title: Cross-Aldol Reaction of Isatin with Acetone Catalyzed by Leucinol: A Mechanistic Investigation.
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) ).
authors.affiliation: Department of Chemistry, Loughborough University, Loughborough, Leics LE11 3TU (UK). mk787@cam.ac.uk.|Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW (UK). mk787@cam.ac.uk.
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Kabeshov
authors.affiliation: FARMAK, Klášterní Hradisko, 77900 Olomouc (Czech Republic).
authors.forename: Ondřej
authors.initials: O
authors.lastname: Kysilka
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague 6 (Czech Republic).
authors.forename: Lubomír
authors.initials: L
authors.lastname: Rulíšek
authors.affiliation: 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).
authors.forename: Yury V
authors.initials: YV
authors.lastname: Suleimanov
authors.affiliation: Department of Chemistry, "Sapienza" University of Rome, Piazzale Aldo Moro 5, 00185 Rome (Italy).
authors.forename: Marco
authors.initials: M
authors.lastname: Bella
authors.affiliation: Department of Chemistry, Loughborough University, Loughborough, Leics LE11 3TU (UK). a.malkov@lboro.ac.uk.
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Malkov
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague 6 (Czech Republic). pavel@organ.su.se.|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). pavel@organ.su.se.
authors.forename: Pavel
authors.initials: P
authors.lastname: Kočovský
keywords: computational studies; enamines; isatins; oxazolidines; self-catalysis