Acid-Assisted Direct Olefin Metathesis of Unprotected Carbohydrates in Water

Article abstract of DOI:10.1002/chem.201903155

The ability to use unprotected carbohydrates in olefin metathesis reactions in aqueous media is demonstrated. By using water-soluble, amine-functionalized Hoveyda–Grubbs catalysts under mildly acidic aqueous conditions, the self-metathesis of unprotected alkene-functionalized α-d-manno- and α-d-galactopyranosides could be achieved through minimization of nonproductive chelation and isomerization. Cross-metathesis with allyl alcohol could also be achieved with reasonable selectivity. The presence of small quantities (2.5 vol %) of acetic acid increased the formation of the self-metathesis product while significantly reducing the alkene isomerization process. The catalytic activity was furthermore retained in the presence of large amounts (0.01 mm) of protein, underlining the potential of this carbon–carbon bond-forming reaction under biological conditions. These results demonstrate the potential of directly using unprotected carbohydrate structures in olefin metathesis reactions under mild conditions compatible with biological systems, and thereby enabling their use in, for example, drug discovery and protein derivatization.

Full text of DOI:10.1002/chem.201903155

A Journal of
Accepted Article
Title: Acid-Assisted Direct Olefin Metathesis of Unprotected
Carbohydrates in Water
Authors: Brian Timmer and Olof Ramström
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201903155
Link to VoR: http://dx.doi.org/10.1002/chem.201903155
Supported by

10.1002/chem.201903155
Chemistry - A European Journal
FULL PAPER
Acid-Assisted Direct Olefin Metathesis of Unprotected
Carbohydrates in Water
Brian J.J. Timmera and Olof Ramström*a,b,c
Abstract: The ability to use unprotected carbohydrates in olefin
metathesis reactions in aqueous media is demonstrated. Using water-
soluble amine-functionalized Hoveyda-Grubbs catalysts under mildly
acidic aqueous conditions, the self-metathesis of unprotected alkene-
functionalized α-D-manno- and α-D-galactopyranosides could be
achieved through minimization of non-productive chelation and
isomerization. Cross-metathesis with allyl alcohol could be also be
achieved with reasonable selectivity. The presence of small quantities
(2.5 vol%) of acetic acid increased the self-metathesis product
formation while significantly reducing the alkene isomerization
process. The catalytic activity was furthermore retained in the
presence of large amounts (0.01 M) of protein (BSA), underlining the
potential of this carbon-carbon bond forming reaction under biological
conditions. These results demonstrate the potential of directly using
unprotected carbohydrate structures in olefin metathesis reactions
under mild conditions compatible with biological systems, thereby
enabling their use in, e.g., drug discovery and protein derivatization.
e.g., resulted in the appearance of commercially available and
bench-stable catalysts,[21–25] Z-selective catalysts,[26–28] and highly
active catalysts for ethenolysis.[29,30] However, while the use of
olefin metathesis in organic solvents has been extensively
demonstrated, applications in aqueous media have been
considerably less explored.[31] The majority of biologically
interesting structures, such as unprotected peptides and
carbohydrates, have therefore been largely incompatible with the
reactions. To address this limitation, several strategies to enable
olefin metathesis in aqueous media have been proposed,
including the use of biphasic systems,[32] immobilized
catalysts,[33,34] nanoreactors and micellar catalysis,[35–39] artificial
metallo-enzymes,[40] as well as modifications of the catalysts or
the reaction conditions to increase the reactivities.[41–50]
Unfortunately, many of these systems are either incompatible with
water-soluble substrates or present a very narrow substrate
scope.[31,51,52]
The olefin metathesis reaction has nevertheless been applied
to the carbohydrate substance class to some extent,[53] in these
cases generally using protected structures in organic solvents.
