An NMR method for determination of configuration of β-substituted carboxylic acids

Article abstract of DOI:10.1016/S0040-4039(00)00163-5

The absolute configuration of the stereogenic center at the β-position of a carboxylic acid can be determined via derivatization with chiral benzylic amines [PhCH(Me)NH₂ or 1-NpCH(Me)NH₂]. Acids of known configuration and with a variety of β-substituents were subjected to derivatization. Analysis of the signs of the chemical shift differences of substituent protons permits determination of the absolute configuration. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00163-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2289–2293
An NMR method for determination of configuration of
β-substituted carboxylic acids
Thomas R. Hoye,∗ Abdel-Sattar S. Hamad,† Dmitry O. Koltun and Manomi A. Tennakoon
Department of Chemistry, 207 Pleasant Street SE, University of Minnesota, Minneapolis, MN 55455, USA
Received 10 December 1999; accepted 17 January 2000
Abstract
The absolute configuration of the stereogenic center at the β-position of a carboxylic acid can be determined via
derivatization with chiral benzylic amines [PhCH(Me)NH2 or 1-NpCH(Me)NH2]. Acids of known configuration
and with a variety of β-substituents were subjected to derivatization. Analysis of the signs of the chemical shift
differences of substituent protons permits determination of the absolute configuration. © 2000 Elsevier Science
Ltd. All rights reserved.
Keywords: carboxylic acids; configuration; NMR spectroscopy; stereochemistry.
NMR-based methods for determination of the absolute configuration of stereogenic centers are popular
in modern organic chemistry.1 Their main advantages are availability of instrumentation, low cost, and
easy derivatization techniques. Typically, the derivatization is necessary to convert a compound with an
isolated stereogenic center into a pair of diastereomers, which possess different NMR properties. Several
methods for assignment of absolute configuration of the stereogenic center in a position beta to the site of
2a
functionalization (1) have been developed. These include the Mosher MTPA/Eu(fod)3 or the anthryl-
methoxyacetate (AMA)2b analyses of primary alcohols (2a), the Pirkle isocyanate method for amines
(2b),3 and the ephedrine-derived oxazolidinone method for aldehydes (2c).4 We have recently reported
the use of amides derived from 1-phenylethylamine or 1-(1-naphthyl)ethylamine for determination of
absolute configuration of β-methyl-substituted carboxylic acids (3, R1=Me, R2=Me).5
Carboxylic acids 3 with substituents other than a methyl group at C(3) were of interest to us since they
are abundantly present in natural compounds.6 We decided to investigate the extension of our method
∗
†
Corresponding author. E-mail: hoye@chem.umn.edu (T. R. Hoye)
Present address: Chemistry Department, Faculty of Science, Ain Shams University, Abbassia 11566, Cairo, Egypt.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00163-5
tetl 16443

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to include this broader spectrum of acid substrates. Chemical shift trends in the diastereomeric pairs of
1-phenylethylamides and 1-(1-naphthyl)ethylamides derived from several such β-substituted carboxylic
acids have now been studied and we present the results here.
The synthesis of the diastereomeric amides is shown in Scheme 1. 3-Phenylglutaric acid (4) was
converted into 3-phenylglutaric anhydride (5) and then ring-opened with R-1-phenylethylamine or R-
1-(1-naphthyl)ethylamine to give diastereomeric mono-amide mono-acids (∼2:1 ratio of diastereomers
in each case). The acids were esterified with DMF·dimethyl acetal. Diastereomers of each phenyl- (6)
and naphthyl-containing (7) amide were separated by MPLC on silica gel. The relative configuration
for the two diastereomers of 6 and of 7 is assigned by analogy with the sense of ring opening of 3-
methylglutaric anhydride (to provide 15 and 16) as we previously reported.5 A similar strategy was
employed starting with tricarballylic acid (8) to give (after opening of anhydride 97 and esterification)
diastereomeric mixtures of amides 10 and 11.
Scheme 1. Reagents and conditions: (i) Ac2O solvent, rt, 24 h; (ii) (1) R-1-phenylethylamine or R-1-(1-naphthyl)ethylamine, 2
equiv., 24 h, CH2Cl2;8 (2) dimethylformamide dimethyl acetal, CH2Cl2, 24 h, 45–55% for two steps; (iii) R-1-phenylethylamine
or R-1-(1-naphthyl)ethylamine, DCC, DMAP cat., CH2Cl2, 24 h, 60–65%; (iv) MeCOCl/MeOH, 1 h, rt, 52–95%
To unambiguously prove the relative configuration of the syn- and anti-diastereomers of 10 and of 11,
S-tricarballylic acid bis-t-butyl ester (12) was synthesized in an enantiomerically enriched form according
to the literature procedure.9 DCC-mediated coupling under standard conditions led to the formation of
amides 13 and 14. Each of these amides was treated with HCl in methanol to form their corresponding
diastereomeric esters 10 and 11, thereby permitting unambiguous assignment of the relative configuration
of each.
As expected, meaningful differences were observed in chemical shifts of various protons associated
with the R1 and R2 substituents at C(3) in each pair of diastereomeric amides. These results are presented
in Table 1,10 along with those of the 3-methyl glutaramide derivatives 15 and 16 we reported earlier.5 The
difference [expressed in ∆δ units, where ∆δ=δ (syn)–δ (anti)] is always positive for the R1 substituent
and negative for the R2 substituent (cf. Fig. 1). Observed magnitudes of chemical shift differences are
consistent with our earlier observation that the 1-naphthyl group usually provides a larger anisotropic
shielding effect than the phenyl group.5

