Synthesis and Evaluation of FICA Derivatives as Chiral Derivatizing Agents

Abstract

1-Fluoroindan-1-carboxyic acid (FICA) derivatives containing a monosubstituted benzene ring (1b–e) were synthesized as their methyl esters and their potential as chiral derivatizing agents (CDAs) were assessed by both ¹⁹F- and ¹H-NMR spectroscopy. Introduction of a substituent at the 4-position in the benzene ring caused a 1.2–2 fold increase in Δδ_F values when compared with that of FICA. This increase was investigated using a correlation model for ¹⁹F-NMR and by the order of the stability of the synperiplanar (sp) and antiperiplanar (ap) conformers of the (R,S) and (S,S) diastereomers from the Gibbs’ free energy at 298.15 K.

Introduction

A convenient and reliable method for assigning the absolute configuration of chiral molecules is ¹H-NMR analysis of diastereomers obtained by reacting these substrates with chiral derivatizing agents (CDAs).^1,2) Among the various CDAs developed, fluorine-containing CDAs are attractive because ¹⁹F-NMR can be used as an additional analytical probe, and the chemical shift differences of ¹⁹F signals are larger than those of ¹H signals and ¹⁹F-NMR spectra are straightforward to analyze.³⁾ CDAs, such as α-methoxy-α-(trifluoromethyl)phenylacetic acid (MTPA),^1,2,4) α-cyano-α-fluoro-p-tolylacetic acid (CFTA),⁵⁾ 1-fluoroindan-1-carboxylic acid (FICA),^6,7) and 8-fluoro-1,2,3,4-tetrahydro-1,4-epoxynaphthalene-1-carboxylic acid (F-THENA)⁸⁾ have been used systematically to determine the absolute configuration of chiral secondary alcohols using both ¹⁹F- and ¹H-NMR spectroscopy (Fig. 1). However, ¹⁹F chemical shifts observed with MTPA cannot be used for configuration assignments because the signs of the Δδ_F values of MTPA esters do not correlate with the absolute stereochemistry of the alcohols.⁴⁾ In contrast, CFTA,⁵⁾ FICA,⁷⁾ and F-THENA⁸⁾ can be reliably used to determine the absolute configuration by both ¹⁹F- and ¹H-NMR spectroscopy. The source of chemical shift differences of CFTA and FICA are explained by an anisotropic effect change from the preferred conformational change in equilibrium.^5,7) F-THENA is a unique CDA where the F atom senses the shielding effect of the aromatic ring of the alcohol and is therefore used for configuration assignments of only chiral secondary aromatic alcohols in ¹⁹F-NMR spectroscopy.⁸⁾

Fig. 1. The Structures of Fluorine-Containing CDAs

Recently, we prepared FICA and revealed that it can be a more reliable CDA than commercially available MTPA for determining the absolute configurations of secondary alcohols (Fig. 1). For all 14 alcohols examined including the nabumetone metabolite (+)-4-(6-methoxy-2-naphthyl)butan-2-ol, the signs of the Δδ_F values for the FICA esters correlated with their absolute configurations.^6,7,9)

For ¹H-NMR, when applied to cyclic alcohols, FICA was superior to MTPA, however, the Δδ_H values of the FICA esters were similar to those of MTPA.⁷⁾ On the one hand, the comparatively small Δδ_H values were attributed to the small amount of the synperiplanar (sp) rotamer, which is likely to be the ¹H-NMR significant conformer.⁷⁾ On the other hand, conformational studies of methoxyphenylacetic acid (MPA) as a CDA showed that the introduction of substituents on the benzene ring shifted the equilibrium between the sp and antiperiplanar (ap) conformers.²⁾ The larger Δδ_H and Δδ_F values make the method very reliable for assigning the absolute stereochemistry of the chiral secondary alcohols. In this research setting, we selected commercially available indanones bearing a bromine atom at the 4-, 5-, or 6-position of the benzene ring and examined the positional effect of the substituent with rac-FICA derivatives (1c–e) and a rac-4-Me-FICA derivative (1b)¹⁰⁾ to obtain larger Δδ_H and Δδ_F values than those of FICA (Fig. 2).

