Cross‐Aldol Reaction of Isatin with Acetone Catalyzed by Leucinol: A Mechanistic Investigation |
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| Authors: | Dr. Mikhail A. Kabeshov Dr. Ondřej Kysilka Dr. Lubomír Rulíšek Dr. Yury V. Suleimanov Dr. Marco Bella Prof. Dr. Andrei V. Malkov Prof. Dr. Pavel Kočovský |
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| Affiliation: | 1. Department of Chemistry, Loughborough University, Loughborough, Leics LE11 3TU (UK);2. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW (UK);3. FARMAK, Klá?terní Hradisko, 77900 Olomouc (Czech Republic);4. Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague 6 (Czech Republic);5. Computation‐based Science and Technology Research Center, Cyprus Institute, 20 Kavafi Str., Nicosia 2121 (Cyprus) & Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 (USA);6. Department of Chemistry, “Sapienza” University of Rome, Piazzale Aldo Moro 5, 00185 Rome (Italy);7. Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE 10691 Stockholm (Sweden) & Department of Organic Chemistry, Charles University, Hlavova 8, 12843 Prague 2 (Czech Republic) |
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| Abstract: | Comprehensive mechanistic studies on the enantioselective aldol reaction between isatin ( 1 a ) and acetone, catalyzed by L ‐leucinol ( 3 a ), 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 kcal mol?1 for the analogous L ‐alaninol, 3 b ) 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)‐ 2 a (calculated ΔG≠=11.6 kcal mol?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 kcal mol?1; and 2) the high preference of the syn‐enamine 6 to produce (S)‐ 2 a on reaction with isatin ( 1 a ) rather than its enantiomer (ΔΔG≠=2.6 kcal mol?1). |
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| Keywords: | computational studies enamines isatins oxazolidines self‐catalysis |
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