Total Spontaneous Resolution by Deracemization of Isoindolinones

Abstract

Separated: 3-hydroxy-3-phenylisoindolin-1-ones have been resolved by dynamic preferential crystallization. The compounds were effectively racemized through ring-opening and ring-closing reactions via achiral intermediates under basic conditions. Crystallization from a toluene solution containing 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) with stirring and evaporation of the solvent gave optically active crystals quantitatively with high ee values.

Viedma ripening: a reliable crystallisation method to reach single chirality

“…11b). 41 Some of the present authors later reported that the isoindolinones can be deracemised completely through Viedma ripening provided that (1) there is sufficient attrition, (2) a suitable solvent is used in which the compounds have a high enough solubility and (3) that racemization is avoided during the ee analysis. Another class of compounds that can be obtained in enantioenriched form through total spontaneous resolution are isoindolinones (Fig.…”

Spontaneous formation and amplification of an enantioenriched α-amino nitrile: a chiral precursor for Strecker amino acid synthesis

“…Progression of the reaction leads to the supersaturation of 1 in the solution, which induces the spontaneous crystallization of 1. Since amino nitrile in solution phase is almost racemic, spontaneous resolution and deracemization 19 are included. S1, ESI †).…”

Enantiopure Isoindolinones through Viedma Ripening

“…Recently it was reported by Yagishita et al. that 3‐hydroxy‐3‐phenylisoindolin‐1‐ones 1 – 3 (Figure 2) crystallize as conglomerate crystals and can also rapidly racemize in solution using 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) as a catalyst through an intramolecular equilibrium reaction via an achiral intermediate 9. This enabled access to all three isoindolinones in high yield and high enantiomeric excess ( ee ) through preferential crystallization from solution (i.e.…”

“…This enabled access to all three isoindolinones in high yield and high enantiomeric excess ( ee ) through preferential crystallization from solution (i.e. total spontaneous resolution) 9. The conglomerate behavior of these compounds should also allow the deracemization of an initial racemic solid state through Viedma ripening (Figure 1), which is a fundamentally different approach to reach an enantiopure end state as compared to total spontaneous resolution.…”

“…The conglomerate behavior of these compounds should also allow the deracemization of an initial racemic solid state through Viedma ripening (Figure 1), which is a fundamentally different approach to reach an enantiopure end state as compared to total spontaneous resolution. However, the reported isoindolinones 1 – 3 surprisingly failed to deracemize through Viedma ripening despite an applied initial solid state ee 9. These results were not investigated further and a recent overview reported that these isoindolinones are one of the rare examples of compounds that cannot be deracemized by using Viedma ripening 10…”