A novel base-induced isomerization gives access to unprecedented (E)-exo-glycals

Article abstract of DOI:10.1002/chem.201300969

Bump the base: This study reports the discovery of the base-induced Z-to-E isomerization of exo-glycals bearing an electron-withdrawing group (EWG). The scope of this novel transformation regarding the carbohydrate unit is also discussed. After elucidating the mechanism, preparation of novel (E)-exo- glycals was performed (TBS=tert-butyldimethylsilyl). Copyright

Full text of DOI:10.1002/chem.201300969

COMMUNICATION
DOI: 10.1002/chem.201300969
A Novel Base-Induced Isomerization Gives Access
to Unprecedented (E)-exo-Glycals
Guillaume Eppe,[a] Lidia Dumitrescu,[a] Olivier Pierrot,[a] Tianlei Li,[a, b]
Weidong Pan,[b] and Stꢀphane P. Vincent*[a]
exo-Glycals, that is, glycosides presenting an exocyclic
enol ether next to the ring oxygen, constitute a very large
family of polyhydroxylated chiral synthons, exploited both
as synthetic intermediates,[1] but also as final molecules for
biochemical applications.[2] Interestingly, the first natural
exo-glycal was recently identified as a precursor of the tuni-
camycins,[3] a family of antibiotics produced by Streptomyces
lysosuperificus and chartreusis strains. exo-Glycals are versa-
tile synthetic building blocks allowing for a straightforward
and stereoselective access to C-glycosides through double
bond reduction.[1,4] As enol-ethers, they are susceptible to
electrophilic addition[5] and may be valuable precursors of
ketosides. Interestingly, they were used in 1,3-cylcoadditions
to prepare N-glycosides[6] as well as spiroglycosides.[7] The
most popular and robust methods to construct exo-glycals
Figure 1. Examples of exo-glycals designed as enzyme inhibitors.
are the Wittig-like olefinations,[8] the Ramberg–Bꢀcklund re-
arrangement,[9] and the stepwise addition-elimination on a
sugar lactone.[10] Newer methods have been developed as
well, including modified Julia olefination[7a,c,11] and alkynol
cycloisomerization.[12] Furthermore, tetrasubstituted exo-gly-
cals have been prepared through different functionaliza-
tions,[13] such as the Sonogashira,[14] the Suzuki[4i,5b,15] and the
Stille cross-coupling reactions.[16]
Beyond their synthetic interest, exo-glycals have been ex-
ploited for the inhibition of biologically relevant enzymes,
including glycosidases and glycosyltransferases.[2] In particu-
lar, phosphonylated exo-glycals (phosphono-exo-glycals),
such as 1–11, have been successfully designed and employed
either as potent inhibitors or as biochemical probes
(Figure 1). For instance, Schmidt et al. developed molecule 1
as a competitive inhibitor of UDP-GlcNAc 2-epimerase,[17]
and nucleotide-sugars analogues 4–11 as inhibitors of a-(2-
6)-sialyl-transferase, an extremely important enzyme in gly-
cobiology. It is noteworthy that Z phosphonate 9 is a low
nanomolar inhibitor of the latter enzyme, and one of the
very best inhibitors of glycosyltransferases in general.[18] Our
group has developed synthetic pathways to prepare phos-
phono-exo-glycals 1–3 and discovered that they displayed
strong inhibition or time-dependent inactivation of UDP-
galactopyranose mutase (UGM).[4d,5a,19] Because it is essen-
tial for the growth of Mycobacterium tuberculosis, the causa-
tive agent of tuberculosis,[20] this enzyme is now a validated
target for the development of novel antitubercular drugs.
It is also worth mentioning the effect of the stereochemis-
try of the exocyclic double bond on the inhibition/inactiva-
tion processes described above has never been assessed be-
cause the (E)-exo-glycals analogues of molecules 1, 2 and 4–
7 have not been synthetically accessible to date. The few
easily accessible (E)-exo-glycals can mainly be obtained as
diastereomeric mixtures through Wittig-like olefinations,
and the diastereoselectivity highly depends on the sugar lac-
tone and the ylide.[4g,k,8a] In those methods, the (E)-exo-
glycal is often the less abundant product or in some cases
not even accessible. However, these methods are not appli-
cable for the synthesis of phosphonylated exo-glycals.
