Synthetic organic chemistry

 

Development of synthetic strategies to prepare different heterocycles using solid-phase chemistry

In regard to our recently developed synthetic pathways, the starting material was typically the natural amino acid immobilized via its C-terminus to Wang resin or primary amines immobilized via reductive amination to aminomethyl resin with the benzaldehyde linker. As shown below, the starting amino acid is converted in a multistep sequence to different heterocyclic scaffolds in which the first building block becomes an integral part of the heterocyclic scaffold or it forms a peripheral substituent.

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Our current projects were devoted to use of C-immobilized serine or cystein for diversity oriented, reagent-based synthesis of hetereocycles bearing oxazine/thiazine scaffolds. After sulfonylation of amino group with nitrobenzensulfonylchlorides and alkylation with bromoketones, the key intermediates were subjected to modification using different reagents, which yielded number of diverse heterocyclic scaffolds. Importantly, addition of triethylsilane in the cleavage cocktail (to liberate the target compounds from the resin) enabled to generate new stereocenter with controlled configuration. Below is demonstration of the high skeletal diversity of target compounds accessible from the key intermediates.

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Solid-phase synthesis concept was also applied in the project devoted to Mitsunobu C-alkylation of beta-alkoxycarbonyl 2-nitrobenzenesulfones.  The results indicated that, depending on the structure of the alcohol, the reaction is sterically controlled and it can selectively yield either dialkylated or monoalkylated products, even when using an excess of reagents or other azodicarboxylates. Furthermore, we have reported the first practical application of alkylated beta-alkoxycarbonyl 2-nitrobenzensulfones. The reduction of the nitro group was followed by cleavage from the polymer support, which provided benzothiazin-3(4H)-one 1,1-dioxides in a traceless manner.

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