On the reactivity and selectivity of galacturonic acid lactones

Article abstract of DOI:10.1002/ejoc.201200717

The reactivity and stereoselectivity of a galacturonic acid 3,6-lactone thioglycosyl donor, previously described as a highly reactive glycosylating agent, has been investigated by using a series of competition experiments and condensation reactions with different thiophilic activator systems. It is revealed that the relative reactivity of the thioglycosides depends on the activator system used and that p-nitrophenylsulfenyl triflate shows overall attenuated reactivity differences with respect to the commonly used N-iodosuccinimide/triflic acid promoter system. With respect to the stereoselectivity of the studied galacturonic acid 3,6-lactone thioglycosyl donor, it is revealed that a preactivation-based glycosylation system gives rise to α-selective glycosylation, whereas an in situ activation protocol leads to the formation of the β-product with good selectivity. It is hypothesized that these opposingstereoselectivities are the result of different product-forming intermediates. Where preactivation of the donor leads to the formation of an intermediate β-triflate, which is substituted in a concerted fashion to provide the α-product, a ³H₄ oxocarbenium ion like species is substituted in the in situ activation experiment to provide the β-linked product.

Full text of DOI:10.1002/ejoc.201200717

Job/Unit: O20717
/KAP1
Date: 30-08-12 16:04:16
Pages: 10
FULL PAPER
DOI: 10.1002/ejoc.201200717
On the Reactivity and Selectivity of Galacturonic Acid Lactones
Alphert E. Christina,[a] Joey A. Muns,[a] Jeremy Q. A. Olivier,[a] Lotte Visser,[a]
Bas Hagen,[a] Leendert J. van den Bos,[a] Herman S. Overkleeft,[a] Jeroen D. C. Codée,*[a]
and Gijs A. van der Marel*[a]
Keywords: Lactones / Glycosides / Glycosylation / Chemoselectivity / Diastereoselectivity
The reactivity and stereoselectivity of a galacturonic acid 3,6-
lactone thioglycosyl donor, previously described as a highly
reactive glycosylating agent, has been investigated by using
a series of competition experiments and condensation reac-
tions with different thiophilic activator systems. It is revealed
that the relative reactivity of the thioglycosides depends on
the activator system used and that p-nitrophenylsulfenyl tri-
flate shows overall attenuated reactivity differences with re-
spect to the commonly used N-iodosuccinimide/triflic acid
promoter system. With respect to the stereoselectivity of the
studied galacturonic acid 3,6-lactone thioglycosyl donor, it is
revealed that a preactivation-based glycosylation system
gives rise to α-selective glycosylation, whereas an in situ acti-
vation protocol leads to the formation of the β-product with
good selectivity. It is hypothesized that these opposing
stereoselectivities are the result of different product-forming
intermediates. Where preactivation of the donor leads to the
formation of an intermediate β-triflate, which is substituted
in a concerted fashion to provide the α-product, a 3H4 oxo-
carbenium ion like species is substituted in the in situ acti-
vation experiment to provide the β-linked product.
which are significantly more reactive than their non-flipped
counterparts. These “super-armed” donors have extended
the relative reactivity spectrum beyond the realm of classi-
cal armed donors. We have recently introduced galacturonic
acid 3,6-lactones as versatile building blocks that can be
used effectively in oligosaccharide synthesis.[3,8] The 3,6-lac-
Introduction
Galacturonic acid and derivatives thereof are found in
various naturally occurring polysaccharides. Due to the
synthetic challenge they present and their interesting bio-
logical profile, several of these polysaccharides, such as pec-
tin[1] and the zwitterionic polysaccharide Sp1,[2,3] have been
the subject of synthetic studies. Selection of the most suit-
able glycosylation partners depends heavily on the desired
stereochemical outcome of the glycosylation reaction, com-
bined with the intrinsic reactivity of both reacting species.
Conformational restriction of glycosyl donors has been
used to influence both the stereoselectivity and reactivity of
the donors at hand.[4] Crich and co-workers have shown
that the installation of a 4,6-O-benzylidene-type protecting
group on a mannosyl donor can give rise to a mannosylat-
ing agent that reacts with excellent stereoselectivity to pro-
vide β-mannosides.[5] The use of conformationally armed
glycosides has been reported by various groups.[6] For in-
stance, Bols and co-workers have shown that placing mul-
tiple bulky silyl ethers on the hydroxy groups of a glycosyl
donor can lead to a conformational flip of the pyranosyl
ring to avoid gauche interactions of the bulky protecting
groups.[7] This provides “axially rich” donor glycosides,
1
tone bridge forces these galacturonic acids in a C4 chair
conformation, which has a major impact on their reactivity,
1
both as a donor and as an acceptor. Because of the C4
conformation, the galactopyranosyl C4-OH group, which is
generally regarded as a poor nucleophile,[9] is positioned in
an accessible equatorial position and is therefore an apt nu-
cleophile. We have also found that S-phenyl galacturonic
acid 3,6-lactones, equipped with a nonparticipating C2-
benzyl ether, are readily activated at low temperature with
the diphenyl sulfoxide (Ph2SO)/trifluoromethanesulfonic
anhydride (Tf2O) couple,[10] to provide a powerful glyc-
osylating species that reacts with excellent stereoselectivity
to provide the α-galacturonic linkage. To put the glycosyl-
ation behavior of galacturonic acid 3,6-lactone thioglyco-
side donors in perspective, we present herein a study of their
reactivity and stereoselectivity in comparison with the reac-
tivity of related galactose and galacturonic acid building
blocks.
[a] Leiden Institute of Chemistry, Leiden University,
Einsteinweg 55, 2333 CC Leiden, The Netherlands
E-mail: jcodee@chem.leidenuniv.nl
Results and Discussion
marel_g@chem.leidenuniv.nl
Homepage: http://biosyn.lic.leidenuniv.nl/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200717.
The set of building blocks used in this study is depicted
in Scheme 1, and includes galacturonic acid 3,6-lactone
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O20717
/KAP1
Date: 30-08-12 16:04:16
Pages: 10
J. D. C. Codée, G. A. van der Marel et al.
FULL PAPER
Scheme 1. Syntheses of the studied thiogalactosyl donors. Reagents and conditions: (i) 1. TBDMSCl, imidazole, DMF; 2. BnBr, NaH,
DMF, 0 °C; 3. TBAF, THF, (66% over 3 steps); (ii) TEMPO, BAIB, CH2Cl2, H2O, 51%; (iii) 1. TsCl, pyridine; 2. NaH, DMF (40% over
2 steps); (iv) 1. TBDMSCl, pyridine, then Ac2O; 2. Et3N·3HF, THF (86% over 3 steps); (v) 1. TEMPO, BAIB, CH2Cl2, H2O; 2. MeI,
K2CO3, DMF (45% over 2 steps); (vi) Ac2O, pyridine (81%).
thioglycoside 1, perbenzylated thiogalactoside 2,[11] 4,6- carboxylate group (in combination with a 4-O-acetyl group)
benzylidenethiogalactoside 3,[11] 4,6-di-O-acetylthiogalacto- was in fact less disarming than the 4,6-O-benzylidene func-
side 4, galacturonic acid thioglycoside 5, and 3,6-anhydro- tionality. In the β-gluco series the effect of the carboxylate
thiogalactoside 6. The latter compound has been included group was more in line with expectations, although the dis-
in our study to investigate the influence of the 3,6-bridge, arming nature proved to be less severe than often presumed.