However, the direct use of unprotected carbohydrates in aqueous
media would significantly increase the application range to
biological systems and other situations where water is desired as
Introduction
The formation of carbon-carbon bonds remains a coveted
transformation in chemistry and is generally required to build
basic architectures of organic molecules and materials. One of
the methods devised to accomplish this, olefin metathesis,[1–3] is
in this context highly useful since it results in efficient formation of
new carbon-carbon double bonds under catalytic conditions. The
scientific impact of this method has been exceptional, leading to
a large number of applications in many areas, such as organic
synthesis, materials science, energy research, molecular
topology, and medicinal chemistry.[4–9] The reaction is furthermore
of dynamic nature, an attractive feature that has been adopted
to generate, e.g., dynamic systems, complex architectures, and
self-healing materials.[10–20]
solvent. Pioneering studies of the groups of Davis,[54–56]
,
Harding,[57], as well as Cai and Yu,[58] show that unprotected
carbohydrates can be used as reactants in olefin metathesis
transformations in mixed solvent systems. Using Hoveyda-
Grubbs 2nd-generation catalyst in tert-butanol-water mixtures,
selective coupling of carbohydrates to proteins could thus be
achieved. In these cases, however, privileged alkenes carrying
allylic chalcogen atoms and high catalyst loadings were generally
required, thereby limiting the application range. Moreover, the
group of Blechert reported that self-metathesis of a C-glycoside
mainly resulted in isomerization rather than the desired
dimerization.[34]
In this study, we have addressed the challenge of applying
olefin metathesis to unprotected carbohydrate structures in
aqueous media. Inspired by previous studies on metathesis and
persistent carbenes, we hypothesized that the introduction of
morpholinium groups on an N-heterocyclic carbene (NHC) ligand
would result in high, overall solubility of the catalyst, thereby
resulting in improved catalytic efficiencies in water phase. In
addition, since the ruthenium carbenoid species would involve the
carbohydrate structures during the reaction, homogeneous
catalysis would be ensured throughout the process. Using this
design, we applied the catalysts to self- and cross-metathesis
Ever since the introduction of the olefin metathesis reaction,
much effort has been invested in improving the catalysts. This has,
[a]
[b]
Dr. B.J.J. Timmer, Prof. Dr. Olof Ramström
Department of Chemistry
KTH - Royal Institute of Technology
Teknikringen 36, S-10044 Stockholm, Sweden
Prof. Dr. O. Ramström
Department of Chemistry,
University of Massachusetts Lowell
1 University Ave., Lowell, MA 01854, USA
E-mail: olof_ramstrom@uml.edu
involving
a range of alkenyl glycosides, and furthermore
evaluated the effects of a weak Brønsted acid on the reactions.
[c]
Prof. Dr. O. Ramström
Department of Chemistry and Biomedical Sciences, Linnaeus
University, SE-39182 Kalmar, Sweden
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.201903155
Chemistry - A European Journal
FULL PAPER
Results and Discussion
rates (Table 1, entries 2-3). On the other hand, doubling the
catalyst loading to 5 mol% resulted in an increase in the formation
of self-metathesis dimer to 13%, however also associated with a
higher formation of isomerization products (Table 1, entry 4).
Based on previous observations by Grubbs and coworkers,[60]
the possibility to increase the metathesis conversion by carrying
out the reaction under slightly acidic conditions was next explored.
Interestingly, addition of 2.5 vol% acetic acid not only increased
the formation of the self-metathesis product, but the isomerization
rate was at the same time significantly reduced (Table 1, entry 5).
This reduced isomerization effect, previously shown in organic
solvents for this additive,[61] was presumed to be due to quenching
of potential ruthenium hydride species formed in the reaction.
However, the acid concentration proved sensitive to the
performance, and increasing the concentration of acetic acid to
5 vol% resulted in reduced self-metathesis (Table 1, entry 6),
while neat acetic acid completely quenched any reactivity. These
results suggest that acetic acid temporarily occupies vacant
coordination sites, thereby preventing ruthenium hydride
formation and, at higher concentrations, alkene coordination.
