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FESTA: an efficient NMR approach for the structural analysis of mixtures containing fluorinated species Laura Castañar, Pinelopi Moutzouri, Thaís M Barbosa, Cláudio Francisco Tormena, Roberto Rittner, Andrew Richard Phillips, Steven R. Coombes, Mathias Nilsson, and Gareth A. Morris Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.8b00753 • Publication Date (Web): 26 Mar 2018 Downloaded from http://pubs.acs.org on March 26, 2018

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Analytical Chemistry

FESTA: an efficient NMR approach for the structural analysis of mixtures containing fluorinated species Laura Castañar,† Pinelopi Moutzouri, † Thaís M. Barbosa,‡ Claudio F. Tormena, ‡ Roberto Rittner, Andrew R. Phillips,§ Steven R. Coombes,¥ Mathias Nilsson, † and Gareth A. Morris*,†

‡ †

School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK.

‡

Chemistry Institute, University of Campinas, – UNICAMP – P. O. Box. 6154, 13083-970 – Campinas – SP – Brazil.

§

Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca, Macclesfield, SK10 2NA, UK.

¥

Pharmaceutical Technology and Development, AstraZeneca, Silk Road Business Park, Macclesfield, SK10 2NA, UK.

ABSTRACT: In complex mixtures, proton NMR spectra are often very crowded, making spectral analysis complicated or even impossible, particularly when detailed structural information about the mixture components is needed. A new 1D NMR method (Fluorine-Edited Selective TOCSY Acquisition, FESTA) is introduced that facilitates the structural analysis of mixtures of species that contain fluorine. It allows simplified 1H spectra to be obtained that show only those protons that are in a spin system coupled to fluorine of interest. The new method is illustrated by factorizing a complex 1H spectrum into subspectra for individual spin systems involving different 19F sites.

In recent years, interest in fluorine-containing compounds has increased significantly, mainly due to their pharmacological activity (e.g. as anticancer, antidepressant or antiviral drugs).1,2 Nuclear Magnetic Resonance (NMR) spectroscopy has proven to be a powerful tool for the analysis of fluorine-containing compounds, whether pure or in mixtures.3-8 Most of the NMR methods currently used are based on the acquisition of 19F NMR spectra, rather than 1H. Fluorine is particularly attractive because of its great susceptibility to chemical environment and high sensitivity, and because its wide chemical shifts range makes overlap between signals far rarer than in 1H NMR. 19F diffusion methods, where the components of a mixture can be virtually separated according to their diffusion coefficients,9 have been used to determine the number of different species present in intact mixtures.10-12 However, if structural and conformational information on the components is needed, multidimensional experiments normally have to be acquired. A well-known and powerful NMR tool for structural studies is to use 1H-19F correlation experiments (such as HETCOR,13-15 hetero-COSY15-19 or HOESY20-22), that provide NMR spectra containing valuable structural information with correlations up to five-bonds. When working with small- and medium-size molecules, the information extracted from these 1H-19F correlations is rarely sufficient

for determining the chemical structures, and knowledge of 1H-1H correlations will still be needed. Some such information can be partially obtained by using heteronuclear-edited correlation experiments (such as 2D HSQCTOCSY23,24 or 3D heteronuclear TOCSY25), where in a first step only the signals of those protons coupled to fluorine19 are retained, and these are subsequently used as starting points for the transfer of magnetization through the 1 H-1H network. Despite the valuable structural information provided by such multidimensional heteronuclear-edited spectra, their usefulness is limited, mostly because data acquisition can be very time-consuming. This is particularly problematic when, as is commonly the case, high spectral resolution is required in an indirect dimension (for example where, as is often the case, some 19 F resonances have similar chemical shifts). Where fluorine is relatively sparse, as for example in most fluorinecontaining mixtures encountered in pharmaceutical chemistry, a much more efficient approach is to use selective 1D/2D analogues of such 2D/3D experiments. One such experiment has been described for the measurement of heteronuclear proton-fluorine coupling constants in pure compounds.26 However, more general methods for the efficient and fast extraction of structural information on fluorinated species are needed, especially for complex and/or high-dynamic-range mixtures where spectral anal-

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ysis using current methods can be complicated or even impossible. Here, we propose a new class of fluorineedited selective TOCSY acquisition (FESTA) 1D NMR experiments for efficient structure elucidation in mixtures of fluorine-containing species.

points. Further experimental details and pulse program codes are given in the Supporting Information. Data Analysis. All data were processed with zerofilling, apodisation equivalent to 2 Hz Lorentzian line broadening, Fourier transformation, and phase and baseline correction using the TOPSPIN program (Bruker Biospin).

