Crystallization-induced dynamic resolution

Oxazolidine 198 was produced from condensation of (R)-phenylg-lycinol and fluoral ethyl hemiacetal as a 62 38 tram/cis diastereomeric mixture. The enantiopure trans-198 was obtained through an epimeriza-tion with p-toluenesulfonic acid that realized the selective precipitation of the desired diastereoisomer. The repetition of this crystallization-induced dynamic resolution (CIDR) protocol on mother liquors allowed an almost complete conversion of the initial mixture into the desired trans-198. This chiral oxazolidine was used as chiral auxiliary for the synthesis of a-fluorocarboxylic acids and P-fluoroalcohols in a one-pot procedure that also allowed its recovery without loss of optical purity (13JOC3487). 

SCHEME 56.4. Manufacture of carmegliptin by employing a crystallization-induced dynamic resolution. 

The dynamic crystallization-induced diastereomeric resolution was further investigated in order to develop practical approaches to obtain one diastereomer by exploiting more diversity of the diastereomeric nitroaldol adducts in the dynamic system [77]. A larger and more diverse dynamic nitroaldol system (CDS-5C) was generated by equimolar amounts of nine different benzaldehydes, nitroethane 38, and triethylamine was used as catalyst as shown in Scheme 15. A total of 36 nitroaldol diastereomers were formed under thermodynamic control in chloroform-d, and the reaction was followed by H-NMR spectroscopy. 

Angelin, M. Fischer, A. Ramstrom, O. Crystallization-induced secondary selection from a tandem driven dynamic combinatorial resolution process. J. Org. Chem. 2008, 73, 3693-3595. 

SCHEME 24. (-)-Sparteine-induced deprotonation of allyl carbamate 170. Dynamic resolution by crystallization and enantioselective homoaldol reaction... 

The above examples demonstrate the DSR concept as a useful approach to generate and interrogate simultaneously complex systems for different applications. A range of reversible reactions, in particular carbon-carbon bond-formation transformations, was used to demonstrate dynamic system formation in both organic and aqueous solutions. By applying selection pressures, the optimal constituents were subsequently selected and amplified from the dynamic system by irreversible processes under kinetic control. The DSR technique can be used not only for identification purposes, but also for evaluation of the specificities of selection pressures in one-pot processes. The nature of the selection pressure applied leads to two fundamentally different classes external selection pressures, exemplified by enzyme-catalyzed resolution, and internal selection pressures, exemplified by transformation- and/or crystallization-induced resolution. Future endeavors in this area include, for example, the exploration of more complex dynamic systems, multiple resolution schemes, and variable systemic control. 

SCHEME 56. Crystallization-induced diastereomeric dynamic resolution of the aminoketone rac-7, a key intermediate in the large-scale synthesis of the antitumor agent R116010. 

In another report by Aelterman et al., the development of a facile and large-scale preparation of the antitumor agent R116010 was demonstrated (Scheme 56.2). In their work, the key strategic improvement was the crystallization-induced diastereomeric dynamic resolution of the aminoketone rac-7, leading to the chiral ketone (S)-7 in 90% yield and 90% enantiomeric purity. After screening 22 chiral acids in numerous solvents, the resolution of aminoketone with ditoluoyltartaric acid in methanol was found to be the optimal process. This new process improves the overall yield from 0.26% to 18.8% without tedious chromatographic separations and hazardous reaction conditions. 

Wu, S. and Mills, D. L. (2002) STM-induced enhancement of dynamic dipole moments on crystal surfaces theory of the lateral resolution. Rhys. Rev. B, 65, 205420-1-205420-7. 

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