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.
Preferential crystallization is a powerful tool to obtain optically active materials from racemic mixtures without any chiral source, and has been utilized widely for optical resolution on large scales for example in industrial processes. [1] To resolve optically active materials by crystallization efficiently, dynamic preferential crystallization involving a racemization process, a so-called total spontaneous resolution, has been developed. [2] Many efforts have been invested in new variations of this method, and the racemization processes can be classified into three groups: 1) involving an intermediate enolate anion or enol at the a-position of a carbonyl group, [3] 2) involving atropisomerism of axially chiral materials, [4] and 3) involving an equilibrium reaction via an achiral intermediate. [5][6][7] We have now developed a new example of total spontaneous resolution of isoindolinones that involves a combination of an intramolecular equilibrium reaction via an achiral intermediate and preferential crystallization.Various heterocyclic compounds containing the isoindolinone skeleton have important biological activities, and many of these have been prepared and examined as pharmaceutical agents. [8] Much effort has also been focused on the asymmetric synthesis of the isoindolinone structure, [9] which is widely used as a building block for the synthesis of natural products. [10] Therefore, development of a new methodology to obtain optically active heterocycles such as isoindolinones is eagerly anticipated.We found that 3-hydroxy-3-phenylisoindolin-1-ones 1 afforded conglomerates by spontaneous crystallization and were racemized under acidic or basic conditions (Scheme 1). The dynamic preferential crystallization resulted in total spontaneous resolution in high ee values.N-Alkylated 3-hydroxy-3-phenylisoindolin-1-ones 1 a-f were synthesized from 2-benzoylbenzoic acid and the corresponding primary amines (Table 1). [11] To perform preferential crystallization, it is a requirement that the materials crystallize as a conglomerate. The crystal structure of 1 c was reported with the chiral space group P2 1 2 1 2 1 . [12] Recrystalli-zation of the other isoindolinones in a chloroform-hexane solution afforded prismatic crystals except in the case of 1 b. These crystals were subjected to X-ray crystallographic analysis to determine the crystal structure. Fortunately, Xray analyses indicated that isoindolin-1-ones 1 d and 1 f also crystallized in a chiral fashion with the orthorhombic chiral space group P2 1 2 1 2 1 . Isoindolinones 1 a and 1 e crystallized in the racemic space groups C2/c and P " 1, respectively. The space group of 1 b could not be determined; however, a racemic crystal system was suggested from the results of dynamic preferential crystallization described below.Racemization must proceed much faster than crystallization to achieve total resolution by dynamic preferential crystallization. All 3-hydroxy-3-phenylisoindolin-1-ones 1 were not easily racemized under neutral conditions or in the solid sta...
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