EXPERIMENTAL SECTION Sample preparation. The illustrative mixture used in this work contained 12 mM fluticasone (Sigma), 26 mM fluconazole (extracted from Diflucan formulation), 32 mM rosuvastatin (supplied by AstraZeneca), 33 mM tertbutyl-E-(6-[-[4-(4-fluorophenyl)-6-isopropyl-2[methyl(methylsulfonyl)amino] pyrimidin-5-yl]- vinyl]((4R,6S)-2,2-dimethyl[1,3]dioxin-4yl) acetic acid (BEM, supplied by AstraZeneca), and sulfur hexafluoride reference (BOC) in 0.7 mL of DMSO-d6 (99.8%, Aldrich). NMR spectroscopy. All spectra were recorded at 298 K on a Bruker Avance NEO 500 MHz spectrometer (Bruker Biospin) with a 5 mm BBO probe equipped with a zgradient coil with a maximum nominal gradient strength of 53 G cm-1. The durations of the hard 90° pulse were set to 10 µs and 14.35 µs for 1H and 19F, respectively. Gaussian 19 F selective 90° pulses, and RSNOB27 1H and 19F selective 180° pulses were typically used. 19F selective 180° refocusing pulses, affecting a single resonance, were only used if homonuclear 19F - 19F coupling was present; otherwise hard pulses are used. TOCSY transfer was achieved using the DIPSI-2 mixing scheme with a mixing time of 30-60 ms depending on the spin system. The trapezoids on either side of the DIPSI-2 isotropic mixing element indicate low power 180° chirp pulses used to suppress the effects of zero quantum coherences; their durations were set to 20 ms and 15 ms respectively. The gradient pulse labels G1, G2, G4 and G5 in the pulse sequence of Figure 1 indicate field gradient pulses of 0.8 ms duration for CTP (coherence transfer pathway) selection. The ratio between G2 and G5 gradients was set to that of the 1H and 19F gyromagnetic ratios, 1:0.9407. Gradient pulses G3 and G7 are homospoil pulses with a duration of 0.8 ms. Gradients G6 and G8 were applied during chirp pulses to suppress the effects of zero-quantum coherences. All CTP and homospoil gradient pulses had smoothed square shape (SMSQ) digitalized using 100 points, and G6 and G8 had square shape. Gradients G1-G8 had strengths of 33%, 47%, 37%, 41%, 44.2%, 3%, 17% and 4%, respectively. All gradient strengths are given as a fraction of the nominal maximum amplitude given above, and all gradient pulses were followed by a recovery delay of 200 µs. The delays ∆, ∆1 and ∆2 were set to 1/(4JHF), 1/(4JHF nH) and 1/(4JHF nF), respectively, where JHF is the heteronuclear coupling constant, nH is the number of selected protons coupled with the selected fluorine, and nF is the number of equivalent fluorines coupled with the selected proton. 1H NMR spectra (conventional, SRI-FESTA, FESTA, and selective TOCSY) were recorded with 10 kHz spectral width and 32k complex points. The 19F CHORUS NMR spectrum was recorded with 140 kHz spectral width and 128k complex

