Fluorine-directed β-galactosylation: Chemical glycosylation development by molecular editing

Article abstract of DOI:10.1002/chem.201200468

Validation of the 2-fluoro substituent as an inert steering group to control chemical glycosylation is presented. A molecular editing study has revealed that the exceptional levels of diastereocontrol in glycosylation processes by using 2-fluoro-3,4,6-tri-O-benzyl glucopyranosyl trichloroacetimidate (TCA) scaffolds are a consequence of the 2R,3S,4S stereotriad. This study has also revealed that epimerization at C4, results in a substantial enhancement in β-selectivity (up to β/α 300:1). Copyright

Full text of DOI:10.1002/chem.201200468

DOI: 10.1002/chem.201200468
Fluorine-Directed b-Galactosylation: Chemical Glycosylation Development
by Molecular Editing
Estelle Durantie, Christoph Bucher, and Ryan Gilmour*[a]
Dedicated to Professor Dr. Rudolf Geyer on the occasion of his retirement
Abstract: Validation of the 2-fluoro substituent as an inert steering group to con-
trol chemical glycosylation is presented. A molecular editing study has revealed
that the exceptional levels of diastereocontrol in glycosylation processes by using
2-fluoro-3,4,6-tri-O-benzyl glucopyranosyl trichloroacetimidate (TCA) scaffolds
are a consequence of the 2R,3S,4S stereotriad. This study has also revealed that
epimerization at C4, results in a substantial enhancement in b-selectivity (up to b/
a 300:1).
Keywords: diastereoselectivity
disaccharides · fluorine · glycosyla-
tion · sphingolipids
·
Introduction
The clinical success of glycomimetic pharmaceuticals is testi-
mony to molecular mimicry as a drug design approach.[1]
Moreover, with advances in statistical data analysis illumi-
nating the vastness of mammalian and bacterial “glyco-
space”,[2,3] the desire to emulate carbohydrates in a therapeu-
tic context is set to continue. Echoing the medical progress
that has derived from understanding nucleic acids and pep-
tides, and emulating them with non-natural analogues, so
the next era of drug development seems set to embrace gly-
coscience.[4] The need to effectively mimic pharmaceutically
relevant oligosaccharides[5] has led many groups to explore
fluoro-sugars as bio-isosteres with desirable pharmacokinet-
ic profiles.[6] This is due to the low van der Waals radius of
ꢀ
fluorine, the inert nature of the C F bond and enhanced hy-
drolytic stability of the glycosidic linkage.[7,8]
Given the galactose-rich nature of numerous glycoconju-
gate epitopes, such as fucosyl GM1 (1)[9] and CD1d (2)[10]
(Figure 1), it is perhaps unsurprising that many fluoro-glyco-
mimics contain the (b)-2-fluorogalactose motif. Pertinent ex-
amples include Withers and co-workersꢀ application of 2-flu-
oroglycosides to mechanistic enzymology,[6c,d,o,p,8] and Hoff-
mann-Rçder and colleaguesꢀ strategic inclusion of this struc-
tural feature in glycopeptide antigen design.[6v,x,y] Moreover,
recent work from Davis, Matthews and co-workers has ele-
Figure 1. Bioactive, galactose-rich oligosaccharides.
gantly demonstrated that 2-F-galactose-containing trisac-
charides, such as 3, bind to the pathogenic protein TgMIC1
from Toxoplasma gondii with equal or improved potency
compared to the natural ligand.[6x] However, despite the
prevalence of 2-fluoro-galactose-containing structures in
chemical biology,[6] stereoselective methods to facilitate
their synthesis remain elusive. To reconcile this dearth of
synthetic precendence with the recent surge of interest in
fluoro-sugars, the development of a highly diastereoselective
2-fluorogalactosylation process was instigated. Central to
this approach was the desire to showcase the strategic appli-
cation of the 2-fluoro substituent as an inert steering group,
with minimal steric footprint, to control chemical glycosyla-
tion.
[a] E. Durantie,+ Dr. C. Bucher,+ Prof. Dr. R. Gilmour
Laboratory for Organic Chemistry
Swiss Federal Institute of Technology (ETH) Zꢁrich
8093 Zꢁrich (Switzerland)
Fax : (+41)44-632-79-34
http://www.gilmour.ethz.ch
E-mail: ryan.gilmour@org.chem.ethz.ch
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200468.
