Fluorine-containing substituents: Metabolism of the α,α-difluoroethyl thioether motif

Article abstract of DOI:10.3762/bjoc.15.144

We report the metabolism of the recently introduced α,α-difluoroethyl thioether motif to explore further its potential as a substituent for bioactives discovery chemistry. Incubation of two aryl-SCF₂CH₃ ethers with the model yeast organism Cunninghamella elegans, indicates that the sulfur of the thioether is rapidly converted to the corresponding sulfoxide, and then significantly more slowly to the sulfone. When the substrate was (p-OMe)PhSCF₂CH₃, then the resultant (demethylated) phenol sulfoxide had an enantiomeric excess of 60%, and when the substrate was the β-substituted-SCF₂CH₃ naphthalene, then the enantiomeric excess of the resultant sulfoxide was 54%. There was no evidence of defluorination, unlike the corresponding oxygen ether (p-OMe)PhOCF₂CH₃, which was converted to the (demethylated) phenol acetate ester during C. elegans incubation. We conclude that the aryl-S-CF₂CH₃ motif is metabolised in a similar manner to aryl-SCF₃, a motif that is being widely explored in discovery chemistry. It is however, significantly less lipophilic than aryl-SCF₃ which may offer a practical advantage in tuning overall phar-macokinetic profiles of molecules in development.

Full text of DOI:10.3762/bjoc.15.144

Fluorine-containing substituents: metabolism of the
α,α-difluoroethyl thioether motif
Andrea Rodil1, Alexandra M. Z. Slawin1, Nawaf Al-Maharik1,2, Ren Tomita1
and David O’Hagan*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 1441–1447.
1School of Chemistry, University of St Andrews, North Haugh, St
Andrews, KY16 9ST, UK and 2An Najah National University, Nablus,
Palestine
doi:10.3762/bjoc.15.144
Received: 24 April 2019
Accepted: 17 June 2019
Published: 28 June 2019
Email:
David O’Hagan* - do1@st-andrews.ac.uk
Associate Editor: K. N. Allen
* Corresponding author
© 2019 Rodil et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
Cunninghamella elegans; cytochrome P450; fluorinated substituents;
organofluorine metabolism; sulfoxidation
Abstract
We report the metabolism of the recently introduced α,α-difluoroethyl thioether motif to explore further its potential as a substitu-
ent for bioactives discovery chemistry. Incubation of two aryl–SCF2CH3 ethers with the model yeast organism Cunninghamella
elegans, indicates that the sulfur of the thioether is rapidly converted to the corresponding sulfoxide, and then significantly more
slowly to the sulfone. When the substrate was (p-OMe)PhSCF2CH3, then the resultant (demethylated) phenol sulfoxide had an
enantiomeric excess of 60%, and when the substrate was the β-substituted-SCF2CH3 naphthalene, then the enantiomeric excess of
the resultant sulfoxide was 54%. There was no evidence of defluorination, unlike the corresponding oxygen ether
(p-OMe)PhOCF2CH3, which was converted to the (demethylated) phenol acetate ester during C. elegans incubation. We conclude
that the aryl–S–CF2CH3 motif is metabolised in a similar manner to aryl–SCF3, a motif that is being widely explored in discovery
chemistry. It is however, significantly less lipophilic than aryl-SCF3 which may offer a practical advantage in tuning overall phar-
macokinetic profiles of molecules in development.
Introduction
Fluorine and fluorinated substituents are routinely used to too, such as aryl–OCF3 and aryl–SCF3 ethers, although these
modify the properties of lead compounds in medicinal chem- substituents can significantly raise lipophilicity (log P) [5,6].
istry and in bioactive discovery programmes [1,2]. To this end, There are relatively few bioactives on the market in this class,
aryl–F and aryl–CF3 are the most common modifications found some of which are illustrated in Figure 1, however, it is notice-
in compounds registered in the patent literature [3], substitu- able that there is an increasingly active methodology focus
ents which are typically introduced to stop metabolism of aryl describing new ways to introduce -OCF3 and -SCF3, and it can
rings [4]. Other fluorinated motifs are gaining in importance be anticipated that the number of bioactives of this class will
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Figure 1: Structures of trifluoromethyl sulfonyl ether bioactives.
