Mannopyranosyl uronicaAcid donor reactivity

Article abstract of DOI:10.1021/ol2016862

The reactivity of a variety of mannopyranosyl uronic acid donors was assessed in a set of competition experiments, in which two (S)-tolyl mannosyl donors were made to compete for a limited amount of promoter (NIS/TfOH). These experiments revealed that the reactivity of mannuronic acid donors is significantly higher than expected based on the electron-withdrawing capacity of the C-5 carboxylic acid ester function. A 4-O-acetyl-β-(S)-tolyl mannuronic acid donor was found to have similar reactivity as per-O-benzyl-α-(S)-tolyl mannose.

Full text of DOI:10.1021/ol2016862

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4360–4363
Mannopyranosyl Uronic Acid Donor
Reactivity
Marthe T. C. Walvoort, Wilbert de Witte, Jesse van Dijk, Jasper Dinkelaar,
ꢀ
Gerrit Lodder, Herman S. Overkleeft, Jeroen D. C. Codee,* and Gijsbert A. van der Marel*
Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA Leiden,
The Netherlands
marel_g@chem.leidenuniv.nl; jcodee@chem.leidenuniv.nl
Received June 23, 2011
ABSTRACT
The reactivity of a variety of mannopyranosyl uronic acid donors was assessed in a set of competition experiments, in which two (S)-tolyl
mannosyl donors were made to compete for a limited amount of promoter (NIS/TfOH). These experiments revealed that the reactivity of
mannuronic acid donors is significantly higher than expected based on the electron-withdrawing capacity of the C-5 carboxylic acid ester
function. A 4-O-acetyl-β-(S)-tolyl mannuronic acid donor was found to have similar reactivity as per-O-benzyl-R-(S)-tolyl mannose.
The substituents on a glycosyl donor have a decisive
effect on its reactivity in glycosylation reactions.1 As first
recognizedby Paulsen and co-workers, electron-withdraw-
ing groups on the carbohydrate core retard the formation
of (partial) positive charge at the anomeric center, thereby
slowing down the rate of hydrolysis and/or glycosylation.2
This observation is formulated in the armedꢀdisarmed
concept, introduced by Fraser-Reid, in which benzylated
(armed) glycosyl donors can be selectively activated (and
coupled) to acylated (disarmed) glycosyl donors.3 Subse-
quently the armedꢀdisarmed concept has evolved into a
system in which glycosyl donor reactivity is regarded to be
a continuum.4 To gain better insight into the exact reac-
tivity of a glycosyl donor, the groups of Ley5 and Wong6
have quantified the reactivity of a large number of thiogly-
cosyl donors and shown that the reactivity of a given
donor is a function of the nature of the mono- (or oligo-)
saccharide at hand, as well as the nature and position of
the substituents. Recently, Bols and co-workers have
shown that “super-armed” donors can be conceived by
forcing the carbohydrate ring substituents in pseudoaxial
orientations, making the electronegative substituents less
deactivating.7 In general, uronic acid donors, being
glycosyl pyranosides of which the C-6 is oxidized to a
carboxylic acid function, are regarded to be among the
most unreactive donors by virtue of the electron-with-
drawing nature of the appended carboxylic acid ester
(1) (a) Comprehensive Glycoscience; Kamerling, J. P., Ed.; Elsevier:
Oxford, 2007; Vol. 1. (b) The Organic Chemistry of Sugars; Levy, D. E.,
F€ugedi, P., Eds.; CRC Press: Boca Raton, FL, 2006.
(2) Paulsen, H.; Richter, A.; Sinnwell, V.; Stenzel, W. Carbohydr.
Res. 1978, 64, 339–364.
function (FCOOMe = 0.34; FCH OH = 0.03).8,9 In our recent
2
(3) (a) Mootoo, D. R.; Konradson, P.; Ududong, U.; Fraser-Reid, B.
J. Am. Chem. Soc. 1988, 110, 5583–5584. (b) Fraser-Reid, B.; Wu, Z.;
Ududong, U.; Ottoson, H. J. Org. Chem. 1990, 55, 6068–6070.
(7) (a) Pedersen, C. M.; Nordstrøm, L. U.; Bols, M. J. Am. Chem.
Soc. 2007, 129, 9222–9235. (b) Pedersen, C. M.; Marinescu, L. G.; Bols,
M. Chem. Commun. 2008, 2465–2467. (c) Pedersen, C. M.; Marinescu,
L. G.; Bols, M. C.R. Chimie 2011, 14, 17–43.
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(4) (a) Codee, J. D. C.; Litjens, R. E. J. N.; van den Bos, L. J.;
Overkleeft, H. S.; van der Marel, G. A. Chem. Soc. Rev. 2005, 34, 769–
782. (b) Wang, Y.; Ye, X.-S.; Zhang, L.-H. Org. Biomol. Chem. 2007, 5,
2189–2200.
