Intramolecular glycosidation by click reaction mediated spacer generation followed by spacer cleavage

Article abstract of DOI:10.1002/ejoc.201201076

2-O-Propargyl-substituted glycosyl donors and O-(2-azidobenzyl)-substituted acceptors having a vicinal hydroxy group readily underwent the click reaction. Intramolecular glycosidation with N-iodosuccinimide/trifluoromethansulfonic acid as the activating system afforded β-(1-3)- and α-(1-2)-linked disaccharides as part of 14-membered macrocycles. Descriptors for these reactions are proposed that consider the donor and acceptor attachment sites and the stereochemistry of the functional groups. Investigation of the influence of 2-O-linked 1-aryl-1,2,3-triazol-4-ylmethyl groups, as contained in the spacer, on the anomeric selectivity exhibited no anchimeric assistance. In addition, it was shown that the spacer group can be readily cleaved under Birch reduction conditions. The 1,2,3-triazole-forming click reaction was employed to generate glycosyl donor-spacer-acceptor constructs. Upon glycosidation, 14-membered macrocycles were obtained with high anomeric selectivity. Spacer cleavage was performed under Birch reduction conditions. Copyright

Full text of DOI:10.1002/ejoc.201201076

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201076
Intramolecular Glycosidation by Click Reaction Mediated Spacer Generation
Followed by Spacer Cleavage
Amit Kumar,[a] Yiqun Geng,[a] and Richard R. Schmidt*[a,b]
Dedicated to Professor Yashwant D. Vankar on the occasion of his 60th birthday
Keywords: Glycosides / Stereoselectivity / Click chemistry / Macrocycles
2-O-Propargyl-substituted glycosyl donors and O-(2-azido-
benzyl)-substituted acceptors having a vicinal hydroxy group
readily underwent the click reaction. Intramolecular glycos-
idation with N-iodosuccinimide/trifluoromethansulfonic acid
as the activating system afforded β-(1–3)- and α-(1–2)-linked
disaccharides as part of 14-membered macrocycles. Descrip-
tors for these reactions are proposed that consider the donor
and acceptor attachment sites and the stereochemistry of the
functional groups. Investigation of the influence of 2-O-
linked 1-aryl-1,2,3-triazol-4-ylmethyl groups, as contained in
the spacer, on the anomeric selectivity exhibited no an-
chimeric assistance. In addition, it was shown that the spacer
group can be readily cleaved under Birch reduction condi-
tions.
tion step between the glycosyl donor and acceptor.[5] Thus,
a 2-O-propargyl-substituted glycosyl donor and an O-(o-
azidomethyl)benzyl-substituted acceptor were separately
prepared and then ligated in high-yielding click reactions.
Basically, this more convergent strategy facilitates the gen-
eration of the starting materials for the intramolecular gly-
coside bond-formation reaction. However, as a result of ro-
tational freedom between the triazolyl and benzyl residues,
and accessible ring sizes of only 15-membered rings and
higher, glycosidation yields and anomeric selectivities are
not always satisfactory. In addition, cleavage of the O-(1-
benzyl-1,2,3-triazol-4-yl)methyl group can be difficult.
To overcome the problems of the previous approaches,
we investigated the o-azidobenzyl (OAB) group to generate
the spacer (Scheme 1). This group, O-linked in the vicinal
position to the accepting hydroxy group, can be regioselec-
tively attached (step 1), offers the desired convenient link-
age between the glycosyl donor and acceptor through a 1-
aryl-1,2,3-triazole spacer (step 2), exhibits lower conforma-
tional mobility than the 2-azidomethylbenzyl group be-
cause of restricted conformational mobility and direct inter-
action between the triazolyl and phenyl moieties, and most
importantly, permits the formation of a 14-membered ring
in the glycosidation step (step 3) and favors convenient de-
protection (step 4).
