Diastereomer Interconversion via Enolization: A Case Study

Abstract

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).

Biosynthesis of the Antibiotic Nematophin and Its Elongated Derivatives in Entomopathogenic Bacteria

“…Compounds 5 and 8 (Figures S13–S16) were synthesized by standard methods using racemic 3-methyl-2-oxopentanoic acid, providing a mixture of diastereomers that displayed spectroscopic properties identical to those of natural 5 . The complex NMR spectra of natural and synthetic 5 arise from the presence of multiple diastereomers due to keto–enol tautomerization and thus racemization of the 3-methyl-2-oxopentanoyl moiety . Furthermore, slowly interconverting conformers at the N -methyl amide, consistent with those reported for the related peptides xenortides A and B from X.…”

“…The complex NMR spectra of natural and synthetic 5 arise from the presence of multiple diastereomers due to keto−enol tautomerization and thus racemization of the 3-methyl-2-oxopentanoyl moiety. 16 Furthermore, slowly interconverting conformers at the N-methyl amide, consistent with those reported for the related peptides xenortides A and B from X. nematophila, 17 add to the complex NMR spectra of 5. Finally, the absolute configuration of the N-methyl-L-valine residue was determined via the "advanced Marfey's method" (Figure S17), confirming the structure as shown in Figure 2a.…”

Determination of the absolute configuration of conformationally flexible molecules by simulation of chiro-optical spectra: a case study

“…10 Due to the reaction conditions employed, the presence of the two stereocenters forged during the reaction entails the formation of four stereoisomers. The two diastereoisomeric pairs can be easily converted into each other by treatment with a base, due to the high acidity of the acetoacetate proton, 11 yielding an equilibrium ratio of 70 : 30 (in ethanol at +25 C). The four stereoisomers resulting from the reaction were resolved by chiral stationary phase HPLC (CSP-HPLC) on Chiralpak IA column (Fig.…”

State of the Art in Crystallization‐Induced Diastereomer Transformations

“…noticed that Yonemitsu‐type trimolecular condensations catalyzed by L‐proline unexpectedly gave a single racemic diastereomer in some cases [66a] . They decided to closely inspect the best performing reaction (Scheme 16) by means of DFT calculations combined with measurements of kinetic and thermodynamic data [66b,c] . As concluded, the high diastereoselectivity of the reaction was likely induced after the reaction itself, by the crystallization.…”