Abstract
Spiro compounds provide attractive targets in drug discovery due to their inherent three-dimensional structures, which enhance protein interactions, aid solubility and facilitate molecular modelling. However, synthetic methodology for the spiro-functionalisation of important classes of penicillin and cephalosporin β-lactam antibiotics is comparatively limited. We report a novel method for the generation of spiro-cephalosporin compounds through a Michael-type addition to the dihydrothiazine ring. Coupling of a range of catechols is achieved under mildly basic conditions (K2CO3, DMF), giving the stereoselective formation of spiro-cephalosporins (d.r. 14:1 to 8:1) in moderate to good yields (28−65%).
Highlights
IntroductionSpiro compounds (or spirocycles) are rigid scaffolds that consist of at least two rings fused through a single atom, known as the spiro atom
Spiro compounds are rigid scaffolds that consist of at least two rings fused through a single atom, known as the spiro atom
We report a novel synthetic strategy to synthesise spirocyclic cephalosporin analogues at site c through a Michael-type reaction
Summary
Spiro compounds (or spirocycles) are rigid scaffolds that consist of at least two rings fused through a single atom, known as the spiro atom. Spiro compounds are an important class of molecule, and spirocycles are found in a number of different natural products with pronounced biological activities. Growing efforts have been made to employ spirocyclic scaffolds as core or periphery structures in drug synthesis, and many show promising biological activities as cholesterol absorption inhibitors [3,4,5], anti-Parkinsonian agents [6,7,8], anti-Alzheimer’s agents [9,10,11], antiviral agents [12,13,14,15], antibacterial agents [16,17,18], β-lactamase inhibitors [19] and anticancer agents [20,21,22,23]. The inherent three-dimensional nature of spiro compounds provides better protein interactions as compared to their planar (hetero)aromatic counterparts [24]
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