Indeed, the only synthetic methodology allowing their effi-
cient preparation consists in the nucleophilic addition of a
lithiated methyl-phosphonate to a sugar lactone followed by
dehydration, a methodology developed by Lin[10a–c] and fur-
ther exemplified by others.[4d,5a,19] Following this methodolo-
gy, the Z stereoisomer is exclusively formed, thus providing
no access to the corresponding E stereoisomer. Here, we
[a] Dr. G. Eppe, Dr. L. Dumitrescu, O. Pierrot, T. Li, Prof. S. P. Vincent
University of Namur (UNamur), Dꢁpartement de Chimie
Laboratoire de Chimie Bio-Organique, rue de Bruxelles 61
5000 Namur (Belgium)
E-mail: stephane.vincent@fundp.ac.be
[b] T. Li, Dr. W. Pan
The Key Laboratory of Chemistry for Natural Products of
Guizhou Province and Chinese Academy of Sciences
202, Sha-chong South Road, Guiyang, 550002 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300969.
Chem. Eur. J. 2013, 19, 11547 – 11552
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11547

conditions, the transformation is very clean. This isomeriza-
tion was not expected since vinyl anions are known to be
configurationally stable.[22]
To understand this unexpected transformation, we first
used NMR spectroscopy techniques to demonstrate the
structure of the newly formed molecule. It is well establish-
ed in the literature that the stereochemistry of a vinyl-phos-
Scheme 1. The base-induced Z-to-E exo-glycal isomerization.
3
phonate can be determined by JCÀP carbon–phosphorus
report the serendipitous discovery of the Z-to-E
isomerization of phosphono exo-glycals, the opti-
mization of the procedure and the scope of this
novel transformation with regards to the carbohy-
drate unit and the electron-withdrawing group
(Scheme 1).
Table 1. Scope and optimization of the isomerization of exo-glycal (Z)-12.
Base
Base
t
T
[8C]
Z
E
Byproducts
[equiv] [h]
[%][a] [%][a] [%][a]
1
2
3
4
5
6
7
8
9
tBuLi
tBuLi
1.05
2.1
1.1
1.0
2.2
3.0
3.2
1.1
2
2
2
2
2
2
0.5
1
À78
À78
À78
À78
À78
À100
À78
0
0
0
RT
RT
88
38
40
40
25
39
48
65
30
70
56
88
12
46
52
52
47
61
33
0
30
30
44
12
61
0
16
8
8
28
0
19
35
40
0
0
0
Given the importance of galactofuranose (Galf)
in the cell wall of major pathogens,[21] we naturally
investigated the synthesis of modified phosphony-
lated analogues of this carbohydrate. Typically, the
phosphonylated exo-glycal 12 was prepared as a
single Z diastereomer.[19] In order to further func-
tionalize 12, we had planned to deprotonate it with
a strong base and quench the vinylic carbanion by
an electrophile. However, treatment of (Z)-12 with
tBuLi for 45 min at À788C afforded a mixture of
two molecules: the starting material (66%) and a
new exo-glycal (34%) isolated and identified as
the E-diastereoisomer (E)-12 (Scheme 2; Table 1,
sBuLi
nBuLi
nBuLi
nBuLi
LDA
KHMDS
NaHMDS 1.1
2
2
10 LiHMDS 1.1
11 LiHMDS 2.2
12 LiHMDS 2.2
13 LiHMDS 3.0
5 min
14
10 min then 2 h RT then À10 39
0
[a] Determined by 31P NMR spectroscopy.
