Synthesis of Spiro[indole-3,5′-isoxazoles] with Anticancer Activity via a Formal [4 + 1]-Spirocyclization of Nitroalkenes to Indoles

Abstract

An acid-assisted [4 + 1]-cycloaddition of indoles with nitrostyrenes affords 4′H-spiro­[indole-3,5′-isoxazoles] in a diastereomerically pure form. Several of these spirocyclic molecules exhibit promising anticancer activity by reducing viability and inducing differentiation of neuroblastoma cells.

Direct Conversion of 3-(2-Nitroethyl)-1H-Indoles into 2-(1H-Indol-2-yl)Acetonitriles

“…Next, deprotonation at the adjacent carbon produces enamine species 8. Subsequent elimination of the phosphoryl moiety affords oxime 9, which, once formed, undergoes a 5-endo-trig cyclization to provide a spirocyclic iminium species 10, which was described in our previous report [18] (Scheme 3). If R 3 = H, a deprotonation may occur, leading to a more stable imine form 5, as shown in Scheme 1 (vide supra).…”

“…We have previously reported that generation of the key 4 H-spiro[indole-3,5 -isoxazole] 5 [18,19] takes place under acidic conditions, while isomerization of the latter into nitrile 6 occurs in the presence of weak bases [20]. Arguably, activation of nitroalkane 4 toward the desired transformation requires generation of nitronic acid 3 (also known as aci-form), which occurs in a basic medium [18]. To test this idea, nitroalkane 4ba was refluxed in benzene in the presence of several carboxylic acids/triethylamine combinations (Table 1, entries 1,2).…”

“…This reaction was repeated in a preparative scale and, after isolation and purification, afforded the target nitrile in 72% yield. Further optimization attempts were unproductive and led to a decreased product yield (entries [15][16][17][18][19][20].…”

“…Thus, synthetic methods for selective preparation of these 1H-indole derivatives remain the focus of many research groups. Recently, we reported an unusual, acid-assisted [4+1]-cycloaddition of indoles 1 with nitroalkenes 2 that provides 4 H-spiro[indole-3,5isoxazoles] 5 in a diastereomerically pure form (Scheme 1) [18,19]. It was confirmed that this spirocyclization occurs via nitronate intermediate 3.…”

Preparation of 3,5-diarylsubstituted 5-hydroxy-1,5-dihydro-2H-pyrrol-2-ones via base-assisted cyclization of 3-cyanoketones

“…During our research involving nitrogen-based heterocyclic compounds [26][27][28] we got very enthusiastic about the possibility of employing synthetic equivalents of bis-electrophilic 3,4-dihydro-2H-pyrrol-1-ium-4-ylium synthon for expeditious assembly of bicyclic and tricyclic heterocyclic scaffolds. Although the structure of 5-hydroxy-1,5-dihydro-2H-pyrrol-2-ones 8 seems to be a suitable synthetic equivalent, lengthy and laborious synthetic approaches to these molecules rendered this idea cost-prohibitive and much less exciting.…”