Chiral Derivatizing Agent for Absolute Configuration

Determination of absolute configurations of optically active compounds by NMR technique can be easily accomplished by derivatizing the chiral compounds with an appropriate reagents, and this technique is finding a wide application as an alterantive approach to the methods using X-ray crystallography or CD. The title products 1a and 1b (MαNP) are excellent derivatizing reagents for the determination of the absolute configurations of chiral alcohols. While reagents such as MTPA (2-Methoxy-2-trifluoromethyl-2-phenylacetic Acid), MNA (2-Methoxy-2-(2-naphthyl)acetic Acid), and MPA (2-Methoxy-2-phenylacetic Acid) are used as traditional derivatizing agents, the advantages of 1a and 1b are that their naphthalene moiety brings a stronger anisotropy effect and that they are inert toward racemization in a derivatization process because of the absence of the active hydrogens on the chiral carbon.

For example, the absolute configurations of (+)-2-butanol can be determined as follows: 1) (+)-2-Butanol is reacted with 1a and 1b, respectively, to form diastereomers. 2) The ¹H-NMR spectra of the two diastereomers are obtained and analyzed. 3) From the chemical shift of the alcohol part, Δδ values (= δ_R-δ) are obtained (see the table on the right).

Toward the asymmetric center, the positions for the ester part and protons are determined as shown in the figure. The groups with a positive Δδ value are placed on the right side and those with a negative α value on the left side leading to the determination of the absolute configurations. Thus (+)-2-butanol is determined to have the (S) absolute configuration as it is shown in right hand-side.

Furthermore, two diastereomers derived from (±)-2-butanol by using either 1a or 1b can be separated by HPLC on silica gel, allowing an enantioresolution of the chiral alcohols.