and the resulting conformational flip, on the reactivity of In the vast majority of competition experiments performed
these donors. The synthesis of donors 1, 4, 5, and 6 is de- to date, thioglycoside donors have been combined with the
picted in Scheme 1. Galacturonic acid lactone 1 was con- N-iodosuccinimide (NIS)/triflic acid (TfOH) activator sys-
structed from tolyl 1-thio-β-d-galactopyranoside 7 by re- tem. Therefore, we initially set out to probe the relative re-
gioselective silylation of the C6-OH and C3-OH groups and activity of the set of thiogalactosyl donors 1–6 under the
subsequent benzylation of the remaining hydroxy groups aegis of this activator system. However, during the course
and desilylation to afford diol 8. 2,2,6,6-Tetramethylpiperi- of our investigation it became apparent that galacturonic
dine-1-oxyl (TEMPO)/[bis(acetoxy)iodo]benzene (BAIB) acid lactone 1 was inert to this activator, and we there-
mediated[12] oxidation and in situ lactone formation yielded fore also studied the donors in a set of competition experi-
lactone 1. Tosylation of the C6-OH group in diol 8 and ments by using para-nitrophenylsulfenyl triflate (p-
treatment of the resulting tosylate with sodium hydride led NO2PhSOTf),[17] generated from para-nitrophenylsulfenyl
to the formation of 3,6-anhydrothiogalactoside 6. From 2,3- chloride (p-NO2PhSCl) and silver triflate (AgOTf), as a
di-O-benzylthiogalactoside 9, donors 4 and 5 were accessed thiophilic promoter system. We currently have no adequate
through acetylation of both hydroxy functions (Ǟ 4) or a explanation for the reluctance of donor 1 to react with NIS/
silylation, acetylation, desilylation, oxidation sequence TfOH, and note that this result is in contrast with a recent
(Ǟ 5).
study reported by Furukawa et al.,[18] who investigated
We first set out to establish the relative reactivity of the glucuronic acid 3,6-lactone donors in combination with this
set of donors. To gain more insight into the relative reactiv- activator; they reported that thiophenyl 2,4-di-O-acetyl-
ity of glycosyl donors, Ley,[13] Wong,[11] and Bols[14] have glucuronic acid 3,6-lactone donors are reactive glucuronyl-
determined the reactivity of a wide variety of thioglycosides ating species when activated with NIS/TfOH, and that its
in a series of competition experiments leading to an exten- 2,4-di-O-benzyl counterpart was too reactive to be used as
sive relative reactivity value (RRV) scale. We have recently a donor.
reported a determination of the relative reactivity of man-
Table 1 compiles the results of the competition experi-
nuronic[15] and glucuronic acid thioglycosyl donors.[16] In ments. In both the NIS/TfOH- and p-O2NC6H4SOTf-medi-
contrast to the common perception that the C-5 carboxylic ated glycosylation, the two donors compete for a limited
acid ester is a strongly electron-withdrawing (“disarming”) amount of activator in the presence of excess nucleophile
substituent, we found that in the β-manno series the C-5- [methyl tri-O-benzyl-α-d-glucopyranoside (11)].
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20717
/KAP1
Date: 30-08-12 16:04:16
Pages: 10
On the Reactivity and Selectivity of Galacturonic Acid Lactones
Table 1. Competitive glycosylation experiments between thioglycosyl donors 1–6.
Entry
Donor A
Donor B
Product[a] ratio[b] (donor A/donor B)
Yield [%]
NIS/TfOH[c]
p-O2NC6H4SCl/AgOTf[c]
Yield [%]
1
2
3
4
5
6
7
8
2
4
3
4
2
3
1
1
3
3
5
5
6
6
6
5
2.2:1
1:5.2
16:1
11:1
1:1.3
1:2.5
–
70
95
86
86
quant.
99
1.8:1
1:1.1
4.8:1
1.3:1
1:1.2
1:2.2
1:2.4
1: 2.4
87
85
80
81
quant.
quant.
quant.
78
–
–
–
1
[a] For structures of the disaccharides, see the Supporting Information. [b] Product ratio was determined by integration of diagnostic H
NMR signals of the four possible disaccharides after size-exclusion chromatography. See the Supporting Information for full experimental
details. [c] In CH2Cl2 at –40 °C to room temp.
From the series of NIS/TfOH-mediated experiments, the ated thiogalactoside 2 can be that the conformational re-
following relative reactivities appear. Perbenzylated donor striction in 6 prohibits the through-space stabilization of
2 is twice as reactive as benzylidene donor 3 (Table 1, En- the developing oxocarbenium ion character by the substitu-
try 1); this result is consistent with the relative reactivities ents.[22]
determined by Wong and co-workers (2: 17000; 3: 7180).[11]
The series of competition reactions with p-O2NC6H4SCl/
The disarming effect of the 4,6-benzylidene group in 3 is AgOTf reveals the same trends as seen with the NIS/TfOH
less than the disarming effect of the two acetyl groups in 4, promoter,[23] albeit with significantly less pronounced reac-
as revealed in Table 1, Entry 2. Notably, in the gluco and tivity differences. Thus, the reactivity order is 3,6-anhydro
manno series the 4,6-benzylidene group proved to be more donor 6 Ͼ perbenzyl donor 2 Ͼ benzylidene donor 3 Ͼ
deactivating than two acetyl groups at the C4- and C6-hy- diacetyl donor 4 Ͼ galacturonic acid donor 5. The competi-
droxy moieties. These results can be explained by taking tion experiments with the galacturonic acid 3,6-lactone 1
into account that the benzylidene group in galactosyl donor indicate that this donor is less reactive than galacturonic
3 imposes less strain on the pyranosyl ring when adopting a acid 5, which is in contrast to our perception of the high
flattened structure to accommodate the developing positive reactivity of these donors. This finding is also surprising in
charge at the anomeric center in an oxocarbenium ion or light of the “axial-rich” nature of this compound as com-
an oxocarbenium ion like intermediate. Furthermore, in the pared to galacturonic acid 5. The explanation put forward
cis-decalin system in 3, the C-6 substituent is positioned in to account for the small increase in reactivity of 3,6-anhyd-
a gg position, which is less disarming than the tg orienta- rothiogalactoside 6, with respect to thiogalactoside 2 (see
tion of the C-6 substituent in the gluco- and manno-4,6- above), can also be valid here. An explanation that accounts
benzylidene donors.[19] Table 1, Entries 3 and 4 show that for the downturned reactivity differences found with the p-
the C-5-carboxylic acid ester has a significant disarming ef- O2NC6H4SCl/AgOTf system and the relatively low reactiv-
fect on the reactivity of the donors studied,[20] and galactu- ity of the lactone donor can also be found in the differences
ronic acid 5 is the least reactive donor in the NIS/TfOH in the rate constants involved in the activation of thioglyco-
series. 3,6-Anhydrothiogalactosyl donor 6 is slightly more sides with the two different activator systems (Scheme 2).
reactive than perbenzylated thiogalactoside 2 and presents In case reversion of the charged thioglycosyl donor (C in
the most reactive donor of the series. This is in line with Scheme 2) into the parent thioglycoside (A) and the acti-
previous studies on the glycosylation behavior of 3,6-anhyd- vator (indicated with rate constant k–3) for the p-O2NC6H4-
rogalactosyl orthoester donors, which were found to be SOTf system is slower than the corresponding reversion
more reactive than comparable orthoesters of glycosides in with the NIS/TfOH system (species B and rate constant
a normal conformation.[21] It is also of interest to note that k–1), the overall competition for the activator will be deter-
Bols and co-workers have reported that forcing a galactosyl mined less by the relative ease of oxocarbenium ion (D)
donor into an “axially rich” conformation, by positioning formation (k2 and k4).[24] In other words, the first step of
three bulky tert-butyldimethylsilyl ethers at C2, C3, and C4, the activation – the attack of the anomeric thio group on
leads to a more reactive donor.[7] A possible explanation for the electrophile – plays a relatively larger role in the p-
the fact that the reactivity of anhydrothiogalactosyl donor O2NC6H4SOTf-activated system and leads to the attenu-
6 is only marginally higher than the reactivity of perbenzyl- ated reactivity differences of the donors studied.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O20717
/KAP1
Date: 30-08-12 16:04:16
Pages: 10
J. D. C. Codée, G. A. van der Marel et al.
FULL PAPER
Scheme 2. Possible reaction pathways upon activation of thioglycosides by using p-O2NC6H4SOTf and NIS/TfOH.
