Utilisation of chiral enaminones and azomethine imines in the synthesis of functionalised pyrazoles

Abstract

Chiral enaminones, derived from commercially available enantipure starting materials, such as (+)-camphor and α-amino acids, were employed in cycloconcensation reactions with hydrazine derivatives to afford the corresponding pyrazoles, functionalised with terpene, alanine, 2-phenylethylamine, and β-amino alcohol moiety. On the other hand, recent study on stereocontrol in cycloadditions of racemic (1Z,4R*,5R*)-1-arylmethylidene-4-benzoylamino-5-phenylpyrazolidin-3-one-1-azomethine imines, available in three steps from hippuric acid, showed, that stereodirecting phenyl group, as well as ortho-substituents at the aromatic ring, control the selectivity of these cycloadditions. In extension, these results are now applied in a study, which is oriented towards combinatorial synthesis of pyrazolo[1,2-a]pyrazolone type of peptidomimetics with variable, yet predictable configuration.

1,3-Dipolar cycloadditions of azomethine imines

“…94 Stereoselective synthesis of fused pyrazolones has been studied with racemic pyrazolidin-3-one 171, which after reaction with benzaldehydes, followed by [3 + 2] cycloadditions of the generated azomethine imines 172 with electron-deficient dipolarophiles such as methyl acrylate, dimethyl acetylene dicarboxylate and dimethyl maleate, gave pyrazolopyrazolone derivatives 173-175 with high stereocontrol (Scheme 66). 96,97 The stereoselective cycloaddition of azomethine imines 172 with maleimides provided cycloadducts 176 when the aldehydes had no substituents at the ortho-position. However, with ortho-substituted aldehydes diastereomeric adducts 177 were formed.…”

Acceleration of the Eschenmoser coupling reaction by sonication: efficient synthesis of enaminones

“…1 Enaminones are important building blocks in organic synthesis. They are used in the synthesis of natural products [2][3][4] and utilized in the development of pharmaceuticals, 5,6 peptidomimetics, 7,8 ligands for catalysis 9,10 and chiral auxiliaries. 11 Additionally, enaminones form part of biologically active compounds.…”

Combinatorial Solution-Phase Synthesis of (2S,4S)-4-Acylamino-5-oxopyrrolidine-2-carboxamides

“…2-Substituted alkyl 3-(dimethylamino)prop-2-enoates and related enaminones are a group of easily available enamino-masked alkyl α-formylacetates, which are versatile reagents in heterocyclic synthesis. They were used in the synthesis of various heterocyclic systems, − including functionalized heterocycles, − and natural product analogs. ,− Recently, the use of 3-(dimethylamino)prop-2-enoates was extended toward combinatorial synthesis of protected 3-(arylamino)alanines and fused heterocycles. − Until now, several reviews on utilization of 3-(dimethylamino)prop-2-enoates and analogous reagents in heterocyclic synthesis have been published. − In connection with the synthesis of γ-aminopyroglutamic acid derivatives, we have previously reported a stereoselective amination of chiral γ-lactams and γ-lactones . The synthetic availability and interesting structural features of these α-amino lactams prompted us to carry out an extension toward the preparation of suitably protected γ-aminopyroglutamic acid derivatives as building blocks and scaffolds in combinatorial synthesis of (2 S ,4 S )-4-acylamino-5-oxopyrrolidine-2-carboxamides as potential peptidomimetics.…”