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FULL PAPER
Recent work from this laboratory has established that the
introduction of a configurationally defined 2-fluoro substitu-
ent in a pyranosyl trichloroacetimidate (TCA) donor can
greatly enhance the glycosylation selectivity when matched
with the electronic nature of the protecting groups.[11,12] The
gluco-configured, trichloroacetimidate donor (2R-F) bearing
benzyl groups at positions 3, 4 and 6 reacts with various gly-
cosyl acceptors in a highly b-selective manner (Scheme 1;
the b-glycoside was isolated as the major product (b/a 21:1)
in a respectable 85% yield over 2 steps. Importantly, no
post-product epimerisation was observed indicating that this
particular process is under kinetic control.[14] Under analo-
gous reaction conditions, the C2 epimer proved to be signifi-
cantly less selective (b/a 3:1, entry 2) thus establishing the
importance of the C2 configuration for selectivity.[15,16] Im-
portantly, the allose-based donor (entry 3, C3 epimer) also
proved to be significantly less effective than the gluco-donor
(entry 1), marginally favouring formation of the a-isopropyl-
glycoside (b/a 1:2, 74% yield over 2 steps). Inversion of the
C2 fluorine centre to give the altrose system (entry 4) had
little influence on the reaction outcome (b/a 1:3, 74% yield
over 2 steps). Remarkably, the C4 epimer (galactose-based
donor) proved to be highly effective in furnishing the de-
sired isopropyl glycoside in a b/a ratio of 40:1 at ꢀ508C
(71% yield over 2 steps). It is noteworthy that by lowering
the temperature to ꢀ788C this ratio could be improved to
150:1 (72% yield over 2 steps, entry 5).
From this investigation, it may be deduced that the pres-
ence of the C2 fluorine substituent, and the relative stereo-
chemical relationship of the three contiguous centres (C2,
C3 and C4), collectively influence the reaction outcome.
Specifically, epimerization of the C2 and/or C3 positions are
not tolerated and lead to essentially non-selective glycosyl
donors (b/a ~3:1 and ~1:3). In essence, deviation from the
2R,3S relationship present in the parent glucose system has
a severe impact on diastereoselectivity. However, the conse-
quence of epimerization at C4 to generate the galacto-
system 2R,3S,4S, is a notable enhancement in b-selectivity
(up to b/a 40:1 versus 21:1 at ꢀ508C; up to b/a 150:1 versus
57:1 at ꢀ788C, also see Table 2, entry 1).
Scheme 1. Overview of 2-fluoro-glucosylation and -mannosylation from
this laboratory (R=protecting group; LG=trichloroacetimidate leaving
group).[11]
left, b/a up to 57:1). Intriguingly, the analogous 3,4,6-tri-O-
Ac/Piv donors are considerably less selective. The epimeric
manno-configured donor (2S-F) is also non-selective when
per-benzylated, although substitution with more polar Ac/
Piv groups furnishes a highly a-selective donor (Scheme 1;
middle, exclusively a). Having established that a reinforcing
combination of C2 fluorine configuration and protecting
group electronics is responsible for selective glycosylation
(2-FGluc/Bn!b; 2-FManno/Piv!a), it seemed prudent to clari-
fy this apparent matched–mismatched relationship in the
gluco-configured donor: this in turn would facilitate devel-
opment of an effective 2-fluoro-galactosyl donor (Scheme 1;
right).
To complete this preliminary structural analysis, it seemed
prudent to investigate the influence of the C1 configuration
of the 2-fluoro-pyranosyl trichloroacetimidate (TCA) on the
stereochemical course of the reaction.[17] To address this
issue, the a- and b-trichloroacetimidates of the gluco- and
galacto-2-fluoropyranoses were independently isolated, char-
acterised and subjected to the standard reaction conditions
used throughout this study (iPrOH, TMSOTf, CH2Cl2,
Scheme 2).