Reducing the reaction temperature to 30 °C decreased the self-
metathesis rate further, but, importantly, no isomerization could
be observed even after prolonged reaction times (Table 1, entry
7). Under these reaction conditions, an optimal reaction
temperature of 35 °C could be identified, leading to useful self-
metathesis yields and only trace isomerization products after
prolonged reaction times (Table 1, entry 8).
The catalysts were designed to contain two tertiary or quaternary
amines, introduced symmetrically at both ends of an
imidazolidine-based NHC core. Installation of the quaternary
amine centers was furthermore devised by late stage methylation
of the non-methylated catalyst structure, allowing for easier
synthesis and purification.[47] Synthesis of carbene precursors
matching similar criteria has been reported by Plenio and
coworkers,[59] and an analogous strategy was adopted in the
present case (Figure 1). Thus, electrophilic aromatic substitution
between 2,6-dimethylaniline and the morpholinium ion of
formaldehyde first yielded morpholine-substituted aniline 1.
Treatment of this compound with glyoxal provided diimine 2,
which upon reduction with lithium aluminum hydride yielded the
corresponding 1,2-diamine 3. Subsequent ring closure of this
species using triethyl orthoformate in the presence of ammonium
chloride provided imidazolinium chloride 4, serving as the NHC
ligand precursor. Deprotonation of compound 4 with KHMDS
yielded the N-heterocyclic carbene, which could then be directly
coupled to Hoveyda-Grubbs 1st-generation catalyst to provide
non-methylated catalyst C1. Finally, straightforward methylation
of the morpholine moieties with methyl triflate provided catalyst
C2 in six steps from commercially available starting materials.
O
O
NH2
O
H
H
NH2
HCOOH
(cat.)
H
H
N
H
O
R
N
N R
EtOH/H2O
reflux, 3 d
69%
MeOH/H2O
rt, 8 d
N
= R
2
56%
O
Table 1. Optimization of self-metathesis reaction of mannoside M5 using
catalyst C2.a
THF
0 °C - rt, 30 h
87%
1
LiAlH4
OEt
EtO
OEt
NH4Cl
H
N+
N
R
R
NH HN R
R
120 °C
2.5 h
41%
Cl-
4
3
2)
Cl
Cl
PHCy3
Ru
1) KHMDS
Toluene
rt, 15 min
O
Entry
C2
(mol%)
T
(°C)
Solvent
self-
metathesis
(%)
isomerization
(%)
40 °C, 5h
58%
O
O
O
O
N
Cl
N
N
N
N
1
2
3
4
5
2.5
2.5
2.5
5
40
50
60
40
40
D2O
D2O
D2O
D2O
5
6
Traces
44
N
N
N
Cl
Cl
TfO-
TfO-
Ru
O
Ru
MeOTf
Cl
CH2Cl2
rt, 3 h
76%
O
C2
C1
5
87
13
28
Figure 1. Synthesis of catalyst C2.
5
D2O + 2.5%
CD3COOD
26/26b
0/6b
Catalyst C2 was first applied to the potential self-metathesis of
two unprotected carbohydrates: allyl α-D-mannoside (M3) and 3-
butenyl α-D-mannoside (M4, cf. structures in Table 2).
Unfortunately, no self-metathesis occurred for either mannoside
in the presence of 2.5 mol% catalyst in D2O at 40 °C and 0.1 M
initial substrate concentration, and only alkene isomerization was
observed in both cases. Interestingly, only single isomerization to
the 2-butenyl isomers was observed for the 3-butenyl species, a
result incidentally also observed for all other tested reactants
(vide infra). However, when applying the catalyst to 4-pentenyl α-
D-mannoside (M5), carrying a longer olefinic aglycone, some self-
metathesis product could be observed (Table 1, entry 1). In this
case, increasing the temperature to 50 °C or 60 °C did not
improve the amount of self-metathesis product, but only led to
faster decomposition of the catalyst and higher isomerization
6c
7
5
5
5
40
30
35
H2O + 5%
CH3COOH
19/22b
16/18b
18/27b
0/13b
0/0b
D2O + 2.5%
CD3COOD
8
D2O + 2.5%
CD3COOD
0/tracesb
a
Initial substrate concentration: 0.1 M. Conversions (combined cis/trans-
isomers) determined by 1H-NMR spectroscopy at 45-130 min. b Conversion at
18 h. c Reaction in non-deuterated solvents.
