β-Selective one-pot fluorophosphorylation of d,d -heptosylglycals mediated by selectfluor

Article abstract of DOI:10.1002/ijch.201400148

This study describes the development of a novel procedure of glycal fluorophosphorylation applied to the synthesis of a fluorinated analogue of an important bacterial metabolite. This procedure was applied to several heptose-derived glycals, and the stereochemical outcome of the reaction was analyzed. Under optimized conditions, the reaction is β-gluco selective, but a significant amount of the α-gluco diastereomer is also generated.

Full text of DOI:10.1002/ijch.201400148

Full Paper
DOI: 10.1002/ijch.201400148
b-Selective One-Pot Fluorophosphorylation of d,d-
Heptosylglycals Mediated by Selectfluor
Stꢀphane P. Vincent* and Abdellatif Tikad[a]
Abstract: This study describes the development of a novel
procedure of glycal fluorophosphorylation applied to the
synthesis of a fluorinated analogue of an important bacterial
metabolite. This procedure was applied to several heptose-
derived glycals, and the stereochemical outcome of the reac-
tion was analyzed. Under optimized conditions, the reaction
is b-gluco selective, but a significant amount of the a-gluco
diastereomer is also generated.
Keywords: antibiotics · fluorosugars · LPS · phosphorylation · Selectfluor
1. Introduction
Lipopolysaccharide (LPS) is the main polysaccharide
present at the surface of gram-negative bacteria.[1] This
molecule may play a major role in the mortality of many
infectious diseases, as well as in the virulence of numer-
ous human pathogens.[2] Moreover, LPS ensures protec-
tion against hydrophobic molecules and participates in
the bacterial cell integrity.
LPS is an amphipathic molecule that can be decom-
posed into three main substructures: lipid A, the oligosac-
charide core, and the O-antigen. The oligosaccharide core
can be divided into two parts: the inner core is formed at
least of one molecule of 3-deoxy-a-d-manno-oct-2-ulo-
sonic acid (Kdo) and two to three molecules of l-glycero-
a-d-manno-heptose (heptose), and the outer core is com-
posed of hexoses. Importantly, Kdo and heptoses are not
present in mammals; targeting the enzymes involved in
their biosynthesis may thus lead to selective antibacterial
inhibitors.[3]
Gram-negative bacteria lacking heptose biosynthesis
display the so-called deep-rough phenotype,[4] and show
an increased sensitivity towards antibiotics.[1a, 5] They also
become more susceptible to the bactericidal effect of the
host, as well as to phagocytosis by macrophages.[6] There-
fore, the inhibition of the heptose biosynthetic pathway is
a novel approach to develop new antibacterial agents
with a novel mechanism of action; instead of targeting
the central metabolism or the cell wall biosynthesis, this
approach consists of attenuating or even annihilating the
virulence of the microorganism, without the need to kill
it.[7]
With this concept in mind, we developed the first inhib-
itors of heptosyltransferase WaaC as a novel approach to
inhibit the bacterial cell wall resistance to the innate
immune response.[8] Later on, we designed and synthe-
sized heptose analogues as inhibitors of the two first en-
zymes of this bacterial biosynthetic pathway.[9] Thus, the
inhibition of heptose biosynthesis seems to be a very
promising field for the development of antivirulence
drugs.[7d,10] Interestingly, the inhibition of this pathway has
been relatively overlooked for two reasons: i) the en-
zymes involved in the heptose biosynthesis have been
cloned and characterized only recently (Figure 1); and ii)
their substrates are not commercially available and their
synthesis is not straightforward.[11]
The biosynthesis of bacterial heptoses starts from sedo-
heptulose-7-phosphate 1, derived from the central metab-
olism.[12] A keto-aldose isomerase, GmhA, transforms
1 into d-glycero-d-manno-heptose 7-phosphate 2, which is
then phosphorylated by the kinase HldE. After hydrolysis
of the 7-phosphate of 3, intermediate 4 is transformed
into nucleotide-sugar 5. Some bacterial strains, such as E.
coli, use the same HldE enzyme for two non-consecutive
steps. A regioselective d to l epimerization is then cata-
lyzed by HldD, yielding ADP-l-heptose 6, the donor sub-
strate of heptosyltransferases (WaaC, WaaF, and
WaaQ).[13]
In 2008, our group described the synthesis and the in-
hibition properties of nucleotide-sugar 7, the 2-fluoro an-
alogue of 6.[8a] Fortunately, we were able to obtain a 3D-
structure of WaaC, in complex with 7, which allowed us
[a] S. P. Vincent, A. Tikad
Chemistry Department
University of Namur (UNamur)
rue de Bruxelles 61
B-5000 Namur (Belgium)
Fax: (+32)81724517
e-mail: stephane.vincent@unamur.be
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/ijch.201400148.
