Amberlyst 15: A Practical, Mild and Selective Catalyst for Methyl Esterification of Carboxylic Acids.<sup>1</sup>

Petrini, Marino; Ballini, Roberto; Marcantoni, Enrico; Rosini, Goffredo

doi:10.1080/00397918808057854

Cited by 64 publications

(41 citation statements)

References 9 publications

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“…Solvents and reagents were reagent-grade, purchased from commercial suppliers, and used without further purification unless otherwise stated. The following compounds were prepared according to literature procedures: 4-bromophenylalanine (12) [57], N-substituted maleimides [58], 4-toluenesulfinic acid [59], cyclopropylmagnesium bromide [60], and methyl (À)-d-mandelate [61]. THF and Et 2 O were freshly distilled from sodium benzophenone ketyl, CH 2 Cl 2 from CaH 2 .…”

Section: Experimental Partmentioning

confidence: 99%

Synthesis of Novel Nonpeptidic Thrombin Inhibitors

Obst¹,

Betschmann²,

Lerner³

et al. 2000

HCA

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A novel class of nonpeptidic, active, and selective thrombin inhibitors has resulted from X‐ray‐structure‐based design and subsequent improvement of the initial lead molecules. These inhibitors possess a bi‐ or tricyclic central core structure with attached side chains to reach the three binding pockets (selectivity S1 pocket, distal D pocket, and proximal P pocket) present in the active site of the enzyme. The key step in the preparation of these compounds is the 1,3‐dipolar cycloaddition between an azomethine ylide, prepared in situ by the decarboxylative method from an aromatic aldehyde and an α‐amino acid, with an N‐substituted maleimide (e.g., see Schemes 1 and 2). All potent inhibitors contain an amidinium residue in the side chain for incorporation into the S1 pocket, which was introduced in the last step of the synthesis by a Pinner reaction. The compounds were tested in biological assays for activity against thrombin and the related serine protease trypsin. The first‐generation lead compounds (±)‐11 and (±)‐19 (Scheme 1) with a bicyclic central scaffold showed Ki values for thrombin inhibition of 18 μM and 0.67 μM, respectively. Conformationally more restricted second‐generation analogs (Scheme 2) were more active ((±)‐22i: Ki=90 nM (Table 1)); yet the selectivity for thrombin over trypsin remained weak. In the third‐generation compounds, a small lipophilic side chain for incorporation into the hydrophobic P pocket was introduced (Schemes 7 and 8). Since this pocket is present in thrombin but not in trypsin, an increase in binding affinity was accompanied by an increase in selectivity for thrombin over trypsin. The most selective inhibitor (Ki=13 nM, 760‐fold selectivity for thrombin over trypsin; Table 2) was (±)‐1 with an i‐Pr group for incorporation into the P pocket. Optical resolution of (±)‐1 (Scheme 9) provided (+)‐1 with a Ki value of 7 nM and a 740‐fold selectivity, whereas (−)‐1 was 800‐fold less active (Ki=5.6 μM, 21‐fold selectivity). The absolute configuration of the stronger‐binding enantiomer was assigned based on the X‐ray crystal structure of the complex formed between thrombin and this inhibitor. Compound (+)‐1 mimics the natural thrombin substrate, fibrinogen, which binds to the enzyme with the Ph group of a phenylalanine (piperonyl in (+)‐1) in the distal D pocket, with the i‐Pr group of a valine (i‐Pr in (+)‐1) in the proximal P pocket, and with a guanidinium side chain of an arginine residue (phenylamidinium group in (+)‐1) in the selectivity S1 pocket of thrombin. A series of analogs of (±)‐1 with the phenylamidinium group replaced by aromatic and aliphatic rings bearing OH or NH2 groups (Schemes 10 – 14) were not effectively bound by thrombin. A number of X‐ray crystal‐structure analyses of free inhibitors confirmed the high degree of preorganization of these compounds in the unbound state. Since all inhibitors prefer similar modes of association with thrombin, detailed information on the strength of individual intermolecular bonding interactions and their incremental con...

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Section: Experimental Partmentioning

confidence: 99%

Synthesis of Novel Nonpeptidic Thrombin Inhibitors

Obst¹,

Betschmann²,

Lerner³

et al. 2000

HCA

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“…Attempts have been made to overcome these disadvantages by using heterogeneous catalyst systems. The heterogeneous catalyst systems include cationic-exchanged resins like Amberlyst-15 [3], zeolites [4], metal oxides like sulphated zirconia and titania [5], heteropolyacids supported on silica and carbon [6], palladium on charcoal [7], silica chloride [8], aluminophosphate and silicoaluminophosphate molecular sieves [9], and cation exchanged montmorillonite K-10 [10]. In particular, the clay catalysts have received considerable attention in different organic syntheses because of their environmental compatibility, low cost, high selectivity, reusability and operational simplicity [11].…”

Section: Introductionmentioning

confidence: 99%

Esterification of dicarboxylic acids to diesters over Mn+-montmorillonite clay catalysts

et al. 2005

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Esterification of dicarboxylic acids with various alcohols and phenols in presence of metal exchanged montmorillonite clay catalyst (M n+ -mont; M nþ ¼ Al 3þ , Fe 3+ , Cr 3+ , Zn 2+ , Mn 2+ , and Ni 2+ ) is studied. Among the catalysts used, Al 3+ -mont was found to be the most effective, as it gave good to excellent yields of esters under mild reaction conditions. The heterogeneous catalyst presented here can be regenerated and reused. All these features indicate the high potential of the reaction as ''green chemistry'' process.

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“…We found the re-the ion-exchange resin Amberlyst 15 in methanol quantita- tively afforded methyl cholate [30] . We found the re-the ion-exchange resin Amberlyst 15 in methanol quantita- tively afforded methyl cholate [30] .…”

Section: Attempted Preparation Of Vinyl Azides By Differentmentioning

confidence: 84%

Synthesis of Cephalostatin Analogues by Symmetrical and Non-Symmetrical Routes

et al. 1998

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The synthesis of the cephalostatin‐analogous bis‐steroidal pyrazines 6, 27a/b and 41 by the transformation of the C2‐symmetrical diketone 6 as a central precursor, as well as the direct preparation of several non‐symmetrical bis‐steroidal pyrazines by coupling of enamino ketones (5, 40) with vinyl azides (17a/b) is reported. Furthermore, an improved procedure for preparation of the diketone 6 described earlier is presented.

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Amberlyst 15: A Practical, Mild and Selective Catalyst for Methyl Esterification of Carboxylic Acids.¹

Cited by 64 publications

References 9 publications

Synthesis of Novel Nonpeptidic Thrombin Inhibitors

Synthesis of Novel Nonpeptidic Thrombin Inhibitors

Esterification of dicarboxylic acids to diesters over Mn+-montmorillonite clay catalysts

Synthesis of Cephalostatin Analogues by Symmetrical and Non-Symmetrical Routes

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Amberlyst 15: A Practical, Mild and Selective Catalyst for Methyl Esterification of Carboxylic Acids.1

Cited by 64 publications

References 9 publications

Synthesis of Novel Nonpeptidic Thrombin Inhibitors

Synthesis of Novel Nonpeptidic Thrombin Inhibitors

Esterification of dicarboxylic acids to diesters over Mn+-montmorillonite clay catalysts

Synthesis of Cephalostatin Analogues by Symmetrical and Non-Symmetrical Routes

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Amberlyst 15: A Practical, Mild and Selective Catalyst for Methyl Esterification of Carboxylic Acids.¹