A Concise, Practical Chiral Resolution Approach of Racemic (E)-4,4-Dimethyl-1-(4-nitrophenyl)pent-1-en-3-ol to Its both Enantiomers via Strategy of Diastereomeric Ester Formation and Crystallization Using both N-Boc-D- and N-Boc-L-phenylglycines as Chiral Auxiliaries

Abstract

Chiral secondary alcohols are an important class of functionalities commonly seen in drugs and other bioactive compounds. In an ongoing drug discovery program in our laboratories, a nitro-bearing racemic allylic secondary alcohol (±)-1 was discovered as a promising drug candidate, and in the following preclinical studies, a concise, reliable, practical synthetic approach to its both enantiomers with high optical purities was greatly needed. In the present study, we developed a chiral resolution approach of (±)-1 to its both enantiomers, i. e., (+)-1 and (−)-1, via the strategy of diastereomeric ester formation and crystallization using both N-Boc-D- and N-Boc-L-phenylglycines as chiral auxiliaries. The absolute configurations of all the four key intermediates were unambiguously determined by single-crystal X-ray diffraction, providing a solid foundation for the stereochemistry of the present study. The two enantiomers were obtained in high optical purities. This approach is characterized by scalability and practicality and is envisaged to enable the chiral resolution of other racemic secondary alcohols, especially those with labile groups, such as NO₂ and olefinic C=C bond.

Keywords

Chiral resolution / Phenylglycine / Chiral auxiliary / Chiral secondary alcohol / Diastereomeric ester formation

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