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(8) (a) van den Bos, L. J.; Codee, J. D. C.; Litjens, R. E. J. N.;
Dinkelaar, J.; Overkleeft, H. S.; van der Marel, G. A. Eur. J. Org. Chem.
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2007, 3963–3976. (b) Codee, J. D. C.; Christina, A. E.; Walvoort,
M. T. C.; Overkleeft, H. S.; van der Marel, G. A. Top. Curr. Chem.
2011, 301, 253–289.
€
(5) Douglas, N. L.; Ley, S. V.; Lucking, U.; Warriner, S. L. J. Chem.
Soc., Perkin Trans. 1 1998, 51–65.
(6) (a) Zhang, Z. Y.; Ollmann, I. R.; Ye, X. S.; Wischna, R.; Baasov,
T.; Wong, C.-H. J. Am. Chem. Soc. 1999, 121, 734–753. (b) Koeller,
K. M.; Wong, C.-H. Chem. Rev. 2000, 100, 4465–4493. (c) Ritter, T. K.;
Mong, K. K. T.; Liu, H. T.; Nakatani, T.; Wong, C.-H. Angew. Chem.,
Int. Ed. 2003, 42, 4657–4660. (d) Lee, J.-C.; Greenberg, W. A.; Wong,
C.-H. Nat. Protoc. 2006, 1, 3143–3152.
(9) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165–195.
(10) (a) van den Bos, L. J.; Dinkelaar, J.; Overkleeft, H. S.; van der
Marel, G. A. J. Am. Chem. Soc. 2006, 128, 13066–13067. (b) Codee,
J. D. C.; van den Bos, L. J.; de Jong, A.-R.; Dinkelaar, J.; Lodder, G.;
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Overkleeft, H. S.; van der Marel, G. A. J. Org. Chem. 2009, 74, 38–47.
r
10.1021/ol2016862
Published on Web 07/21/2011
2011 American Chemical Society

studies on the use of mannuronic acids in the construction
of complex bacterial oligosaccharides,10ꢀ13 we investi-
gated the activation and glycosylation behavior of a series
ofdiversely substituted mannuronic aciddonors, including
mono- and diazidomannuronic acids. We found that these
donors are readily activated to provide glycosylating spe-
cies, which reacted in a stereoselective manner to pro-
vide β-mannosidic linkages. Besides the stereoselectivity of
these reactions, the reactivity of the donors studied was
also remarkable. The latter became apparent in our NMR
experiments to study the formation of anomeric triflates by
the sulfonium-ion-mediated preactivation of mannuronic
acid donors. 2,3-Di-O-benzyl mannuronate donor 1 was
rapidly activated using Ph2SOꢀTf2O at low temperature
(ꢀ80 °C) to give mannosyl triflate 2, which could be used
as a glycosylating species at the same low temperature
(Figure 1).11 Analogous results were obtained for the
mono- and diazidomannuronates 3 and 5, which contain,
in addition to the “disarming” C-5 carboxylate, electron-
and 6,6,6-trifluoromannosyl triflate 916 (FCF = 0.38)9
3
are ꢀ30, ꢀ10, and þ10 °C, respectively. Thus, the reactiv-
ity of the mannuronate donors and the stability of the
intermediate triflates do not match the expectations. To
gain more insight into the reactivity of mannopyranosyl
uronic acid donors, we set out to investigate their relative
reactivity with respect to their non-oxidized counterparts.
