N-(3-Phenylprop-2-yn-1-yl)-sulfonamides derived from serine and threonine were synthesized using solid-phase synthesis and subjected to reaction with trimethylsilyl trifluoromethanesulfonate (TMSOTf). In contrast to the previously reported formation of 1,4-oxazepanes, this reaction afforded pyrrolidin-3-ones. A mechanistic explanation for this unexpected outcome is proposed, and the limitations and scope of the rearrangement are outlined.
Drug discovery efforts largely depend on access to structural diversity. Multicomponent reactions allow for time-efficient chemical transformations and provide advanced intermediates with three or four points of diversification for further expansion to a structural variety of organic molecules. This review is aimed at solid-phase syntheses of small molecules involving isocyanide-based multicomponent reactions. The majority of all reported syntheses employ the Ugi four-component reaction. The review also covers the Passerini and Groebke-Blackburn-Bienaymé reactions. To date, the main advantages of the solid-phase approach are the ability to prepare chemical libraries intended for biological screening and elimination of the isocyanide odor. However, the potential of multicomponent reactions has not been fully exploited. The unexplored avenues of these reactions, including chiral frameworks, DNA-encoded libraries, eco-friendly synthesis, and chiral auxiliary reactions, are briefly outlined.
We present the solid-phase synthesis of 1,2-dihydroquinazoline-2-carboxylate derivatives with a quaternary carbon in position 2 and their subsequent cyclization in solution into compounds with unique 3D architectures and pharmacological relevance-spiroquinazolines, namely, 1' H-spiro[pyrrolidine-3,2'-quinazolin]-2-ones and 1' H-spiro[piperidine-3,2'-quinazolin]-2-ones. Acyclic precursors were prepared from commercially available building blocks: protected amino acids (2,4-diaminobutyric acid and ornithine), 2-nitrobenzensulfonyl chlorides and α-bromoacetophenones. The crucial step of the synthesis was a base-mediated tandem reaction including C-arylation followed by cyclization into indazole oxides, and the formation of a 5-membered heterocycle was accomplished by ring expansion into quinazolines. These derivatives were cyclized into spiro compounds in solution after cleavage from the resin.
- MeSH
- acetofenony chemie MeSH
- aminobutyráty chemie MeSH
- chinazoliny chemická syntéza MeSH
- cyklizace MeSH
- nitrobenzeny chemie MeSH
- ornithin chemie MeSH
- piperidiny chemická syntéza MeSH
- pyrrolidiny chemická syntéza MeSH
- spirosloučeniny chemická syntéza MeSH
- techniky syntézy na pevné fázi metody MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A preloaded resin consisting of a thalidomide moiety and an ethylene-oxy linker allows the simple and fast formation of PROTACs. The feasibility of the procedure was illustrated by conjugating different protein kinase inhibitors. The biological functionality of an ibrutinib-like conjugate was then confirmed by a cellular experiment.
- MeSH
- amidy chemická syntéza MeSH
- inhibitory proteinkinas MeSH
- ligandy MeSH
- močovina chemická syntéza MeSH
- proteolýza MeSH
- syntetické pryskyřice MeSH
- techniky syntézy na pevné fázi metody MeSH
- thalidomid * chemická syntéza MeSH
- triazoly chemická syntéza MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
We present the application of a Glaser-Hay diyne coupling for the synthesis of conformationally constrained Nα-amino acid amides with different diyne ring sizes. Twelve-membered rings were the smallest rings that could be prepared by this approach. We observed the formation of triethylammonium adducts in the cases of smaller (10- and 11-membered) rings. Calculation of the conformational barriers for the cyclization reactions of various ring sizes demonstrated that the formation of amino acid-derived smaller rings by this reaction is thermodynamically unfavorable.