increase [7]. The -OCF3 substituent is not directly metabolised, Having explored synthetic routes and log P evaluations, we now
however, the sulphur associated with the -SCF3 group is report our initial studies on the metabolism of the ArSCF2CH3
susceptible to in vivo oxidation.
substituent. In this context, the potential for P450 oxidation at
sulphur is the most obvious metabolic vulnerability, and also
Tiflorex, an appetite suppressant, toltrazuril, a coccidiostat used hydrolytic susceptibility to release fluoride. We chose to
as an additive to poultry feed, and SKA-19, an anticonvulsant explore the metabolism of aryl α,α-difluoroethyl thioethers 4
as shown in Figure 1, are three such compounds that are of and 5 by Cunninghamella elegans as representative compounds
commercial significance [8-10]. Metabolism studies in both of of this class. This fungus is rich in cytochrome P450 activity
these cases show that the major metabolites are their corre- and has been used as a model organism in which to mimic
sponding sulfoxides (Ar–S(O)CF3) and sulfones phase one mammalian metabolism of xenobiotics [19-21].
(Ar–S(O)2CF3) [8,9]. Indeed, in the case of the insecticide
fipronil it is actually the sulfoxide (Ar–S(O)CF3) that is Results and Discussion
marketed as the active component [11,12]. The increase in The two aryl α,α-difluoroethyl thioethers 4 and 5 in Figure 3
lipophilicity associated with these substituents is not always were selected for C. elegans incubations rather than 1, as they
desirable. In this regard, partially fluorinated alkyl substituents are less volatile, to avoid evaporation losses during extended
become an interesting alternative, as the fluorines polarise the incubations and work-up. Cultures of C. elegans were grown in
adjacent hydrogens and lipophilicity reduces relative to the Saboraud dextrose medium and incubated on an orbital shaker
perfluoro substituents [13-15]. In this context we recently intro- at 28 °C for 72 hours. New metabolites could be conveniently
duced aryl α,α-difluoroethyl thioethers such as 1 as a motif of observed by extracting aliquots of the media into diethyl ether
this class [16-18]. Log P assessments of PhSCF2CH3 (1) indi- and dichloromethane (DCM) and then carrying out HPLC
cate that it is more polar than the PhSCF3 (2) and also the ali- analyses.
phatic PhSCH2CH3 ether 3 as shown in Figure 2. Therefore,
there is potential for the inclusion of this motif in candidate
molecules without a significant increase in log P.
Figure 3: α,α-Difluoroethyl thioether substrates for metabolism
studies.
Incubation of thioether 4 with C. elegans led to the identifica-
tion of three metabolites 6–8 as illustrated in Scheme 1. These
were isolated by semi-preparative HPLC. Two of these (6 and
7) displayed an AB system in the 19F NMR spectrum consis-
tent with non-equivalence of the fluorines, immediately indica-
Figure 2: Comparison of log P values of comparative aryl thioether
motifs [18].
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Scheme 1: Fluorometabolites 6–8 isolated after incubation of 4 with C. elegans. Ratios are the average of three incubations. The structure of 7 was
confirmed by X-ray structure analysis.
tive of sulfoxide formation. Isolation and subsequent 1H and from the assay that there was a significant enantiomeric ratio
19F NMR analyses as well as high-resolution mass spectrome- (4:1) of 6 which translates to a 60% enantiomeric excess (ee,
try secured the identity of these metabolites as sulfoxides 6 and see Supporting Information File 1). We note that there have
7 and sulfone 8. The structure of sulfoxide 7 was also con- been chemical methods developed for the synthesis of enantio-
firmed by X-ray structure analysis. The incubation of 4 in merically enriched aryl fluoroalkyl sulfoxides, however, this
C. elegans, and then HPLC purification, was repeated three appears to be the first enzymatic approach [23-25].
times all with very similar results. These incubations showed
full conversion into the metabolites, and no starting thioether 4 Although the fungus was able to both oxidise the sulfur and
was observed by NMR or HPLC.
demethylate the para-methoxy group of 4, there was no obvious
presence of novel metabolites which did not contain fluorine.