RESULTS AND DISCUSSION The basic FESTA pulse sequence of Figure 1a generates H spectra showing only those protons that are in a spin system containing a chosen fluorine. At the beginning, the favorable high equilibrium polarization and excellent chemical shift dispersion of 19F are exploited in the initial excitation of a fluorine resonance of interest. The resultant coherence is transferred to its proton coupling partner or partners, giving antiphase magnetization in a doubly selective reverse INEPT28,29 (SRI) sequence element. A 1 H selective modulated echo28 (SME) then refocuses the 1 H-19F coupling to provide in-phase magnetization at the starting point of the final TOCSY transfer. The complete pulse sequence of Figure 1a is thus a 19F-decoupled doubly selective 19F → 1H refocused INEPT-TOCSY. This approach using selective reverse INEPT (SRI-FESTA) is just one of a number of ways of implementing fluorine-edited selective TOCSY that differ in how the initial signal is excited. 1

The use of 1H-selective refocusing pulses here is important for two reasons: it restricts the complexity of the resultant TOCSY spectrum, and it avoids the evolution of homonuclear 1H-1H couplings during the 19F → 1H coherence transfer delay (2∆1) and the refocusing period (2∆2). Because 1H-1H and 1H-19F coupling constants are similar in magnitude, failure to suppress the effects of JHH when refocusing those of JHF leads to distortion of the proton signals (Figure S10b’) and signal loss (Figure S10c’), especially when z-filtration is used, as in the zz-TOCSY mixing element of the sequence of Fig.1 1a, to enforce in-phase magnetization before TOCSY transfer.30 In molecules containing more than one fluorine-19 site (e.g. 19F1 and 19F2), any homonuclear 19F1-19F2 couplings will evolve during the first 19F1 → 1H coherence transfer delay (2∆1). Any passive 1 H-19F2 couplings will also evolve during the refocusing period (2∆2). The evolution of such couplings can lead to significant loss of signal in the final spectrum (see Figure S11). In such cases, the use of 19F-selective refocusing pulses is needed to ensure maximum sensitivity. For the study of unknown samples containing fluorinated species, the first step is usually to acquire conventional 1D 1H and 19F spectra with and without heteronuclear decoupling and compare them. In simple mixtures, it is sometimes possible to tell which protons are coupled to which fluorine, and with what coupling constant JHF, simply by comparing coupled and decoupled NMR spectra. This information can then be used to set up SRIFESTA experiments. However, in mixtures with crowded proton spectra, extraction of this information is often

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Analytical Chemistry difficult or impossible. It is then useful to acquire data with just the 19F-selective reverse INEPT (SRI) sequence element (Figure 1b) to show which protons are coupled to each 19F and with what value of coupling constant. Figure 2 illustrates how to determine the experimental parameters needed to acquire the SRI-FESTA experiments for a given sample [Further details of the protocol are given in the Supporting Information].

confirmed by repeating the experiment, selectively refocusing the other proton coupled to this fluorine, at 1.49 ppm (Figure 3c). When the SRI experiment is acquired exciting the fluorine signal at –164.19 ppm, two intense antiphase proton signals appear in the spectrum, at 2.53 ppm and 4.21 ppm (Figure S9c). If the SRI-FESTA experiment is performed refocusing the proton signal at 2.53 ppm, the TOCSY spectrum (Figure 3d) shows the same spin system as when refocusing H6 and H7b. This establishes that both fluorine signals belong to the same molecule, and assigns the signal at 2.53 ppm as H8 and the fluorine at –164.19 ppm as F9 of fluticasone (1). Finally, refocusing the proton signal at 4.21 ppm allows the assignment of fluticasone (1) protons H11, H12 and OH (Figure 3e).

Figure 1. (a) SRI-FESTA and (b) SRI pulse sequences. The narrow and wide rectangles denote hard 90° and 180° radiof19 requency pulses, respectively. The first F selective 90° pulse 19 1 is applied to a single F resonance, and the H selective 180° 1 19 19 pulse to a H resonance coupled with that F. F selective 180° refocusing pulses, affecting a single resonance, are only 19 19 needed if homonuclear F - F coupling is present; otherwise hard pulses are used (Figure S3). The trapezoids on either side of the DIPSI-2 isotropic mixing element indicate low power 180° chirp pulses used to suppress the effects of zero quantum coherences. Further details are given in the Supporting Information.

