Autocatalytic enantiomerisation at the crystal surface in deracemisation of scalemic conglomerates.
Deracemisation of racemic or scalemic conglomerates of intrinsically chiral compounds appears to be a promising method of chiral resolution. By combining the established methods of asymmetric synthesis and the physical process of crystal growth, we were able to achieve a complete deracemisation (with 100% ee) of an asymmetric Mannich product conglomerate--vigorously stirred in its saturated solution--from a starting enantiomeric excess value of 15.8% in the presence of pyrrolidine (8 mol %) as an achiral catalyst for the CC bond-forming reaction. Strong activation of this deracemisation process was observed on mild isothermal heating to only 40 degrees C, resulting in dramatic acceleration by a factor of about 20 with respect to the results obtained at room temperature. Despite the fact that the racemisation half-life time of the nearly enantiopure Mannich product (with 99% ee) in the homogenous solution at the reaction temperature is eight days, the deracemisation process took only hours in a small-scale experiment. This apparent paradox is explained by a proposed rapid enantiomerisation at the crystal/solution interface, which was corroborated by a (13)C labelling experiment that confirmed the involvement of rapid enantiomerisation. Frequent monitoring of the solution-phase ee of the slowly racemising compound further revealed that the minor enantiomer dominated in solution, supporting an explanation based on a kinetic model. A generalisation of the process of "aymmetric autocatalysis" (resulting in automultiplication of chiral products in homogenous media) to encompass heterogeneous systems is also suggested.
Wei
Shengwei
S
Department of Chemistry and Pharmacy, University of Erlangen-Nuremberg, Henkestrasse 42, 91054 Erlangen, Germany.
Mauksch
Michael
M
Tsogoeva
Svetlana B
SB