The 2-fluoroglucose system: Due to difficulties in separating
the 3,4,6-tri-O-benzyl-2-fluoro-glucopyranosyl-trichloroaceti-
midates,[11] the per-methylated system was used as a substi-
tute, and converted to the corresponding isopropylglycoside
at ꢀ508C. The a-trichloroacetimidate furnished the desired
product with good b-selectivity (b/a 10.3:1). Similarly, the b-
TCA also proved to be b-selective under the standard reac-
tion conditions (b/a 5.3:1), consistent with a pathway exhib-
iting substantial SN1-type behaviour (Scheme 2; upper). Im-
portantly, Poletti and co-workers have shown that treatment
of the a-2,3,4,6-tetra-O-benzyl-glucopyranosyl trichloroace-
timidate (2-OBn) with iPrOH and TMSOTf in CH2Cl2
(ꢀ408C) favours formation of the b-isopropylglycoside (b/
a 5.3:1).[18] However, the b-trichloroacetimidate favoured
formation of the a-product (b/a 1:2.3): this is reminiscent of
Results and Discussion
It was envisaged that a logical process of molecular editing
would identify which structural features are important in
promoting diastereoselectivity. For comparison, the effect of
systematic inversion of the C2, C3 and C4 substituents was
investigated (Table 1). As a starting point, the glycosylation
of isopropanol with the gluco-donor (entry 1) was investigat-
ed. The starting aldopyranose was converted to the
Schmidt-trichloroacetimidate[13] and subjected to glycosyla-
tion conditions (TMSOTf, CH2Cl2, ꢀ508C). As expected,
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R. Gilmour et al.
Table 1. Towards a highly stereoselective 2-fluoro-galactosylation reaction: investigating the influence of the
configuration at C2, C3 and C4 on selectivity.[a]
anomeric configuration of the
starting
trichloroacetimidate.
Consequently, induction models
invoking a transient 2-fluoro-
oxocarbenium ion intermediate
are helpful in rationalising the
selectivity of the process.[11]
However, a SN2-type mechanis-
tic component of reactions in-
volving the a-2-F-trichloroaceti-
midates cannot be totally dis-
counted.
To evaluate the influence of:
1) the peripheral protecting
groups, and 2) the C2 substitu-
ent (X=F, H and OR) on ste-
reoselectivity a succinct compa-
rative analysis was completed
(Table 2). In previous glycosyla-
tion studies with C2-modified
glucopyranosyl TCA donors, it
was noted that fluorinated spe-
cies imparted higher levels of
selectivity than the correspond-
ing deoxy or benzyloxy systems
(b/a 57:1, 6:1 and 7:1, respec-
Entry
1
Substrate
Product
T [8C]
ꢀ50
Yield [%][c]
b/a[d]
85
21:1
2
ꢀ50
ꢀ50
ꢀ50
71
74
74
3:1
3[b]
4[b]
5
1:2 tively; entry 1).[11] Interestingly,
the epimeric (C4) galactose
donor that is the subject of this
study gave superior levels of
diastereoselectivity (b/a 150:1,
72% yield versus b/a 57:1 and
71% yield, entries 1 and 2, re-
spectively). Noteworthy are the
lower levels of diastereocontrol
observed with the 2-deoxy and
2-OBn donors of both the glu-
cose and galactose derivatives
under comparable conditions.[18]
A similar selectivity trend was
noted for the 3,4,6-tri-O-meth-
1:3
ꢀ50
ꢀ78
71
72
40:1
150:1
[a] Reagents and conditions: a) Cl3CCN, DBU, CH2Cl2, 08C!room temperature; b) iPrOH, TMSOTf,
CH2Cl2, temperature indicated. [b] Reaction performed with a mixture of allo- and altro configured substrates
due to separation difficulties (see the Supporting Information). [c] Yield after the 2 step activation/glycosyla-
tion sequence. [d] a/b Ratios determined by 1H and/or 19F NMR spectroscopy of the crude reaction mixture.
ylgalactopyranosyl
donor
(entry 3, for X=F, H, OMe, b/
a 22:1, 1:1.4 and 3.9:1, respec-
a SN2-type process.[19] Naturally, these observations are sub-
ject to the caveat that the ancillary protecting groups are
slightly different, albeit both are weakly inductive (Me and
Bn).