We here report the results of this study.17
The most extensive donor reactivity study to date has
been reported by Wong and co-workers, who quantified
the reactivity of more than 100 (S)-tolyl glycosides.6 In
their experimental setup, relative reactivity values (RRVs)
were established in competition experiments in which two
donors were forced to compete for a limited amount of
NIS/TfOH as the stoichiometric promoter in the presence
of excess acceptor (MeOH). Although the kinetics of
halonium-mediated thioglycoside activation are complex
and not fully understood,18ꢀ20 it is generally assumed that
formation of an intermediate with oxacarbenium ion
character from the charged thioglycoside is the rate-deter-
mining step in these reactions. To establish the relative
donor reactivity of a series of mannopyranosyl uronic
acids and mannopyranoside reference donors, we chose
to use (S)-tolyl mannosides in combination with the NIS/
TfOH promoter system, staying close to the system devised
by Wong and co-workers.6 The donors used in this study
are depicted in Figure 2 and include a set of R-configured
mannosides (10r, 11r, and 12r), a set of the analogous β-
configured donors (10β, 11β, and 12β), three C-2-azido
mannosides (10N, 11N, and 12N), and 2,3-diazido- and
2-fluoromannuronic acid, 5 and 12F, respectively. We
employed methyl 2,3,4-tri-O-benzyl-R-D-glucopyranoside
13 as a model acceptor glycoside. In our experiments, we
used two donors, NIS, a catalytic amount of TfOH, and
the acceptor in a molar ratio of 1:1:1:0.1:3. All condensa-
tions were performed under standardized conditions (0.05
M of donor in methylene chloride, ꢀ40 °C to rt). The crude
product mixtures were purified by size exclusion chroma-
tography to isolate the disaccharide fraction, and the
relativeratios of the formeddisaccharides were determined
by NMR spectroscopy. The results of the competition
experiments are summarized in Table 1.
withdrawing azide functionalities at C-2/3 (FN = 0.48).9
3
Figure 1. Previously studied mannuronic acid donors and man-
nosyl triflates. (/) Triflates 2, 4, and 6 exist as a conformational
4C1/1C4 mixture.11ꢀ13
Triflates 4 and 6 were rapidly formed at ꢀ80 °C from their
respective donors and shown to be apt glycosylating
species.12ꢀ14 In addition, the decomposition temperatures
of triflates 2, 4, and 6 proved to be unexpectedly low,
as indicated in Figure 1. For comparison, the decomposi-
tion temperatures of per-O-methylmannosyl triflate 7,15
4,6-O-benzylidene-2,3-di-O-methylmannosyl trilfate 8,15
From the series of reactions using the R-donors (entries
1ꢀ3), it becomes apparent that the 4,6-di-O-acetyl donor
10r is the most reactive of the three R-donors surveyed,
followed by the 4,6-benzylidene mannoside 11r, with the
mannuronic acid 12r being the least reactive. Apparently,
the combined torsional and electronic disarming effect of
(17) The relative donor reactivity of pyranosyl uronic acids has not
been quantified today. For a study on the relative rates of anomerization
of glucopyranosyl uronic acids and glucopyranosides, see: Pilgrim, W.;
Murphy, P. V. J. Org. Chem. 2010, 75, 6747–6755.
(18) The activation of thioglycosides using NISꢀTfOH can involve
activation by iodonium triflate, the generated sulfenyliodide, and iodide
and can proceed through direct activation of the promoter or via
halonium transfer or aglycone transfer. See refs 19 and 20.
(19) Ravindranathan Kartha, K. P.; Cura, P.; Aloui, M.; Readman,
K.; Rutherford, T. J.; Field, R. A. Tetrahedron: Asymmetry 2000, 11,
581–593.
(11) Walvoort, M. T. C.; Lodder, G.; Mazurek, J.; Overkleeft, H. S.;
ꢀ
Codee, J. D. C.; van der Marel, G. A. J. Am. Chem. Soc. 2009, 131,
12080–12081.
ꢀ
(12) Walvoort, M. T. C.; Lodder, G.; Overkleeft, H. S.; Codee,
J. D. C.; van der Marel, G. A. J. Org. Chem. 2010, 75, 7990–8002.
ꢀ
(13) Walvoort, M. T. C.; Moggre, G.-J.; Lodder, G.; Overkleeft,
H. S.; Codee, J. D. C.; van der Marel, G. A. Submitted for publication.
ꢀ
(14) The anomeric triflates can act as product-forming intermediates
or serve as a reservoir for oxacarbenium ion intermediates.
(15) Crich, D.; Sun, S. J. Am. Chem. Soc. 1998, 120, 435–436.
(16) Crich, D.; Vinogradova, O. J. Am. Chem. Soc. 2007, 129, 11756–
11765.
ꢀ
ꢀ
(20) Fraser-Reid, B.; Christobal Lopez, J.; Gomez, A. M.; Uriel, C.
ꢀ
Eur. J. Org. Chem. 2004, 1387–1395.