Next, we evaluated the stereoselectivity of the set of do- now well appreciated that (pre)activation of thioglycosides
nors under the two different activation conditions with glu- with electrophiles featuring a triflate counterion can pro-
coside 11 as a nucleophile; Table 2 records the outcomes of duce intermediate anomeric triflates. These species can be
these experiments. It is readily apparent from these results displaced in an SN2-like process leading to the coupled
that most condensations proceed with very little to no selec- product with inversion of configuration at the anomeric
tivity, the most important exception being the p-O2NC6H4- center (with regard to the intermediate anomeric triflate).
SOTf-mediated condensations of the bridged galacturonic We therefore studied the preactivation of donor 1 with the
acid lactone 1 and its non-oxidized counterpart 3,6-anhyd- Ph2SO/Tf2O couple in a low-temperature NMR experi-
rothiogalactoside 6. The condensations of these donors and ment. This experiment revealed that, with this activator sys-
alcohol 11 proceed with very high (in the case of lactone 1) tem, donor 1 was rapidly transformed at –80 °C into β-tri-
or high (for the anhydrogalactoside 6) stereoselectivity to flate 12 (see Scheme 3 and Figure 1), which proved to be
provide the β-linked disaccharides. The former result stands stable up to –10 °C. Having identified triflate 12 as a pos-
in sharp contrast to our previous findings that galacturonic sible intermediate in the condensations of the galacturonic
acid lactones such as 1 are highly α-selective glycosyl do- acid lactone donors, the contrasting stereochemical out-
nors by using the Ph2SO/Tf2O preactivation protocol. It is come of the condensations under Ph2SO/Tf2O preactivation
and in situ activation with p-O2NC6H4SCl and AgOTf can
be rationalized (Scheme 3). Preactivation of donor 1 leads
Table 2. Glycosylations of thioglycosyl donors 1–6 and glycosyl ac-
ceptor 11 by using different thiophilic activator systems.
to an intermediate triflate, which is substituted in a con-
certed fashion to provide the α-linked product. When donor
1 is activated in the presence of a reactive glycosyl acceptor
such as 11, the nucleophile can intercept the intermediate
oxocarbenium ion 13, which will adopt a structure that is
3
close to a H4 half chair because of the geometrical con-
straints imposed by the bridging lactone ring. Nucleophilic
attack on this reactive species will occur preferentially from
the diastereotopic face leading to the product through a
chair-like transition state, i.e., the β-face. Notably, a similar
stereochemical result has been reported for the condensa-
tion of acceptor 11 with pentenyl 2,4-di-O-benzyl-3,6-anhy-
droglucopyranoside.[25] To examine whether preactivation
of 3,6-anhydrogalactopyranoside 6 can also lead to the α-
linked disaccharide upon condensation with acceptor 11,
donor 6 was treated with Ph2SO/Tf2O at –80 °C, after
which glucoside 11 was added. As revealed in Table 2, En-
Product[a] ratio[b] (α/β) and yield [%]
Entry Donor NIS/TfOH[c] p-O2NC6H4SCl/AgOTf[c] Ph2SO/Tf2O[d]
1
2
3
4
5
6
1
2
3
4
5
6
0:1 (73)
1:1.6 (quant.)
1:1.8 (82)
1:1.8 (94)
1:3.4 (84)
10:1 (69)
1:1.1 (99)
1:1.2 (70)
1:1.2 (76)
1:1.3 (77)
1.2:1 (65)
1:5.3 (quant.)
5.2:1 (70)
[a] For structures of the disaccharides, see the Supporting Infor-
1
mation. [b] Anomeric ratios were determined by integration of H try 6, this condensation protocol indeed led to the predomi-
NMR signals of the disaccharides. [c] In CH2Cl2 at –40 °C to room
nant formation of the α-linked product, showing that 3,6-
temp. [d] In the presence of 2,4,6-tri-tert-butylpyrimidine (TTBP)
anhydrogalactopyranoside 6 and lactone 1 behave in a
(2.5 equiv.) in CH2Cl2 at –50 °C, then acceptor 11, warming to
stereochemical analogous manner.
room temp.
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20717
/KAP1
Date: 30-08-12 16:04:16
Pages: 10
On the Reactivity and Selectivity of Galacturonic Acid Lactones
Scheme 3. Rationale for the formation of the dimers 14α and 14β by using a preactivation and an in situ activation protocol.
Figure 1. Part of the 1H NMR spectrum of donor 1 obtained before and after treatment with Ph2SO/Tf2O in CD2Cl2 at –80 °C. The
1
anomeric configuration of 12 was deduced from the JC1–H1 coupling constant (189 Hz).[26]
Conclusions
significant effect on the relative reactivities of the studied
We have investigated the reactivity and stereoselectivity galactosyl donors. The use of a p-O2NC6H4SCl/AgOTf in
of a galacturonic acid 3,6-lactone donor in comparison to situ activation protocol leads to attenuated reactivity differ-
a set of galactosyl donors using two different activator sys- ences with respect to the NIS/TfOH system. In the estab-
tems, NIS/TfOH and p-O2NC6H4SCl/AgOTf, respectively. lishment of the relative reactivity of galacturonic acid 3,6-
The mode of action not only affects the stereoselectivity lactone donor 1, only the p-O2NC6H4SCl/AgOTf could be
of the glycosylation reactions reported here, but also has a used, because lactone 1 proved to be completely inert to
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20717
/KAP1
Date: 30-08-12 16:04:16
Pages: 10
J. D. C. Codée, G. A. van der Marel et al.
FULL PAPER
MeOH, 1:1, v/v) enabled isolation of the disaccharide products and
recovery of a monosaccharide rest fraction.
activation with NIS/TfOH. By using the former activator,
lactone donor 1 proved to be less reactive than the galactu-
ronic acid donor 5, revealing that, in this case, the relatively
axial-rich conformation is not beneficial for reactivity. The
use of the different thiophilic activator systems also led to
p-Tolyl 2,4-Di-O-benzyl-1-thio-β-D-galactopyranosidurono-3,6-lac-
tone (1): To a vigorously stirred mixture of 8 (5.39 g, 11.5 mmol,
1 equiv.) in CH2Cl2/H2O (54 mL, 2:1, v/v) were added TEMPO
greatly varying stereochemical outcomes. With the bridged (358 mg, 2.3 mmol, 0.2 equiv.) and iodobenzene diacetate (9.28 g,
28.8 mmol, 2.5 equiv.). After complete conversion, the reaction was
quenched by the addition of 10% aq. Na2S2O3 and satd. aq.