Sulfone 8 was a relatively minor metabolite, at only 10% of This points to a hydrolytically stable motif over the period of
sulfoxide 6. A chiral HPLC (IC column, solvent: 5% the incubation. In an effort to establish the sequence of events
isopropanol in hexane; 1 mL/min) enantiomeric assay was con- through which these metabolites are generated, each was
ducted for sulfoxide 6 and the outcome compared with a separately re-incubated with C. elegans to establish if they
racemic sample of 6, prepared by chemical oxidation of could be further metabolised. Product profiles were again deter-
thioether 4 [22]. Although we could not determine the absolute mined by HPLC analysis and relationships are summarised in
stereochemistry of the predominant enantiomer, it was clear Scheme 2.
Scheme 2: Putative pathways for (α,α-difluoroethyl)(4-methoxyphenyl)sulfane (4) metabolism.
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Incubation of racemic sulfoxide 6 led to a similar outcome to dominates, but the second oxidation of the sulfoxide to a
that for 4 with the formation of phenol sulfoxide 7 and phenol sulfone appears to be a slower process, and is outcompeted by
sulfone 8 suggesting that sulfoxide 6 is the first formed metabo- aryl hydroxylation reactions. The experiment was conducted
lite with demethylation following subsequently at a slower rate. three times under similar conditions, all with very similar
The experiments on the re-incubation of phenols 7 and 8 failed outcomes.
to lead to any further metabolism, where they appeared to be
stable metabolites, certainly for the period (72 h) of the incuba- In order to explore the stereoselectivity of this sulfoxidation,
tion. We were unable to observe a transformation from sulf- sulfoxide 11 isolated from the C. elegans incubation was
oxide 6 to sulfone 9 in these re-incubation experiments. It may analysed by chiral HPLC (IC column, solvent: 5% isopropanol
be that there is a barrier to uptake of the phenols into the fungal in hexane; 1 mL/min). This was compared to a racemic refer-
cells and that they are actively exuded when generated within ence sample of 11 prepared by chemical oxidation of thioether
the cell. As a final experiment sulfone 9, which was not ob- 5. The resultant enantiomeric ratio for 11 was determined to be
served as a metabolite, was prepared by mCPBA oxidation of 3.3:1, which translates to a 54% ee (absolute stereochemistry
thioether 4. This sulfone was then incubated with C. elegans not determined). Again, the sulfoxidation shows a significant
and it gave rise to demethylated phenol 8 as the sole metabolite, stereochemical bias.
consistent with an active demethylation capacity of this fungus.
Non-oxidised phenol 10 was also not observed in this study. The stability of the aryl thioethers can be contrasted with the
Overall this suggests that sulfoxidation is very active and hydrolytic lability of the analogous oxygen ethers. By way of
outcompetes demethylation, however, that demethylation is sig- example α,α-difluoroethyl ether 14 [18] was incubated with
nificantly more active that the second oxidation of sulfoxides to cultures of C. elegans under the standardised conditions, as
sulfones.
illustrated in Scheme 4. 19F NMR of the extract indicated a
trace of residual starting material with one major metabolite
Incubation of naphthalene 5 with C. elegans, generated three which was isolated by HPLC. This was identified as
new metabolites 11–13 which arose by oxidations at sulphur 4-acetoxyphenol (15). Aryl ether demethylation remains highly
and hydroxylations of the naphthalene ring, as summarised in active, but unlike the α,α-difluoroethyl thioethers 4 and 5, the
Scheme 3. These metabolites were isolated by reversed-phase oxygen ether is vulnerable to hydrolytic fluoride release.
HPLC and characterised by 1H and 19F NMR and mass spec- Oxygen ether 14 is particularly labile, and the incubation
trometry. This identified sulfoxides 11 and 12 as the major proceeds to full conversion to generate acetate ester 15.
metabolites and a trace amount of a minor sulfone which had
the general structure 13 as determined by mass spectrometry. The incubation of 14 was carried out four times, all affording
Naphthalene 5 was fully converted. Again, initial sulfoxidation consistent results and generating 15 as the clearly identifiable
Scheme 3: C. elegans incubation of 5. Ratios are the average of three incubations.
Scheme 4: Incubation (four times) of oxygen ether 14 with C. elegans, gave 4-acetoxyphenol (15) as the major metabolite. On one occasion 16 was
tentatively observed as a minor metabolite.
