State of the Art in Crystallization‐Induced Diastereomer Transformations

Abstract

Crystallization-induced diastereomer transformations (CIDT) enable isolation of the target compounds in high enantio-and diastereomeric purities and with up to quantitative yields simply by filtration. Numerous inspiring examples of this appealing synthetic strategy reported over the last fifteen years are reviewed. Important observations along with aspects to consider when designing CIDT experiments are discussed. 3.3. Formation of Schiff Base or Related Intermediates 3.4. Aza-Michael and Mannich-Type Reactions 3.5. Strecker Reaction 3.6. Aldol Reactions 3.7. Epimerization at Phosphorus-Based Stereocenters 3.8. Racemization/Epimerization through Change of Conformation 3.9. Miscellaneous Examples of CIDT 4.Conclusions and Perspectives

Stereochemical switch driven by crystallization: Interplay between stoichiometry and configuration of the products

“…CIDT reactions featuring aza-Michael additions to 3-acylacrylic acids have proven to provide a straightforward access to diversely functionalized α-amino acids in a highly stereoselective fashion (for reviews, see Kolarovic ˇand Jakubec. 9 Recent examples: Siv ak et al 24 and Valachov a et al 25 For a cognate Mannich-type system, see Marc ˇekov a et al 26 Examples of CIDT in aza-Michael additions to other substrates: Bravo et al 27 and Amara et al 28 ). The syntheses are not sensitive to air or moisture and typically proceed at ambient or close to ambient temperatures.…”

“…However, on the other side of the coin, both the stereochemical outcome and occurrence of CIDT itself still remain challenging to plan or predict due to numerous interrelated factors that can possibly influence the final result (for an example of a seemingly suitable aza‐Michael substrate, which failed to deliver CIDT, see Sivák et al 19 Additional references can be found in Kolarovič and Jakubec 9 ). It is presumable that these circumstances constitute a major cause why CIDT, otherwise considered to be a “dream reaction” on an industrial scale, 20 has not found more widespread use in stereoselective synthesis.…”

“…In the realms of stereoselective synthesis, the option of driving a reaction equilibrium towards a selectively crystallizing stereoisomer appears to be particularly appealing. Supposing that these reactions provide diastereomeric species, the phenomenon is termed crystallization-induced diastereomer transformation (CIDT) (for reviews, see Kolarovic ˇand Jakubec 9 and Brands and Davies 10 and for the most up-to-date examples, see previous studies [11][12][13][14][15][16][17][18] ). A thermodynamic nature of the process typically allows for a straightforward reaction setup, and even syntheses featuring complex reaction equilibria can furnish crystalline products in very good yields and high purities.…”

Doubly stereoconvergent crystallization enabled by asymmetric catalysis

“…For reactions that generate stereoisomeric mixtures, simple recrystallizations cannot overcome the fact that valuable material will be lost as undesired stereoisomers; however, for cases in which equilibration between stereoisomers is mechanistically feasible, convergence to a single stereoisomer of the product can be achieved by engineering crystallization-induced diastereomer transformations (CIDTs). CIDTs are highly desirable in synthetic chemistry and industrial applications because they provide a means to generate highly stereoenriched products without requiring additional tedious purifications ( 12 , 13 ). CIDT selectivity is governed by crystallization thermodynamics: Diastereomers undergoing CIDT contain one or more static asymmetric centers and at least (and commonly) one labile element of chirality that is subjected to equilibration.…”

“…Implementation of CIDT strategies into synthetic routes reduces the effort required to access a single stereoisomer of a complex molecule: 100% theoretical yield of a single stereoisomeric product can be obtained from an initial mixture of interconverting epimers. CIDT reactions are usually applied to specific problems in industrial chemistry, they are difficult to predict, and generalizable non-auxiliary–based CIDT methods are currently underdeveloped ( 12 , 13 ). We were interested in testing the notion that by leveraging epimerization to achieve stereoconvergence in complex systems, we could accrue unique advantages through the merged application of asymmetric catalysis and crystallization-driven selectivity.…”