NaHCO3. The mixture was extracted twice with EtOAc, and the
combined layers were dried with MgSO4, filtered, and concentrated
in vacuo. Purification by column chromatography gave 1 (2.72 g,
5.88 mmol, 51%) as an oil. Rf = 0.46 (toluene). [α]2D2 = –192 (c =
lactone and anhydro donors 1 and 6, both the α- and β-
linked products can be selectively accessed depending on
the activator system and the timing of the activation. Preac-
tivation of these donors with Ph2SO/Tf2O provides α-selec-
tive glycosylations, presumably through the intermediacy of
an axial β-triflate, whereas the in situ activation protocol
with p-O2NC6H4SCl/AgOTf leads to the corresponding β-
products, through a direct substitution of an oxocarbenium
ion like intermediate.
1, CH Cl ). IR (neat): ν = 2952, 1802, 1495, 1455, 1154, 1101,
˜
2
2
1
813, 741, 699, 510 cm–1. H NMR (400 MHz, CDCl3, HH-COSY,
HSQC): δ = 7.40–7.24 (m, 12 H, ArH), 7.11 (d, J = 8.0 Hz, 2 H,
ArH), 5.34 (s, 1 H, 1-H), 4.80 (dd, J = 4.7, 1.3 Hz, 1 H, 3-H), 4.63
(d, J = 11.8 Hz, 1 H, CH2 Bn), 4.58 (2 s, 2 H, CH2 Bn), 4.53 (d, J
= 11.8 Hz, 1 H, CH2 Bn), 4.39 (d, J = 1.2 Hz, 1 H, 4-H), 4.25 (d,
J = 4.7 Hz, 1 H, 2-H), 4.03 (br. s, 1 H, 5-H), 2.32 (s, 3 H, CH3 Tol)
ppm. 13C NMR (100 MHz, CDCl3, HH-COSY, HSQC): δ = 172.7
(C=O), 138.5, 136.6, 136.5 (Cq), 133.3, 129.9, 129.7, 128.7, 128.6,
128.4, 128.2, 127.9, 127.8 (CHAr), 86.0 (C-1), 78.9 (C-3), 78.4 (C-
2), 76.0 (C-4), 72.9, 71.4 (CH2 Bn), 70.8 (C-5), 21.1 (CH3 Tol) ppm.
HRMS: calcd. for C27H26O5SNa [M + Na]+ 485.13932; found
485.13905.
Experimental Section
General Procedure for Competitive and Noncompetitive NIS/TfOH-
Promoted Glycosylation: The donor(s) (ca. 0.1 mmol, 1 equiv. each)
and the acceptor (3 equiv.) were mixed in a round-bottomed flask
and coevaporated twice with toluene. Freshly distilled CH2Cl2 (do-
nor concentration 0.05 m) and activated molecular sieves (3 Å) were
added, and the mixture was stirred under argon at room tempera-
ture for 30 min. NIS (1 equiv.) was added, and the mixture was
cooled to –40 °C. TfOH (0.1 equiv., 0.1 m stock solution in distilled
CH2Cl2) was added, and the mixture was warmed to 0 °C in about
3 h. Triethylamine (0.1 mL) was added, and the mixture was diluted
with EtOAc, washed with satd. aq. Na2S2O3 and brine, dried with
Na2SO4, and concentrated in vacuo. Size exclusion chromatog-
raphy on Sephadex LH-20 (CH2Cl2/MeOH, 1:1, v/v) enabled isola-
tion of the disaccharide products and recovery of the monosaccha-
ride fraction.
p-Tolyl 4,6-Di-O-acetyl-2,3-di-O-benzyl-1-thio-β-D-galactopyrano-
side (4): A solution of 9 (4.00 g, 8.57 mmol) in pyridine/Ac2O
(60 mL, 3:1 v/v) was stirred at room temperature overnight. After
complete conversion, the reaction was quenched by the addition of
MeOH at 0 °C. The mixture was concentrated in vacuo, and the
residue was taken up in EtOAc. The organic mixture was washed
with 1 m aq. HCl, satd. aq. NaHCO3, and brine, dried with MgSO4,
filtered, and concentrated in vacuo to give 4 (3.82 g, 6.94 mmol,
81%). Rf = 0.31 (EtOAc/PE, 1:4). [α]2D2 = +25 (c = 1, CH2Cl2). IR
(neat): ν = 2870, 1745, 1494, 1454, 1370, 1229, 1104, 810, 737,
˜
698 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.53–7.24 (m, 12 H,
ArH), 7.09 (d, J = 7.9 Hz, 2 H, ArH), 5.53 (d, J = 1.6 Hz, 1 H, 4-
H), 4.81–4.69 (m, 3 H, CH2 Bn), 4.63–4.57 (m, 1 H, 1-H), 4.49 (d,
J = 11.0 Hz, 1 H, CH2 Bn), 4.16 (d, J = 6.5 Hz, 2 H, 6-H), 3.81–
3.74 (m, 1 H, 5-H), 3.68–3.60 (m, 2 H, 2-H, 3-H), 2.32 (s, 3 H,
CH3 Tol), 2.14 (s, 3 H, CH3 Ac), 2.06 (s, 3 H, CH3 Ac) ppm. 13C
NMR (101 MHz, CDCl3): δ = 170.5, 170.3 (C=O), 138.1, 137.8,
137.4 (Cq), 132.7, 129.5 (CHAr), 129.4 (Cq), 128.4, 128.3, 128.1,
127.8, 127.8 (CHAr), 87.9 (C-1), 81.0, 76.5 (C-2, C-3), 75.7 (CH2
Bn), 74.3 (C-5), 72.0 (CH2 Bn), 66.5 (C-4), 62.3 (C-6), 21.0 (CH3
Tol), 20.8, 20.7 (CH3 Ac) ppm. HRMS: calcd. for C31H34O7SNa
[M + Na]+ 573.19175; found 573.19140.
General Procedure for Competitive and Noncompetitive AgOTf/p-
NO2PhSCl-Promoted Glycosylation: A suspension of the donor(s)
(ca. 0.11 mmol, 1 equiv. each), acceptor 11 (1.5–3 equiv.), silver
triflate (72 mg, 0.33 mmol, ca. 3 equiv.), and molecular sieves (3 Å)
in anhydrous CH2Cl2 (1 mL) was stirred, with the exclusion of
light, at room temperature under Ar for 10 min before it was cooled
to –40 °C. A solution of p-nitrobenzenesulfenyl chloride (95% pu-
rity, ca. 0.11 mmol, 1 equiv.) in anhydrous CH2Cl2 (0.5 mL) was
added dropwise into the above suspension at –40 °C, and the mix-
ture was warmed to 0 °C in about 3 h. Triethylamine (0.2 mL) was
added, and the suspension was diluted with CH2Cl2 and filtered
through Celite. Size exclusion chromatography on Sephadex LH-
20 (CH2Cl2/MeOH, 1:1, v/v) enabled isolation of the disaccharide
products and recovery of a monosaccharide rest fraction.
