MαNP acid, a powerful chiral molecular tool for preparation of enantiopure alcohols by resolution and determination of their absolute configurations by the ¹H NMR anisotropy method

Abstract

A novel methodology using a chiral molecular tool of MalphaNP acid (1), 2-methoxy-2-(1-naphthyl)propionic acid, useful for preparation of enantiopure secondary alcohols and determination of their absolute configurations by the (1)H NMR anisotropy method was developed; racemic MalphaNP acid (1) was enantioresolved with (-)-menthol, and the enantiopure MalphaNP acid (S)-(+)-(1) obtained was allowed to react with racemic alcohol, yielding a mixture of diastereomeric esters, which was clearly separated by HPLC on silica gel. By applying the sector rule of (1)H NMR anisotropy effect, the absolute configuration of the first-eluted MalphaNP ester was unambiguously determined. Solvolysis or reduction of the first-eluted MalphaNP esters yielded enantiopure alcohols.

Novel Chiral Molecular Tools for Preparation of Enantiopure Alcohols by Resolution and Simultaneous Determination of Their Absolute Configurations by the 1H NMR Anisotropy Method

“…The Mƒ¿NP acid 2 was enantioresolved with natural (-)-menthol, the enantiopurity of which was confirmed as 100% by the gas chromatography using chiral stationary phase. 41) As described here, Mƒ¿NP acid has excellent enantioresolving power regardless of its simple molecular structure and the absence of so-called hetero atoms. Besides, the chiral acid 2 is superior to Mosher's MTPA and Trost's MPA acids in the magnetic anisotropy effect, and, therefore, further development of this method is expected.…”

Determination of absolute configuration—An overview related to this Special Issue

“…The method requires knowledge of the most stable solution conformations of the respective diastereomer for an interpretation of the chemical shift difference observed due to the difference in anisotropy effects. 19 So far, it has been used mainly for AC determination of monofunctional compounds, like alcohols, amines and carboxylic acids, and of bifunctional species such as diols and amino alcohols. Several chiral reagents for this purpose have been developed from the initially used Mosher's acid (a-methoxy-a-(trifluoromethyl)phenylacetic acid, MTPA).…”

Enantiomeric separation and determination of absolute stereochemistry of asymmetric molecules in drug discovery—Building chiral technology toolboxes

“…[198][199][200][201][202][203] These and structurally-related acids as well as several types of optically-active alcohols have found great utility to determine the absolute stereochemistry of enantiomerically pure or enriched secondary alcohols [353][354][355][356][357][358] and diols, 359,360 b-chiral alcohols, 361,362 a-chiral amines, [363][364][365][366][367] mixed chiral amines and alcohols, 368,369 chiral carboxylic acids, [370][371][372] and chiral 3-hydroxy b-lactams. 373 These reagents have also found combined utility in enantiomeric separation, including LC-NMR, plus determination of absolute stereochemistry of various types of compounds such as diastereomeric alcohols [374][375][376][377] and 2-hydroxypyrrolizidinones. 378 In our labs, MPTA, MPA, boc-phenylglycine, and ethyl-2-(9-anthryl)-2-hydroxyacetate have been used on various occasions to derivatize compounds for determination of absolute stereochemistry.…”