- MeSH
- alkyny chemie MeSH
- amidy chemická syntéza MeSH
- aminokyseliny chemie MeSH
- aminy chemie MeSH
- cyklizace MeSH
- diyny chemie MeSH
- katalýza MeSH
- molekulární konformace MeSH
- molekulární modely MeSH
- techniky syntézy na pevné fázi metody MeSH
- termodynamika MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The synthesis of different diketomorpholines via N-acyl-3,4-dihydro-2 H-1,4-oxazine-3-carboxylic acids is reported in this article. The key intermediates were prepared using a convenient solid-phase synthesis starting from polymer-supported Ser( tBu)-OH. After subsequent sulfonylation with 4-nitrobenzenesulfonyl chloride (4-Nos-Cl), alkylation with an α-bromoketone, cleavage of the 4-Nos group and acylation with an α-halocarboxylic acids, acid-mediated cleavage from the resin yielded dihydrooxazine-3-carboxylic acids in high crude purities. Depending on the reaction conditions, exposure to base resulted in cyclization to either oxazino[3,4- c][1,4]oxazine-diones or 3-methylidenemorpholine-2,5-diones. Further reaction with triethylsilane-trifluoroacetic acid (TES/TFA) led to olefin reduction, in the case of oxazino[3,4- c][1,4]oxazine-dione with full control of the newly formed stereocenter.
- MeSH
- acylace MeSH
- alkylace MeSH
- cyklizace MeSH
- kyselina trifluoroctová chemie MeSH
- kyseliny karboxylové chemie MeSH
- molekulární struktura MeSH
- morfoliny chemická syntéza MeSH
- nitrobenzeny chemie MeSH
- oxaziny chemie MeSH
- polymery chemie MeSH
- silany chemie MeSH
- stereoizomerie MeSH
- techniky syntézy na pevné fázi metody MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
In this review, we summarize synthetic approaches to preparing single or fused oxazine and thiazine derivatives using solid-phase synthesis (SPS). The literature survey revealed that diverse compounds bearing variously functionalized 1,2-oxazine, 1,3-oxazine, or 1,4-oxazine scaffolds and the corresponding thiazines are accessible by SPS. The latest contributions involving the stereoselective polymer-supported syntheses of morpholines indicate that the field is continuing to expand.
- MeSH
- cykloadiční reakce MeSH
- knihovny malých molekul chemie MeSH
- molekulární struktura MeSH
- morfoliny chemie MeSH
- oxaziny chemická syntéza MeSH
- oxidace-redukce MeSH
- polymery chemie MeSH
- pyrazoly chemie MeSH
- stereoizomerie MeSH
- techniky syntézy na pevné fázi metody MeSH
- thiaziny chemická syntéza MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Herein we report the polymer-supported synthesis of 3,4-dihydro-2H-1,4-oxazine-3-carboxylic acid derivatives using immobilized Fmoc-Ser(tBu)-OH and Fmoc-Thr(tBu)-OH as the starting materials. After the solid-phase-synthesis of N-alkyl-N-sulfonyl/acyl intermediates, the target dihydrooxazines were obtained using trifluoroacetic acid-mediated cleavage from the resin. This approach was also studied for the preparation of dihydrothiazines from immobilized Fmoc-Cys(Trt)-OH. Inclusion of triethylsilane in the cleavage cocktail resulted in the stereoselective formation of the corresponding morpholine/thiomorpholine-3-carboxylic acids. Stereochemical studies revealed the specific configuration of the newly formed stereocenter and also the formation of stable N-acylmorpholine rotamers.
- MeSH
- fluoreny chemie MeSH
- kyseliny karboxylové chemická syntéza chemie MeSH
- morfoliny chemická syntéza chemie MeSH
- oxaziny chemická syntéza chemie MeSH
- polymery chemie MeSH
- stereoizomerie MeSH
- techniky syntézy na pevné fázi metody MeSH
- thiaziny chemická syntéza chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
This Review summarizes all of the currently described strategies applicable for the solid-phase synthesis of purine derivatives. The individual approaches are classified according to the immobilization procedure used resulting in a linkage of the final scaffold at various positions.
Synthesis of 2,3-dihydrobenzo[f][1,2,5]thiadiazepin-4(5H)-one 1,1-dioxides from polymer-supported α-amino acids is described herein. Different α-amino acids immobilized on Wang resin were sulfonylated with various 2-nitrobenzenesulfonyl chlorides. The resulting 2-nitrobenzenesulfonamides were alkylated with alcohols according to the Fukuyama-Mitsunobu procedure. After reduction of the nitro group and cleavage from the polymer support, the final intermediates were reacted with thionyl chloride, and target compounds of good crude purity and acceptable overall yields were obtained. The chiral HPLC studies revealed the impact of the cyclization step on the resulting stereochemistry. The developed strategy allows for simple production of desired compounds with the application of parallel/combinatorial solid-phase synthesis using commercially available building blocks.
