Asymmetric Synthesis of Indoline from Achiral Phthalimide Involving Crystallization‐Induced Deracemization

Abstract

Asymmetric synthesis was performed by combining the photochemical reaction of an achiral substrate followed by crystallization-induced deracemization. The results indicated that a fused indoline produced by photochemical intramolecular δ-hydrogen abstraction and cyclization of N-(5-chloro-2-methylphenyl)phthalimide crystallized as a racemic conglomerate. Since this substrate has an aminal skeleton, racemization involving a ring-opening and ring-closing equilibrium process occurred under suitable conditions. Efficient racemization was observed in acetone containing a catalytic base, 1,8-diazabicyclo[5.4.0]undec-7ene (DBU). Crystallization-induced dynamic deracemization by Viedma ripening from racemic indoline was performed with an excellent enantioselectivity of 99 % ee. Furthermore, one-pot asymmetric synthesis of the indoline was achieved by the photochemical reaction of achiral phthalimide followed by continuous attrition-enhanced deracemization converging to 99 % ee of enantiomeric crystals. This is the first example of asymmetric expression and amplification by photochemical hydrogen abstraction and crystallizationinduced dynamic deracemization.

Cyclization Strategies Using Imide Derivatives for the Synthesis of Polycyclic Nitrogen‐Containing Compounds

“…In this context, Sakamoto and co‐workers developed a remarkable reaction sequence involving an intramolecular photochemical transformation (UV light‐mediated) for the conversion of N ‐aryl‐phthalimide 155 to racemic isoindolo[2,1‐a]indol‐6‐one derivative rac ‐ 156 , followed by a crystallization‐induced deracemization process ( cf . Viedma ripening) [97] in the presence of a 30 mol% of DBU, at 50 °C, involving the formation of achiral intermediate 157 , followed by its conversion to highly enantioenriched 156 [98] (Scheme 35).…”

Recent Advances in Photocatalytic Deracemization

“…根据已有文献报道, 目前实现去消旋化主要有氧化 还原去消旋化(redox deracemization)和光催化去消旋化 (photocatalytic deracemization)两种策略(图 4). 还有一些 是基于物理过程, 通过从溶液中选择性结晶的方式实现 的去消旋化 [10][11][12][13][14][15] . 氧化还原法是使消旋底物经历氧化还 原级联反应, 通过手性中心的破坏与重建实现去消旋 化, 其中至少有一个过程具有对映选择性.…”

Behavior of All Chiral Standard Amino Acids for Chiral Symmetry Breaking of p-Anisoin

“…41−43 Dynamic deracemization of conglomerate crystals is also an attractive asymmetric amplification system that can produce highly optically pure enantiomer crystals from a slightly asymmetric bias. 20,22,25 Therefore, it is imperative to develop a dynamic crystallization reaction system capable of asymmetric amplification with various additives. The purpose of this study was to create an asymmetric amplification system that can control crystal growth under the influence of many optically active additives in dynamic crystallization.…”

“…By utilizing this property, optical resolution by preferential crystallization is performed on an industrial scale. − In addition, under crystallization conditions, the crystallization-induced dynamic deracemization method, which combines rapid racemization in the mother liquor, realizes complete optical resolution of the racemic mixture into one type of enantiomer (chiral symmetry breaking). − This is a simple and effective method for creating optically active compounds and is also called spontaneous asymmetric synthesis, total optical resolution, crystallization-induced dynamic resolution (CIDR), or crystallization-induced enantiomer transformation (CIET). Several valuable and interesting examples of deracemization have been reported. − …”

“…The Soai reaction, which is well-known as a solution-based asymmetric amplification reaction, proceeds with a self-asymmetric amplification reaction by the addition reaction of pyrimidine carboxaldehyde and diisopropylzinc with various chiral initiators. − Dynamic deracemization of conglomerate crystals is also an attractive asymmetric amplification system that can produce highly optically pure enantiomer crystals from a slightly asymmetric bias. ,, Therefore, it is imperative to develop a dynamic crystallization reaction system capable of asymmetric amplification with various additives. The purpose of this study was to create an asymmetric amplification system that can control crystal growth under the influence of many optically active additives in dynamic crystallization.…”