Methyl (p-Tolyl 4-O-acetyl-2,3-di-O-benzyl-1-thio-β-D-galactopyr-
anoside)uronate (5): To a solution of 10 (1.70 g, 3.35 mmol,
1 equiv.) in CH2Cl2/H2O (24 mL, 2:1, v/v), TEMPO (105 mg,
0.67 mmol, 0.2 equiv.) and BAIB (2.70 g, 8.38 mmol, 2.5 equiv.)
were added. The reaction was quenched by the addition of 10%
Na2S2O3, and the mixture was extracted twice with CH2Cl2 and
once with EtOAc. The combined extracts were dried with MgSO4,
filtered, and concentrated. To a solution of the crude acid in DMF
(32 mL) were added K2CO3 (2.31 g, 16.75 mmol, 5 equiv.) and MeI
(271 μL, 4.36 mmol, 1.3 equiv.). After complete conversion, the
mixture was quenched with AcOH (1.9 mL), and the mixture was
partitioned between EtOAc and H2O. The organic layer was
washed with satd. aq. NaHCO3 and brine, dried with MgSO4, fil-
tered, and concentrated. Purification by column chromatography
(EtOAc/PE, 3:17Ǟ1:4) gave 5 (45% over 2 steps). Rf = 0.56
General Procedure for Ph2SO/Tf2O-Promoted Glycosylation: A
solution of the donor (ca. 0.11 mmol, 1 equiv.), diphenyl sulfoxide
(1.2 equiv.) and tri-tert-butylpyrimidine (2.5 equiv.) in CH2Cl2
(0.05 m) was stirred in the presence of activated molecular sieves
(3 Å) for 30 min. The mixture was cooled to –60 °C before triflic
anhydride (1.1 equiv.) was added. The mixture was warmed to
–50 °C in 15 min followed by addition of acceptor 11 (2 equiv.) in
CH2Cl2 (0.15 m). The mixture was warmed to 0 °C in about 3 h,
then triethylamine (0.5 mL) was added, and the mixture was di-
luted with CH2Cl2, washed once with satd. aq. NaHCO3, and the
aqueous layer was extracted with CH2Cl2. The combined organic
fractions were dried (MgSO4), filtered, and concentrated in vacuo.
Size exclusion chromatography on Sephadex LH-20 (CH2Cl2/
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20717
/KAP1
Date: 30-08-12 16:04:16
Pages: 10
On the Reactivity and Selectivity of Galacturonic Acid Lactones
(EtOAc/PE, 3:7). [α]2D2 = +25 (c = 5, CH Cl ). IR (neat): ν = 1746,
aqueous layer was extracted with EtOAc, and the combined or-
ganic layers were dried (MgSO4), filtered, and concentrated. Purifi-
˜
2
2
1371, 1265, 1227, 1101, 1061, 1028, 810, 731, 696 cm–1. H NMR
1
(400 MHz, CDCl3): δ = 7.56 (dd, J = 8.1 Hz, 2 H, ArH), 7.39 (d, cation by flash column chromatography (EtOAc/PE, 3:7Ǟ1:1) af-
J = 7.0 Hz, 2 H, ArH), 7.36–7.22 (m, 8 H, ArH), 7.08 (d, J = forded 8 (7.9 g, 16.9 mmol, 66% over 3 steps). Rf = 0.2 (EtOAc/
8.0 Hz, 2 H, ArH), 5.80 (s, 1 H, 4-H), 4.73 (m, 3 H, CH2 Bn), 4.58 PE, 3:7). [α]2D2 = +2 (c = 1, CH Cl ). IR (neat): ν = 3420, 2868,
˜
2
2
(d, J = 8.9 Hz, 1 H, 1-H), 4.47 (d, J = 11.1 Hz, 1 H, CH2 Bn), 4.11
(s, 1 H, 5-H), 3.72 (s, 3 H, CH3 OMe), 3.66 (s, 1 H, 3-H), 3.64 (s,
1 H, 2-H), 2.29 (s, 3 H, CH3 Tol), 2.07 (s, 3 H, CH3 OAc) ppm.
1494, 1454, 1358, 1055, 866, 809, 734, 697, 530 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 7.44 (d, J = 8.1 Hz, 2 H, ArH), 7.40–7.26
(m, 10 H, ArH), 7.05 (d, J = 8.0 Hz, 2 H, ArH), 4.92 (d, J =
13C NMR (101 MHz, CDCl3): δ = 169.6, 166.9 (C=O), 137.9, 10.9 Hz, 1 H, CH2 Bn), 4.76 (d, J = 11.6 Hz, 1 H, CH2 Bn), 4.66–
137.7, 137.1 (Cq), 133.0, 129.3 (CHAr), 128.9 (Cq), 128.2, 128.1,
127.9, 127.6, 127.5 (CHAr), 87.5 (C-1), 80.3 (C-3), 75.8 (C-2), 75.4
4.60 (m, 2 H, CH2 Bn), 4.58–4.51 (m, 1 H, 1-H), 3.84 (dd, J = 11.3,
7.3 Hz, 1 H, 6-H), 3.75 (s, 1 H, 4-H), 3.69–3.65 (m, 2 H, 2-H, 3-
(CH2 Bn), 75.2 (C-5), 71.7 (CH2 Bn), 67.4 (C-4), 52.3 (CH3 OMe), H), 3.59–3.50 (m, 1 H, 6-H), 3.44 (dd, J = 6.8, 5.4 Hz, 1 H, 5-H),
20.8 (CH3 Tol), 20.5 (CH3 OAc) ppm. HRMS: calcd. for
2.43 (s, 1 H, OH), 2.31 (s, 3 H, CH3 STol), 2.05 (s, 1 H, OH) ppm.
13C NMR (101 MHz, CDCl3): δ = 138.1 (Cq), 138.0 (Cq), 137.4
(Cq), 132.7, 131.9 (CHAr), 129.9 (Cq), 129.7, 128.5, 128.4, 128.2,
128.2, 128.0, 128.0, 127.9, 127.6 (CHAr), 87.5 (C-1), 78.9 (C-5), 78.2
(C-2), 75.8, 75.7 (C-3, C-4), 75.2, 74.7 (CH2 Bn), 62.1 (C-6), 21.0
(CH3 Tol) ppm. HRMS: calcd. for C27H30O5SNa [M + Na]+
489.17062; found 489.17017.
C30H32O7SNa [M + Na]+ 559.17610; found 559.17566.
p-Tolyl 3,6-Anhydro-2,4-di-O-benzyl-β-D-galactopyranoside (6): To
a solution of 8 (3.9 g, 8.25 mmol, 1 equiv.) in pyridine (41 mL) was
added tosyl chloride (1.75 g, 9.08 mmol, 1.1 equiv.) at 0 °C. The
mixture was stirred under argon at room temperature for 3 d, then
the reaction was quenched by the addition of MeOH (3.3 mL), and
the mixture was partitioned between EtOAc and aq. 1 m HCl solu-
tion. The aqueous layer was extracted with EtOAc, and the com-
bined organic layers were washed with satd. aq. NaHCO3 solution,
H2O, and brine, dried with MgSO4, filtered, and concentrated. The
p-Tolyl
4-O-Acetyl-2,3-di-O-benzyl-1-thio-β-D-galactopyranoside
(10): To a solution of 9 (1.74 g, 3.72 mmol, 1 equiv.) in pyridine
(20 mL) was added TBDMSCl (673 mg, 4.46 mmol, 1.2 equiv.),
and the reaction mixture was stirred at room temperature over-
crude product was dissolved in DMF (100 mL), and NaH (60% in night. Ac2O (5 mL) was added, and the reaction mixture was
mineral oil, 300 mg, 12.4 mmol, 1.5 equiv.) was added at 0 °C. The
mixture was stirred at room temperature overnight, then parti-
tioned between H2O and diethyl ether and the aqueous layer was
extracted. The combined organic layers were washed with satd. aq.
