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[small 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[small 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[small 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 CHO hydrogen bond, and a [small pi][small pi] interaction. These crystal structures suggest that the molecular length from the M[small alpha]NP 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, NHO and CHO hydrogen bonds, and aromatic CH[small pi], CH[small pi], and [small pi][small pi] interactions). Finally, diastereomeric amides 11 and 12 were prepared from (S)-2-methoxy-2-(2-naphthyl)propanoic acid [(S)-M[small beta]NP acid, (S)-2] and (R)-2 with (S)-1-(1-naphthyl)ethylamine [(S)-10]. The solution-phase structures of the M[small 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[small beta]NP amide more flexible and less polar than the M[small alpha]NP amide. Acid 2 was more efficient than acid 1 in separating amides 11 and 12.