Scaffold structures Michael addition

Langer and coworkers constructed diverse O- and N-heterocydic scaffolds, such as y-alkylidene-a-hydroxybutenolides and pyrrolo[3,2-b]pyrrol-2,5-diones, exploiting the well-established cyclization strategy of bisnucleophiles with oxalic acid derivatives [163], while Stockman s research group reported in this context on a novel oxime formation/Michael addition providing the structural core of the alkaloid perhydrohistrionicotoxin [164]. 

Trisubstituted six-member carbocycles were also prepared. Condensation of LI with commercial acetoacetanUides 9.14a-f produced, by one-pot Michael addition and Robinson annulation, the cyclohexenone library L4 (7680 members. Fig. 9.11). Noncommercial acetoacetamides Mi, prepared by condensation of diketene 9.15 with 40 primary and secondary amines (structures not shown in the paper), were used as monomers and condensed with a 320-member LI subset to give the expanded cyclohexenone library L5 (12,800 members). Difficulties in preparing extremely large discrete libraries, even using fuUy automated robotic workstations, and the need to diversify the screening set obliged the authors to limit the number of monomers and chalcones for any specific library/scaffold (see also LIO below). 

This type of compounds showed weak or moderate antibacterial and antifungal activities, with selectivity toward Bacillus subtilis and Candida albicans [5]. These bicyclic structures may offer a sterical hindrance to the nucleophilic attack to the electrophilic double bond conjugated to the carbonyl group, thus rendering it less susceptible to a Michael addition. Nevertheless, these molecules are unique scaffolds for further transformations into analogues of biologically active compounds, for example, pamlin, aiming at new, active, and nontoxic products. 

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