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

Harada, Nobuyuki; Watanabe, Masataka; Kuwahara, Shunsuke; Sugio, Akinori; Kasai, Yusuke; Ichikawa, Akio

doi:10.1016/s0957-4166(00)00053-7

Cited by 105 publications

(74 citation statements)

References 6 publications

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“…Based on these characteristics of acid 1, we previously proposed a method for determining the absolute configuration of chiral alcohols using racemic M␣NP acid (±)-1. 3 This was a striking contrast to the conventional method where both enantiomeric (R)-and (S)-acids have been required. In our previous method, however, one of the diastereomeric M␣NP acid esters of chiral alcohol separated by HPLC had to be converted to methyl ester from the CD (circular dichroism) spectrum of which the absolute configuration of acid part was determined.…”

Section: Recently We Reported That 2-methoxy-2-(1-naphthyl)-propionimentioning

confidence: 59%

“…[1][2][3][4][5][6][7] The acid 1 is superior to conventional chiral acids, e.g., Mosher's ␣-methoxy-␣-trifluoromethylphenylacetic acid (MTPA acid) 8 and Trost's ␣-methoxyphenylacetic acid (MPA acid), 9 because of its stronger anisotropy effect. Furthermore, the M␣NP acid 1 has the advantage of not racemizing because the ␣-position of carboxylic acid is fully substituted and therefore acid 1 excels methoxy(1-and 2-naphthyl)acetic acids (1-NMA and 2-NMA) having a hydrogen atom at the ␣-position.…”

Section: Recently We Reported That 2-methoxy-2-(1-naphthyl)-propionimentioning

confidence: 99%

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Convenient method for determining the absolute configuration of chiral alcohols with racemic ¹H NMR anisotropy reagent, MαNP acid: Use of HPLC‐CD detector

2003

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A convenient method for determining the absolute configuration of chiral secondary alcohols using the racemic NMR anisotropy reagent, (±)-2-methoxy-2-(1-naphthyl)propionic acid [(±)-M␣NP acid], and an HPLC-CD detector was developed. The method was successfully applied to some chiral alcohols derived from (-)-␣-santonin. Chirality 15: 295-299, 2003. © 2003 KEY WORDS: chiral secondary alcohols; racemic derivatizing agent; 2-methoxy-2-(1-naphthyl)propionic acid; diastereomeric esters; HPLC separation; 1 H NMR anisotropy effect; ␣-santonin derivatives Recently, we reported that 2-methoxy-2-(1-naphthyl)-propionic acid (M␣NP acid, (S)-(+)-1 or (R)-(-)-1 in Fig. 1) is a very powerful chiral derivatizing agent for determining the absolute configuration of chiral alcohols by the 1 H NMR anisotropy method.1-7 The acid 1 is superior to conventional chiral acids, e.g., Mosher's ␣-methoxy-␣-trifluoromethylphenylacetic acid (MTPA acid) 8 and Trost's ␣-methoxyphenylacetic acid (MPA acid), 9 because of its stronger anisotropy effect. Furthermore, the M␣NP acid 1 has the advantage of not racemizing because the ␣-position of carboxylic acid is fully substituted and therefore acid 1 excels methoxy(1-and 2-naphthyl)acetic acids (1-NMA and 2-NMA) having a hydrogen atom at the ␣-position. 10,11The best quality of this acid 1 is the power to enantioresolve racemic alcohols or to be enantioresolved with chiral alcohols by HPLC separation of M␣NP esters. For example, racemic acid 1 was esterified with (1R,3R,4S)-(-)-menthol yielding a diastereomeric mixture of esters which was easily separated by HPLC on silica gel (hexane/EtOAc 10:1): separation factor ␣ = 1.83; Rs = 4.55 (Scheme 1, Fig. 2a). Based on these characteristics of acid 1, we previously proposed a method for determining the absolute configuration of chiral alcohols using racemic M␣NP acid (±)-1. 3This was a striking contrast to the conventional method where both enantiomeric (R)-and (S)-acids have been required. In our previous method, however, one of the diastereomeric M␣NP acid esters of chiral alcohol separated by HPLC had to be converted to methyl ester from the CD (circular dichroism) spectrum of which the absolute configuration of acid part was determined. It was then possible to calculate ⌬␦ values (⌬␦ = ␦(R,X) -␦(S,X)), where R, S, and X denote the absolute configurations of the acid part of M␣NP esters and that of the alcohol part, respectively. By applying the sector rule, the absolute configuration X of chiral alcohol was determined. The chemical conversion to methyl ester and CD measurement, however, require more work, and therefore the previous method was complicated and laborious. We report here an improved and more convenient method using an HPLC-CD detector.Instead of measurement of the CD spectra of M␣NP acid methyl ester, we measured the CD spectra of M␣NP acid esters of chiral alcohol separated by HPLC. As shown in Figure 3, the first-eluted menthol ester (S)-2a exhibits weak negative CD around 280 nm, positive CD of medium intensity around 23...