tively). Finally, to establish the importance of the electronic
nature of the peripheral substituents, the Bn groups were
substituted by polar Ac groups (entry 4). Complete erosion
of stereocontrol proved to be the consequence of this modi-
fication (b/a 1:1), with a lower 45% yield (over 2 steps)
being recorded even at an elevated temperature (08C); no
reaction was observed at ꢀ508C. Importantly, repeating
entry 2 (X=F) at 08C for comparison gave the b-glycoside
(b/a 6:1). This total loss of diastereocontrol in the acetylated
donor is consistent with previous findings pertaining to
gluco-configured systems (Scheme 1).[11]
The 2-fluorogalactose system: Treatment of the a-2-F-galac-
tose-TCA with TMSOTf in CH2Cl2 (ꢀ788C) proceeds with
configurational inversion to furnish the b-isopropylglycoside
(b/a 150:1). Likewise, the b-2-F-galactose-TCA displayed
the same propensity to form the b-glycoside, albeit to
a lesser extent.[20] From these preliminary data, it is evident
that the reactions of 2-fluoro-donors are stereoconvergent,
favouring the b-isopropylglycoside irrespective of the
To demonstrate the importance of the 2-fluoro substituent
in controlling stereoselectivity, a series of fluoro-galactosyla-
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Fluorine-Directed b-Galactosylation
FULL PAPER
tion reactions were performed with various acceptors
(Table 3; X=F). In parallel, an analogous set of reactions
was conducted using the 2-deoxy galactose donor (Table 3;
X=H) for comparison. It is important to note that treat-
ment of the starting 2-fluoro aldopyranose with Cl3CCN and
DBU generates the a-anomer as the major reaction product
(see the Supporting Information). Furthermore, isolation of
this major a-TCA is facile by column chromatography; this
was not the case for the b-TCA. In the case of the analogous
2-deoxy system, formation of the trichloroacetimidate is no-
tably less selective (b/a 1.5–2.5:1).
The initial fluoro-galactosylation by using ethanol as the
glycosyl acceptor furnished the desired product in excellent
yield (68%, 2 steps) and with exquisite levels of diastereo-
control (b/a 300:1 by 19F NMR spectroscopy; entry 1). The
analogous reaction with the 2-deoxy donor proved to be
almost non-selective (b/a 1.5:1, entry 2), a most compelling
argument for the importance of the 2-fluoro substituent in
controlling b-galactosylation. A similar phenomenon was
observed with bulkier acceptors, such as isopropanol (b/
a 150:1 versus 1.5:1 for X=F and X=H, entries 3 and 4, re-
spectively). Even sterically demanding acceptors, such as
tBuOH, furnished the expected galactoside with lower, but
still synthetically useful, b/a ratios (b/a 15:1 versus 1.3:1 for
X=F and X=H, entries 5 and 6, respectively).[21] It was also
possible to generate the allyl fluorogalactoside with excel-
lent levels of diastereocontrol
Scheme 2. Reagents and conditions: a) TMSOTf, CH2Cl2, ꢀ508C.
b) TMSOTf, CH2Cl2, ꢀ408C.[18] c) TMSOTf, CH2Cl2, ꢀ788C.
Table 2. Investigating the influence of protecting groups and the C2 substituent on stereoselectivity.[a]
(b/a 120:1 versus 1:1 for X=F
and X=H, entries 7 and 8, re-
spectively). Employing phenol
as the acceptor was highly a-se-
lective when using the deoxy
donor, yet introduction of the
2-fluoro substituent overrides
the inherent substrate based
stereocontrol of the reaction to
furnish the b-galactoside (b/
a 6:1 versus a only; entries 9
and 10, respectively). Finally,
a highly b-selective process was
observed when benzyl alcohol
was used as the acceptor (b/
a 120:1, entry 11), whereas the
2-deoxy donor was unselective
(b/a 1:1, entry 12).
To assess the viability of this
2-F-galactosyl donor in disac-
charide synthesis, the galactosy-
lation of various, commonly
used monosaccharide acceptors
was evaluated (Table 4). The
corresponding transformation
was repeated this time using
the 2-deoxy donor for compari-
son. The sterically demanding
galactose derivative (entry 1)
was smoothly processed to the
Entry
1
Substrate
Product
X
Yield [%][d]
b/a[f]
F
H
OBn
71
82
55
57:1[11]
6:1[11]
7:1[11]
F
H
OBn
72
69
72
150:1
1.5:1
7.5:1
2
F
H
OMe
58
22:1
1:1.4
3.9:1
n.d.[e]
53
3[b]
F
H
OAc
45
63
32
1:1
1:3
>20:1
4[c]
[a] Reagents and conditions: a) Cl3CCN, DBU, CH2Cl2, 08C!room temperature; b) iPrOH, TMSOTf,
CH2Cl2, ꢀ788C. [b] Reactions were performed at ꢀ508C. [c] No reaction was observed at ꢀ78, ꢀ50 and
ꢀ308C, therefore, the reaction was performed at 08C. [d] Yield after the two-step activation/glycosylation se-
quence. [e] Analysis of the deoxy analogue (X=H) proved problematic; no yield determined. [f] Ratios were
1
determined by H and/or 19F NMR spectroscopy of the crude reaction mixture.