Fig. 2. FICA Derivatives

Results and Discussion

Methyl esters of FICA derivatives (2c–e) (Chart 1) were prepared in 74–79% overall yield starting from commercially available 1-indanone derivatives according to a reported method,¹⁰⁾ except for methyl esterification of α-hydroxycarboxylic acids. Esterification of the acids was improved by using trimethylsilyl-diazomethane¹¹⁾ instead of Blanchfield’s method¹⁰⁾ to give the methyl esters in high yields within 15 min.

Chart 1. The Ester Exchange Reaction

Each methyl ester (2b–e) was converted to the esters of secondary alcohols (3–7) by an ester exchange reaction (Chart 1). These esters (3–7) were examined by ¹H- and ¹⁹F-NMR to determine their suitability as CDAs.

Δδ_H values of selected methyl protons of each aliphatic and cyclic ester were obtained from the ¹H-NMR spectra of the diastereomeric mixtures of the esters. The example of 2-butyl esters is shown in Table 1, and other results are listed in Tables 4–7 (Supplementary Materials). For 2-butyl esters, the Δδ_H values of 1′-Me and 4′-Me groups of substituted FICA esters (3b–e) were similar to those of 3a. The same results were obtained from 2-hexyl, 1-phenylethyl, l-menthyl, and (−)-bornyl esters of the mono-substituted FICAs (4–7) (Tables 4–7 in Supplementary Materials). These data indicated that introducing a substituent on the benzene ring did not generally improve the capability of FICA to separate the signals of diastereomers.

Table 1. ¹H-NMR Properties of Substituted FICA Esters (3a–e)

R	ΔδH (ppm)
	1′-H	4′-H
H (3a)	0.07a)	0.15a)
4-Me (3b)	0.06	0.14
4-Br (3c)	0.07	0.15
5-Br (3d)	0.06	0.13
6-Br (3e)	0.06	0.13

a) Ref. 6.

Δδ_F values were obtained from ¹⁹F-NMR spectra of the diastereomeric mixtures of the esters (3–7), and the results are shown in Table 2. Δδ_F values of the corresponding CFTA esters are also provided in the last row of Table 2 for comparison. Δδ_F values of FICA esters were smaller than those of CFTA esters for phenylethyl (5) and bornyl esters (7) but larger for 2-butyl (3) and menthyl esters (6).

Table 2. ¹⁹F-NMR Properties of Substituted FICA Esters (3–7) and the Corresponding CFTA Esters

R	ΔδF (ppm)
	3	4	5	6	7
H (a)	0.23a)	0.42a)	0.51a)	1.02a)	0.04b,c)
4-Me (b)	0.21	0.52d)	0.60d)	1.54d)	0.05d)
4-Br (c)	0.23	0.58d)	0.49	1.58d)	0.08d)
5-Br (d)	0.11	0.44d)	0.44	0.99	0.03
6-Br (e)	0.23	0.27	0.33	0.66	0.05 d)
CFTAe)	0.08c,e)	—	0.87c,e)	0.59 c,e)	0.74c,e)

a) Ref. 6. b) Ref. 7. c) Δδ_F values were obtained from the optically active diastereomers. d) The values larger than those of the corresponding FICA esters are underlined. e) Ref. 5.

In contrast to the ¹H-NMR data, introducing a substituent on the benzene ring improved the capability of FICA to separate the ¹⁹F signals of diastereomers. The position of a substituent affected the Δδ_F values. Apart from 3b, 3c and 5c, the Δδ_F values of 4-substituted FICAs increased by 1.2–2 fold when compared with that of FICA, whereas 5- or 6-substituted FICAs gave Δδ_F values that were smaller than that of FICA.