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Section: Recently We Reported That 2-methoxy-2-(1-naphthyl)-propionimentioning

confidence: 59%

Section: Recently We Reported That 2-methoxy-2-(1-naphthyl)-propionimentioning

confidence: 99%

Convenient method for determining the absolute configuration of chiral alcohols with racemic ¹H NMR anisotropy reagent, MαNP acid: Use of HPLC‐CD detector

2003

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“…Recently, MαNP acid was reported to be an auxiliary reagent for chiral separation and a shift reagent for the determination of the absolute confi guration of secondary alcohols 9,10 . In addition, chiral separation columns for HPLC are commercially available and are used for separation analysis of drugs, intravital substances, and their metabolites 12 29 .…”

Section: Resultsmentioning

confidence: 99%

“…The residue was purifi ed by silica gel column chromatography to yield 5a or 5b as a type of oil. Then, 5a or 5b was subjected to 1 H-NMR and the absolute confi gurations of the derived 3-hydroxy acids were determined by the sector rule 9,10 The enantiomeric 3-hydroxy acids 4a or 4b were converted to CoA ester 6a or 6b as described previously 11 as follows. First, trimethylamine 0.11 mmol in 1 mL of anhydrous tetrahydrofuran was added to 1 mL of anhydrous tetrahydrofuran containing 0.1 mmol of acid 4a or 4b at 0 .…”

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confidence: 99%

Chiral Separation, Determination of Absolute Configuration, and High-performance Liquid Chromatography Detection of Enantiomeric 3-hydroxyhexadecanoyl-CoA

et al. 2011

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“…A solution to the difficulty mentioned above was found through the use of 2-methoxy-2-(1-naphthyl)propionic acid (MαNP), which had been used in determining the absolute configuration of chiral secondary alcohols (33,34). The naphthyl ring of MαNP esters exerts greater anisotropic shielding effects on substituents than phenyl group.…”

Section: S)-3b Was Also Used As a Key Intermediate In The Synthesis Omentioning

confidence: 99%

Highly enantioselective synthesis of γ-, δ-, and ε-chiral 1-alkanols via Zr-catalyzed asymmetric carboalumination of alkenes (ZACA)–Cu- or Pd-catalyzed cross-coupling