Introduction
The rigid spacer concept for intramolecular glycoside
bond formation consisting of (i) rigid spacer attachment to
the glycosyl donor, (ii) regioselective attachment of the do-
nor–spacer adduct to the acceptor, (iii) glycosidation, and
(iv) cleavage of the spacer (and concomitantly the carbo-
hydrate protecting groups) has led to excellent results re-
garding yield and anomeric selectivity, for instance, with m-
xylylene spacers.[1,2] The results could be rationalized based
on linkage- and configuration-dependent conformational
preferences. Generally, attachment of the spacer to func-
tional groups on the carbohydrate residues, which allows
the formation of a 14-membered transition state in the gly-
coside bond-forming reaction and thus leads to a 14-mem-
bered glycoside bond containing a macrocycle, is favorable
in the glycosidation step. However, the ligation of the glyc-
osyl donor and acceptor with the m-xylylene spacer by
using α,αЈ-dibromo-m-xylene as the alkylating agent is
often a major hurdle, as in this linear approach to the prod-
uct, the regioselective attachment of the donor–spacer ad-
duct to the acceptor (step ii) does not always give good
yields. Therefore, we recently turned our attention to the
1,2,3-triazole-forming click reaction[3,4] as a decisive liga-
[a] Fachbereich Chemie, Universität Konstanz,
Fach 725, 78457 Konstanz, Germany
Fax: +49-7531-88-3135
E-mail: richard.schmidt@uni-konstanz.de
[b] Chemistry Department, Faculty of Science,
King Abdulaziz University,
A precondition for these promising intramolecular gly-
cosidation studies is the investigation of eventual an-
chimeric assistance through the attack of the nitrogen in
the 3-position of the 1,2,3-triazolyl moiety at the anomeric
carbenium ion generated in the glycosidation step
(Scheme 2). Hence, the anomeric stereocontrol could be
Jeddah 21589, Saudi Arabia
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201076.
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Eur. J. Org. Chem. 2012, 6846–6851

Intramolecular Glycosidation by Spacer Generation/Cleavage
Scheme 1. Intramolecular glycosidation by click reaction mediated spacer generation.
strongly influenced by the 2-O-(1-aryl-1,2,3-triazol-4-yl)- lyst[3,4] led to 2-O-(1-phenyl-1,2,3-triazol-4-yl)methyl-pro-
methyl moiety; thus, selective access to both α- and β-gly- tected compound 3. Selective acid-catalyzed debenzyliden-
cosides governed mainly by the relative stereochemistry of ation and immediate O-acetylation afforded glycosyl donor
the spacer attachment sites and the ring size in the glycosid- 4. Glycosylation of 3-O-unprotected acceptor 5[8] with an
ation step could be limited. In addition, cleavage of the 2- excess amount of N-iodosuccinimide (NIS) and a catalytic
O-(1-aryl-1,2,3-triazol-4-yl)methyl group to liberate the amount of trifluoromethanesulfonic acid (TfOH)[9,10] at
carbohydrate hydroxy groups (Scheme 1, step 4) is a further –40 °C to room temperature afforded a ca. 1:1 mixture of
precondition for the investigation of this approach to intra- anomers 6α/6β in good yield. Replacement of the 2-O-(1-
molecular glycosidation.
phenyl-1,2,3-triazol-4-yl)methyl group by the nonpartici-
pating benzyl group, as in known glucosyl donor 7,[11] fur-
nished, with 5 as the acceptor under the same conditions, a
1.2:1 mixture of anomers 8α/8β[12] in high yield that could
be separated. Hence, the 2-O-linked (1-phenyl-1,2,3-triazol-
4-yl)methyl group exerts practically no anchimeric assist-
ance in these glycosidation reactions,[13] though, as shown
in Scheme 2, participation of N-3 in the stabilization of the
anomeric carbenium ion via six-membered ring formation
could take place from the α- and/or the β-side. Hence, the
electron-donating character of the 1,2,3-triazolyl group
seems to be rather low.[13]
The structural assignments and the anomeric ratios of
disaccharides 6α,β and 8α,β were readily obtained from
their NMR spectroscopic data. HSQC spectra furnished the
shifts of anomeric C-1b and 1b-H and the 1b-H/2b-H cou-
pling constants (Table 1) that support the structural assign-
ments. The anomeric ratios were obtained from the integra-
tion of the signal of the anomeric O-methyl groups at C-
1a.
Scheme 2. Possible anchimeric assistance of a 2-O-(1-aryl-1,2,3-tri-
azol-4-yl)methyl group in glycosidation reactions. LG = leaving
group; Pr = promoter.