Employing the optimized reaction conditions of mannoside M5,
the effects of the aglycone chainlength on the metathesis process
were further evaluated. In principle, the catalytic performance
This article is protected by copyright. All rights reserved.

10.1002/chem.201903155
Chemistry - A European Journal
FULL PAPER
may be reduced from chelation to the ruthenium center,
previously observed to play a major role in the metathesis of
ammonium-functionalized alkenes.[45] To probe if such non-
productive chelation indeed played a role in the reactions with
unprotected carbohydrates, we synthesized a series of alkene-
functionalized α-D-mannosides and β-D-galactosides containing
different aglycone linker lengths (allyl, 3-butenyl, 4-pentenyl, 5-
hexenyl, Table 2). In this series, the longer linker lengths were
expected to contribute to the entropic factor, thereby decreasing
the stability of the hypothesized chelated resting state of the
catalyst.
entries 4 and 8) and 5-hexenyl derivatives (M6/G6, Table 2,
entries 5 and 9) followed the same trend, with a highest observed
conversion of 41% after 300 min. Increasing the reaction time to
24 h did not result in any significantly improved dimerization
efficiency, and the conversion increased up to 5%. Furthermore,
both the mannosides and galactosides showed a similar trend in
reactivity, with the galactosides showing only slightly lower yields.
Since the optimized procedure included the use of 2.5 vol%
acetic acid, we next evaluated if the non-methylated catalyst C1
could be used directly under the same conditions. Interestingly,
this proved to be the case, and catalyst C1 was even slightly more
efficient than methylated catalyst C2 in self-metathesis of the
evaluated carbohydrates (Table 2). A likely explanation for this
observation is the small increase in solubility of the catalyst as
compared to catalyst C2, which comprises partly hydrophobic
triflate anions. With catalyst C1, further attempts to raise the self-
metathesis yields were based on observations made by the
groups of Davis,[54] and Hirota,[62] where addition of a chloride salt
prevented non-productive chelation/deactivation of the catalysts.
In the present case, addition of magnesium chloride (100 mM)
improved the self-metathesis conversions only marginally in the
reactions with the functionalized carbohydrates. In contrast to the
conditions without magnesium chloride, traces of product could
be observed even for the allyl glycosides. However, the
conversions were overall lower than observed without added salt
(cf. supporting information, Table S1).
Table 2. Self-metathesis reactions catalyzed by catalysts C2 or C1.a
Entry
Substrate
Conversion w/ C2/C1 (%)
15 min
60 min
78/74
0/0
300 min
1
2
55/58
0/0
93/82
0/0
3
4
2/4
7/11
11/13
16/24
6/13
14/18
Table 3. Self-metathesis of 5-hexenyl glycosides M6 and G6 in the presence of
additives.a
5
6
7
8
24/28
0/0
38/33
0/0
41/41
45/50b
Entry
Substrate
Additive
Conversion (%)
15
min
60
min
300
min
24
h
0/0
6/5
1
-
28
33
41
50
1/2
2/4
2
3
5 mol%
C1
48
29
65
36
76
41
81
50
6/13
14/21
16/22
BSA
(0.01
mM)
9
18/25
25/31
29/33
34/47b
4
5
BSA
(0.06
mM)b
23
25
35
31
35
33
36
47
aReactions performed using
5 mol% catalyst at 35 °C. Initial substrate
concentration: 0.1 M in D2O containing 2.5 vol% CD3COOD. Conversions
(combined cis/trans-isomers) determined by 1H-NMR spectroscopy.
bConversion at 24 h.