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product. However, in one experiment minor traces of a fluori- [bis(acetoxy)iodo]benzene (BAIB, 7.3 mg, 0.025 mmol). The
nated metabolite was observed. Although a full characterisation reaction was left to stir overnight. After 16 h, the solvents were
was not possible due to the low levels recovered, 1H and evaporated under reduced pressure. The remaining mixture
19F NMR for this metabolite showed an intact -OCF2CH3 showed the formation of 6 with 66% conversion from the
motif, as well as a para-substitution pattern, which suggested starting material 4. Further purification was achieved by
the identity of 4-(1,1-difluoroethoxy)phenol (16).
reversed-phase HPLC in a Phenomenex Luna SP column, with
60:40 AcCN/water (supplemented with 0.05% TFA) at a flow
rate of 1 mL/min. The product 6 was isolated at tR = 24 min,
Conclusion
In conclusion, we have explored Cunninghamella elegans which was consistent with the metabolic experiment’s data.
fungal metabolism of the α,α-difluoroethyl thioether 1H NMR (500 MHz, chloroform-d) δH 7.65 (d, J = 8.9 Hz, 2H),
(Ar–SCF2CH3) motif, which we introduced recently as a more 7.08 (d, J = 8.9 Hz, 2H), 3.89 (s, 1H), 1.81 (t, J = 18.4 Hz, 1H);
polar alternative to RSCF3. It emerges to have a similar metabo- 19F NMR (471 MHz, chloroform-d) δF −93.4 (d, J = 225.1 Hz),
lism to ArSCF3 in that it progresses to the sulfoxide and then −97.1 (d, J = 225.1 Hz).
the sulfone, although in this study the initial oxidation to the
sulfoxide was significantly more rapid than the second oxida- 1–(α,α-Difluoroethyl)sulfonyl)-4-hydroxybenzene (8)
tion to the sulfone. The first oxidation gave enantiomerically (1,1-Difluoroethyl)(4-methoxyphenyl)sulfane (4, 5 mg,
enriched sulfoxides (Ar–S(O)CF2CH3) in the 54–60% ee range. 0.025 mmol) was added to a round bottom flask containing a
This could arise by the action of more than one P450 enzyme. stirring bar, and dissolved in CH2Cl2 (1.5 mL). mCPBA was
There was no evidence of defluorination, or hydroxylation at added to the solution (21 mg, 0.122 mmol), and the mixture was
the terminal -CH3 group. The corresponding oxygen ether 14 stirred at rt overnight. The reaction was quenched by addition of
was susceptible to hydrolytic defluorination to generate an a saturated solution of NaHCO3. The aqueous phase was
acetate ester. The α,α-difluoroethyl thioether (Ar–SCF2CH3) extracted into CH2Cl2 (3 × 3 mL). The combined organic
motif can be readily prepared from thiols and emerges as a phases were combined, dried over Na2SO4, filtered and concen-
potentially attractive substituent for consideration by medicinal trated under reduced pressure, yielding to 8 with 100% conver-
chemists and for other areas of bioactives discovery research, to sion. Further purification was carried out by column chromatog-
complement the widely used ROCF3 and RSCF3 groups and raphy, starting with 100% petroleum ether, followed by 15%
there is a clear similarity to the ‘polar lipophilic’ groups EtOAc in petroleum ether, affording 8 in quantitative yield.
ROCF2H, and RSCF2H [26].
1H NMR (500 MHz, chloroform-d) δH 7.84 (d, J = 8.6 Hz, 2H),
7.02 (d, J = 8.6 Hz, 2H), 3.91 (s, 3H), 2.02 (t, J = 18.3 Hz, 3H);
19F NMR (471 MHz, chloroform-d) δF −97.3 (s); 13C NMR
(126 MHz, chloroform-d) δC 165.2, 133.1, 122.9, 114.7, 55.8,
Experimental
Microorganism growth
Cunninghamella elegans DSM1908 was grown on Saboraud 16.6 (t, J = 22.2 Hz); HMRS (ESI) m/z: [M + H]+ calcd for
dextrose agar gel plates for 120 h at 28 °C, from previous C9H11F2O3S, 236.0310; found, 236.0390; [M + Na]+ calcd,
stocks. The plates were stored at 4 °C for a maximum of 259.0211; found, 259.0216.
4 months. Liquid cultures were prepared by inoculation from
mycelium from the plates, into Saboraud dextrose broth 2–(α,α-Difluoroethyl)sulfinyl)naphthalene (11)
(50 mL), and grown on an incubator shaker for 72 h at 28 °C (1,1-Difluoroethyl)(naphthalene-2-yl)sulfane (5, 5 mg,
and 180 rpm.