Results and Discussion
For the investigation of potential anchimeric assistance
of the 2-O-(1-aryl-1,2,3-triazol-4-yl)methyl group in glycos-
idation reactions, ethyl 3-O-benzyl-4,6-O-benzylidene-2-O-
To investigate the cleavage of an O-linked (1-aryl-1,2,3-
propargyl-1-thio-β-d-glucopyranoside (2) was prepared triazol-4-yl)methyl group, known 6-O-unprotected gluco-
from known ethyl 4,6-O-benzylidene-1-thio-β-d-glucopyr- pyranoside 9[14] was treated with propargyl bromide under
anoside[6] that gave selectively, upon treatment with dibu- standard conditions to afford 10;[15] with phenyl azide in
tyltin oxide (Bu2SnO) in methanol and benzylation in the the presence of Hünig’s base and CuI, compound 10 gave
presence of cesium fluoride (CsF), 3-O-benzyl-protected de- 6-O-(1-phenyl-1,2,3-triazol-4-yl)methyl-substituted
11
rivative 1[7] (Scheme 3). Reaction with propargyl bromide in (Scheme 4). Hydrogenation of this compound with Pd/C as
the presence of sodium hydride as base afforded compound catalyst in ethanol as solvent in the presence of trifluoro-
2. Reaction with phenylazide in the presence of Hünig’s acetic acid (CF3CO2H) under different pressures (1, 8 atm)
base (DIPEA; N,N-diisopropylethylamine) and CuI as cata- or with Rh/C as catalyst led to O-debenzylation to afford,
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A. Kumar, Y. Geng, R. R. Schmidt
SHORT COMMUNICATION
Scheme 3. Investigation of anchimeric assistance of the (1,2,3-triazol-4-yl)methyl group. Reagents and conditions: (a) Propargyl bromide,
NaH, DMF, 0 °C (86%); (b) CuI, DIPEA, CH2Cl2 (81%); (c) pTsOH, CH2Cl2/MeOH (1:1), r.t.; Ac2O, Pyr (98%); (d) NIS, TfOH,
CH2Cl2, –40 °C (6α,β: 73%, α/β ≈ 1:1; 8α,β: 86%, α/β ≈ 1.2:1).
Table 1. 1H (1b-H) and 13C (C-1b) NMR chemical shift assign-
ments of compounds 6α,β and 8α,β.[a]
Compound
C-1b shift
[ppm]
1b-H shift
[ppm]
3J1b,2b [Hz]
6α
6β
8α
8β
95.6
102.9
97.1
5.62
4.86
5.48
5.04
3.6
6.4
4.0
6.8
102.4
[a] 1H (600.3 MHz) and 13C (90.6 MHz) NMR spectra were re-
corded in CDCl3 with tetramethylsilane as internal standard. For
the complete 1H and 13C NMR spectroscopic data, see the Sup-
porting Information.
after O-acetylation, product 12; if at all, only very minor
cleavage of the (1-aryl-1,2,3-triazol-4-yl)methyl group took
place. Therefore, Birch reduction conditions were applied
to compound 11, which led to full deprotection as shown
with known, fully O-acetylated derivative 13.[16] Hence, the
products to be received in the intramolecular glycosidation
should also be accessible by this deprotection procedure.
As first proof, disaccharide 6α,β was treated under Birch
conditions to afford, after per-O-acetylation, desired and
known disaccharide 14α,β.[17] Therefore, omission of the
methylene group, contained between N-1 of the triazolyl
and the benzyl residue in the previously employed spacer,[5]
Scheme 4. Deprotection of O-(1-phenyl-1,2,3-triazol-4-yl)methyl-
substituted compounds. Reagents and conditions: (a) see ref.[15]
HCϵC–CH2Br, NaH, DMF, 0 °C (84%); (b) CuI, DIPEA,
CH2Cl2, r.t. (76%); (c) Pd/C, H2, CF3CO2H, EtOH, 1 atm; Ac2O,
Pyr (81%); at 8 atm (76%); with Rh/C as cat. (74%); (d) liq. NH3,
Na, –78 °C; Ac2O, Pyr (13: 72%; 14: 63%).
:
is decisive for convenient cleavage of the O-linked (1,2,3- high regioselectivity as obtained in the synthesis of 2) af-
trizazol-4-yl)methyl group. forded a 3:1 mixture of desired isomers 17a/17b that could
Synthesis of the acceptor for the intramolecular glycosid- be readily separated. Standard click reaction with glycosyl
ation studies started from 4,6-O-benzylidene-protected glu- donor 3 furnished desired donor–spacer–acceptor interme-
copyranoside 15 (Scheme 5). Treatment of 15 with o-azido- diates 18a and 18b, respectively, in high yield. Their struc-
benzyl bromide (16)[18] in NaOH/dichloromethane in the tures were independently confirmed by transforming 15
presence of tetrabutylammonium iodide (TBAI) (to avoid into known p-methoxybenzyl (PMB)-protected derivatives
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Intramolecular Glycosidation by Spacer Generation/Cleavage
Scheme 5. Intramolecular glycosidation with donor–spacer–acceptor-linked intermediates 18a and 18b. Reagents and conditions:
(a) NaOH/CH2Cl2, TBAI, r.t. (17a: 48%; 17b: 16%); (b) CuI, DIPEA, CH2Cl2, r.t. (18a: 78%; 18b: 82%); (c) NIS, TfOH, CH2Cl2, –40 °C
to r.t. (19a: 68%; β/α Ͼ 25:1; 19b: 79%, α/β = 8:1); (d) liq. NH3; Na, –78 °C; Ac2O, Pyr (14β: 70%; 20α: 72%).
