Comparative Analysis of Fluorine-Directed Glycosylation Selectivity: Interrogating C2 [OH → F] Substitution in d- Glucose and d- Galactose

Article abstract of DOI:10.1002/ejoc.201501081

The influence of C2 [OH → F] substitution on the stereochemical course of chemical glycosylation was interrogated in both D-glucose and its C4 epimer D-galactose. Molecular editing at C2 and configurational inversion at C4 were simultaneously investigated

Full text of DOI:10.1002/ejoc.201501081

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201501081
Comparative Analysis of Fluorine-Directed Glycosylation Selectivity:
Interrogating C2 [OHǞF] Substitution in D-Glucose and D-Galactose
Nico Santschi[a,b] and Ryan Gilmour*[a,b]
Keywords: Physical organic chemistry / Stereoelectronic effects / Carbohydrates / Glycosylation / Fluorine
The influence of C2 [OHǞF] substitution on the stereochem-
oxofluorination at the C2 position induces an enthalpic bias
ical course of chemical glycosylation was interrogated in
that augments β-stereoselection. Intriguingly, the enhanced
both D-glucose and its C4 epimer D-galactose. Molecular ed- stereoselectivity of the C4 epimer D-galactose was found to
iting at C2 and configurational inversion at C4 were simulta-
neously investigated by variable-temperature glycosylation
studies of both systems. Extrapolation of the differences in
enthalpic (ΔΔHβα‡) and entropic (ΔΔSβα‡) contributions that
be entropic in nature. Given the prominence of these scaf-
folds in chemical biology, delineating the factors that under-
pin selectivity will be critical in developing novel glycosyl-
ation methods and in rationalizing differences with the natu-
discriminate these closely similar systems revealed that de- ral systems post facto.
ferred to as [18F]FDG (Figure 1, top right). Recurrently em-
Introduction
ployed as a radiotracer for positron emission tomography
(PET), this essential radiopharmaceutical is consumed
worldwide for routine noninvasive imaging, which renders
it essential for diagnostic medicine.[9] The molecule’s clinical
success relies on both the introduction of the [18F] radio-
label and the position of this radiolabel on the pyranose
scaffold. The OHǞF substitution at C2 ensures that the
conventional glycolysis pathway[10] is blocked following
The prominence of 2-fluoroglucose in glycomimesis[1,2]
and clinical medicine[3] is attributable to a shift in properties
caused by the seemingly subtle OHǞF substitution at C2
of the pyranose ring. The negligible steric penalty incurred
by this subtle editing process is in stark contrast to the dra-
matic variation in molecular structure (Figure 1, left).[4]
Owing to the unrivaled electronegativity of fluorine, the
C–F bond is highly polarized (i.e., Cδ+–Fδ–), which leads
to a lowering of the antibonding orbital. The stabilizing
interactions involving this σC–F* orbital with electron-rich
σ bonds and free electron pairs is responsible for the diver-
sity of fluorine conformational effects that are routinely
used in focused molecular design.[5] The strategic incorpo-
ration of fluorine can induce significant changes in molecu-
lar properties: an extreme case is that of Teflon® [cf. poly-
tetrafluoroethylene (PTFE) and polyethylene (PE)].[6] In
drug discovery, fluorination often confers a bioactive mol-
ecule with increased lipophilicity, which thus renders the
process advantageous in improving pharmacokinetics.[7]
Moreover, fluorination can be exploited to attenuate amine
basicity (pKa), alter hydrogen-bonding patterns, or simulta-
neously achieve multiple effects.[8] In carbohydrate chemis-
try, the strategic value of fluorine introduction is exem-
plified by 2-deoxy-2-(18F)fluoro-d-glucose, commonly re-
[a] Institut für Organische Chemie,
Westfälische Wilhelms-Universität Münster,
Corrensstrasse 40, 48149 Münster, Germany
E-mail: ryan.gilmour@uni-muenster.de
http://www.uni-muenster.de/Chemie.oc/gilmour/
[b] Excellence Cluster EXC 1003 “Cells in Motion”,
Westfälische Wilhelms-Universität Münster,
Corrensstrasse 40, 48149 Münster, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201501081.