-
For comparison, the self-metathesis reaction was first performed
using allyl alcohol, a substrate less likely to produce non-
productive chelation since it would lead to the formation of a
disfavored 4-membered ring. Interestingly, the self-metathesis of
allyl alcohol showed fast initiation and led to 93% conversion after
only 300 min reaction time (Table 2, entry 1). As expected from
the previous results, neither of the allyl glycosides M3 or G3 was
active in the self-metathesis or isomerization reactions (Table 2,
entries 2 and 6). However, higher yields were observed when the
distance between the carbohydrate ring and the alkene group was
increased, and the 3-butenyl glycosides M4 and G4 showed up to
11% conversion to the dimer (Table 2, entries 3 and 7). Further
extension of the chain length to the 4-pentenyl- (M5/G5, Table 2,
6
7
5 mol%
C1
38
27
43
32
49
31
63
41
BSA
(0.01
mM)
8
BSA
(0.06
mM)b
17
26
26
28
a
Reactions performed using 5 mol% of catalyst C1 at 35 °C. Initial substrate
concentration: 0.1 M in D2O containing 2.5 vol% CD3COOD. Conversions
(combined cis/trans-isomers) determined by 1H-NMR spectroscopy. b 100 wt%
of BSA compared to catalyst C1.
This article is protected by copyright. All rights reserved.

10.1002/chem.201903155
Chemistry - A European Journal
FULL PAPER
The reactions of the best reacting 5-hexenyl substrates M6 and Conclusions
G6 were further studied with respect to loading and protein
addition (Table 3). First, an attempt was made to improve the
conversions through the addition of 5 mol% of catalyst C1. This
increase in catalyst loading resulted in up to 81% self-metathesis
of mannoside M6, whereas galactoside G6 could be dimerized to
an extent of 63% (Table 3, entries 2 and 6). Furthermore, to probe
the compatibility of the optimized system with biologically relevant
entities, such as proteins, the catalytic activity of catalyst C1 was
evaluated in the presence of bovine serum albumin (BSA). At a
concentration of 0.01 mM protein, potentially acting as an external
chelating moiety not participating in the catalytic cycle, the self-
metathesis reaction rate was not reduced and similar conversions
were observed at all time points (Table 3, entries 3 and 7). Only
at the point of 0.06 mM of BSA, corresponding to 100 wt% BSA
compared to catalyst C1, some retardation was observed. In this
case, the conversion was reduced to 36% and 28% for 5-hexenyl
glycosides M6 and G6, respectively (Table 3, entries 4 and 8).
To expand the applicability further, the possibility to achieve
cross-metathesis with the developed catalysts was explored.
Similar conditions as those developed for the 5-hexenyl
glycosides M6 and G6 were used, where allyl alcohol was added
to the reaction mixtures to a final concentration of 0.1 M. Analysis
of the 1H-NMR spectra showed appearance of a new set of peaks
corresponding to the cross-metathesis product (Figure 2).
Filtration of the reaction mixture over a short path of silica and
analysis by mass spectrometry confirmed the formation of the
cross-metathesis products. Interestingly, after only 15 min, 35 and
36% of cross metathesis was observed for mannoside M6 and
galactoside G6, respectively. Simultaneously, only traces of the
self-metathesis products of the glycosides could be observed.
After 300 min of reaction time, the conversion to the cross-
metathesis product increased by a few percent to 40 and 39%,
respectively, while up to 4% of the glycoside dimers were formed.
When the reaction mixture was left to stir for a total of 24 h, the
conversions to the cross-metathesis products remained
unchanged, whereas a significant increase in self-metathesis
products could be observed with conversions up to 21 and 19%
for M6 and G6, respectively (Figure 2).