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Figure 1. Biosynthesis of bacterial l-heptosides found in LPS.
to map the interactions of the glycosyltransferase and its
donor substrate 6.[14]
methodology, consisting of performing Wongꢁs fluoro-
phosphorylation with the concomitant presence of the flu-
orinating and the phosphorylating agents, which had
never previously been realized. In this article, we wish to
describe this novel methodology for l- and d-heptosyl
glycals, the comparative stereoselectivities between
Wongꢁs initial stepwise procedure and this new protocol,
and finally the synthesis of the deprotected molecule 8.
In this study, we will first describe the synthesis of d,d-
heptosylglycals 12 and 13, then the fluorophosphorylation
reaction, and finally, the synthesis of heptose-phosphate 8.
The preparation of fluorinated analogue 7 required an
18-step synthesis whose central step was Wongꢁs Select-
fluor mediated fluorophosphorylation of glycals
(Scheme 1).[15] This reaction allows the installation, in
a single synthetic operation, of the fluorine atom at the 2-
position and the protected phosphate at the 1-position,
regio- and stereoselectively.
With this methodology in hand, we decided to synthe-
size the fluorinated analogue 8 of the biosynthetic inter-
mediate 4, displaying the d-glycero-d-manno configura-
tion (Figure 1). To do so, we explored a new synthetic
Scheme 1. The fluorophosphorylation of glycals.
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cedure represented in Scheme 1: 1) a syn-addition of Se-
lectfluor is first performed under anhydrous conditions,
yielding intermediate 10; and 2) a substitution of the
anomeric DABCO biscation by a dialkylphosphate is per-
formed, usually at 1008C.[15a]
In our preliminary synthesis of 2-fluoro-l,d-heptose 7,
we found that we could improve the stereoselectivity of
the stepwise fluorophosphorylation by decreasing the re-
action temperature (down to 45–608C), and by enhancing
the nucleophilicity of the phosphate (using the phosphate
sodium salt and [15]-crown-5).[8a]
2. Results and Discussion
2.1 Synthesis of d,d-Heptosylglycals 12–13
The synthesis of d,d-heptosylglycal followed the same
global strategy of the synthesis of its l-glycero-d-manno
epimer that we previously published.[8a] The synthesis
began with the known alkene 16,[16] easily prepared on
a large scale, in a few steps, from d-glucose.[17] The dihy-
droxylation of 16 under standard conditions, followed by
an acetylation of the resulting diol, yielded intermediate
18 in 80% yield for the d-epimer. The observed d/l selec-
tivity (9/1) corroborates literature data.[18] A direct con-
version of benzylated intermediate 18 into d-glycero-d-
manno-heptose peracetate 19 could directly be achieved
under acetolysis conditions. Bromination of the anomeric
position, followed by a zinc-mediated b-elimination, af-
forded the d,d-heptal tetraacetate 12 in 87 % yield. Pro-
tective group manipulation finally yielded the corre-
sponding tetrasilylated glycal 13.
In view of the synthesis of 2-fluoro-d,d-heptoside 8, we
decided to investigate again the opportunity to perform
the fluorophosphorylation in a one-pot fashion. Indeed,
we were interested to determine whether the stereochem-
ical outcome of the reaction (a/b and gluco/manno)
would be affected if all the reagents are present from the
very beginning of the reaction. We reasoned that at lower
temperatures (compared to the initial stepwise proce-
dure), it might be possible to start the reaction with the
two nucleophilic species (the glycal and the phosphate),
in competition for the electrophilic fluorinating agent.
The results of this investigation are gathered in Table 1.