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R. Gilmour et al.
Table 3. Glycosylation reactions of the 2-fluorogalactose trichloroaceti-
midate: probing the steric influence of the glycosyl acceptor on stereose-
lectivity.[a]
Table 4. Stereocontrolled 2-fluoro-galactosylation.[a]
Entry
Glycosyl acceptor
X
Yield
[%][b]
b/a[c]
Entry
Acceptor
(ROH)
X
Yield
[%][b]
b/a[c]
F
H
41
56
5:1
ACHTUNGTRENNUNG
[d]
1
2
3
4
5
6
7
8
EtOH
EtOH
F
H
F
H
F
H
F
H
F
H
F
68
71
72
69
51
84
72
71
62
67
76
71
300:1
1.5:1
150:1
1.5:1
15:1
1.3:1
120:1
1:1
1
iPrOH
iPrOH
tBuOH
tBuOH
AllylOH
AllylOH
PhOH
PhOH
BnOH
BnOH
F
H
31
54
5:1
[d]
2
3
9
6:1
F
H
56
47
11:1
[d]
10
11
12
a only
120:1
[d]
H
F
H
53
51
10:1
[d]
[a] Reagents and conditions: a) Cl3CCN, DBU, CH2Cl2, 08C!room tem-
perature; b) ROH, CH2Cl2, TMSOTf, ꢀ788C. [b] Yield following a two-
step activation/glycosylation sequence from the starting aldopyranose.
[c] Ratios were determined by 1H and/or 19F NMR spectroscopy of the
crude reaction mixture. [d] Not determined since the anomeric proton of
the b-glycoside was obscured by the benzyl signals (a-glycoside dH =
5.10–5.11 ppm); separation by column chromatography furnished a b/
a ratio 1:1.1.
4
F
H
43
46
1.3:1
[d]
5
6
F
H
49
54
40:1
1.7:1
product disaccharide in a respectable 41% yield favouring
the expected b-product (b/a 5:1): only the a-anomer was
isolated from the analogous reaction when using the 2-
deoxy donor. Using the related glucose-acceptor (entry 2)
gave the identical result, albeit with a reduction in yield (b/
a 5:1, 31% yield). Modifying the acceptor scaffold (deletion
of the C2 OBn) to reduce its steric impact resulted in an im-
provement in both yield (56 versus 31%) and diastereose-
lectivity (b/a 11:1 versus 5:1), further indicating that this
transformation is sensitive to the steric demands of the ac-
ceptor (Table 3). Once again, the process using the non-fluo-
rinated congener was a-selective (entry 3). A similar pro-
clivity to form the b-adduct was recorded when using diace-
tone glucose (entry 4, b/a 10:1, 53%), thus overriding the
inherent a-preference of the non-fluorinated system. The
impact of the steric environment on reaction efficiency is
best illustrated by entries 5 and 6. Whereas the use of the
benzylated acceptor bearing a free C4-hydroxyl group
proved to be poorly selective (b/a 1.3:1, entry 5), the same
acceptor scaffold bearing a free C6-hydroxyl group fur-
nished the target disaccharide in a b-selective fashion (b/
a 40:1). In general, introduction of the (2R)-fluoro substitu-
ent allows the intrinsic substrate-based stereocontrol of the
reaction to be superseded (a!b).
[a] Reagents and conditions: a) Cl3CCN, DBU, CH2Cl2, 08C!room re-
mperature; b) ROH, CH2Cl2, TMSOTf, ꢀ788C; [b] yield following
a 2 step activation/glycosylation sequence from the starting aldopyranose;
[c] ratios were determined by 1H and/or 19F NMR spectroscopy; [d] not
determined since the anomeric proton of the b-glycoside was obscured
by the benzyl signals; only the a-glycoside was isolated after column
chromatography of the reaction mixture.
and co-workers and sheds light upon the mechanism of au-
toreactivity of T cell antigen receptors on natural killer
T cells (NKT) involving the b-linked agonists b-GalCer and
iGb3.[23] The 4 step synthesis began by unification of the a-
trichloroacetimidate 6 with the ceramide precursor 7[24] in
the presence of catalytic TMSOTf at ꢀ608C. Gratifyingly,
the desired b-glycoside 8 was formed in an excellent 80%
yield (b/a 28:1). Subsequent reduction under standard Stau-
dinger conditions furnished the expected primary amine 9
(43%), which in turn was coupled with N-succinimidyl octa-
decanoate to yield the protected target scaffold 10 (73%).
