Chapter 21
Asymmetric Synthesis Involving
Dynamic Enantioselective Crystallization
Masami Sakamoto
Abstract An approach to obtain products with high enantiomeric purity by utilizing
the chirality generated by crystallizing organic materials is introduced. If a racemic
mixture forms a conglomerate in which each single crystal is assembled from a
single-handed enantiomer, it is possible to resolve each enantiomer from the racemic
mixture by the preferential crystallization method. Furthermore, when preferential
crystallization is applied under conditions in which fast racemization proceeds in
the mother liquor, it becomes possible to converge the entire system to the desired
single-handed enantiomer. This method is called crystallization-induced enantiomer
transformation (CIET), a type of crystallization-induced stereoisomer transformation (CIST), and is a total resolution method realized by amino acids, pharmaceutical intermediates, axially chiral materials, etc. In recent years, even dynamic
systems with relatively low racemization rates have been applied to chiral amplification by attrition-enhanced deracemization. In this chapter, recent advances in
asymmetric synthesis by a methodology combining a chemical reaction that forms
a chiral center from prochiral starting materials with deracemization by dynamic
enantioselective crystallization are introduced. This method is applied to various
asymmetric syntheses and is a phenomenon in which crystals of a product with high
enantiomeric purity can be obtained only by crystallizing the product from the reaction system in solution. Various types of reactions have been developed by adjusting
the conditions for the reversible reaction or the racemization of asymmetric centers
with enantioselective crystallization. This method will be widely developed in the
future and is also applicable on an industrial scale.
Keywords Crystal chirality · Conglomerate · Asymmetric synthesis · Absolute
asymmetric synthesis · Total resolution · Deracemization · Dynamic crystallization
M. Sakamoto (B)
Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba
University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
e-mail: sakamotom@faculty.chiba-u.jp
© Springer Nature Singapore Pte Ltd. 2020
M. Sakamoto and H. Uekusa (eds.), Advances in Organic Crystal Chemistry,
https://doi.org/10.1007/978-981-15-5085-0_21
433
Asymmetric Synthesis Involving
Dynamic Enantioselective Crystallization
Masami Sakamoto
Abstract An approach to obtain products with high enantiomeric purity by utilizing
the chirality generated by crystallizing organic materials is introduced. If a racemic
mixture forms a conglomerate in which each single crystal is assembled from a
single-handed enantiomer, it is possible to resolve each enantiomer from the racemic
mixture by the preferential crystallization method. Furthermore, when preferential
crystallization is applied under conditions in which fast racemization proceeds in
the mother liquor, it becomes possible to converge the entire system to the desired
single-handed enantiomer. This method is called crystallization-induced enantiomer
transformation (CIET), a type of crystallization-induced stereoisomer transformation (CIST), and is a total resolution method realized by amino acids, pharmaceutical intermediates, axially chiral materials, etc. In recent years, even dynamic
systems with relatively low racemization rates have been applied to chiral amplification by attrition-enhanced deracemization. In this chapter, recent advances in
asymmetric synthesis by a methodology combining a chemical reaction that forms
a chiral center from prochiral starting materials with deracemization by dynamic
enantioselective crystallization are introduced. This method is applied to various
asymmetric syntheses and is a phenomenon in which crystals of a product with high
enantiomeric purity can be obtained only by crystallizing the product from the reaction system in solution. Various types of reactions have been developed by adjusting
the conditions for the reversible reaction or the racemization of asymmetric centers
with enantioselective crystallization. This method will be widely developed in the
future and is also applicable on an industrial scale.
Keywords Crystal chirality · Conglomerate · Asymmetric synthesis · Absolute
asymmetric synthesis · Total resolution · Deracemization · Dynamic crystallization
M. Sakamoto (B)
Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba
University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
e-mail: sakamotom@faculty.chiba-u.jp
© Springer Nature Singapore Pte Ltd. 2020
M. Sakamoto and H. Uekusa (eds.), Advances in Organic Crystal Chemistry,
https://doi.org/10.1007/978-981-15-5085-0_21
433