Figure 3 illustrates the power of this method for the structural analysis of the components of a mixture of four fluorinated pharmaceuticals (Chart 1): fluticasone propionate (1), rosuvastatin calcium (2) and its precursor BEM (3), and fluconazole (4). The new SRI-FESTA experiment is used to generate a set of clean 1D 1H TOCSY spectra, one for each of 7 fluorine-proton coupling partners. When the fluorine resonance at –186.21 ppm is excited using just the SRI component of the sequence (Figure 1b), two antiphase proton signals appear in the spectrum, at 5.62 ppm and 1.49 ppm (Figure 2c). If the SRI-FESTA experiment (Figure 1a) is then performed selectively refocusing the proton at 5.62 ppm, the TOCSY spectrum shown in Figure 3b is obtained. Correlations with aliphatic protons and with one olefinic proton (H4) tell us that this fluorine has to be F6 of fluticasone (1). This can be

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Figure 2. (a) Conventional H { F}, and (b) F { H} CHORUS, NMR spectra of a mixture containing fluticasone (1), rosuvastatin (2), BEM (3), fluconazole (4), and C6F6 in DMSO-d6. (c) 19 1 F →H SRI spectrum obtained using the pulse sequence of Figure 1b with selective excitation of the fluorine resonance at –186.21 ppm (blue asterisk in b). Information about the 1 19 protons coupled with the chosen fluorine and their H- F 1 19 coupling constants can then be extracted. (d) H { F} SRIFESTA spectrum obtained by exciting the fluorine resonance at –186.21 ppm and refocusing the proton resonance at 1.49 19 1 ppm (red asterisk in c). Initial F → H magnetization trans1 1 fer is represented by blue arrows, and H → H TOCSY transfer by red arrows. Further experimental details are given in the Supporting Information.



is marked with a red arrow in each experiment. Further experimental details are given in the Supporting Information. Chart 1: Mixture components used in this study: fluticasone propionate (1), rosuvastatin calcium (2) and its precursor BEM (3), and fluconazole (4).

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F is very sensitive to chemical environment; even very small changes in the latter are reflected in the 19F chemical shift. This makes 19F NMR very attractive for discriminating between structurally similar mixture components. In our mixture, two of the fluorine signals appear at – 111.85 ppm and –111.92 ppm respectively (Figure 4b), because the local environments of the two species concerned are almost identical. These resonances are from rosuvastatin (2) and its precursor BEM (3), which differ only in whether the hydroxyls and the carboxylate group are free or protected. To identify which protons are coupled with each fluorine, two SRI-FESTA experiments were performed, giving subtly different TOCSY spectra (Figures 3f and 3g). It was then possible to assign H2’/H6’ from rosuvastatin (Figure 3f) and BEM (Figure 3g) to signals resonating at 7.71 ppm and 7.67, respectively. These distinguished cleanly between the two spin systems, but to identify which is which in the intact mixture would require further experiments, for example using the NOE. Identifying the fluorine signals of the fourth mixture component, fluconazole (4), is easier. The coupling between the two fluorines at –107.42 ppm and –111.36 ppm is readily apparent in the conventional 19F {1H} CHORUS 1D spectrum (Figure 4b). To assign them, a 19F →1H SRI spectrum was acquired for each 19F resonance. When the fluorine signal at –107.42 ppm was excited, only two proton correlations were observed (Figure 4c), but when the signal at –111.36 ppm was excited there were three (Figure 4d). It is therefore possible to assign these signals as F3 and F5 of fluconazole, respectively. Finally, to assign protons H4, H6 and H7, a SRI-FESTA experiment was acquired selectively exciting the resonance at –111.36 ppm and selectively refocusing the proton at 6.86 ppm (Figure 3h).