Org. Lett., Vol. 13, No. 16, 2011
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Table 1. Competing Donors in Glycosylation of 13
Figure 2. Donors and acceptor used in this study. (/) Donor
12r exists as a 1:1.5 4C1/1C4 conformer mixture (see Supporting
Information).
the benzylidene function in 11r, which locks the C-6-O-
substituent in the tg conformation,21 renders this manno-
side less reactive than mannosyl donor 10r, having two
electron-withdrawing acyl functions. The strong electron-
withdrawing effect of the C-5 carboxylic acid ester in 12r
makes the mannuronate donor approximately 30 and
5 times less reactive than donor 10r and 11r. Interestingly,
for the β-series (entries 4ꢀ6), the reactivity order is chan-
ged and mannuronic acid donor 12β is 7 times more
reactive than benzylidene donor 11β. In this series, diacyl
donor 10β is only twice as reactive asmannuronic acid 12β.
For the 2-azido series, an analogous trend is seen (entries
7ꢀ9). Diacyl donor 10N is more reactive than mannuronic
acid 12N, which in turn outcompetes benzylidene donor
11N. To assess the reactivity of the 2,3-diazido- and
2-fluoromannuronates 5 and 12F, these donors were com-
peted with 3 and 1, respectively, showing that the azide and
fluorine substituents are equally disarming, as expected on
the basis of their similar F values (0.48 vs 0.45). The
introduction of two azides leads to a less reactive donor
(entry 12), in line with expectations.
To verify the unexpectedly high reactivity of the β-
mannuronic acid 12β, this donor competed with R-benzy-
lidene mannoside 11r and led to the predominant forma-
tion of the mannuronic acid disaccharide (entry 13).
2-Azidomannuronic acid 12N also outcompeted R-config-
ured 11r, confirming the high reactivity of the β-anomer
(entry 14). We have previously established that there is
a substantial difference between the reactivity of R- and
β-anomeric mannuronic acid donors.12,13 For example,
donors 3 and 5 (Figure 1) can be readily activated
at ꢀ80 °C, whereas their R-configured counterparts re-
quire ꢀ40 and ꢀ10 °C for complete activation. This
a Product ratio was determined by NMR of the disaccharide mix-
tures. The disaccharides were obtained predominantly as β-anomers (see
Supporting Information), except for the disaccharide derived from 14.
b (S)-Phenyl donors were used. c Combined yield of disaccharides.
reactivity difference was established here in a direct com-
petition experiment in which 12r and 12β competed for
activator. Since both donors lead to the same product, we
determined the ratio of unreacted donor after the reaction,
revealing that 9 times more R-donor 12r than β-donor 12β
remained in the mixture. In a similar experiment involving
donors 10r and 10β, the reactivity difference between the
anomers of the “non-oxidized” mannosyl donor 10 was
shown to be smaller: after the coupling reaction, the
unreacted R- and β-donors were recovered in a 61:39 ratio.
From the results described above, it is clear that the β-
mannuronic acid donors are reactive glycosyl donors.
Wong and co-workers have previously established that
donor 11r has a RRV of 315, on a scale in which the per-O-
acetylated R-(S)-tolyl mannose donor has a relative reac-
tivity of 1 and the most reactive perbenzylated R-(S)-tolyl
mannoside (14) a RRV of 5000.6 The result recorded in
entry 13 of Table 1 indicates that the reactivity of man-
nuronic acid donor 12β is actually of the same order of
magnitude as the reactivity of the “armed” perbenzylated
R-mannoside. This was confirmed in an experiment in
which 12β was made to compete with perbenzylated donor
14 (entry 15). The disaccharides formed from donors 12β
and 1422 were obtained in a 45:55 ratio, revealing the
similar reactivity of both donors. We hypothesize that
the unexpectedly high reactivity of 12β results from the
(21) (a) Jensen, H. H.; Nordstrøm, M.; Bols, M. J. Am. Chem. Soc.
2004, 126, 9205–9213. (b) Crich, D. Acc. Chem. Res. 2010, 43, 1144–
1153.
(22) Ye, X.-S.; Wong, C.-H. J. Org. Chem. 2000, 65, 2410–2431.