Figure 1. Molecular editing at C2 [OHǞF] and the effects on
structure. Right: Selected examples of biomolecules containing the
2-fluoro d-glucose and/or d-galactose moiety.
Eur. J. Org. Chem. 2015, 6983–6987
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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N. Santschi, R. Gilmour
SHORT COMMUNICATION
cellular uptake; this assures that the tracer accumulates in reaction reflects the significant SN1 character of 2-fluoro-
target cells and subsequently decays by positron emission, glycosylation: Independently submitting the α- and β-con-
which can be detected to generate a three-dimensional figured trichloroacetimidates to standard glycosylation con-
image.[11] In the field of mechanistic enzymology, the corre- ditions has been shown to furnish the β-glycoside predomi-
sponding 2-deoxy-2-fluoro-d-glucose system bearing the natly (1,2-trans).[19]
natural isotope at C2 has an equally distinguished lineage
(Figure 1, bottom right).
Intriguingly, the configuration of the C4 stereocenter was
found to play a decisive role in determining the β/α selectiv-
Seminal interrogations of glycosidase mechanism by ity (rβα) in subsequent glycosylation events (Figure 2).
Withers and co-workers established that the C2 [OHǞF] Upon individually treating the 2-deoxy-2-fluoro-d-glucose
substitution destabilizes the oxocarbenium ion like transi- and 2-deoxy-2-fluoro-d-galactose trichloroacetimidate do-
tion state by virtue of the inductive effects of fluorine.[12] nors with iPrOH as the acceptor [–78 °C, trimethylsilyl tri-
Moreover, this modification removes a key H-bond between fluoromethanesulfonate (TMSOTf) in CH2Cl2], this ratio
‡
the active site and substrate whilst imposing a negligible increased from 57:1 (ΔΔGβα = –6.6 kJmol–1) to 150:1
‡
steric impact on interactions with the enzyme.[13] The corre- (ΔΔGβα = –8.1 kJmol–1).[19] Consequently, this study was
sponding C4 epimer based on d-galactose has also found extended to explore the effect of C2 substitution in both d-
application in the design of probes of adhesion in Toxoplas- glucose and d-galactose (Figure 3). Given that the observed
mosis[14] and in the construction of fluoroglycopeptides and selectivity (rβα) reflects the relative rates of addition to the
glycoproteins.[15,16] In recent years, the unraveling of mam- incipient oxocarbenium ion under the SN1 paradigm, infor-
malian and bacterial glycospace[17] has been an incentive to mation concerning this selectivity-determining step can be
delineate the role of natural carbohydrates and to design extracted. Thus, by carrying out a series of glycosylation
‡
structural analogues. The 2-fluoroglycosyl unit has emerged experiments at various temperatures the enthalpic (ΔΔHβα
)
as a vital building block in this field, and this trend is set and entropic (ΔΔSβα‡) contributions to the differences in
to continue. The growing interest in this motif necessitates free energy between the transition states (TS‡) leading to
‡
‡
‡
that stereoselective methods be developed to facilitate the the β- and α-anomers (ΔΔGβα = ΔΔHβα – TϫΔΔSβα
construction of fluorinated glyco structures.[18] This labora- can be derived by Eyring analysis.[21,22]
tory has reported an orthogonal set of highly selective 2-
)
fluoroglycosyl donors based on the d-glucose, d-mannose,
and d-galactose scaffolds (Figure 2).[19] Mechanistic analy-
ses revealed that high diastereoselectivity (β/α ratio) was a
consequence of a synergistic match between the configura-
tion at C2 and the inductive nature of the peripheral pro-
tecting groups. The 1,2-trans relationship in the major glyc-
oside product is consistent with a Felkin–Anh–Eisenstein
induction model (Figure 2).[20] Invoking an oxocarbenium
ion model to rationalize the stereochemical course of the
Figure 3. The aims and objectives of this study. Delineating the
entropic (ΔΔSβα) and enthalpic (ΔΔHβα) factors that distinguish
the selectivity differences between X = OBn vs. X = F for d-glucose
(top) and d-galactose (bottom). R = C(NH)CCl3.
