Total Spontaneous Resolution by Deracemization of Isoindolinones

Abstract

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...

Enantiopure Isoindolinones through Viedma Ripening

“…Extrapolating this to time zero, we indeed find that the ee after a deracemization experiment is 100 % within the accuracy of the experiment (Figure 3 b). The racemization rate increases from 1 – 3 – 2 which is in the same order as the racemization rate with a catalyst 9. The rate of racemization in an ethanol solution becomes slower if acetic acid is present (see the Supporting Information).…”

“…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…”

“…We also found that the isoindolinones racemize in ethanol, allowing Viedma ripening without the need for a catalyst. Our working method resembles the previous Viedma ripening attempt by Yagishita et al.,9 but was optimized in three ways:…”