A simple formamide catalyst facilitates the efficient transformation of alcohols into alkyl chlorides with benzoyl chloride as the sole reagent. These nucleophilic substitutions proceed through iminium-activated alcohols as intermediates. The novel method, which can be even performed under solvent-free conditions, is distinguished by an excellent functional group tolerance, scalability (>100 g) and waste-balance (E-factor down to 2). Chiral substrates are converted with excellent levels of stereochemical inversion (99 %→≥95 % ee). In a practical one-pot procedure, the primary formed chlorides can be further transformed into amines, azides, ethers, sulfides, and nitriles. The value of the method was demonstrated in straightforward syntheses of the drugs rac-Clopidogrel and S-Fendiline.
Miuraenamides, secondary metabolites of the marine myxobacterium Paraliomyxa miuraensis do not only show a high structural similarity to other cyclodepsipeptides isolated from sponges or terrestrial myxobacteria but they also exhibit a similar mode of action. They accelerate nucleation and polymerization of actin, and therefore interfere with cell division processes, at concentrations in the low nanomolar range. A late stage peptide modification allows the synthesis of a library of (simplified) miuraenamide derivatives with different halogenation and substitution pattern. Detailed SAR studies indicate, that bromination of the central tyrosine is essential for good biological activity, while the side chain of the C‐terminal amino acid can be varied or can even be removed.
Ein einfacher Formamidkatalysator ermöglicht effiziente Transformationen von Alkoholen zu Alkylchloriden mit Benzoylchlorid als einzigem Reagenz. Diese nukleophilen Substitutionsreaktionen verlaufen über iminiumaktivierte Alkohole als Intermediate. Die neue Methode, die sogar lösungsmittelfrei durchgeführt werden kann, zeichnet sich durch eine exzellente Kompatibilität mit funktionellen Gruppen, Skalierbarkeit (>100 g) und Abfallbilanz aus (E‐Faktor bis zu 2). Chirale Substrate werden unter einem hohen Grad an stereochemischer Inversion in die entsprechenden Chloride überführt (99 %→≥95 % ee). In einem praktischen Eintopfverfahren konnten die primär gebildeten Chloride direkt zu Aminen, Aziden, Ethern, Sulfiden und Nitrilen weiter umgesetzt werden. Der praktische Nutzen der Methode wurde darüber hinaus in kurzen Synthesen von rac‐Clopidogrel und S‐Fendilin bewiesen.
Introduction: Miuraenamides belong to marine natural compounds with interesting biological properties. Materials and Methods: They initiate polymerization of monomeric actin and therefore show high cytotoxicity by influencing the cytoskeleton. New derivatives of the miuraenamides have been synthesized containing a N-methylated amide bond instead of the more easily hydrolysable ester in the natural products. Results: Incorporation of an aromatic side chain onto the C-terminal amino acid of the tripeptide fragment also led to highly active new miuraenamides. Conclusion: We could show that the ester bond of the natural product miuraenamide can be replaced by an N-methyl amide. The yields in the cyclization step are high and generally much better that with the corresponding esters. On the other hand, the biological activity of the new amide analogs are lower compared to the natural products, but the activity can significantly be increased by incorporation of a p-nitrophenyl group at the C-terminus of the peptide fragment.
Miuraenamides, a group of marine cyclodepsipeptides, closely related to jasplakinolide and geodiamolide are found to accelerate nucleation and polymerization of actin, and therefore interfere with cell division processes, at concentrations in the low nanomolar range. For SAR studies derivatives are synthesized via Ugi reaction, which provides the complete tripeptide fragment in only one step. While a wide range of modifications are possible at the C-terminus of the peptide, variations at the central position are not tolerated. Neither modifications in the polyketide.
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