Whereas the physical ramifications of the C2 [OHǞF]
substitution have found widespread application in molecu-
lar design, and synthetic routes to the target glyco structures
have been developed, a comparative analysis based on ex-
perimentally derived reaction parameters would assist in
delineating the enthalpic and entropic contributions that
underpin the selectivity observed by this seemingly trivial
structural adjustment. Herein,
a variable-temperature
glycosylation study of perbenzylated 2-deoxy-2-fluoro-d-
glucose and 2-deoxy-2-fluoro-d-galactose is reported by
using iPrOH as a model glycosyl acceptor. By determining
ΔΔGβα and by extension the entropic (ΔΔSβα‡) and en-
‡
Figure 2. Fluorine-directed glycosylation: An overview of stereose-
lective 2-fluoroglycoslyation and 2-fluorogalactosylation, and the
respective Felkin–Anh–Eisenstein induction models based on the
assumption that the transformation has significant SN1 character.
thalpic (ΔΔHβα‡) data, the contributions to the β/α selectiv-
ity of these popular systems can be garnered and placed in
context with the natural systems.
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 6983–6987

Comparative Analysis of Fluorine-Directed Glycosylation Selectivity
Table 1. Summary of selectivity data for donors S1–S4 at various
temperatures.
Results and Discussion
As a starting point for this study, trichloroacetimidate
(TCA) donors S1–S3 were prepared according to estab-
lished literature precedent:[19] the α anomer was obtained
almost exclusively (β/α Ͻ 1:20, Table 1 top). Subsequently,
the donors were subjected to standard glycosylation condi-
tions by using iPrOH (1.2 equiv.) and TMSOTf (0.1 equiv.)
at temperatures ranging from 25 to –60 °C. To minimize
solvent participation, CH2Cl2 was employed as the reaction
medium (0.05 m). After 2 h at the specified temperature, the
reactions were quenched by the addition of NEt3 and then
concentrated under reduced pressure, and the crude mix-
tures were directly analyzed by 19F NMR (for S1 and S2) or
1H NMR (for S3) spectroscopy. Each reaction was repeated
three times to ensure reproducibility, and this led to relative
standard deviations (σβα/rβα) ranging from 2.1 to 11.1%.
These selectivity data were further complemented with val-
[b]
Donor
T [K][a]
rβα
σβα
rЈβα
rЈβα/rβα
S1
(X = F, Gal)
298.15 (25)
273.15 (0)
232.15 (–41)
223.15 (–50)
212.15 (–61)
195.15 (–78)
4.29
7.97
0.47 (11.1)
0.24 (3.1)
26.62 3.08 (11.6)
4.25
7.73
27.32 1.03
38.35 0.96
60.36 1.18
134.54 0.90
0.99
0.97
S1
S1
S1
S1
S1
40[c]
–
51.18 4.91 (9.6)
150[c]
–
S2
ues available in the literature for reactions performed at –50 (X = F, Glu)
298.15 (25)
273.15 (0)
228.15 (–45)
223.15 (–50)
212.15 (–61)
195.15 (–78)
1.98
4.26
0.14 (7.2)
0.10 (2.3)
2.25
4.02
15.85 0.90
19.09 0.91
29.68 1.01
64.73 1.14
1.13
0.94
and –78 °C.[19] Hence, a total of six and five data points
S2
S2
S2
S2
S2
17.68 0.56 (3.2)
were obtained for fluorinated compounds S1/S2 and parent
galactose system S3, respectively. These data are summa-
21[c]
–
29.41 1.02 (3.5)
57[c]
–
rized in Table 1. Furthermore, predicted selectivity ratios
‡
‡
(rЈβα) based on experimentally derived ΔΔHβα and ΔΔSβα
S3
values (see above) are provided (Table 1, right).
(X = OBn, Gal)
S3
S3
298.15 (25)
273.15 (0)
232.15 (–41)
212.15 (–61)
195.15 (–78)
1.94
2.29
3.50
5.44
7.5[c]
0.04 (2.1)
0.06 (2.7)
0.09 (2.5)
0.14 (2.7)
–
1.84
2.34
3.86
5.28
7.26
0.95
1.02
1.10
0.97
0.97
Consistent with previous studies,[19] these data support
the initial report that the C4 configuration is decisive in
orchestrating diastereocontrol, and the 2-deoxy-2-fluoro- S3
S3
galactose scaffold significantly outperforms the glucose
congener, even at ambient temperature.