Contrary to our expectations, introducing a substituent on the benzene ring did not increase Δδ_H values but improved Δδ_F values. The reason for this result was then investigated by a correlation model of 4-Br-FICA (S)-2-hexyl ester for ¹⁹F-NMR that gave a 1.4-fold larger Δδ_F value than that of the corresponding FICA ester^12,13) (Fig. 3). We have reported that the non-equivalence in the measured ¹⁹F-NMR shifts can be rationalized by the bias associated with the existence of the sp and ap rotamers.^7,14) The observed NMR signals report a population weighted average between the sp and ap rotamers due to conformational exchange. In the sp rotamers (8, 10), the F atom is affected by an anisotropic deshielding of the ester carbonyl, which is absent in the ap rotamers (9, 11). The conformational equilibrium is less biased to sp- (10) in the (S,S) pair (10 and 11) of the 4-Br-FICA ester when compared with that of the original FICA esters because of a repulsion between the 4-Br group on the benzene ring of the agent and the larger substituent (ⁿBu) on the alcohol. Consequently, the Δδ_F values of 4-Br-FICA esters are larger than those of the original FICA esters. Since the distance between the ester carbonyl and F atom is shorter than that between the benzene ring and alkoxy group, the influence of increasing or decreasing the ratio of the sp rotamer might have a larger effect on the Δδ_F values than on the Δδ_H values.

Fig. 3. A Correlation Model of 4-Br-FICA (S)-2-Hexyl Ester for ¹⁹F-NMR

To support the correlation model of 4-Br-FICA (S)-2-hexyl ester for ¹⁹F-NMR, we performed density functional theory (DFT) calculations on the corresponding four conformations of 4-Br-FICA (S)-2-hexyl ester (8–11; Fig. 4). All calculations including geometry optimization were performed at the B3LYP/6-31G(d, p) level.¹⁵⁾ The vibrational frequency analyses were successively performed, and it was confirmed that there were no imaginary frequencies and that these four geometries were local minima of the potential energy surface.

Fig. 4. DFT Calculation Models (8–11)

The total energies, relative energies, and differences of Gibbs’ free energy (ΔG) of 8–11 at 298.15 K are shown in Table 3. From the total energy, the order of the stability of the conformations was 10 > 11 > 9 > 8; however, from the Gibbs’ free energy at 298.15 K, the order of the stability was 11 > 9 > 8 > 10. The latter supports the model shown in Fig. 3.

Table 3. B3LYP/6-31G(d, p) Total Energies, Relative Energies, and Differences of Gibbs’ Free Energy (ΔG) at 298.15 K of the Four Models of the 4-Br-FICA (S)-2-Hexyl Ester (8–11)

Model	Total energy [a.u.]	Relative energy [kcal/mol]	ΔG [kcal/mol]
(R,S)-sp (8)	−3443.805707	1.68	−0.17
(R,S)-ap (9)	−3443.805330	1.20	−0.64
(S,S)-sp (10)	−3443.803027	0.00	0.00
(S,S)-ap (11)	−3443.803797	0.23	−1.64

Conclusion

The magnitudes of Δδ_H values of FICA derivatives containing a monosubstituted benzene ring were similar to that of FICA. Therefore, FICA derivatives can be used as CDAs in the same way as FICA by ¹H-NMR. However, the aim of improving the capability of FICA derivatives as CDAs for ¹⁹F-NMR to separate the signals of diastereomers was achieved by using the 4-Me- and 4-Br-FICA compounds. The 4-position of the substituent affected the Δδ_F values. A correlation model explained the increase in Δδ_F values, which showed that the repulsion between the 4-substituent on the benzene ring of the CDA and the larger substituent on the alcohol changed a bias because of the existence of the sp and ap rotamers in each diastereomer. This was supported by the order of the stability of the corresponding four models from the Gibbs’ free energy at 298.15 K. The readily available substituted FICA CDAs offer greater sensitivity for determining the absolute stereochemistry of chiral secondary alcohols by ¹⁹F- and ¹H-NMR spectroscopy and should be promising and popular reagents in organic synthesis and medicinal chemistry. We are currently preparing both enantiomers of 4-Br-FICA Me ester by asymmetric synthesis and/or optical resolution for application to the FICA-based method in assigning the absolute configuration of secondary alcohols based on ¹⁹F- and ¹H-NMR.^7,9)

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials.