Global debenzylation proved facile under Birch conditions
furnishing the target molecule 5 in 69% yield. The substitu-
tion of hydrogen or hydroxyl by fluorine to create bioisos-
teres with modulated properties is a validated concept in
bio-organic chemistry.[7] In view of the importance of sphin-
golipids and their analogues in modulating molecular recog-
nition and membrane dynamics, we envisage that this meth-
odology will find future application.
Finally, to showcase the utility of this methodology, the
synthesis of a fluorinated analogue (F-b-GalCer 5) of the
glycosphingolipid b-galactose ceramide (b-GalCer; 4) was
undertaken (Scheme 3).[22] This target molecule selection
was influenced by the recent study by Godfrey, Rossjohn
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Fluorine-Directed b-Galactosylation
FULL PAPER
Curiously, both the presence and configuration of the 2-
fluoro-substituent directly influence diastereoselectivity. Fur-
thermore, introduction of the 2-fluoro substituent results in
a stereoconvergent process favouring formation of the b-gly-
coside. This is particularly noteworthy in the 2-fluoro-3,4,6-
tri-O-methylglucopyranosyl TCA (Scheme 2, upper; a-
TCA!b/a 10.3:1 and b-TCA!b/a 5.3:1). However, a SN2
component to the mechanism of reactions involving a-2-F-
trichloroacetimidates cannot be totally discounted.
This constitutes a preliminary validation of the 2-fluoro
substituent as an inert steering group, with minimal steric
footprint, to control chemical glycosylation. Although the
fluorine substituentꢀs influence on diastereoselectivity is ex-
traordinary, it is inextricably linked to the properties of the
ancillary benzyl groups. The selectivity of the reaction
cannot be explained exclusively in terms of fluorineꢀs pro-
pensity to influence conformation,[12,25] rather this phenom-
enon appears to be synergistic in nature. The importance of
electrostatic interactions from ancillary groups on the con-
formational equilibria of substituted oxocarbenium ions, and
the diastereoselectivities of their reactions, is exemplified by
the elegant work of Woerpel and co-workers.[26,27] In addi-
tion to this ground state analysis, it is also conceivable that
the transition state topology would be consistent with the
Anh-Eisenstein 1,2-induction model,[28] such that orbital
overlap is maximised when the sCꢀF* orbital antiperiplanar
to the approach trajectory of the nucleophile. This may ac-
count for the consistent formation of 1,2-trans glycosides.[29]
The possibility of a reactive conformer scenario,[30] accentu-
ated by the 2-fluoro substituent, also cannot be ruled out at
this time. To refine the induction model, a thorough compu-
tational investigation of these processes has been initiated.
Results will be disclosed as the information becomes avail-
able.
Scheme 3. Synthesis of a fluorinated analogue of b-GalCer. Reagents and
conditions: a) TMSOTf, CHCl3, ꢀ608C, 2 h, 80 %; b/a 28:1; b) Ph3P, H2O,
THF, 22.5 h, room temperature, 43%; c) N-succinimidyl octadecanoate,
THF, 40 h, room temperature, 73%; d) Na, NH3(l), THF, 2 h, ꢀ508C,
69%.
Conclusion
A molecular editing approach to chemical glycosylation de-
velopment has revealed that the exceptional levels of diaste-
reocontrol in glycosylation processes using the 2-F-3,4,6-tri-
O-benzyl glucopyranosyl TCA scaffold[11] are a consequence
of the native 2R,3S,4S stereotriad. In general, configuration-
al permutations are not tolerated, having severe ramifica-
tions on diasterocontrol (Table 1). However, a systematic
study has revealed that epimerization at C4, to generate the
2-fluorogalactose scaffold, results in a substantial enhance-
ment in b-selectivity (up to b/a 300:1, Table 3). Implicit is
the notion that the peripheral protecting groups (Bn) play
an important ancillary role in governing selectivity. A
simple substitution of Bn by Ac erodes selectivity (b/a 1:1,
Table 2), signifying that a match between protecting group
electronics and C2 fluorine configuration is imperative for
selective glycosylation (Scheme 4).