NaHCO3 solution, H2O, and brine, dried with MgSO4, filtered,
and concentrated. Flash column chromatography (EtOAc/PE,
1:19Ǟ1:4) afforded 6 (1.6 g, 3.5 mmol, 40% over 2 steps). Rf = 0.6
stirred overnight again. The reaction was quenched by the addition
of MeOH (10 mL), and the solvent was removed under reduced
pressure. The crude material was coevaporated with toluene and
dissolved in THF (20 mL). TEA·3HF (4.85 mL, 29.8 mmol,
8 equiv.) was added, and the reaction mixture was stirred at 70 °C
for 1 h. The reaction mixture was allowed to cool to room tempera-
ture and partitioned between EtOAc and satd. aq. NaHCO3. The
aqueous phase was extracted with EtOAc, and the combined or-
ganic layers were washed with satd. aq. NaHCO3 and brine. After
(EtOAc/PE, 3:7, v/v). [α]2D2 = –21 (c = 1, CH Cl ). IR (neat): ν =
˜
2
2
2938, 1494, 1455, 1069, 805, 738, 698, 632, 536 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 7.39–7.27 (m, 10 H, ArH), 7.27–7.22 (m, drying with MgSO4, filtration, and concentration, the crude mix-
2 H, ArH), 7.09 (d, J = 8.0 Hz, 2 H, ArH), 5.28 (s, 1 H, 1-H), 4.84 ture was purified by column chromatography (EtOAc/PE, 1:4Ǟ2:3)
(d, J = 9.6 Hz, 1 H, 6-H), 4.62–4.52 (m, 3 H, CH2 Bn), 4.46–4.43 to yield 10 (1.64 g, 3.21 mmol, 86% over 3 steps). Rf = 0.21
(m, 2 H, 3-H, CH2 Bn), 4.37 (br. s, 1 H, 5-H), 4.28 (d, J = 1.7 Hz,
1 H, 4-H), 4.10 (d, J = 5.9 Hz, 1 H, 2-H), 3.96 (dd, J = 9.6, 2.7 Hz,
1 H, 6-H), 2.31 (s, 3 H, CH3 Tol) ppm. 13C NMR (101 MHz,
CDCl3): δ = 137.6, 137.3, 137.1, 132.3 (Cq), 131.1, 129.7, 129.7,
(EtOAc/PE, 3:7). [α]2D2 = +17 (c = 1, CH Cl ). IR (neat): ν = 3462,
˜
2 2
1
2870, 1741, 1494, 1454, 1369, 1232, 1090, 734, 699 cm–1. H NMR
(400 MHz, CDCl3, HH-COSY, HSQC): δ = 7.50–7.22 (m, 12 H,
ArH), 7.08 (d, J = 8.0 Hz, 2 H, ArH), 5.46 (d, J = 2.6 Hz, 1 H, 4-
128.4, 128.4, 127.9, 127.8, 127.7, 127.6, 125.2 (CHAr), 84.9 (C-1), H), 4.81–4.70 (m, 2 H, CH2 Bn), 4.67 (d, J = 11.2 Hz, 1 H, CH2
82.1 (C-2), 77.9 (C-4), 77.6 (C-3), 76.9 (C-5), 72.4, 71.1 (CH2 Bn), Bn), 4.61 (d, J = 9.0 Hz, 1 H, 1-H), 4.50 (d, J = 11.2 Hz, 1 H, CH2
69.9 (C-6), 21.0 (CH3 STol) ppm. HRMS: calcd. for C27H28O4SNa
Bn), 3.74–3.61 (m, 3 H, 6-H, 2-H, 3-H), 3.57 (t, J = 6.4 Hz, 1 H,
5-H), 3.50 (dd, J = 11.2, 6.2 Hz, 1 H, 6-H), 2.67 (s, 1 H, OH), 2.30
(s, 3 H, CH3 Tol), 2.13 (s, 3 H, CH3 Ac) ppm. 13C NMR (101 MHz,
CDCl3, HH-COSY, HSQC): δ = 171.2 (C=O), 138.0, 137.7, 137.3
(Cq), 132.4, 129.5 (CHAr), 129.3 (Cq), 128.3, 128.2, 128.0, 127.9,
127.8, 127.7 (CHAr), 87.7 (C-1), 80.8 (C-3), 77.1 (C-5), 76.7 (C-2),
75.6, 71.8 (CH2 Bn), 67.0 (C-4), 60.8 (C-6), 21.0 (CH3 Ac), 20.7
(CH3 STol) ppm. HRMS: calcd. for C29H32O6SNa [M + Na]+
531.18118; found 531.18093.
[M + Na]+ 471.16005; found 471.15984.
p-Tolyl 2,4-Di-O-benzyl-1-thio-β-D-galactopyranoside (8): To a mix-
ture of 7 (7.3 g, 25.4 mmol, 1 equiv.) in DMF (130 mL) were added
imidazole (6.1 g, 88.9 mmol, 3.5 equiv.) and TBSCl (11.5 g,
76.2 mmol, 3 equiv.). After stirring for 2 h, TLC analysis showed
complete consumption of the starting material. The reaction was
quenched by the addition of MeOH (3 mL) and partitioned be-
tween H2O and EtOAc. The aqueous layer was extracted, and the
combined organic phases were washed with aq. 1 m HCl, satd. aq.
NaHCO3, and brine, dried with MgSO4, filtered, and concentrated.
The crude product was dissolved in DMF (130 mL), and benzyl
bromide (9.1 mL, 76.2 mmol, 3 equiv.) and NaH (60% in mineral
oil, 3.11 g, 76.2 mmol, 3 equiv.) were added at 0 °C. After stirring
at ambient temperature overnight, the reaction was quenched by
the addition of MeOH at 0 °C, and the mixture was taken up in
Et2O, washed with 5% aq. LiCl and brine. After drying with
MgSO4, filtration, and concentration under reduced pressure, the
residue was dissolved in THF (34 mL) and treated with TBAF (1 m
in THF, 102 mL, 101.6 mmol, 4 equiv.). The mixture was stirred
for 3 h and subsequently partitioned between EtOAc and H2O. The
Methyl
O-(2,4-Di-O-benzyl-β-D-galactopyranosylurono-3,6-lac-
tone)-(1Ǟ6)-2,3,4-tri-O-benzyl-α-glucopyranoside (14β): Prepared
according to the procedure described for AgOTf/p-NO2C6H4SCl-
promoted glycosylation by using donor 1 (49 mg, 109 μmol) and
acceptor 11 (77 mg, 165 μmol, 1.5 equiv.). The β-coupled product
was obtained in 73% yield (64 mg, 79 μmol), whereas its α-config-
ured epimer was observed in trace amounts only. Rf = 0.7 (EtOAc/
PE, 3:7, v/v). IR (neat): ν = 2919, 1800, 1498, 1454, 1362, 1058,
˜
1028, 927, 736, 696, 531, 458, 354 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.40–7.16 (m, 25 H, ArH), 4.96 (d, J = 10.8 Hz, 1 H,
CH2 Bn), 4.89–4.83 (m, 2 H, 1Ј-H, CH2 Bn), 4.80–4.74 (m, 2 H,
CH2 Bn), 4.73 (dd, J = 4.6, 1.3 Hz, 1 H, 3Ј-H), 4.65 (d, J = 12.1 Hz,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20717
/KAP1
Date: 30-08-12 16:04:16
Pages: 10
J. D. C. Codée, G. A. van der Marel et al.
FULL PAPER
1 H, CH2 Bn), 4.58–4.49 (m, 5 H, 1-H, CH2 Bn), 4.42 (d, J =
11.8 Hz, 1 H, CH2 Bn), 4.33 (d, J = 0.9 Hz, 1 H, 4Ј-H), 4.03–3.95
(m, 3 H, 3-H, 2Ј-H, 5Ј-H), 3.91 (dd, J = 11.1, 1.9 Hz, 1 H, 6-H),
3.83–3.77 (m, 1 H, 5-H), 3.53–3.43 (m, 2 H, 2-H, 6-H), 3.35 (s, 3
H, CH3 OMe), 3.27 (dd, J = 10.0, 9.0 Hz, 1 H, 4-H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 172.8 (C=O), 138.6, 138.1, 136.8,
136.7 (Cq), 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9,
127.8, 127.7, 127.6, 127.5 (CHAr), 100.3 (C-1Ј), 97.7 (C-1), 81.8 (C-
3), 79.9 (C-2), 78.6 (C-3Ј), 78.3 (C-4), 77.2 (C-2Ј), 75.9 (C-4Ј), 75.7,
74.5, 73.3, 72.8, 71.2 (CH2 Bn), 70.6 (C-5Ј), 69.7 (C-5), 67.6 (C-6),
55.0 (CH3 OMe) ppm. 13C-HMBC NMR (100 MHz, CDCl3): δ =
100.3 (JC1Јβ,H1Јβ = 172.8 Hz, C-1Ј), 97.7 (JC1β,H1β = 167.8 Hz, C-1)
ppm. HRMS: calcd. for C48H50O11Na [M + Na]+ 825.32453; found
825.32458.
