New Heterocyclic Product Space for the Castagnoli–Cushman Three-Component Reaction

Abstract

Significant expansion of heterocyclic product space accessible by the Castagnoli-Cushman reaction (CCR) has been achieved via the use of glutaric anhydride analogues containing endocyclic substitutions with oxygen, nitrogen, and sulfur. Incorporation of these heteroatoms in the anhydride's backbone results in enhanced reactivity and generally lower temperatures that are required for the reactions to go to completion. These findings are particularly significant in light of the CCR recently recognized as an efficient tool for lead-oriented synthesis.

The rare cis-configured trisubstituted lactam products obtained by the Castagnoli–Cushman reaction in N,N-dimethylformamide

“…4 Considering the challenges of inventing new LOS methods 5 and our recent interest in developing lead-like compound libraries, 6 particularly those employing the CCR, 7 we thought it important to try and overcome certain limitations of the CCR, which were evident from the literature. 4 Considering the challenges of inventing new LOS methods 5 and our recent interest in developing lead-like compound libraries, 6 particularly those employing the CCR, 7 we thought it important to try and overcome certain limitations of the CCR, which were evident from the literature.…”

Diversity-Oriented Synthesis and Chemoinformatic Analysis of the Molecular Diversity of sp3-Rich Morpholine Peptidomimetics

“…As case study to install quaternary stereocenters on the morpholine nucleus, we explored simple synthetic methodologies capable of transforming the sp 3 carbon atom in the α-position of the carbomethoxy group of different morpholin-3-one compounds. In particular, we selected methyl 5-oxomorpholine-2-carboxylate 25 derived by the application of the Castagnoli-Cushman reaction (Dar'in et al, 2015 ) between imine 23 and 1,4-dioxane-2,6-dione ( 24 ), and methyl 5-oxomorpholine-3-carboxylates 28 and 29 , obtained respectively from serine and threonine derivatives 26 - 27 after the acylation with α-bromoacetylbromide and subsequent NaH-mediated intramolecular cyclization reaction (Scheme 4 ). To improve the scaffold complexity and to install quaternary stereocenters on these compounds, we firstly studied the Staudinger reaction (Alcaide et al, 2007 ; Cossío et al, 2008 ; Omidvari and Zarei, 2018 ) with different aromatic imines to generate polycyclic spiro-β-lactams, in agreement with previous studies on 3-aza-6,8-dioxabicyclo[3.2.1]octane bicycles giving compounds 4 (Trabocchi et al, 2007 ).…”

Brønsted acid-mediated cyclization–dehydrosulfonylation/reduction sequences: An easy access to pyrazinoisoquinolines and pyridopyrazines

“…Sulfonamides also participate in amide hydrolysis with external nucleophiles such as phosphide anions [33] or phenyldimethylsilyllithium [34]. The combinations of thiophenol/K 2 CO 3 [35] or NaOH/MeOH [36] are also known to hydrolyse sulfonamides. These methods lead to the formation of the corresponding free amines.…”