entry 1). The 31P NMR analysis of the crude reaction mix-
ture showed no detectable side-products at all: under these
coupling.[23] In the 13C NMR spectra, the carbon atoms being
cis to a phosphorus have a smaller coupling constant than
their trans counterparts. The difference is clear in this case
since C-2 is a singlet for (E)-12 and a doublet (3JCÀP
=
12.0 Hz) for (Z)-12. The next evidence for the determination
of the stereochemistry of exo-glycals is the relative chemical
shift of the allylic H-2.[4g,k,8a] Indeed, in (E)-exo-glycals, H-2
are deshielded by a value of, typically, 0.5 ppm. In this case,
the allylic H-2 is indeed strongly deshielded: d=5.2 ppm for
(E)-12 and d=4.5 ppm for (Z)-12. In the case of (Z)-12, a
nOe correlation of the protons H-1’ and H-2 is also ob-
served. On the contrary, the absence of nOe correlation for
the vinylic proton in (E)-12 confirmed the E stereochemistry
for the new compound. Complete NMR analysis of (E)-12
ruled out other possible isomeric structures, such as a C-2
epimer or a double-bond migration to the C-1:C-2 position.
Indeed, the chemical shift of the phosphonate in 31P as well
as the chemical shift of C-1’ in the 13C NMR spectra demon-
1
strate that the double bond is exocyclic. Moreover, H–1H
coupling constants and nOe analysis proved that an epimeri-
zation at C-2 did not occur.
Screening other lithiated strong bases showed that besides
tBuLi, LDA, sBuLi and nBuLi can also be used (Table 1).
Moreover, by increasing the amount of base the proportion
of the desired E isomer can be drastically improved, howev-
er, with an increased amount of side products (entries 1, 2,
4, 6). Eventually, we found that 3 equivalents of nBuLi at
À1008C (entry 6) gave a very reproducible 61% yield in
(E)-12 without any detectable side products. Overall, a
lower temperature seems to result in a larger amount of
Scheme 2. a) nBuLi (3.0 equiv), THF, À1008C, 2 h, (Z)-12 66%, (E)-12
34%; b) phosphate buffer aqueous, pH 7; c) CD3COOD/CD3OD (6:1),
À788C to RT; d) TMSCl, À788C to RT.
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Base-Induced Isomerization
COMMUNICATION
E isomer. The same yield could be obtained from the dime-
thylphosphonate corresponding to 12 (data not shown), thus
showing that the reaction is not limited to dibenzylphospho-
nate and that the change of protective group on the phos-
phonate does not affect the yield in E isomer. Although
tBuOK, DBU or KHMDS did not produce any E isomer in
our hands, we could show that bases such as LiHMDS and
NaHMDS can also be used (Table 1, entries 8–10). Although
lithiated bases seem to give far better results in general, all
attempts to use lithium chloride and crown-ethers as adju-
vants did not change the course of the reaction (data not
shown). In the case of LiHMDS, the larger range of possible
reaction temperature allowed a better understanding of the
process. At room temperature, the (E)-exo-glycal is formed
very quickly but isomerizes back to the Z isomer over time
(entries 11 and 12). We could also observe that the reaction
is much slower if the temperature of the deprotonation step
is lowered to À10 or À408C. These results clearly show that
a sufficiently high temperature is necessary to allow the de-
protonation of the vinylphosphonate by LiHMDS whereas a
subsequent lower temperature is necessary to enhance the
ratio in the desired E isomer. We could thus optimize a
novel procedure taking advantage of LiHMDS which is easy
to handle: 1) addition of three equivalents of LiHMDS at
room temperature, 2) stirring at the same temperature for
ten minutes to ensure the deprotonation of the substrate,
3) cooling at À1008C for two hours to favor the E isomer
(entry 13). This simple procedure gives very reproducible
yields and, interestingly, the E/Z diastereomeric ratio is the
same as that with nBuLi at À1008C (entry 6).
(E)-15 was obtained as sole product, thus demonstrating the
formation of a vinylic anion.
To investigate the scope of this reaction, we turned our at-
tention to exo-glycal 16, the pyranosidic isomer of 12. When
we applied the conditions optimized for the furanoside 12
(Table 1, entry 6) to pyranoside (Z)-16, we surprisingly ob-
served the formation of furanosides (Z)-12 and (E)-12 in 10
and 8%, respectively (Scheme 3). This result suggested a
To the best of our knowledge, there is, currently, no
known reaction describing a base catalyzed isomerization of
an exo-glycal, or a cyclic enol ether to its diastereoisomer.