S4
The ratio rβα(P1)/rβα(P2) remains constant and/or
slightly increases at lower temperatures, the implications of
which will be discussed later. For the parent 2-benzyloxy
systems, a more favorable β/α ratio is also observed for the
galacto-configured donor, although the difference is less
pronounced than in the fluorinated case. In addition, the
ratio rβα(P3)/rβα(P4) constantly decreases as the tempera-
ture is lowered with values of 1.6 and 1.1 at 25 and –78 °C,
respectively. To extract the thermodynamic parameters of
interest from the selectivity data measured, linearization by
means of an Eyring plot [Equation (1) and Figure 4] was
performed.
(X = OBn, Glu)[d] 298.15 (25)
1.22
1.44
3.27
5.52
6.82
0.06 (4.7)
0.10 (6.7)
0.19 (5.7)
0.22 (4.1)
0.33 (4.9)
1.24
1.69
2.68
4.84
7.94
1.01
1.18
0.82
0.88
1.16
S4
S4
S4
S4
273.15 (0)
243.15 (–30)
213.15 (–60)
193.15 (–80)
[a] Values in parentheses are the temperatures in °C. [b] Relative
standard deviations σβα/rβα are given in parentheses. [c] Values
taken from ref.[19] [d] Values taken from ref.[22] rЈβα = calculated
selectivity. rβα = measured selectivity.
ln(rβα) = –ΔΔHβα‡ ϫ(RT)–1 + ΔΔSβα‡ ϫR–1
(1)
By linear regression analyses on the acquired data sets
[ln(rβα) ~ T–1] the enthalpic (ΔΔHβα‡) and entropic
(ΔΔSβα‡) contributions to the difference in free energy be-
‡
tween the β and α transition states (ΔΔGβα‡ = ΔGβ‡ – ΔGα )
were calculated, as summarized in Table 2. All fits afforded
high correlation coefficients (R2 Ͼ 0.99). The quality of the
data was further supported by considering the ratio of
predicted selectivities (rЈβα) and experimental values
(rβα), rЈβα/rβα. This descriptor ranged from 0.82 to 1.18: the
optimal value is rЈβα/rβα = 1 for perfect congruence.
Perhaps most prominent from inspection of the rβα-
(P1)/rβα(P2) ratio is that the 2-fluoro-2-deoxy sugars
studied feature identical enthalpic stabilizations of the β-TS
over the α-TS, within the precision of the measurements,
Figure 4. Eyring plot of the selectivity data summarized in Table 1.
Error bars are presented as 2ϫσЈβα with σЈβα = σβα/rβα; data for
P4 included from ref.[22]
with respective values of –16.2Ϯ0.6 (for S1) and sented in the Eyring plot that correspond to these measure-
–15.8Ϯ0.7 kJmol–1 (for S2). That is, the set of lines repre- ments are parallel (Figure 4, black top set of lines). This
Eur. J. Org. Chem. 2015, 6983–6987
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6985

N. Santschi, R. Gilmour
SHORT COMMUNICATION
Table 2. Compilation of experimentally determined thermo- effect should be more pronounced for the lower-lying ac-
dynamic data for donors S1–S4.