References and Notes

• 1) Kusumi T., J. Synth. Org. Chem. Jpn., 51, 462–470 (1993), and references cited therein.
• 2) Seco J. M., Quiñoá E., Riguera R., Chem. Rev., 104, 17–117 (2004), and references cited therein.
• 3) Takeuchi Y., Takahashi T., “Enantiocontrolled Synthesis of Fluoro-organic Compounds,” ed. by Soloshonok V.A., Wiley, Chichester, 1999, pp. 497–534.
• 4) Ohtani I., Kusumi T., Kashman Y., Kakisawa H., J. Am. Chem. Soc., 113, 4092–4096 (1991).
• 5) Takahashi T., Fukushima A., Tanaka Y., Takeuchi Y., Kabuto K., Kabuto C., Chem. Commun., 787–788 (2000).
• 6) Takahashi T., Kameda H., Kamei T., Ishizaki M., J. Fluor. Chem., 127, 760–768 (2006).
• 7) Takahashi T., Kameda H., Kamei T., Koyanagi J., Pichierri F., Omata K., Ishizaki M., Nakamura H., Tetrahedron Asymmetry, 24, 1001–1009 (2013).
• 8) Dolsophon K., Soponpong J., Kornsakulkarn J., Thongpanchang C., Prabpai S., Kongsaeree P., Thongpanchang T., Org. Biomol. Chem., 14, 11002–11012 (2016).
• 9) Kamei T., Kimura Y., Koyanagi J., Matsumoto K., Hasegawa T., Akimoto M., Takahashi T., Chem. Pharm. Bull., 67, 75–78 (2019).
• 10) Koyanagi J., Kamei T., Ishizaki M., Nakamura H., Takahashi T., Chem. Pharm. Bull., 62, 816–819 (2014).
• 11) Shioiri T., Aoyama T., Synth. Org. Chem. Jpn., 44, 149–159 (1986).
• 12) The esters of (R)-acids with (S)-alcohols are designated (R,S), and those of (S)-acids with (S)-alcohols are denoted (S,S).
• 13) A correlation model is explained with (R,S) and (S,S) diastereomers because each of the enantiomer pairs, the (R,S) and (S,R) pair or the (S,S) and (R,R) pair, are identical in NMR properties.
• 14) These rotamers arise upon rotation about the C_α–CO bond: synperiplanar (sp), with the C–F and C=O bonds oriented in the same direction, and antiperiplanar (ap), with these same bonds oriented in opposing directions.
• 15) Gaussian 16, Revision B.01, Frisch M.J., Trucks G.W., Schlegel H.B., Scuseria G.E., Robb M.A., Cheeseman J.R., Scalmani G., Barone V., Petersson G.A., Nakatsuji H., Li X., Caricato M., Marenich A.V., Bloino J., Janesko B.G., Gomperts R., Mennucci B., Hratchian H.P., Ortiz J.V., Izmaylov A.F., Sonnenberg J.L., Williams-Young D., Ding F., Lipparini F., Egidi F., Goings J., Peng B., Petrone A., Henderson T., Ranasinghe D., Zakrzewski V.G., Gao J., Rega N., Zheng G., Liang W., Hada M., Ehara M., Toyota K., Fukuda R., Hasegawa J., Ishida M., Nakajima T., Honda Y., Kitao O., Nakai H., Vreven T., Throssell K., Montgomery J.A., Jr., Peralta J.E., Ogliaro F., Bearpark M.J., Heyd J.J., Brothers E.N., Kudin K.N., Staroverov V.N., Keith T.A., Kobayashi R., Normand J., Raghavachari K., Rendell A.P., Burant J.C., Iyengar S.S., Tomasi J., Cossi M., Millam J.M., Klene M., Adamo C., Cammi R., Ochterski J.W., Martin R.L., Morokuma K., Farkas O., Foresman J.B., Fox D.J., Gaussian, Inc., Wallingford CT, 2016.