In conclusion, the results show that olefin metathesis of
unprotected carbohydrate structures carrying non-privileged
olefin groups is feasible directly in water. Homogeneous catalytic
conditions could be enabled using Hoveyda-Grubbs catalysts
functionalized
with
morpholinium groups, conveniently
synthesized in few steps. Both self-metathesis and cross-
metathesis could be achieved using the catalysts, and the
addition of small quantities of acetic acid to the solutions was
found to deter alkene isomerization and increase the formation of
the metathesis products. This simultaneously allowed for direct
use of the non-methylated catalyst C1, thereby further shortening
the synthetic route to this catalyst. The catalytic activity of catalyst
C1 was furthermore maintained in the presence of large amounts
of albumin, demonstrating the stability and high compatibility of
the catalyst under challenging conditions. Overall, the results of
this study demonstrate a broadened substrate scope of aqueous
olefin metathesis, increasing the capability of forming carbon-
carbon bonds under catalytic conditions in demanding aqueous
environments. The results furthermore indicate the potential of
using these catalysts for biological applications, such as in drug
discovery and protein derivatization.
Experimental Section
Experimental Details.
Acknowledgments
This project was in part funded by the European Union’s Seventh
Framework Programme for research, technological development
and demonstration under grant agreement no 289033, and the
Swedish Research Council.
Keywords: olefin metathesis • carbohydrates • homogeneous
catalysis • aqueous media • synthetic methods
[1] R. R. Schrock, C. Czekelius, Adv. Synth. Catal. 2007, 349,
55–77.
[2] A. H. Hoveyda, A. R. Zhugralin, Nature 2007, 450, 243–251.
[3] R. H. Grubbs, Tetrahedron 2004, 60, 7117–7140.
[4] O. M. Ogba, N. C. Warner, D. J. O’Leary, R. H. Grubbs,
Chem. Soc. Rev. 2018, 47, 4510–4544.
[5] F. Sarabia, I. Cheng-Sánchez, Synthesis 2018, 50, 3749–
3786.
[6] D. Hughes, P. Wheeler, D. Ene, Org. Process Res. Dev.
2017, 21, 1938–1962.
[7] A. Fürstner, Science 2013, 341, 1229713–1229713.
[8] L. Oehninger, R. Rubbiani, I. Ott, Dalton Trans. 2013, 42,
3269–3284.
[9] R. S. Forgan, J.-P. Sauvage, J. F. Stoddart, Chem. Rev.
2011, 111, 5434–5464.
[10] C. Liu, E. Park, Y. Jin, J. Liu, Y. Yu, W. Zhang, S. Lei, W.
Hu, Angew. Chem. Int. Ed. 2018, 57, 1869–1873.
[11] J. A. Neal, D. Mozhdehi, Z. Guan, J. Am. Chem. Soc. 2015,
137, 4846–4850.
[12] C. A. Denard, H. Huang, M. J. Bartlett, L. Lu, Y. Tan, H.
Zhao, J. F. Hartwig, Angew. Chem. Int. Ed. 2014, 53, 465–469.
[13] J.-F. Ayme, J. E. Beves, D. A. Leigh, R. T. McBurney, K.
Rissanen, D. Schultz, Nat. Chem. 2012, 4, 15–20.
Figure 2. Alkene region of 1H-NMR spectra showing the metathesis of allyl
alcohol and mannoside M6 with catalyst C1. Top two spectra: self-metathesis
of each substrate; bottom two spectra: cross-metathesis after 300 min or 24 h
reaction time.
This article is protected by copyright. All rights reserved.

10.1002/chem.201903155
Chemistry - A European Journal
FULL PAPER
[14] Y.-X. Lu, F. Tournilhac, L. Leibler, Z. Guan, J. Am. Chem.
Soc. 2012, 134, 8424–8427.
[15] Y. Jin, A. Zhang, Y. Huang, W. Zhang, Chem. Commun.
2010, 46, 8258–8260.
[47] K. Skowerski, G. Szczepaniak, C. Wierzbicka, L. Gulajski,
M. Bieniek, K. Grela, Catal. Sci. Technol. 2012, 2, 2424–2427.
[48] J. Jordan, R. Grubbs, Angew. Chem. Int. Ed. 2007, 46,
5152–5155.