cepting antibonding orbital (σC–F* vs. σC–O*). This more
‡
‡
ΔΔHβα [kJmol–1]
ΔΔSβα [Jmol–1 K–1]
favorable enthalpy of activation reflects a more bonded, or
presumably later, transition state. Importantly, the orthogo-
nal orientation of the πC=O system and σ* orbital is absent
in the 4H3 configured transition state, which ultimately
leads to the minor α anomer. In all cases, the negative dif-
ferences in entropic contributions are consistent with re-
duced translational and rotational freedom in the β transi-
tion state, which in turn is fully consistent with augmented
fluorine stereoelectronic (σǞσ*) and electrostatic (dipole)
effects in the incipient oxocarbenium ion. In conclusion,
this study demonstrated that the seemingly innocent instal-
lation of fluorine at the C2 position of a perbenzylated
pyranose scaffold induces an enthalpic bias that augments
S1 (X = F, Gal)
S2 (X = F, Glu)
S3 (X = OBn, Gal)
–16.2Ϯ0.6
–15.8Ϯ0.7
–6.4Ϯ0.4
–42.4Ϯ2.5
–46.4Ϯ2.9
–16.6Ϯ1.7
–26.8Ϯ4.5
S4 (X = OBn, Glu)[a] –8.6Ϯ1.1
[a] Values taken from ref.[22]
suggests that the enhanced selectivity observed for the C4
galacto configuration likely arises from a less entropically
disfavored β-TS than in the C4 gluco system, that is,
ΔΔSβα‡(S1)Ͼ ΔΔSβα‡(S2). The situation for the parent 2-
benzyloxy systems is more complex, as is reflected by con-
vergence of the two lines as the temperature decreases (Fig-
ure 4, gray bottom set of lines). Taking into consideration
only the enthalpic term ΔΔHβα‡, it is reasonable to expect
that glucose-derived donor S4 (–8.6Ϯ1.1 kJmol–1) might
furnish higher levels of diastereoselectivity (rβα) than S3
(–6.4Ϯ0.4 kJmol–1) on account of a larger stabilization of
the β-TS. Conversely, the difference in entropy of activation
β-stereoselection in
a model glycosylation reaction.
Furthermore, this analysis indicated that the origin of the
enhanced stereoselectivity of the C4 epimer d-galactose is
entropic in nature. The increasing prominence of fluorin-
ated glyco structures in chemical biology will create a de-
mand for more versatile and selective glycosylation method-
ologies. Delineating the factors that underpin selectivity will
be pivotal both in the development of novel technologies
and in the post facto rationalization of anomalous differ-
ences between fluorinated structures and their natural
counterparts.
‡
associated with S3 is more favorable (ΔΔSβα = –16.6Ϯ1.7
‡
Jmol–1 K–1) than in S4 (ΔΔSβα = –26.8Ϯ4.5 Jmol–1 K–1)
for achieving β-selectivity. Ultimately, this should lead to a
situation in which gluco system S4 outperforms galactose-
derived donor S3; this is indicated by the intersection on
the Eyring plot.
Conclusions
The influence of C2 [OHǞF] substitution on the stereo-
chemical course of chemical glycosylation was interrogated
in both d-glucose and its C4 epimer d-galactose. These
scaffolds remain at the forefront of carbohydrate mimesis
and medicine. C2 fluorine installation confers significant
improvements in glycosylation selectivity in the d-glucose
system; this is even more pronounced in d-galactose. Vari-
able-temperature glycosylation studies of both systems al-
lowed the effect of molecular editing at C2 and configura-
tional inversion at C4 to be simultaneously investigated. As-
suming a mechanism with significant SN1 character, the ob-
served selectivity (rβα) reflects the relative rates of addition
to one of two faces of the planar oxocarbenium ion.
Through a series of temperature-dependent glycosylation
experiments it was possible to extrapolate the differences in
enthalpic (ΔΔHβα‡) and entropic (ΔΔSβα‡) contributions
Figure 5. Tentative transition states implicating orbital control
(σC–F*) to account for β selectivity in chemical glycosylation.
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental details.
Acknowledgments
This work was generously supported by the Westfälische Wilhelms-
Universität Münster, Germany, the Swiss National Science Foun-
that discriminate these closely similar systems. These data dation (P2EZP2-148757), the Deutsche Forschungsgemeinschaft
(DFG) (SFB 858 and Excellence Cluster EXC 1003 “Cells in Mo-
tion - Cluster of Excellence”), and the European Research Council
(ERC-2013-StG Starter grant number, project number 336376-
ChMiFluorS).
indicate that deoxofluorination at C2 results in significant
stabilization of the β transition state in terms of enthalpy
with differences between C2–F and C2–OBn of 9.8 and
7.2 kJmol–1 for the galacto and gluco configurations,
respectively. This data is in line with the original supposi-
tion that orbital control by a Felkin–Anh–Eisenstein model
(Figure 5) is of central importance in the creation of the
1,2-trans (i.e., β) glycosidic linkage. Whereas orbital mixing
in the developing transition state is expected for both the
BnO and F systems in the 3H4 half-chair conformation, the
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