The mechanism was thus investigated by different means.
When the isolated (E)-12 was put into reaction under the
same isomerization conditions, it gave the same mixture of
(E)-12 and (Z)-12 (Scheme 2), thus evidencing that this Z-
to-E transformation is in fact an equilibrium between the
two stereoisomers. Thus, if a deprotonation occurs at the vi-
nylic position, the two carbanions (E)-13 and (Z)-13 must
be able to transform into one another (Scheme 2). The hy-
pothesis of a vinylic deprotonation driven by the adjacent
electron-withdrawing phosphonate and thus the existence of
(E)-13 and (Z)-13, was demonstrated by the quantitative
deuteration of the two exo-glycals 12 (Scheme 2). Deproto-
nation by nBuLi followed by an addition of a mixture of
CD3OD/CD3CO2D afforded the two deuterated exo-glycals
(E)-14 and (Z)-14. Mass spectrometry confirmed the mono-
deuteration whereas only the C-1’ and H-1’ signals disap-
peared from the NMR spectra.[24] It must be noted that this
deuteration was surprisingly difficult. Attempts to quench
the anions (E)-13 and (Z)-13 with D2O or CD3OD failed.
As a control experiment, we could show that when (Z)-12
was treated with CD3OD/CD3CO2D, no deuteration occur-
red. To further confirm the formation of carbanionic species,
we performed this trapping experiment by using trimethyl-
silyl chloride (TMSCl, Scheme 2). In that case exo-glycal
Scheme 3. Proposed equilibrium between vinylic carbanions 13.
mechanism involving a trans-silylation and retro-Michael ad-
dition (Scheme 3). The trans-silylation from position O-4 to
O-5 under basic conditions has already been observed by
our group for TBS protected galactosides.[4d] This rearrange-
ment results in a pyranose to furanose ring contraction. It is
thus reasonable to postulate that the intermediates that
allow the formation of the furanosides 12 from pyranosides
17 are the two acyclic alkynyl phosphonate 18 and 19, prod-
ucts of a reversible retro-Michael reaction (Scheme 3). A
subsequent 5-exo-dig intramolecular Michael addition ex-
plains the interconversion of (Z)-13 and (E)-13, the direct
precursors of (Z)-12 and (E)-12. Such a mechanism is sup-
ported by precedents on standard organic molecules, such as
the alkynol cyclization under basic conditions[25] and the hy-
droalkoxylation of conjugated 7-hydroxyheptynoates.[26]
However, the trapping experiments described in Scheme 2
(deuteration and TMSCl quenches) did not allow the isola-
tion of acyclic species showing that the hypothetical inter-
mediates 18 and 19 would be transient species rather than
highly concentrated intermediates.
To assess the scope of this novel reaction, we varied both
the carbohydrate unit and the substituent on the exo-glycal
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11549

S. P. Vincent et al.
structure. Due to the vinylic deprotonation and the required
Michael acceptor intermediate, we hypothesized that the
prerequisite for the isomerization was the presence of an
electron-withdrawing substituent on the double bond. exo-
Glycals 20–22 were thus prepared from the same g-galacto-
nolactone[19] with different electron-withdrawing substituents
(Table 2; see the Supporting Information for the proce-
dures).
The phosphonylated exo-glycals 23–28 were also prepared
as single Z stereoisomers using Linꢃs procedure.[10c] The opti-
mized procedures employing nBuLi or LiHMDS were first
applied to exo-glycals 20–22. Pleasingly, the E configured
sulfonyl and cyano derivatives could be generated in 37 and
68% yield, respectively (Table 2, entries 1–3). However, the
isomerization of ester 22 never generated the expected iso-
merization product, whatever the nature of the base (en-
tries 4–7). Surprisingly, deuteration of the putative carba-
nionic intermediate did not provide any deuterated species
but only the starting material (Z)-22 (entries 4 and 5). We
hypothesized that the steric hindrance might prevent the de-
protonation by the base, thus explaining the lack of isomeri-
zation. Forcing the conditions (entries 6 and 7) resulted in
the decomposition of the starting material. Gratifyingly, ara-
binofuranosyl 23, ribofuranosyl 24, fucofuranosyl 25, fuco-
pyranosyl 26 and galactopyranosyl 27 exo-glycals could also
be isomerized in the presence nBuLi (Table 1). These novel
exo-glycals displayed the characteristic coupling constants
and chemical shifts of E isomers (see discussion above).