Org. Lett., Vol. 13, No. 16, 2011
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1
fashion,26 after the mannosyl ring flips to the C4 con-
3
formation, to produce the favorable H4-oxacarbenium
Scheme 1. Proposed Reaction Mechanism for the Formation of
Oxacarbenium Ions 16 and 18
ion 16. Benzylidene donor 11 cannot access this favorable
oxacarbenium ion conformation and is therefore less re-
active. The lowerreactivity of theR-anomer 12r can also be
accounted for using the oxacarbenium ion conformers 16
and 18. After reaction of R-anomer 12r with NIS/TfOH,
the antiperiplanar expulsion of the charged aglycone from
4C1 mannoside 17r leads to the formation of the higher
energy 4H3-oxacarbenium ion 18, making this a less favor-
able process than the formation of 16 from 12β.27
In conclusion, we have determined the relative reactiv-
ities of a series of mannuronic acid donors, and it is
revealed that β-(S)-tolyl mannuronic acids are relatively
reactive donors. The high reactivity of these donors con-
trasts the common perception that uronic acid donors are
unreactive glycosylating agents because of the electron-
withdrawing nature of the C-5 carboxylic acid ester func-
tion. It is postulated that the high reactivity of the man-
nuronic acids originates from the formation of a relatively
favorable 3H4-oxacarbenium ion-like intermediate. We
have previously hypothesized that the β-selectivity, ob-
tained in glycosylations using various mannuronic acid
donors, originates (in part) from this oxacarbenium ion or
a species with substantial oxacarbenium ion character. The
high reactivity of the mannuronic acid donors lends sup-
port tothis mechanism. The relatively high reactivity of the
mannuronic acid donors opens the way to combine these
donors in armedꢀdisarmed coupling strategies using non-
oxidized thioglycosides as the less reactive coupling part-
ner. The investigation of the relative reactivity of other
pyranosyl uronic acids will be reported in due course.
fact that the β-mannuronic acid donor can relatively easily
access the 3H4-oxacarbenium ion 16 (Scheme 1).23,24 This
oxacarbenium ion is relatively stable because it positions
all of its substituents in favorable orientations on the
mannosyl half-chair. Woerpel and co-workers have shown
that the substituents at C-3 and C-4 prefer to occupy
pseudoaxial positions in the mannosyl oxacarbenium
ion,23 in line with various studies that axial substituents
are less disarming than equatorial substituents.25 Theyalso
established that the C-2 substituent has a slight preference
for a pseudoequatorial position. We have reported that the
C-5 carboxylic acid has a strong preference for a pseudoax-
ial position in an oxacarbenium ion intermediate.10b,23c As
depicted in Scheme 1, reaction of donor 12β with NIS and
TfOH leads to the reversible formation of “charged”
mannoside 15β. The phenylsulfenyl iodide aglycone can
be expelled by the ring oxygen lone pair in an antiperiplanar
Acknowledgment. This work was supported by The
Netherlands Organization of Scientific Research (NWO)
and Top Institute Pharma (TIP).
Supporting Information Available. Experimental proce-
dures for the synthesis of the donors and competition experi-
ments. 1Hand13C spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(23) (a) Lucero, C. G.; Woerpel, K. A. J. Org. Chem. 2006, 71, 2641–
2647. (b) Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem.
Soc. 2000, 122, 168–169. (c) Dinkelaar, J.; de Jong, A.-R.; van Meer, R.;
Somers, M.; Lodder, G.; Overkleeft, H. S.; Codee, J. D. C.; van der
Marel, G. A. J. Org. Chem. 2009, 74, 4982–4991.
(24) For recent reviews on oxacarbenium ions, see: (a) Walvoort,
(26) (a) Deslongchamps, P. Stereoelectronic Effects in Organic Chem-
istry; Pergamon: New York, 1983. (b) Deslongchamps, P. Pure Appl. Chem.
1993, 65, 1161–1178.
ꢀ
(27) Differences in ground state energy also contribute to the
reactivity difference between the R- and β-anomers. In D-mannopyr-
anosides, the stabilizing anomeric effect is often at the basis of the
higher stability and lower reactivity of the R-anomer with respect to its
β-isomer. However, donor 12r, predominantly occupying a 1C4 con-
formation, does not benefit from a stabilizing anomeric effect. A
difference in ground state energy of 12r and 12β can be caused by
the destabilizing Δ2 effect present in 12β. Taken together, ground state
energy differences can not alone account for the larger difference in
reactivity between 12β and 12r compared to the reactivity difference
between 10r and 10β.
M. T. C.; Dinkelaar, J.; van den Bos, L. J.; Lodder, G.; Overkleeft, H. S.;
ꢀ
Codee, J. D. C.; van der Marel, G. A. Carbohydr. Res. 2010, 345, 1252–
1263. (b) Smith, D. M.; Woerpel, K. A. Org. Biomol. Chem. 2006, 4,
1195–1201. (c) Horenstein, N. A. Adv. Phys. Org. Chem. 2006, 41, 275–
ꢀ
314. (d) Bohe, L.; Crich, D. C.R. Chimie 2011, 14, 3–16. (e) Whitfield,
D. M. Adv. Carbohydr. Chem. Biochem. 2009, 62, 83–159.
(25) See for example: Jensen, H. H.; Bols, M. Acc. Chem. Res. 2006,
39, 259–265 and references therein.
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