Acknowledgment
We thank The Netherlands Organization for Scientific Research
(NWO) for financial support.
[1] For examples of syntheses of pectin fragments and for the use
of uronic acids in synthesis in general, see: J. D. C. Codée, A. E.
Christina, M. T. C. Walvoort, H. S. Overkleeft, G. A.
van der Marel, Top. Curr. Chem. 2011, 301, 253–289.
[2] X. Y. Wu, L. N. Cui, T. Lipinski, D. R. Bundle, Chem. Eur. J.
2010, 16, 3476–3488.
[3] A. E. Christina, L. J. van den Bos, H. S. Overkleeft, G. A.
van der Marel, J. D. C. Codée, J. Org. Chem. 2011, 76, 1692–
1706.
[4] B. Fraser-Reid, Z. Wu, U. E. Udodongh, H. Ottosson, J. Org.
Chem. 1990, 55, 6068–6070.
[5] D. Crich, S. Sun, J. Am. Chem. Soc. 1997, 119, 11217–11223.
[6] C. M. Pedersen, L. G. Marinescu, M. Bols, C. R. Chim. 2011,
14, 17–43.
[7] C. M. Pedersen, L. U. Nordstrøm, M. Bols, J. Am. Chem. Soc.
2007, 129, 9222–9235.
Methyl
O-(2,4-Di-O-benzyl-α-D-galactopyranosylurono-3,6-lac-
tone)-(1Ǟ6)-2,3,4-tri-O-benzyl-α-glucopyranoside (14α): Prepared
according to the procedure described for Ph2SO/Tf2O-promoted
glycosylation by using donor 1 (46 mg, 100 μmol, 1 equiv.) and ac-
ceptor 11 (93 mg, 0.2 mmol, 2 equiv.). This gave a 10:1 α/β mixture
(55 mg, 69 μmol, 69%). IR (neat): ν = 694, 734, 979, 1026, 1141,
˜
1203, 1355, 1436, 1759 cm–1. 1H NMR (400 MHz, CDCl3): δ (α-
coupled product) = 3.22 (s, 3 H, CH3 OMe), 3.42 (dd, J = 10.0,
3.5 Hz, 1 H, 2-H), 3.54 (t, J = 9.5 Hz, 1 H, 4-H), 3.68 (d, J =
11.0 Hz, 1 H, 6-H), 3.73 (d, J = 9.5 Hz, 1 H, 5-H), 3.97 (t, J =
9.5 Hz, 1 H, 3-H), 4.00 (br. s, 1 H, 2Ј-H), 4.11 (s, 1 H, 5Ј-H), 4.19
(dd, J = 11.0, 3.5 Hz, 1 H, 6-H), 4.44 (s, 1 H, 4Ј-H), 4.54 (s, 1 H,
1-H), 4.55 (s, 2 H, CH2Ph), 4.57 (d, J = 12.5 Hz, 1 H, CHHPh),
4.62 (d, J = 12.0 Hz, 1 H, CHHPh), 4.65 (d, J = 10.0 Hz, 1 H,
CHHPh), 4.69 (d, J = 5.0 Hz, 1 H, 3Ј-H), 4.76 (d, J = 10.5 Hz, 1
H, CHHPh), 4.79 (d, J = 12.0 Hz, 1 H, CHHPh), 4.83 (d, J =
11.0 Hz, 1 H, CHHPh), 4.89 (s, 1 H, 1Ј-H), 4.90 (d, J = 12.5 Hz,
1 H, CHHPh), 4.96 (d, J = 11.0 Hz, 1 H, CHHPh), 7.24–7.65 (m,
25 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 55.1 (CH3
OMe), 68.5 (C-6), 69.8 (C-5), 71.9 (C-5Ј), 71.6 (CH2 Bn), 73.3 (CH2
Bn), 74.2 (CH2 Bn), 74.4 (C-2Ј), 75.1 (CH2 Bn), 76.0 (C-4Ј), 77.7
(C-4), 79.9 (C-2), 80.2 (C-3Ј), 81.7 (C-3), 98.0 (C-1), 98.8 (C-1Ј),
124.7–130.9 (CHAr), 136.7 (Cq Bn), 137.5 (Cq Bn), 138.0 (Cq Bn),
138.1 (Cq Bn), 138.7 (Cq Bn), 171.6 (C=O lactone) ppm. 13C-
GATED NMR (125 MHz, CDCl3): 98.0 (JC1,H1 = 161 Hz, C-1),
102.4 (JC1Ј,H1Ј = 163 Hz, C-1Ј). MS (ESI): m/z = 825.3 [M +
Na]+.
[8] L. J. van den Bos, R. Litjens, R. J. B. H. N. van den Berg, H. S.
Overkleeft, G. A. van der Marel, Org. Lett. 2005, 7, 2007–2010.
[9] D. Magaud, R. Dolmazon, D. Anker, A. Doutheau, Y. L.
Dory, P. Deslongchamps, Org. Lett. 2000, 2, 2275–2277.
[10] a) J. D. C. Codée, L. J. van den Bos, R. Litjens, H. S. Overk-
leeft, C. A. A. van Boeckel, J. H. van Boom, G. A. van der Ma-
rel, Tetrahedron 2004, 60, 1057–1064; b) J. D. C. Codée, R.
Litjens, R. den Heeten, H. S. Overkleeft, J. H. van Boom, G. A.
van der Marel, Org. Lett. 2003, 5, 1519–1522; c) B. A. Garcia,
D. Y. Gin, J. Am. Chem. Soc. 2000, 122, 4269–4279; d) B. A.
Garcia, J. L. Poole, D. Y. Gin, J. Am. Chem. Soc. 1997, 119,
7597–7598.
[11] a) Z. Y. Zhang, I. R. Ollmann, X. S. Ye, R. Wischna, T. Baasov,
C.-H. Wong, J. Am. Chem. Soc. 1999, 121, 734–753; b) K. M.
Koeller, C.-H. Wong, Chem. Rev. 2000, 100, 4465–4493; c)
T. K. Ritter, K. K. T. Mong, H. T. Liu, T. Nakatani, C.-H.
Wong, Angew. Chem. 2003, 115, 4805; Angew. Chem. Int. Ed.
2003, 42, 4657–4660; d) J.-C. Lee, W. A. Greenberg, C.-H.
Wong, Nat. Protoc. 2006, 1, 3143–3152; e) C.-Y. Wu, C.-H.
Wong, Top. Curr. Chem. 2011, 301, 223–252.
[12] a) J. B. Epp, T. S. Widlanski, J. Org. Chem. 1999, 64, 293–295;
b) A. De Mico, R. Margarita, L. Parlanti, A. Vescovi, G. Pian-
catelli, J. Org. Chem. 1997, 62, 6974–6977; c) L. J. van den Bos,
J. D. C. Codée, J. van der Toorn, T. J. Boltje, J. H. van Boom,
H. S. Overkleeft, G. A. van der Marel, Org. Lett. 2004, 6, 2165–
2168.