[16] S.-A. Poulsen, L. F. Bornaghi, Bioorg. Med. Chem. 2006,
14, 3275–3284.
[49] S. H. Hong, R. H. Grubbs, J. Am. Chem. Soc. 2006, 128,
3508–3509.
[17] P. C. M. van Gerven, J. A. A. W. Elemans, J. W. Gerritsen,
S. Speller, R. J. M. Nolte, A. E. Rowan, Chem. Commun. 2005,
3535–3537.
[18] A. Fürstner, O. R. Thiel, L. Ackermann, Org. Lett. 2001, 3,
449–451.
[19] K. C. Nicolaou, R. Hughes, S. Y. Cho, N. Winssinger, C.
Smethurst, H. Labischinski, R. Endermann, Angew. Chem. Int.
Ed. 2000, 39, 3823–3828.
[50] A. Michrowska, L. Gulajski, Z. Kaczmarska, K. Mennecke,
A. Kirschning, K. Grela, Green Chem. 2006, 8, 685–688.
[51] E. Levin, E. Ivry, C. E. Diesendruck, N. G. Lemcoff, Chem.
Rev. 2015, 115, 4607–4692.
[52] J. Tomasek, J. Schatz, Green Chem. 2013, 15, 2317–2338.
[53] Y. M. Chabre, R. R. Roy, Chem. Soc. Rev. 2013, 42, 4657.
[54] Y. A. Lin, J. M. Chalker, B. G. Davis, J. Am. Chem. Soc.
2010, 132, 16805–16811.
[20] C. Brändli, T. R. Ward, Helv. Chim. Acta 1998, 81, 1616–
1621.
[55] Y. A. Lin, J. M. Chalker, B. G. Davis, ChemBioChem 2009,
10, 959–969.
[21] L. Ondi, G. M. Nagy, J. B. Czirok, A. Bucsai, G. E. Frater,
Org. Process Res. Dev. 2016, 20, 1709–1716.
[22] J. Heppekausen, A. Fürstner, Angew. Chem. Int. Ed. 2011,
50, 7829–7832.
[56] Y. A. Lin, J. M. Chalker, N. Floyd, G. J. L. Bernardes, B. G.
Davis, J. Am. Chem. Soc. 2008, 130, 9642–9643.
[57] L. Hunter, G. C. Condie, M. M. Harding, Tetrahedron Lett.
2010, 51, 5064–5067.
[23] S. B. Garber, J. S. Kingsbury, B. L. Gray, A. H. Hoveyda, J.
Am. Chem. Soc. 2000, 122, 8168–8179.
[58] F. Fan, C. Cai, L. Gao, J. Li, P. Zhang, G. Li, C. Li, G. Yu,
Polym. Chem. 2017, 8, 6709–6719.
[24] M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett.
1999, 1, 953–956.
[59] V. Sashuk, D. Schoeps, H. Plenio, Chem. Commun. 2009,
770–772.
[25] L. Jafarpour, H.-J. Schanz, E. D. Stevens, S. P. Nolan,
Organometallics 1999, 18, 5416–5419.
[60] J. P. Gallivan, J. P. Jordan, R. H. Grubbs, Tetrahedron Lett.
2005, 46, 2577–2580.
[26] W. Smit, V. Koudriavtsev, G. Occhipinti, K. W. Törnroos, V.
R. Jensen, Organometallics 2016, 35, 1825–1837.
[27] M. J. Koh, R. K. M. Khan, S. Torker, M. Yu, M. S. Mikus, A.
H. Hoveyda, Nature 2015, 517, 181–186.
[61] S. H. Hong, D. P. Sanders, C. W. Lee, R. H. Grubbs, J. Am.
Chem. Soc. 2005, 127, 17160–17161.