Experimental Section
All reactions that required air or moisture sensitive compounds were car-
ried out in flame-dried and evacuated glassware under an atmosphere of
argon. Solvents for these reactions were dried according to standard pro-
cedures or were taken from the solvent drying system. All chemicals
were reagent grade and used as supplied unless otherwise stated. Sol-
vents for extractions and chromatography were technical grade and dis-
tilled prior to use. Extracts were dried over technical grade Na2SO4. Ana-
lytical thin layer chromatography (TLC) was performed on precoated
Merck silica gel 60 F254 plates (0.25 mm). Visualisation was accomplished
by using ultraviolet light (l=254 nm) or by dipping in cerium ammonium
molybdate (CAM) stain (50 g (NH4)6Mo7O24·4H2O, 10 g CeACHTUNGTRENNUNG(SO4)2 and
100 mL H2SO4 in 900 mL water) followed by heating. Flash column chro-
matography was carried out on Fluka silica gel 60 (230–400 mesh). Con-
centration in vacuo was performed at about 10 mbar and 408C, and
drying was carried out at approximately 10ꢀ2 mbar at room temperature.
1H, 19F and 13C NMR spectra were recorded on
a Varian Avance
300 MHz, a Bruker DRX 400 MHz or a Bruker AV 400 MHz spectrome-
ter at ambient temperature. Chemical shifts (d) are reported in ppm rela-
tive to the residual solvent. Coupling constants J are reported in Hz. The
multiplicities are reported as: s=singlet, brs=broad singlet, d=doublet,
t=triplet, q=quartet, m=multiplet. Melting points were measured on
a Bꢁchi B540 melting point apparatus and are uncorrected. IR spectra
were measured on a Perkin–Elmer Spectrum 100 FTIR spectrometer and
Scheme 4. Overview of this study.
Chem. Eur. J. 2012, 18, 8208 – 8215
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8213

R. Gilmour et al.
reported in cmꢀ1. The intensities of the bands are reported as: w=weak,
m=medium, s=strong. Optical rotations were obtained by using a Jasco
P-2000 polarimeter. High-resolution mass spectra (HR ESI and EI MS)
were performed by the MS service at the Laboratory for Organic
Chemistry, ETH Zꢁrich.
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Synthesis and structure determination: See the Supporting Information
for full experimental details.
Representative protocol for trichloroacetimidate formation; 3,4,6-tri-O-
benzyl-2-deoxy-2-fluoro-a-d-galactopyranosyl
trichloroacetimidate:[6x]
Cl3CCN (546 mL, 5.50 mmol, 10.0 equiv) and DBU (8 mL, 0.06 mmol,
0.1 equiv) were added to a solution of the 3,4,6-tri-O-benzyl-2-fluoro-a-
d-galactopyranose (249 mg, 0.55 mmol, 1.0 equiv) in dry CH2Cl2 (11 mL,
0.05m) at 08C under an atmosphere of Ar. After being stirred for 5 min
at 08C, the reaction mixture was allowed to warm to room temperature
over a period of 1 h before being concentrated, in vacuo. Purification by
flash column chromatography (SiO2, cyclohexane/EtOAc 7:1) afforded
the a-trichloroacetimidate as a colourless oil (279 mg, 85%). Rf =0.50
(cyclohexane/EtOAc 3:1); [a]2D0 = +79.1 (c 0.2, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=8.63 (s, 1H, NH), 7.40–7.25 (m, 15H, Ph), 6.57 (d,
J=3.6 Hz, 1H, H-C1), 5.17 (dm, 2JHF =49.2 Hz, 1H, H-C2), 4.97 (d, J=
11.6 Hz, 1H, Bn), 4.82 (d, J=11.9 Hz, 1H, Bn), 4.73 (d, J=11.9 Hz, 1H,
Bn), 4.60 (d, J=11.1 Hz, 1H, Bn), 4.48 (d, J=11.6 Hz, 1H, Bn), 4.42 (d,
J=11.6 Hz, 1H, Bn), 4.16 (dd, J=7.8, 5.6 Hz, 1H, H-C5), 4.13–4.07 (m,
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2H, H-C3, H-C4), 3.64 (dd, J=9.2, 7.8 Hz, 1H, H-C6), 3.57 (dd, J=9.2,
2
5.6 Hz, 1H, H-C6); 19F NMR (376 MHz, CDCl3): d=ꢀ208.8 (ddd, JHF
=
3
49.2, JHF =9.4, 4.5 Hz).