0.022 mmol) was added to a round bottom flask with a stirring
bar and dissolved in a mixture of DCM (3 mL) and methanol
(0.3 mL). The solution was stirred at room temperature until
Synthesis of substrates
Thioethers 4 and 5 and oxygen ether 14 were prepared as previ- homogenisation (5 min). AlCl3 (1.5 mg, 0.011 mmol) was
ously described [18]. Compounds 6, 8 and11 were prepared as added, and the solution stirred for 5 min, prior to the addition of
described below.
[bis(acetoxy)iodo]benzene (BAIB, 11.1 mg, 0.022 mmol). The
reaction was left to stir overnight. After 16 h, the solvents were
evaporated under reduced pressure. Further purification was
1-(α,α-Difluoroethyl)sulfinyl)-4-methoxybenzene (6)
(1,1-Difluoroethyl)(4-methoxyphenyl)sulfane (4, 5 mg, achieved by reversed-phase HPLC in a Phenomenex Luna SP
0.025 mmol) was added to a round bottom flask with a stirring column, with 60:40 AcCN/water (supplemented with 0.05%
bar and dissolved in a mixture of DCM (3 mL) and methanol TFA) at a flow rate of 1 mL/min, which afforded 11 in 30%
(0.3 mL). The solution was stirred at room temperature until yield. The product 11 was isolated at tR = 37 min, which was
homogenisation (5 min). AlCl3 (1.8 mg, 0.012 mmol) was consistent with the metabolic experiments’ data. 1H NMR
added, and the solution stirred for 5 min, prior to the addition of (500 MHz, chloroform-d) δH 8.28 (s, 1H), 8.01 (d, J = 8.7 Hz,
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Beilstein J. Org. Chem. 2019, 15, 1441–1447.
1H), 7.99–7.92 (m, 2H), 7.69 (ddt, J = 8.7, 2.6, 1.3 Hz, 1H), tometer, using multi-layer mirror monochromed Mo Kα radia-
7.67–7.60 (m, 2H), 1.77 (t, J = 18.5 Hz, 3H); 19F NMR tion.
(471 MHz, chloroform-d) δF −92.9 (d, J = 227.0 Hz), −96.0 (d,
J = 227.0 Hz); 13C NMR (126 MHz, chloroform-d) δC 145.9
(C-Ar, visible in HMBC), 135.1 (s, C-Ar), 133.6 (t, J =
Supporting Information
218.8 Hz, CF2), 129.3 (s, C-Ar), 128.8 (s, C-Ar), 128.5 (s,
Supporting Information File 1
Further details of equipment specifications and compound
characterisation.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-144-S1.pdf]
C-Ar), 128.1 (s, C-Ar), 127.5 (s, C-Ar), 126.8 (s, C-Ar), 121.0
(s, C-Ar), 111.7 (C-Ar, visible in HMBC), 16.5 (t, J = 22.1 Hz,
CF2CH3); HRMS (ESI+) m/z: [M + H]+ calcd for C12H11OF2S,
241.0420; found, 241.0491.
Biotransformations and extraction conditions
Culture media was purchased from Sigma-Aldrich. Each
thioether (5–10 mg) was dissolved in DMF (50 µL) and inocu-
lated into cultures of C. elegans. The cultures were incubated at
28 °C and 180 rpm for 72 h. Blank experiments were carried
out in the absence of C. elegans. After 72 h, the fungal biomass
was removed and washed with diethyl ether. The supernatant
was extracted into diethyl ether (3 × 50 mL) and dichloro-
methane (3 × 50 mL), and the combined organic extracts were
dried over anhydrous Na2SO4, filtered and evaporated under
reduced pressure. The extracts were analysed by 1H and
19F NMR before further purification by HPLC.
Acknowledgements
We thank Professor Cormac D. Murphy, University College
Dublin, for cultures and advice on incubating Cunninghamella
elegans. The Marie Curie-ITN Programme (FLUOR-21: Syn-
thesis structure and function of fluorinated systems) is thanked
for a Studentship (AR) and financial support.
ORCID® iDs
Alexandra M. Z. Slawin - https://orcid.org/0000-0002-9527-6418
Nawaf Al-Maharik - https://orcid.org/0000-0002-7014-6190
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