1H NMR Anisotropy Research Articles

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 development and applications of novel chiral molecular tools, (S) - (+) -2-methoxy-2- (l-naphthyl)propionic acid (MαNP acid (2)) and (S) - (+) -2-methoxy-2- (9-phenanthryl) propionic acid (M9PP acid (3)), useful for preparation of enantiopure secondary alcohols and simultaneous determination of their absolute configurations by the 1H NMR anisotropy method are explained. Racemic MαNP acid 2 was enantioresolved with (-) -menthol, and the enantiopure MαNP acid (S) - (+) -2 obtained was allowed to react with racemic alcohols yielding diastereomeric esters, which were easily and clearly separated by HPLC on silica gel. By applying the sector rule of 1H NMR anisotropy effect, the absolute configurations of the first-eluted MαNP esters were unambiguously determined. MαNP acid (S) - (+) -2 has thus a great power to discriminate the chirality of various alcohols, especially that of aliphatic alcohols, in both HPLC and 1H NMR. The solvolysis or reduction of the first-eluted MαNP esters yielded enantiopure alcohols, whose absolute configurations were simultaneously determined. Another chiral molecular tool, M9PP acid (S) - (+) -3, was similarly applied to prepare both enantiomers of sulcatol, an insect pheromone, in enantiopure forms.

Enantioresolution of fluorinated diphenylmethanols and determination of their absolute configurations by X-Ray crystallographic and 1H NMR anisotropy methods.

Various fluorinated diphenylmethanols were enantioresolved by the methods of chiral camphorsultam-dichlorophthalic acid (CSDP acid) and/or 2-methoxy-2-(1-naphthyl)propionic acid (MalphaNP acid) yielding enantiopure alcohols. Their absolute configurations were unambiguously determined by X-ray crystallography of CSDP esters and/or by the (1)H NMR anisotropy method of MalphaNP esters for the first time.

Absolute configuration of the thyroid hormone analog KAT-2003 as determined by the 1H NMR anisotropy method with a novel chiral auxiliary, MalphaNP acid.

The absolute configuration of the chiral thyroid hormone analog KAT-2003 (+)-2, showing hypocholesterolemic activities, decreases of hepatic triglyceride contents with lowering cardiac side effects, and significant inhibitory effect for the second primary hepatocellular carcinoma, was determined as S by the (1)H NMR anisotropy method using a novel chiral auxiliary, 2-methoxy-2-(1-naphtyl)propionic acid (MalphaNP acid).

MYP08 Analysis of protein-protein interaction in formation of a bacterial cytoskeleton in Mycoplasma pneumoniae

Enantioresolution of 3-octanol, 6-methyl-5-hepten-2-ol (sulcatol), and 1-octen-3-ol was conducted using (S)-(+)-2-methoxy-2-(1-naphthyl)propionic acid (MαNP acid) and (S)-(+)-2-methoxy-2-(9-phenanthryl)propionic acid (M9PP acid). In each case, the diastereomeric esters obtained were readily separated by HPLC. The stereochemistry of the esters could be assigned from their respective 1H NMR analyses. Solvolyses of the esters gave enantiopure alcohols and acids. MαNP and M9PP acids displayed almost equivalent properties in 1H NMR anisotropy. The chiral resolving ability of M9PP acid was slightly superior to that of MαNP acid in HPLC.

Crystalline state conformation of 2-methoxy-2-(1-naphthyl)propionic acid ester.

The enantioresolution method using (S)-(+)-2-methoxy-2-(1-naphthyl)propionic acid (MalphaNP acid 1) was applied to 1,2,3,4-tetrahydro-4-phenanthrenol (4). Racemic alcohol (+/-)-4 was esterified with (S)-(+)-1, and a diastereomeric mixture of esters formed was separated by HPLC on silica gel giving the first-eluted ester 5a and the second-eluted one 5b. Ester 5a was reduced with LiAlH4 yielding enantiopure alcohol (+)-4. A single crystal of ester 5a was subjected to X-ray crystallography to determine its absolute configuration as (S,S), and therefore to assign the S absolute configuration to (+)-4. The most striking finding in the X-ray analysis is that the methoxyl oxygen atom is syn to the ester carbonyl oxygen even in the crystalline state. This is just the preferred conformation of MalphaNP acid esters assumed in the 1H NMR anisotropy method. The S absolute configuration of (+)-4 was also confirmed by the CD and 1H NMR anisotropy methods.

Absolute configurations of 2-methoxy-2-(1-naphthyl)propionic acid and 2-methoxy-2-(2-naphthyl)propionic acid as determined by the phenylglycine methyl ester (PGME) method

The absolute configurations of 2-methoxy-2-(1-naphthyl)propionic acid and 2-methoxy-2-(2-naphthyl)propionic acid were reconfirmed by NMR analyses of phenylglycine methyl ester (PGME) derivatives. Their absolute configurations determined by the PGME method are consistent with those obtained by the 1H NMR anisotropy method and X-ray crystallography.

Absolute configuration of 2-methoxy-2-(2-naphthyl)propionic acid as determined by the 1H NMR anisotropy method

2-Methoxy-2-(2-naphthyl)propionic acid 1 and 2-hydroxy-2-(2-naphthyl)propionic acid 2 were prepared by the Grignard reaction of 2-naphthylmagnesium bromide with (1R,2S,5R)-(−)-menthyl pyruvate. The absolute configurations of (+)-1 and (+)-2 were determined to be S by the 1H NMR anisotropy method.

2-Methoxy-2-(1-naphthyl)propionic acid, a powerful chiral auxiliary for enantioresolution of alcohols and determination of their absolute configurations by the 1H NMR anisotropy method

Racemic 2-methoxy-2-(1-naphthyl)propionic acid ( 1, MαNP acid) was enantioresolved as its esters derived from various chiral alcohols. For example, a diastereomeric mixture of esters prepared from (±)- 1 and (1 R,3 R,4 S)-(−)-menthol was easily separated by HPLC on silica gel yielding esters (−)- 2a and (−)- 2b, the separation factor α=1.83 being unusually large. The 1H NMR chemical shift differences, Δδ=δ( R)–δ( S), between diastereomers 2a and 2b, are much larger than those of conventional chiral auxiliaries, e.g. Mosher’s MTPA and Trost’s MPA acids. This acid 1 is therefore very powerful for determining the absolute configuration of chiral alcohols by the 1H NMR anisotropy method. Solvolysis of the separated esters yielded enantiopure acids ( S)-(+)- 1 and ( R)-(−)- 1, which are useful for enantioresolution of racemic alcohols.

Absolute configuration of 2-hydroxy-2-(1-naphthyl)propionic acid as determined by the 1H NMR anisotropy method

Enantiopure 2-hydroxy-2-(1-naphthyl)propionic acid (+)- 2 was prepared by the stereoselective Grignard reaction of 1-naphthylmagnesium bromide with (1 R,3 R,4 S)-menthyl pyruvate 3 or (1 R,3 R,4 S)-8-phenylmenthyl pyruvate 4, and the absolute configuration of acid (+)- 2 was unambiguously determined to be S by the 1H NMR anisotropy method.