Rationalization of Racemate Resolution: Predicting Spontaneous Resolution through Crystal Structure Prediction

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• 作者：Matthew D. Gourlay ; John Kendrick ; Frank J. J. Leusen
• 刊名：Crystal Growth & Design
• 出版年：2007
• 出版时间：January 2007
• 年：2007
• 卷：7
• 期：1
• 页码：56 - 63
• 全文大小：207K
• 年卷期：v.7,no.1(January 2007)
• ISSN：1528-7505

文摘

Crystal structure prediction simulations are reported on 5-hydroxymethyl-2-oxazolidinone and 4-hydroxymethyl-2-oxazolidinone to establish the feasibility of predicting the spontaneous resolution of racemates of small organic molecules. It isassumed that spontaneous resolution occurs when the enantiomorph is more stable than the racemic solid. The starting point is a gasphase conformational search to locate all low-energy conformations. These conformations are used to predict the possible crystalstructures of 5- and 4-hydroxymethyl-2-oxazolidinone. In both cases, the racemic crystal structure is predicted to have the lowestenergy. The energy differences between the lowest-energy racemic solids and the lowest-energy enantiomorphs are 0.2 kcal mol^-1for 5-hydroxymethyl-2-oxazolidinone and 0.9 kcal mol^-1 for 4-hydroxymethyl-2-oxazolidinone. In the case of 4-hydroxymethyl-2-oxazolidinone, where the racemic crystal is known to be more stable and the experimental crystal structures of both the racemateand the enantiomorph are available, the simulation results match the observed data. For 5-hydroxymethyl-2-oxazolidinone, whereonly enantiopure crystals are observed experimentally, the known experimental structure is found 1.6 kcal mol^-1 above the lowest-energy predicted structure. This work shows that it is possible to predict whether the racemate of a small chiral molecule can beresolved spontaneously, although further advances in the accuracy of lattice energy calculations are required.