcohols into the corresponding alk... more A novel procedure for the conversion of primary and secondary alcohols into the corresponding alkyl chlorides, bromides and iodides is described. The transformation is high-yielding in the case of chlorides and bromides, tolerates a range of functional groups, and does not rely on the use of phosphines.