[62] T. Matsuo, T. Yoshida, A. Fujii, K. Kawahara, S. Hirota,
Organometallics 2013, 32, 5313–5319.
[28] B. K. Keitz, K. Endo, M. B. Herbert, R. H. Grubbs, J. Am.
Chem. Soc. 2011, 133, 9686–9688.
[29] J. Bidange, C. Fischmeister, C. Bruneau, Chem. Eur. J.
2016, 22, 12226–12244.
[30] V. M. Marx, A. H. Sullivan, M. Melaimi, S. C. Virgil, B. K.
Keitz, D. S. Weinberger, G. Bertrand, R. H. Grubbs, Angew.
Chem. Int. Ed. 2015, 54, 1919–1923.
[31] V. Sabatino, T. R. Ward, Beilstein J. Org. Chem. 2019, 15,
445–468.
[32] Á. Gómez Baraibar, D. Reichert, C. Mügge, S. Seger, H.
Gröger, R. Kourist, Angew. Chem. Int. Ed. 2016, 55, 14823–
14827.
[33] M. R. Buchmeiser, Chem. Rev. 2009, 109, 303–321.
[34] S. J. Connon, S. Blechert, Bioorg. Med. Chem. Lett. 2002,
12, 1873–1876.
[35] B. Ö. Öztürk, B. Durmuş, S. K. Şehitoğlu, Catal. Sci.
Technol. 2018, 8, 5807–5815.
[36] J. Pauly, H. Gröger, A. V. Patel, Green Chem. 2018, 20,
5179–5187.
[37] B. H. Lipshutz, S. Ghorai, A. R. Abela, R. Moser, T.
Nishikata, C. Duplais, A. Krasovskiy, R. D. Gaston, R. C.
Gadwood, J. Org. Chem. 2011, 76, 4379–4391.
[38] A. K. Diallo, E. Boisselier, L. Liang, J. Ruiz, D. Astruc,
Chem. Eur. J. 2010, 16, 11832–11835.
[39] B. H. Lipshutz, G. T. Aguinaldo, S. Ghorai, K. Voigtritter,
Org. Lett. 2008, 10, 1325–1328.
[40] M. Jeschek, R. Reuter, T. Heinisch, C. Trindler, J. Klehr, S.
Panke, T. R. Ward, Nature 2016, 537, 661–665.
[41] Ł. Gułajski, A. Tracz, K. Urbaniak, S. J. Czarnocki, M.
Bieniek, T. K. Olszewski, Beilstein J. Org. Chem. 2019, 15, 160–
166.
[42] C. Kim, H. Chung, J. Org. Chem. 2018, 83, 9787–9794.
[43] Y. Jeong, G. Y. Tonga, B. Duncan, B. Yan, R. Das, C.
Sahub, V. M. Rotello, Small 2018, 14, 1702198.
[44] E. C. Gleeson, Z. J. Wang, W. R. Jackson, A. J. Robinson,
J. Org. Chem. 2015, 80, 7205–7211.
[45] Z. J. Wang, W. R. Jackson, A. J. Robinson, Green Chem.
2015, 17, 3407–3414.
[46] A. Kajetanowicz, A. Chatterjee, R. Reuter, T. Ward, Catal.
Lett. 2014, 144, 373–379.
This article is protected by copyright. All rights reserved.

10.1002/chem.201903155
Chemistry - A European Journal
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
FULL PAPER
Water-soluble Hoveyda-Grubbs
catalysts were synthesized and
applied to metathesis of unprotected
alkene-functionalized
glycopyranosides under mildly acidic
aqueous conditions. Through
Brian J.J. Timmer and Olof Ramström*
Page No. – Page No.
Acid-Assisted Direct Olefin
Metathesis of Unprotected
Carbohydrates in Water
minimization of non-productive
chelation and isomerization, both self-
metathesis and cross-metathesis
could be achieved. The catalytic
activity was furthermore retained in
the presence of serum albumin.
This article is protected by copyright. All rights reserved.