[13] N. L. Douglas, S. V. Ley, U. Lücking, S. L. Warriner, J. Chem.
Soc. Perkin Trans. 1 1998, 51–65.
[14] C. M. Pedersen, L. G. Marinescu, M. Bols, Chem. Commun.
2008, 2465–2467.
[15] M. T. C. Walvoort, W. de Witte, J. van Dijk, J. Dinkelaar, G.
Lodder, H. S. Overkleeft, J. D. C. Codée, G. A. van der Marel,
Org. Lett. 2011, 13, 4360–4363.
[16] A.-R. de Jong, B. Hagen, V. van der Ark, H. S. Overkleeft,
J. D. C. Codée, G. A. van der Marel, J. Org. Chem. 2011, 77,
108–125.
[17] a) D. Crich, F. Cai, F. Yang, Carbohydr. Res. 2008, 343, 1858–
1862; b) for the use of the related p-toluenesulfenyl triflate, see
for example: X. Huang, L. Huang, H. Wang, X.-S. Ye, Angew.
Chem. 2004, 116, 5333; Angew. Chem. Int. Ed. 2004, 43, 5221–
5224.
[18] T. Furukawa, H. Hinou, K. Shimawaki, S.-I. Nishimura, Tetra-
hedron Lett. 2011, 52, 5567–5570.
2,4-O-Dibenzyl-β-D-galacturonic Acid 3,6-Lactone Triflate (12):
Uronic acid lactone donor 1 (13 mg, 30 μmol, 1 equiv.) and Ph2SO
(8 mg, 39 μmol, 1.3 equiv.) were coevaporated with toluene (2ϫ).
The residue was dissolved in CD2Cl2 (0.6 mL) and transferred to
an NMR tube under argon. The NMR probe was cooled to –80 °C,
and the sample was locked and shimmed. In an acetone/dry ice
bath (–80 °C) the sample was treated with Tf2O (39 μmol,
1.3 equiv.), shaken thrice and placed back into the NMR magnet.
The stability of the observed anomeric triflate 12 was checked by
repeatedly allowing the temperature to rise by 10 °C and recording
the 1H NMR spectrum. The triflate was stable up to –10 °C. 1H
NMR (400 MHz, CD2Cl2, T = 193 K): δ = 6.06 (s, 1 H, 1-H), 4.91
(d, J = 4.5 Hz, 1 H, 3-H), 4.69 (d, J = 11.4 Hz, 1 H, CH2 Bn),
4.61–4.50 (m, 3 H, CH2 Bn), 4.40 (s, 1 H, 4-H), 4.35 (s, 1 H, 5-H),
4.27 (d, J = 4.6 Hz, 1 H, 2-H) ppm. 13C NMR (100 MHz, CD2Cl2,
HH-COSY, HSQC, T = 193 K): δ = 170.4 (C=O), 104.2 (C-1), 77.5
(C-3), 75.1 (C-2), 73.4 (C-4), 73.1, 71.1 (CH2 Bn), 71.0 (C-5) ppm.
13C-GATED NMR (125 MHz, CDCl3): δ = 104.2 (JC1,H1
=
[19] H. H. Jensen, L. U. Nordstrøm, M. Bols, J. Am. Chem. Soc.
2004, 126, 9205–9213.
[20] a) D. Magaud, C. Grandjean, A. Doutheau, D. Anker, V. Shev-
chik, N. Cotte-Pattat, J. Robert-Baudouy, Tetrahedron Lett.
1997, 38, 241–244; b) D. Magaud, C. Grandjean, A. Doutheau,
189 Hz).
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures for the glycosylations and 1D and
2D NMR spectra.
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20717
/KAP1
Date: 30-08-12 16:04:16
Pages: 10
On the Reactivity and Selectivity of Galacturonic Acid Lactones
D. Anker, V. Shevchik, N. Cotte-Pattat, J. Robert-Baudouy, [25]
Carbohydr. Res. 1998, 314, 189–199; c) K. Yamamoto, N. Wat-
C. McDonnell, O. López, P. Murphy, J. G. Fernández Bolaños,
R. Hazell, M. Bols, J. Am. Chem. Soc. 2004, 126, 12374–12385.
1
anabe, H. Matsuda, K. Oohara, T. Araya, M. Hashimoto, K.
Miyairi, I. Okazaki, M. Saito, T. Shimizu, H. Kato, T. Okuno,
Bioorg. Med. Chem. Lett. 2005, 15, 4932–4935.
[21] A. F. Bochkov, V. M. Kalinevitch, Carbohydr. Res. 1974, 32, 9–
14.
[26] The JC1,H1 coupling constant for an equatorial anomeric pro-
ton is generally larger (by approximately 10 Hz) than that of
the corresponding axial anomeric proton. In analogy to the
coupling constant obtained for 4,6-O-benzylidene-2,3-O-
methyl-α-d-mannosyl triflate (1JC1,H1 = 185 Hz), having an
equatorially oriented anomeric proton (D. Crich, S. Sun, J. Am.
[22] When 3,6-anhydrothiogalactoside 6 is regarded as a deoxy
sugar, the anhydro bridge does not seem to contribute favor-
ably to the reactivity of the donor. For comparison: Wong and
co-workers[11] have established that perbenzylated fucose (RRV
72000) is four times as reactive as the corresponding perbenzyl-
ated galactosyl donor.
[23] The RRVs in the p-NO2C6H4SCl/AgOTf glycosylations do not
show a quantitative correlation throughout the series, and
therefore our analysis is limited to the trends observed in this
series.
1
Chem. Soc. 1997, 119, 11217–11223), and the JC1,H1 coupling
constant in methyl (4-O-acetyl-2-azido-3-O-benzyl-2-deoxy
mannopyranosyl uronosyl) triflate, having an axially oriented
1
proton when adopting a C4 conformation (1JC1,H1 = 177 Hz)
(M. T. C. Walvoort, G. Lodder, J. Mazurek, H. S. Overkleeft,
J. D. C. Codée, G. A. van der Marel, J. Am. Chem. Soc. 2009,
131, 12080–12081), the large value for the 1JC1,H1 coupling con-
stant in 12 is indicative of an axial triflate.
Received: May 29, 2012
[24] K. P. R. Ravindranathan, P. Cura, M. Aloui, S. K. Readman,
T. J. Rutherford, R. A. Field, Tetrahedron: Asymmetry 2000,
11, 581–593.
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O20717
/KAP1
Date: 30-08-12 16:04:16
Pages: 10
J. D. C. Codée, G. A. van der Marel et al.
FULL PAPER
Glycosylation Reactivity and Selectivity
A. E. Christina, J. A. Muns,
J. Q. A. Olivier, L. Visser, B. Hagen,
L. J. van den Bos, H. S. Overkleeft,
J. D. C. Codée,*
G. A. van der Marel* ....................... 1–10
On the Reactivity and Selectivity of Galac-
turonic Acid Lactones
Keywords: Lactones / Glycosides / Glycos-
ylation / Chemoselectivity / Diastereoselec-
tivity
The reactivity and stereoselectivity of a gal-
acturonic acid 3,6-lactone thioglycosyl do-
nor has been investigated by using thio-
philic activator systems. The reactivity of
the thioglycosides depend on the activator
system used. The stereoselectivity arises
from preactivation of the glycosylation sy-
stem, giving rise to α-selective glycosyl-
ation, whereas in situ activation gives the
β-product.
10
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0