The first attempts using acetylated glycal 12 were unsuc-
cessful (entry 1). This result was tentatively attributed to
the fact that, in general, peracetylated glycals are poor
substrates in Selectfluor mediated reactions, due to the la-
bility of the acetates under these specific reaction condi-
tions.[8a,15a,21]
The following attempts employing persilylated glycal
13 were more encouraging, but generally suffered from
low conversions and, depending on the reaction tempera-
ture, some unidentified side-products were also observed
(data not shown). However, we could clearly observe the
formation of the desired 2-fluoro-heptose phosphates 15
by 31P- and 19F-NMR of the crude reaction mixtures. Our
main conclusion from these preliminary assays was that
this reaction could indeed be performed in a one-pot
fashion, at 608C. To resolve the conversion problem, we
assumed that the fluorinating reagent might slowly de-
2.2 Fluorophosphorylation of Heptose Glycals
In their pioneering work on the Selectfluor mediated re-
gioselective fluorination of glycals, Wong et al. developed
the first protocol, on a wide range of glycals, adapted for
weak nucleophiles, such as alcohols, including protected
sugars.[19] Two years later, the same team described
a second procedure, allowing the use of more challenging
nucleophiles such as amines, thiols and phosphates.[15a]
Thanks to this improvement, the access to nucleotide-flu-
orosugars became more straightforward, and was eventu-
ally exploited to study the mechanism of glycosyltransfer-
ases.[20]
The difficulty that can be encountered in the one-pot
fluorophosphorylation of glycals is that two nucleophilic
species might be in competition for a single electrophile:
indeed, dialkylphosphates are nucleophilic enough to
react with Selectfluor, thus yielding undesired side-reac-
tions. This problem was resolved by using a stepwise pro-
Scheme 2. Synthesis of d,d-heptose glycals 12 and 13. Reagents and conditions: (a) OsO4, NMO, acetone, H2O, 08C and rt, 92%; (b) Ac2O,
Py, rt, quant; (c) H2SO4, Ac2O, CHCl3, 08C and rt, 83%; (d) HBr-AcOH, AcOH, Ac2O, CH2Cl2, rt; Zn, CuSO4, AcONa, AcOH, H2O, rt, 87%; for 2
steps; (e) Na, MeOH, rt; TBSCl, Im, DMF, 08C and rt, 87% for 2 steps.
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Table 1. Fluorophosphorylation of heptosyl glycals 12–13 and 20–21.
entry
Glycal
(BnO)2PO2Na (eq.)
Addition method[a]
T (8C)[b]
t (h)
Yield (%)[c]
Products a :b :c :d[d]
[e]
1
2
12
13
5
5
A
A
60
60
4
4
–
14
15
70[d]
39 :61:0 :0
22
24 :76 :0 :0
23
3
4
20
21
5
3
A
B
60
60
4
2
61
53
6 :94 :0 :0
[a] A: No-stepwise method, all the reagents were simultaneously added, and 1 eq. Selectfluor was added every hours; B: Stepwise method,
Selectfluor and glycal were reacted first at room temperature; the phosphorylating reagent was then added after disappearance of the glycal
1
and heated. [b] The temperature was maintained during all the reaction. [c] Isolated yield. [d] Assessed by H-, 19F- and 31P-NMR. a: a-gluco,
b: b-gluco, c: a-manno, d: b-manno. [e] Complex mixtures of non-separable products and side-products.
compose under the reaction conditions. We therefore de-
cided to use an excess of Selectfluor, by adding 1 equiva-
lent of fluorinating reagent every hour (entry 2) until the
starting glycal totally disappeared (as monitored by
TLC). Gratifyingly, we could generate the desired 2-
fluoro-heptose phosphate 15 in 70% as a mixture of two
diastereomers. Similar results were obtained with the l-
glycero-heptosyl glycal 20 that we had previously synthe-
sized (entry 3).[8a] The yields were in the same range than
with the stepwise procedures of Selectfluor mediated
glycal fluorophosphorylation.
However, the stereochemical outcome of the reaction
is slightly different when the reaction is conducted in
a non-stepwise manner. For both epimeric glycals 13 and
20 the major product were the desired b-gluco configured
fluorophosphates (entries 2 and 3). The a-gluco diastereo-
mers are always the sole side-products of these reactions,
indicating that, as initially proposed by Wong et al., a syn-
addition of Selectfluor occurs first, yielding a single
gluco-configured intermediate 10. The following nucleo-
philic substitution by the phosphate gives an anomeric a/
b mixture in favor of the b-product.
might be found in the reaction mechanism. Wongꢁs mech-
anistic study, performed on fucosides, showed that Select-
fluor addition occurs in a syn manner and that the inter-
mediate adduct can anomerize after a ring flip.[15a] It is
thus reasonable to invoke that the first intermediate of
the syn-addition of 24 is the ammonium 25 (Scheme 3).