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Figure 3. (a) Conventional H { F} NMR spectrum of a mixture containing fluticasone (1), rosuvastatin (2), BEM (3), 1 19 fluconazole (4), and C6F6 in DMSO-d6. (b-h) H { F} SRIFESTA spectra exciting the fluorine resonances at (b,c) – 186.21 ppm, (d,e) –164.19 ppm, (f) –111.85 ppm, (g) –111.92 ppm, and (h) –111.36 ppm. The proton selectively refocused


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Analytical Chemistry 1

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Figure 4. (a) Conventional H { F} and (b) F { H} CHORUS NMR spectra of a mixture containing fluticasone (1), rosuvastatin (2), BEM (3), fluconazole (4), and C6F6 in DMSO-d6. 19 1 (c,d) F → H SRI spectra after selective excitation of the fluorine resonance at –107.42 ppm and -111.36 ppm, respectively. Further experimental details are given in the Supporting Information.

A priori, it may seem that the information obtained with the SRI-FESTA method could be obtained from the conventional 1H-only 1D selective TOCSY spectrum. However, using the 1H selective TOCSY experiment30-32 it is not possible to know if only one proton signal is excited, and therefore if all signals appearing in the spectrum belong to the same spin system, or not. Figure 5 shows the benefits of using SRI-FESTA instead of selective TOCSY if unequivocal information on individual spin systems is needed. If a conventional 1D selective TOCSY experiment is acquired exciting the proton signal at 4.21 ppm, because of signal overlap in the 1H spectrum (Figure S4), the final spectrum will contain proton signals from different spin systems (Figure 5b), making discrimination between them impossible. On the other hand, when the SRI-FESTA experiment is performed exciting the fluorine resonance at –164.19 ppm and refocusing the proton signal at 4.21 ppm (H11), only those protons that belong to its spin system (H12a, H12a, and OH) appear in the spectrum (Figure 5c).

formation about the mixture components is needed. Here it is shown that the proposed FESTA method can help provide valuable structural information by factorising a complex 1H spectrum into subspectra for spin systems involving different 19F sites. Where fluorine-containing contiguous coupled spin systems span much of a molecule, as in fluticasone, information about almost all resonances in a molecule can be extracted by this means (Figure 3b-e). Where spin systems are more fragmented, because of missing couplings, as in rosuvastatin, BEM or fluconazole (Figure 3f-h), further experiments are needed for complete analysis, for example modifying the pulse sequence of Figure 1a to use NOE transfer,33 or successive NOE and TOCSY transfers. When spectral overlap is a problem, FESTA and pure shift34-38 experiments can be combined to provide further resolution. The new method is not limited to fluorinated species and can be easily adapted to other nuclei, e.g. silicon-edited selective TOCSY acquisition (SIESTA).

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: XXX Additional figures as noted in the text, full NMR pulse sequences, experimental parameters, NMR spectral assignment, recommended protocol, and pulse program codes for Bruker spectrometers (PDF).

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected]

Author Contributions L.C. and P.M. performed the experiments; the pulse sequences were designed by L.C., P.M., T.M.B. and G.A.M.; the results were analyzed by L.C., P.M., T.M.B., C.F.T., M.N., and G.A.M. The drug mixture was suggested by S.R.C. and A.R.P.; the work was supervised by C.F.T., R.R., S.R.C., A.R.P., M.N., and G.A.M. All authors contributed to the writing of the manuscript and the Supporting Information.

Notes 1

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Figure 5. (a) Conventional H { F} NMR spectrum of a mixture containing fluticasone (1), rosuvastatin (2), BEM (3), 1 fluconazole (4), and C6F6 in DMSO-d6. (b) Conventional Honly 1D selective TOCSY spectrum from exciting the signal at 19 1 4.21 ppm. (c) F → H SRI-FESTA spectrum after selective excitation of the fluorine resonance at –164.19 and refocusing the proton resonance at 4.21 ppm. Further experimental details are given in the Supporting Information.

CONCLUSIONS

The authors declare no competing financial interest. All raw experimental data and pulse program codes can be freely downloaded from DOI:10.17632/8ppg333jtm.2.

ACKNOWLEDGMENT This work was funded by the Engineering and Physical Sciences Research Council (grant numbers EP/L018500 and EP/R018790), by AstraZeneca, and by São Paulo Research Foundation (grant numbers 2014/12776-6, 2015/19229-3, 2015/08541-6, and 2016/24109-0).

The study of intact mixtures poses very significant challenges in NMR analysis, particularly when structural in-



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