Representative glycosylation protocol; 1-O-isopropyl-3,4,6-tri-O-benzyl-2-
deoxy-2-fluoro-d-galactopyranose: solution of 3,4,6-tri-O-benzyl-2-
A
fluoro-a-d-galactopyranosyl trichloroacetimidate (120 mg, 0.2 mmol,
1.0 equiv) and iPrOH (18 mL, 0.24 mmol, 1.2 equiv) in dry CH2Cl2 (4 mL,
0.05m) under an atmosphere of Ar was treated with TMSOTf (3.6 mL,
0.02 mmol, 0.1 equiv) at ꢀ788C and stirred for 2 h. The reaction mixture
was quenched by addition of Et3N (0.1 mL) and concentrated, in vacuo.
NMR analysis of the crude reaction mixture revealed a b/a ratio of
150:1. Purification by flash column chromatography (SiO2, cyclohexane/
EtOAc 7:1) afforded the product b-isopropylglycoside as a colourless oil
(84 mg, 85 or 72% from the starting aldopyranose). Rf =0.32 (cyclohex-
ane/EtOAc 3:1); [a]D20 =ꢀ9.0 (c 0.2, CH2Cl2); nmax (neat)/cmꢀ1 =3031w,
2973w, 2868w, 1497w, 1454m, 1382m, 1369s, 1348w, 1304w, 1258w, 1208w,
1159m, 1067s, 1026s, 940m, 908m, 820s, 732s, 695s; 1H NMR (400 MHz,
CDCl3): d=7.39–7.23 (m, 15H, Ph), 4.92 (d, J=11.6 Hz, 1H, Bn), 4.78
2
(d, J=12.0 Hz, 1H, Bn), 4.67 (ddd, JHF =51.5 Hz, J=9.3, 7.7 Hz, 1H, H-
C2), 4.69 (d, J=12.0 Hz, 1H, Bn), 4.62 (d, J=11.6 Hz, 1H, Bn), 4.48 (dd,
J=7.7, 3JHF =4.2 Hz, 1H, H-C1), 4.49 (d, J=11.8 Hz, 1H, Bn), 4.44 (d,
J=11.8 Hz, 1H, Bn), 4.00 (sept, J=6.3 Hz, 1H, H-C7), 3.95 (t, J=3.1 Hz,
ꢀ
ꢀ
ꢀ
1H, H-C4), 3.66–3.57 (m, 3H, H C3, 2H C6, H C5), 1.29 (d, J=6.3 Hz,
1H, C8), 1.23 (d, J=6.3 Hz, 1H, C8); 13C NMR (100 MHz, CDCl3): d=
2
138.4 (iPh), 138.1 (iPh), 137.9 (iPh), 128.5–127.6 (Ph), 99.4 (d, JCF
=
23.7 Hz, C1), 91.9 (d, 1JCF =182.5 Hz, C2), 80.5 (d, 2JCF =15.8 Hz, C3),
74.7 (Bn), 74.2 (d, 3JCF =8.9 Hz, C4), 73.6 (C5), 73.6 (Bn), 72.7 (d, JCF
=
4
2.3 Hz, Bn), 71.9 (C7), 68.6 (C6), 23.4 (C8), 21.8 (C8); 19F NMR
2
3
(376 MHz, CDCl3): d=ꢀ204.9 (dd, JHF =51.6, JHF =12.7 Hz); m/z (ESI)
[M+Na]+ C30H35FNaO5 calcd 517.2361, found 517.2354.
Acknowledgements
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We gratefully acknowledge generous support from the Alfred Werner
Foundation (assistant professorship to R.G.), der Stipendienfonds der
Schweizerischen Chemischen Industrie (doctoral fellowship to C.B.), No-
vartis AG (Dr. Fabrice Gallou) and the ETH Zꢁrich. We thank Dr. Lucie
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Chem. Eur. J. 2012, 18, 8208 – 8215

Fluorine-Directed b-Galactosylation
FULL PAPER
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change in the a/b ratios by 1H and/or 19F NMR spectroscopy. More-
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tive example: TMSOTf (0.7 mL, 4 mmol, 0.1 equiv) was added to a so-
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for 2 h. 1H and 19F NMR spectroscopy of the reaction mixture indi-
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and 19F NMR analysis of the reaction mixture indicated that no epi-
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Received: February 13, 2012
Published online: May 16, 2012
Chem. Eur. J. 2012, 18, 8208 – 8215
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8215