Synthesis of enantiopure 2‐aryl‐2‐methoxypropionic acids and determination of their absolute configurations by X‐ray crystallography

Abstract

Racemic 2-aryl-2-methoxypropionic acids were enantioresolved by the use of (S)-(-)-phenylalaninol 4. For instance, racemic 2-methoxy-2-phenylpropionic acid (+/-)-7 was condensed with phenylalaninol (S)-(-)-4 yielding a diastereomeric mixture of amides, which was easily separated by HPLC on silica gel affording the first-eluted amide (-)-13a and the second-eluted amide (+)-13b: alpha = 3.19, Rs = 3.49. The absolute configuration of amide (-)-13a was determined to be (R;S) by X-ray crystallography by reference to the S configuration of the phenylalaninol moiety. Amide (R;S)-(-)-13a was converted to oxazoline (R;S)-(-)-14a, from which enantiopure 2-methoxy-2-phenylpropionic acid (R)-(-)-7 was recovered. Other 2-aryl-2-methoxypropionic acids, (R)-(-)-8, (R)-(-)-9, (R)-(+)-10, (R)-(-)-11, and (R)-(-)-12, were similarly prepared in enantiopure forms with the use of phenylalaninol (S)-(-)-4, and their absolute configurations were clearly determined by X-ray crystallography or by chemical correlation.

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

“…26 In addition to the methoxyassisted salt bridge (see above), conventional salt bridges were observed between the ammonium and carboxylato groups: both the interatomic distances between H23/O1 and H24/O2 were 1.87 (3) A. A CH/O interaction was observed between H17, the hydrogen atom in the methyl group of PEA cation and the neighbouring carboxylate oxygen atom O1 at a distance of 2.39 (3) A. Furthermore, a CH/p interaction was observed between H14, the hydrogen atom attached to the chiral centre of PEA cation and the neighbouring naphthyl group at a distance of 2.9 A.…”

“…11 The carboxy groups of (S)-3 formed a chain-like motif called a catemer. 10 X-Ray crystallographic data and NMR spectra of the (R)-MaNP amide 3,11 suggested that the methine group of the amine moiety and the carbonyl group were syn, while the carbonyl and the methoxy groups were anti (Fig. 9 The crystalline conformation of the (S)-MaNP ester was similar to those of acids (S)-1 and (S)-3 as follows (Fig.…”

“…1,3,[9][10][11] These properties make acids 1-3 useful as stereochemical internal standards for X-ray crystallography, which is considered the most reliable method for elucidating stereochemistry. 1,3,[9][10][11] These properties make acids 1-3 useful as stereochemical internal standards for X-ray crystallography, which is considered the most reliable method for elucidating stereochemistry.…”

“…In crystalline (S)-3, the hydroxy and carbonyl groups were syn, as were the carbonyl and methoxy groups. 3,[9][10][11] The methine group of the alcohol moiety and the carbonyl group were syn. 11 The carboxy groups of (S)-3 formed a chain-like motif called a catemer.…”

“…For this reason, solutionphase structures of diastereomeric MbNP amides 11 and 12 were determined by two-dimensional NMR analyses. 3 The 1 H NMR anisotropy method, which can be used to assign relative stereochemistry, was applied to amides 11 and 12. Therefore, the conformation of the MbNP moiety was more flexible than the MaNP moiety ( Fig.…”