Crystal structures and chiral recognition of the diastereomeric salts prepared from 2-methoxy-2-(1-naphthyl)propanoic acid

This paper is the first to report the structures of crystalline diastereomeric salts 8 and 9 prepared from (R)-2-methoxy-2-(1-naphthyl)propanoic acid [(R)-M alpha NP acid, (R)-1] and (S)-1 with (R)-1-phenylethylamine [(R)-PEA, (R)-7], respectively. These crystal structures helped elucidate a novel chiral recognition mechanism characteristic of M alpha NP salts. The less-soluble diastereomeric salt 8 prepared from (R)-1 and (R)-7 formed an ammonium-carboxylate ion pair by means of a methoxy-assisted salt bridge and an aromatic CH center dot center dot center dot pi interaction. The more-soluble diastereomeric salt 9 prepared from (S)-1 and (R)-7 formed an ion pair by a methoxy-assisted salt bridge in which the 1-naphthyl and phenyl groups did not overlap. Instead, salt 9 formed a close ion pair by means of a salt bridge, a CH center dot center dot center dot O hydrogen bond, and a pi center dot center dot center dot pi interaction. These crystal structures suggest that the molecular length from the MaNP plane containing the carboxy and methoxy groups is critical to the crystallisation of diastereomeric salts. The crystal packing in both salts was investigated with regard to the weak interactions (i.e., salt bridges, NH center dot center dot center dot O and CH center dot center dot center dot O hydrogen bonds, and aromatic CH center dot center dot center dot pi, CH center dot center dot center dot pi, and pi center dot center dot center dot pi interactions). Finally, diastereomeric amides 11 and 12 were prepared from (S)-2-methoxy-2-(2-naphthyl)propanoic acid [(S)-M beta NP acid, (S)-2] and (R)-2 with (S)-1-(1-naphthyl) ethylamine [(S)10]. The solution-phase structures of the M beta NP amides, and their separation, was investigated by NMR spectroscopy and high-performance liquid chromatography (HPLC). The less-stereochemically demanding and longer 2-naphthyl group made the M beta NP amide more flexible and less polar than the M alpha NP amide. Acid 2 was more efficient than acid 1 in separating amides 11 and 12.