Introduction. 3-Hydroxy-3-substituted oxindole’s motifs have gained deal of pharmacological interest over the years. There substituted oxindoles are present in many biologically active molecules, ranging from naturally occurring to synthetically produced ones. The inflexibility of the quaternary carbon locks the adjoined the stereogenic center at the C-3 position into a fixed conformation such that it must receive some responsibility for its interaction with a given receptor. Popp F.D et al (J. Pharm. Science, 1983, 72, 318-321) reported that cyclohexanone have been condensed with isatin to give racemic the 3-hydroxy-3-substituted oxindole with anticonvulsant activity in the maximal electroshock seizure screen. In connection with our ongoing research towards the synthesis of both natural products and industrially relevant molecules, we are interested in the enantioselective synthesis of the 3-hydroxy-3-(2-oxocyclohexyl)indolin-2-one as anticonvulsant.
Aim. The aim of this investigation dedicated to demonstrate the selective formation of (-)(R)-3-hydroxy-3-[(R)-2-oxocyclohexyl]indolin-2-one. Our attention is to employ the resulting isatin and cyclohexanone as acceptors in cross-aldol additions, for the preparation of target molecule in aqueous medium.
Materials and methods. Commercially available and inexpensive chiral 1,2-amino alcohols cross-condensation reaction at room temperature, using both electron rich and poor ketones, have been achieved in good yield. Enantioselectivity of the asymmetric direct aldol reaction has been confirmed by chiral-phase HPLC analyses using Agilent Technologies 1100 series, a ChiralCel OD column: 0,46cm I.D. X 25cm, temp. 20oC (95:5 hexanes/i-PrOH at 1,5ml/min), UV-VIS 254nm, results in parentheses refer to the minor diastereoisomer.
Results and discussion. Our experiments shown that isatine and cyclohexanone in presence of 10 mol % catalysts have been converted into adduct. All reactions were performed at room temperature in mixture CH2Cl2/H2O and under completely heterogeneous conditions. Its structure has been elucidated by 2D-NMR.
A clear NOE difference interaction was observed between OH and CH, which suggests structure as (R)-3-hydroxy-3-[(R)-2-oxocyclohexyl]indolin-2-one. Absolute configurations assigned by comparison with literature data.
Enantioselectivity (up to 99% ee) and diastereoselectivity (98:2) of the direct aldol reaction has been confirmed by chiral-phase HPLC analyses using Agilent Technologies 1100 series, a ChiralCel OD column: 0,46cm I.D. X 25cm, temp.20oC (95:5 hexanes/i-PrOH at 1,5ml/min), UV-VIS 254nm, results in parentheses refer to the minor diastereomer.
Conclusions. We describe here synthetic route to enantiomerically pure 3-hydroxy-3-(2-oxocyclohexyl)indolin-2-one, which previously have been reported as potent anticonvulsant.