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Table 1
1H NMR ∆δ values for amides derived from β-chiral acids with known relative configurations
A useful conformational model that accounts for the observed signs of the chemical shift differences
between the syn and anti diastereomers is shown in Fig. 1. It is based on two assumptions: (i) the
predominant rotamer around the benzylic carbon to nitrogen bond is that having the benzylic proton
eclipsed with the carbonyl group; (ii) one of the two non-hydrogen substituents at C(3) essentially always
occupies the anti position relative to the carbonyl group, forcing the other non-hydrogen substituent
gauche to the carbonyl. In the case of the anti-diastereomer, this results in preferential anisotropic
shielding of the R1 substituent by the aromatic phenyl or 1-naphthyl group. In the case of the syn-
Fig. 1. Conformational model for determination of the sign of ∆δ=δ (syn)–δ (anti) or protons in R1 and R2

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diastereomer, preferential shielding of the R2 substituent is observed. It follows that the ∆δ [=δ (syn)–δ
(anti)] values of protons in R1 are positive and those in R2 are negative (cf. Table 1).
In conclusion, the NMR strategy for determination of the absolute configuration of a stereogenic
center in the β-position of a carboxylic acid has been extended to include a variety of (non-methyl) β-
substituents. The strategy involves derivatization of the acid with each enantiomer of 1-phenylethylamine
or 1-(1-naphthyl)ethylamine and measurement of the chemical shifts of groups attached to C(3).
Acknowledgements
This work was supported in part by the National Institutes of Health and an Egyptian Ministry of
Education Fellowship (to A.-S.S.H.). We thank Drs. Maren Pink and Victor J. Young of the University
of Minnesota X-ray Crystallographic Laboratory for determination of the structure of syn-vi.
References
1. (a) Yamaguchi, S. In Asymmetric Synthesis; Morrison, J. D., Ed. Analytical methods; Academic Press: New York, 1983; Vol.
1, pp. 125–152. (b) Parker, D. Chem. Rev. 1991, 91, 1441. (c) Uray, G. In Houben–Weyl Methods in Organic Chemistry;
Helmchen, G., Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; Thieme: Stuttgart, New York, 1996; Vol. 1, p. 253.
2. (a) Yasuhara, F.; Yamaguchi, S. Tetrahedron Lett. 1977, 18, 4085. cf. (b) Latypov, S. K.; Ferreiro, M. J.; Quiñoá, E.; Riguera,
R. J. Am. Chem. Soc. 1998, 120, 4741.
3. For example, see: (a) Pirkle, W. H.; Simmons, K. A. J. Org. Chem. 1983, 48, 2520. (b) Pirkle, W. H.; Robertson, M. R.;
Hyun, M. H. J. Org. Chem. 1984, 49, 2433.
4. Agami, C.; Meynier, F.; Berlan, J.; Besace, Y.; Brochard, L. J. Org. Chem. 1986, 51, 73.
5. Hoye, T. R.; Koltun, D. O. J. Am. Chem. Soc. 1998, 120, 4638.
6. A search of the Beilstein database indicates that there are over 350 known natural products that contain the substructure
shown in 3 in which R1 and R2 are both carbon substituents. A nearly equal number are known in which one of the two is a
hetereoatom substituent.
7. (a) Nuzzo, R. G.; Haynie, S. L.; Wilson, M. E.; Whitesides, G. M. J. Org. Chem. 1981 46, 2861. (b) Reaction of anhydride 9
with ArCH(Me)NH2 gave (following esterification) a ∼3 to 1 ratio of the diastereomeric amides 10 (∼1.2:1) or 11 (∼1.5:1)
to the symmetrical amide, ArCH(Me)NHCOCH(CH2CO2Me)2, arising from amine attack at the α-branched carbonyl group.
8. In the case of tricarballylic acid anhydride, products arising from α- and β-openings were separated using MPLC.
9. Iwasawa, Y.; Shibata, J.; Nonoshita, K.; Arai, S.; Masaki, H.; Tomimoto, K. Tetrahedron 1996, 52, 13 881.
10. We have found additional examples of analogous amide derivatives of 3-substituted carboxylic acids (i–vi) that complement
the NMR data reported in Table 1. The ∆δ [=δ (syn)–δ (anti)] value for the relevant protons of the two diastereomers is
indicated (with sign) directly beside the relevant proton.

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(a) Sita, L. R. J. Org. Chem. 1993, 58, 5285. (b) Huffman, J. W.; Lainton, J. A. H.; Banner, W. K.; Duncan, S. G.; Jordan,
R. D.; Yu, S.; Dai, D.; Martin, B. R.; Wiley, J. L.; Compton, D. R. Tetrahedron 1997, 53, 1557. (c) Yamamoto, Y.; Iwasa,
M.; Sawada, S.; Oda, J. Agric. Biol. Chem. 1990, 54, 3269. (d) Yamamoto, Y.; Yamamoto, K.; Nishioka, T.; Oda, J. Agric.
Biol. Chem. 1988, 52, 3087. (e) Chapleo, C. B.; Hallett, P.; Lythgoe, B.; Waterhouse, I.; Wright, P. W. J. Chem Soc., Perkin
1 1977, 1211. (f) Nagao, Y.; Ikeda, T.; Inoue, T.; Yagi, M.; Shiro, M.; Fujita, E. J. Org. Chem. 1985, 50, 4072.11
11. The signs of the ∆δ values for diastereomers vi deduced from Ref. 10f are opposite to those that our method predicts.
Concerned that this represents an exception to our method, we independently synthesized each of syn-vi and anti-vi and
unambiguously determined the relative configuration of syn-vi by single crystal X-ray analysis. It is now clear that the 1H
NMR data in Ref. 10f are reversed for syn-vi and anti-vi (although the mp and specific rotation values as reported are
associated with the correct diastereomeric structures). The signs and magnitudes of the ∆δ values shown in structure vi
above are from our NMR data and are unambiguously consistent with the method.