As previously demonstrated on fucosides, the hindered
DABCO ammonium can force the carbohydrate to flip to
1
a C4 conformation, giving a new intermediate 26. More-
over, an anomerization can also occur to generate the b-
adduct 27, in which the leaving group is now equatorial in
4
a relaxed C1 conformation. The stereochemical outcome
of the global reaction is directly linked to the distribution
of 25–27 because it is expected that intermediates 25 and
26 will favor nucleophilic substitutions from their b-face,
whereas 27 should give an a-selectivity. The distribution
of intermediates 25–27 is likely to be strongly dependent
on all reaction parameters, including the temperature of
the two steps (Selectfluor addition and nucleophilic sub-
stitution). In contrast to the stepwise procedure in which
the first step is always performed at room temperature,
the temperature of the whole process has been fixed at
608C, which can modify the distribution of Selectfluor ad-
ducts but also the initial conformation of starting glycal
24. The a/b selectivity may also be affected by the fact
that the nucleophilic phosphate is present from the begin-
ning of the reaction in the non-stepwise procedure, and is
thus allowed to react with the intermediate adducts im-
mediately after their formation. The results detailed in
Table 1 show that, indeed, changing the reaction tempera-
ture and the addition sequence of this reaction does
affect the stereoselectivity of the fluorophosphorylation.
The b-gluco stereoselectivity of the fluorophosphoryla-
tion, following this one-pot procedure, is moderate and
lower than similar reactions performed under stepwise
conditions.[8a] A typical example is detailed in entry 4,
with a pivaloylated glycal 21. In the latter case, a much
higher b-gluco selectivity was achieved, while the yield
was slightly lower than with the novel non-stepwise pro-
cedure.
The origin of the differences of product distributions
between the stepwise and non-stepwise/one-pot methods
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Scheme 3. Plausible mechanism of the fluorophosphorylation of heptosides.
2.3 Synthesis of the Final d,d-Heptoside 8
dure, but allowed slightly higher yields. Thanks to this
procedure, the fluorinated analogue of an important bac-
terial metabolite was achieved. This work contributes to
the field of biochemically relevant carbohydrate mimet-
ics:[22] the final molecule 8 will be exploited as a probe of
the heptose biosynthetic pathway. This fluorophosphate
will be first assessed as an inhibitor of HldE and GmhB.
Then, it could be interesting to determine whether 8 is
a substrate of the AMP-transfer activity of HldE, thus
opening the way to the chemo-enzymatic synthesis[23] of
a fluorinated analogue of ADP-d-heptose 5.
The deprotection of intermediate 15b (Scheme 4), was
not so straightforward, given the polarity of the final mol-
ecule. The classical strategy, consisting of deprotecting
the TBS group first to allow hydrogenolysis as the last
step, failed in our hands.
4. Experimental Section
Scheme 4. Synthesis of d,d-heptoside 8. Reagents and conditions:
(a) i) H2, Pd/C, EtOAc, EtOH; ii) TBAF, THF, rt, 78% for 2 steps.
See the electronic supplementary information for the ex-
perimental procedures and product characterizations.
Instead, we managed to obtain the pure final molecule
in 78% yield by performing the hydrogenolysis first, fol-
lowed by a TBAF desilylation. After a cation exchange of
the tetrabutylammoniums, the final molecule was purified
by size-exclusion chromatography. Analytical data were
in excellent agreement with related fluorosugars. The
gluco and the anomeric configurations were easily de-
duced from the 3J(H,H) coupling constants.
Acknowledgments
The authors are grateful to FRS-FNRS (PDR T.0170.13),
Marie Curie Actions (ITN 289033), and Mutabilis S. A.
(France) for financial support, and to Professor Chi-Huey
Wong for his mentorship. We are extremely grateful to
Dr. Hirofumi Dohi and Dr. Rꢀgis Pꢀrion for their pio-
neering work on this topic.
3. Conclusion
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a stepwise procedure. This procedure was applied to sev-
eral heptose-derived glycals and allowed a comparison of
the stereochemical outcome of the reaction. The b-gluco
selectivity was less pronounced than the stepwise proce-
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Received: October 6, 2014
Accepted: November 7, 2014
Published online: && &&, 0000
Isr. J. Chem. 0000, 00, 1 – 7
ꢀ 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.ijc.wiley-vch.de
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Full Paper
FULL PAPERS
S. P. Vincent,* A. Tikad
&& – &&
b-Selective One-Pot
Fluorophosphorylation of d,d-
Heptosylglycals Mediated by
Selectfluor
Isr. J. Chem. 0000, 00, 1 – 7
ꢀ 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.ijc.wiley-vch.de
&7
&
ÞÞ
These are not the final page numbers!