Diastereomer Interconversion via Enolization: A Case Study.
The three-component reaction of indole, isobutyraldehyde, and methyl acetoacetate affords methyl 2-(acetyl)-3-(1H-indol-3-yl)-4-methylpentanoate as a single diastereomer. To investigate the origin of the observed diastereoselectivity, the thermodynamics and kinetics of interconversion of diastereomers 1 and 2 in solution were studied by a combination of (1)H nuclear magnetic resonance (NMR) spectroscopy, high-performance liquid chromatography (HPLC), mass spectrometry, and deuteration experiments. The results indicate that interconversion is both acid- and base-catalyzed, and that the alpha carbon is the only stereolabile center in the molecule. The evidence points to an enolization mechanism for the interconversion process. The selective precipitation of 1 in the presence of the equilibrium 1⇆2 eventually results in the exclusive formation of 1 (crystallization-induced asymmetric transformation).
Department of Chemistry, University of Cambridge, Cambridge, UK.
Andrea
A
Renzetti
Dipartimento di Farmacia, Università "G. d'Annunzio" di Chieti-Pescara, Chieti, Italy.
Antonello
A
Di Crescenzo
Department of Chemistry, University of Cambridge, Cambridge, UK.
Feilin
F
Nie
Department of Chemistry, University of Cambridge, Cambridge, UK.
Andrew D
AD
Bond
Institut de Chimie Moléculaire de Reims, UMR CNRS 7312, Université de Reims Champagne-Ardenne, Faculté de Pharmacie, Reims, France.
Stéphane
S
Gérard
Institut de Chimie Moléculaire de Reims, UMR CNRS 7312, Université de Reims Champagne-Ardenne, Faculté de Pharmacie, Reims, France.
Janos
J
Sapi
Dipartimento di Farmacia, Università "G. d'Annunzio" di Chieti-Pescara, Chieti, Italy.
Antonella
A
Fontana
Dipartimento di Chimica e Tecnologie del Farmaco, Università di Roma "La Sapienza,", Rome, Italy.
Claudio
C
Villani
D000090:Acetoacetates / Q000737:chemistry*; D000447:Aldehydes / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D007211:Indoles / Q000737:chemistry*; D066244:Proton Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism
D000090:Acetoacetates; D000447:Aldehydes; D007211:Indoles; C017439:isobutyraldehyde
HPLC; MS; NMR; asymmetric; crystallization; deuteration; keto-enol; kinetics; multicomponent; tautomerization