Moreover, for the fuco-, arabino-, and ribofuranosyl deriva-
tives, higher amounts of (E)-exo-glycals could be reached
with a lower excess of base compared to the galactofurano-
syl-exo-glycal 12. In a general manner, similarly to 12, an in-
crease in the amount of base and/or in reaction time results
in a larger amount of E isomer. The results depicted in
Table 2 show that the final E/Z diastereomeric ratio was
highly dependent on the structures of both carbohydrate
Table 2. Scope of the base promoted exo-glycal isomerization.
exo-Glycal
Base (equiv)
Time (T [8C])
Z
E
Byproducts
[%][a]
[%][a]
[%][a]
1
LiHMDS (3.0)
10 min (RT) then 2 h (À1008C)
53
47
0
2
3
LiHMDS (3.0)
nBuLi (1.5)
10 min (RT) then 2 h (À1008C)
1 h (À1008C)
42
32
49
68
8
0
4
5
6
7
LiHMDS (3.0)
LDA (2.0)
nBuLi (3.0)
tBuLi (1.2)
10 min (RT) then 2 h (À1008C)
1 h (À788C)
100
100
0
0
0
0
0
0
0
100
100
45 min (À1008C)
2 h (À788C)
0
8
9
nBuLi (1.2)
nBuLi (2.0)
1 h (À1008C)
1 h (À1008C)
30
29
70
71
0
0
10
11
nBuLi (3.0)
nBuLi (1.5)
1.5 h (À1008C to RT)
2 h (À1008C)
21
35
79
31
0
34
12
13
nBuLi (2.0)
nBuLi (1.5)
2 h (À1008C)
2 h (À1008C)
31
0
44
0
25
100
[a] Determined by 31P NMR spectroscopy.
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Base-Induced Isomerization
COMMUNICATION
and electron-withdrawing groups. In general, the reactions
performed with all the furanosides were very clean, but we
could observe the formation of side-products, under the
same conditions, when pyranosides were used (entries 11
and 12). Interestingly, (E)-exo-glycals were very easy to sep-
arate from their Z diastereomers, since they displayed very
different Rf values on silica-gel chromatography. As ob-
served for the fluoro-exo-glycals,[5a] the (Z)-exo-glycals were
always more polar than their E isomers. As illustrated in
Scheme 3, some of the side-reactions were due to trans-sily-
lations giving the corresponding furanosides. Then, we ex-
plored the effect of protective groups on the isomerization
process. Changing the dibenzyl phosphonate into a dime-
thylphosphonyl group (for instance in the galactofuranose
series, see the Supporting Information, and entry 12 of
Table 1 for the corresponding galactopyranose) did not
change the course of the reaction. On the other hand, the
standard isomerization protocols (using BuLi or LiHMDS)
applied to perbenzylated exo-glycal 28 only led to the de-
composition of the starting material, even at À1008C. More-
over, with perbenzylated molecule 28, a decrease of the
number of equivalent of base, to prevent side-reactions, did
not allow us to generate the corresponding E isomer. The
latter results evidence that silylated protective groups are
mandatory to cleanly generate (E)-exo-glycals by this iso-
merization protocol.
Keywords: carbohydrates · enol ethers · isomerization ·
phosphonates · stereochemistry
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Acknowledgements
This work was funded by an ARC grant from the Acadꢁmie Louvain
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Received: March 13, 2013
Published online: July 25, 2013
11552
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Chem. Eur. J. 2013, 19, 11547 – 11552