Comprehensive mechanistic studies on the enantioselective aldol reaction between isatin (1a) and acetone, catalyzed by L-leucinol (3a), unraveled that isatin, apart from being a substrate, also plays an active catalytic role. Conversion of the intermediate oxazolidine 4 into the reactive syn-enamine 6, catalyzed by isatin, was identified as the rate-determining step by both the calculations (ΔG≠=26.1 kcalmol-1 for the analogous L-alaninol, 3b) and the kinetic isotope effect (kH/kD=2.7 observed for the reaction using [D6]acetone). The subsequent reaction of the syn-enamine 6 with isatin produces (S)-2a (calculated ΔG≠=11.6 kcalmol-1). The calculations suggest that the overall stereochemistry is controlled by two key events: 1) the isatin-catalyzed formation of the syn-enamine 6, which is thermodynamically favored over its anti-rotamer 7 by 2.3 kcalmol-1; and 2) the high preference of the syn-enamine 6 to produce (S)-2a on reaction with isatin (1a) rather than its enantiomer (ΔΔG≠=2.6 kcalmol-1).

Cross-aldol reaction of isatin with acetone catalyzed by leucinol: a mechanistic investigation / Kabeshov, Mikhail A.; Kysilka, Ondřej; Rulíšek, Lubomír; Suleimanov, Yury V.; Bella, Marco; Malkov, Andrei V.; Kocovsky, Pavel. - In: CHEMISTRY-A EUROPEAN JOURNAL. - ISSN 0947-6539. - STAMPA. - 21:34(2015), pp. 12026-12033. [10.1002/chem.201500536]

Cross-aldol reaction of isatin with acetone catalyzed by leucinol: a mechanistic investigation

BELLA, Marco;KOCOVSKY, PAVEL
2015

Abstract

Comprehensive mechanistic studies on the enantioselective aldol reaction between isatin (1a) and acetone, catalyzed by L-leucinol (3a), unraveled that isatin, apart from being a substrate, also plays an active catalytic role. Conversion of the intermediate oxazolidine 4 into the reactive syn-enamine 6, catalyzed by isatin, was identified as the rate-determining step by both the calculations (ΔG≠=26.1 kcalmol-1 for the analogous L-alaninol, 3b) and the kinetic isotope effect (kH/kD=2.7 observed for the reaction using [D6]acetone). The subsequent reaction of the syn-enamine 6 with isatin produces (S)-2a (calculated ΔG≠=11.6 kcalmol-1). The calculations suggest that the overall stereochemistry is controlled by two key events: 1) the isatin-catalyzed formation of the syn-enamine 6, which is thermodynamically favored over its anti-rotamer 7 by 2.3 kcalmol-1; and 2) the high preference of the syn-enamine 6 to produce (S)-2a on reaction with isatin (1a) rather than its enantiomer (ΔΔG≠=2.6 kcalmol-1).
2015
computational studies; enamines; isatins; oxazolidines; self-catalysis
01 Pubblicazione su rivista::01a Articolo in rivista
Cross-aldol reaction of isatin with acetone catalyzed by leucinol: a mechanistic investigation / Kabeshov, Mikhail A.; Kysilka, Ondřej; Rulíšek, Lubomír; Suleimanov, Yury V.; Bella, Marco; Malkov, Andrei V.; Kocovsky, Pavel. - In: CHEMISTRY-A EUROPEAN JOURNAL. - ISSN 0947-6539. - STAMPA. - 21:34(2015), pp. 12026-12033. [10.1002/chem.201500536]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/947390
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