21a and 21b[19] (Scheme 6). Reaction of 21a and 21b with
For the description of intramolecular glycosidation reac-
16 in the presence of NaH as base and in DMF as solvent tions, the linkage of the spacer to the donor (position of
furnished 22a and 22b, respectively. Click reaction with 3 spacer attachment and accepting hydroxy group and their
led to 23a and 23b that upon removal of the PMB group relative stereochemistry) was previously employed.[1a] Thus,
with DDQ in CH2Cl2/H2O furnished starting materials 18a for the reaction of 18a, the descriptor is 2b-O(α)/(2aǞ3a)-
and 18b for the intramolecular glycosidation. Standard gly- O-l-threo glycosidation. Isomer 18b also possesses a 2b-
cosidation conditions (NIS, TfOH) applied to 18a led to the O(α)/(3aǞ2a)-O-l-threo connection between the donor and
disaccharide moiety contained in 14-membered macrocycle acceptor. Hence, as the ring size and the spacer are the same
19a; practically, only β(1–3)-linkage formation was ob- as those in 18a, the same glycosidation result, that is, β(1–
served. This could be confirmed by complete deprotection 2)-linkage in the product, was expected. However, under
of 19a under Birch reduction conditions and then O-acetyl- standard glycosidation conditions from 18b, mainly α-(1–
ation with acetic anhydride in pyridine to afford known 2)-linked product 19b was obtained, as was confirmed after
methyl laminaribioside 14β[17] in 70% yield over the two deprotection under Birch reduction conditions and then O-
steps. Hence, the anomeric selectivity difference between the acetylation to afford methyl kojibioside 20α[20] in 72% yield
intramolecular glycosidation (Scheme 5) and the related over the two steps. A more careful look at the accepting
intermolecular variant of 4 with 5 shown in Scheme 3 is hydroxy groups in 18a and 18b reveals that the stereochem-
noteworthy.
istry of the functional groups vicinal to the accepting hy-
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A. Kumar, Y. Geng, R. R. Schmidt
SHORT COMMUNICATION
Scheme 6. Alternative synthesis of compounds 18a and 18b. Reagents and conditions: (a) NaH, DMF, 0 °C to r.t. (22a: 88%; 22b: 84%);
(b) CuI, DIPEA, CH2Cl2, r.t. (23a: 89%; 23b: 85%); (c) DDQ, CH2Cl2/H2O, 0 °C (18a: 76%; 18b: 79%).
droxy groups also has to be considered and included in the Besides the ring size, the relative orientation of the spacer
description of intramolecular glycosidations. Thus, for 18a attachment site, the accepting hydroxy group, and the vici-
a 2b-O(α)/(2aǞ4a)-O-l-xylo and for 18b a 2b-O(α)/ nal functional groups seem to be of particular importance
(3aǞ1a)-O-l-lyxo descriptor is assigned. Obviously, the ac- for the anomeric selectivity. On the basis of these descrip-
cepting hydroxy group in 18b is comparable to the 3-hy- tors of the donor–spacer–acceptor constructs, the chemical
droxy groups in galactopyranosides that, as a result of the and stereochemical results of glycosidation reactions should
accumulation of lone pair orbitals on the β-side, exhibit in- become predictable. Thus, the design of a reliable building
creased nucleophilicity. In 18b, this effect is gained when block for programmable oligosaccharide syntheses should
the donor moiety approaches with its α-side.
become available.
The practical validity of this proposal for the description
of intramolecular glycosidations has to be displayed by fur-
ther studies. It is hoped that with this readily accessible
spacer between O-benzyl- and/or O-benzylidene-protected
donors and acceptors data for the α/β-selectivities of intra-
molecular glycosidations may finally become available,
which would permit reliable planning of the required build-
ing blocks for stereoselective glycosidation reactions. As the
number of different combinations between d-gluco-, d-ga-
lacto-, and d-mannoypranoses and their 2-amino-2-deoxy
derivatives is quite limited, this task is within experimental
reach.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details and 1H and 13C NMR spectra of new
compounds (2, 3, 4, 6α,β, 8α, 8β, 11–14α,β, 17a–19a, 14β, 17b–19β,
20β, 22a, 23a, 18a, 21b–23b, 18β) and H NMR spectra of known
compounds (1, 5, 7, 9, 10, 15, 16).
1
Acknowledgments
This work was supported by the University of Konstanz and the
Fonds der Chemischen Industrie.
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Received: August 8, 2012
Published Online: November 7, 2012
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