Oda

Kamada

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Despite recent advances of asymmetric synthesis, the preparation of enantiomerically pure (≥99% ee) compounds remains a challenge in modern organic chemistry. We report here a strategy for a highly enantioselective (≥99% ee) and catalytic synthesis of various γ-and more-remotely chiral alcohols from terminal alkenes via Zr-catalyzed asymmetric carboalumination of alkenes (ZACA reaction)-Cu-or Pd-catalyzed cross-coupling. ZACA-in situ oxidation of tert-butyldimethylsilyl (TBS)-protected ω-alkene-1-ols produced both (R)-and (S)-α,ω-dioxyfunctional intermediates (3) in 80-88% ee, which were readily purified to the ≥99% ee level by lipase-catalyzed acetylation through exploitation of their high selectivity factors. These α,ω-dioxyfunctional intermediates serve as versatile synthons for the construction of various chiral compounds. Their subsequent Cu-catalyzed cross-coupling with various alkyl (primary, secondary, tertiary, cyclic) Grignard reagents and Pd-catalyzed cross-coupling with aryl and alkenyl halides proceeded smoothly with essentially complete retention of stereochemical configuration to produce a wide variety of γ-, δ-, and e-chiral 1-alkanols of ≥99% ee. The MαNP ester analysis has been applied to the determination of the enantiomeric purities of δ-and e-chiral primary alkanols, which sheds light on the relatively undeveloped area of determination of enantiomeric purity and/or absolute configuration of remotely chiral primary alcohols.A symmetric synthesis remains as a significant challenge to synthetic organic chemists as the demand for enantiomerically pure compounds continues to increase. Chirality plays a vital role in chemical, biological, pharmaceutical, and material sciences. The US Food and Drug Administration requires that all chiral bioactive molecules have to be as pure as possible, containing a single pure enantiomer, because chirality significantly influences drugs' biological and pharmacological properties. As a consequence, development of new methods for asymmetric synthesis of enantiomerically pure compounds (≥99% ee) continues to be increasingly important (1-5). We recently reported a highly selective and efficient method (6) for the preparation of 2-chirally substituted 1-alkanols via a sequence consisting of (i) Zr-catalyzed asymmetric carboalumination of alkenes (ZACA reaction hereafter) (7-10)-in situ iodinolysis of allyl alcohol, (ii) enantiomeric purification by lipase-catalyzed acetylation (11, 12) of both (S)-and (R)-ICH 2 CH (R)CH 2 OH (1), the latter obtained as acetate, i.e., (R)-2, and (iii) Cu-or Pd-catalyzed cross-coupling (13, 14) (Scheme 1).As satisfactory as the procedure shown in Scheme 1 is, however, its synthetic scope is limited to the preparation of 2-chirally substituted 1-alkanols. In search for an alternative and more generally applicable procedure, we came up with a strategy shown in Scheme 2, which, in principle, should be applicable to the synthesis of γ-and more-remotely chiral alcohols of high enantiomeric purity. In contrast to Scheme 1, the alkylalane int...

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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

Cited by 105 publications

References 6 publications

Convenient method for determining the absolute configuration of chiral alcohols with racemic ¹H NMR anisotropy reagent, MαNP acid: Use of HPLC‐CD detector

Convenient method for determining the absolute configuration of chiral alcohols with racemic ¹H NMR anisotropy reagent, MαNP acid: Use of HPLC‐CD detector

Chiral Separation, Determination of Absolute Configuration, and High-performance Liquid Chromatography Detection of Enantiomeric 3-hydroxyhexadecanoyl-CoA

Highly enantioselective synthesis of γ-, δ-, and ε-chiral 1-alkanols via Zr-catalyzed asymmetric carboalumination of alkenes (ZACA)–Cu- or Pd-catalyzed cross-coupling

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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

Cited by 105 publications

References 6 publications

Convenient method for determining the absolute configuration of chiral alcohols with racemic 1H NMR anisotropy reagent, MαNP acid: Use of HPLC‐CD detector

Convenient method for determining the absolute configuration of chiral alcohols with racemic 1H NMR anisotropy reagent, MαNP acid: Use of HPLC‐CD detector

Chiral Separation, Determination of Absolute Configuration, and High-performance Liquid Chromatography Detection of Enantiomeric 3-hydroxyhexadecanoyl-CoA

Highly enantioselective synthesis of γ-, δ-, and ε-chiral 1-alkanols via Zr-catalyzed asymmetric carboalumination of alkenes (ZACA)–Cu- or Pd-catalyzed cross-coupling

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Convenient method for determining the absolute configuration of chiral alcohols with racemic ¹H NMR anisotropy reagent, MαNP acid: Use of HPLC‐CD detector

Convenient method for determining the absolute configuration of chiral alcohols with racemic ¹H NMR anisotropy reagent, MαNP acid: Use of HPLC‐CD detector