Application of the 2-nitrobenzyl group in glycosylation reactions: A valuable example of an arming participating group

Article abstract of DOI:10.1002/ejoc.201300123

The application of the o-nitrobenzyl (oNBn) group is demonstrated. This practical methodology allows the stereocontrolled synthesis of glucosides with a 1,2-trans linkage. This new ether-type arming group can broadly extend the concept of the use of participating groups in glycosylation reactions. Easy protection and deprotection of the oNBn group further confirms its usefulness in synthesis. The application of o-nitrobenzyl (oNBn) ether as an arming participating group is demonstrated. This practical methodology allows the stereocontrolled synthesis of glucosides with a 1,2-trans linkage. Copyright

Full text of DOI:10.1002/ejoc.201300123

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300123
Application of the 2-Nitrobenzyl Group in Glycosylation Reactions: A Valuable
Example of an Arming Participating Group
Szymon Buda,[a] Patrycja Gołebiowska,[a] and Jacek Mlynarski*[a]
˛
Keywords: Carbohydrates / Glycosylation / Protecting groups / Stereoselectivity
The application of the o-nitrobenzyl (oNBn) group is demon-
strated. This practical methodology allows the stereocon-
trolled synthesis of glucosides with a 1,2-trans linkage. This
new ether-type arming group can broadly extend the con-
cept of the use of participating groups in glycosylation reac-
tions. Easy protection and deprotection of the oNBn group
further confirms its usefulness in synthesis.
Introduction
The synthesis and application of carbohydrate derivatives
is still the subject of enormous interest because of the re-
markable biological relevance of carbohydrate units.[1] Most
carbohydrates found in nature exist as polysaccharides,
glycosides, or glycoconjugates, and thus, particular effort
has been constantly devoted to the stereoselective genera-
tion of the O-glycosidic bond between carbohydrate resi-
dues and the aglycon. Various methodologies and ideas are
now available for the efficient and stereocontrolled synthesis
of structurally defined complex oligosaccharides, but this
field still deserves additional attention.[2] The most com-
monly used strategy for the synthesis of glycosidic bonds
involves the coupling of a fully protected donor bearing a
leaving group at its anomeric center with a suitably pro-
tected glycosyl acceptor.
The most reliable method for stereoselective glycosyl-
ation is still based on the neighboring group participation
of the 2-O-acyl functionality [Scheme 1, III, benzoyl (Bz)].
An alcohol acceptor can attack the anomeric center from
only one face to provide the 1,2-trans-glycoside. The pres-
ence of an ester-type substituent that electronically deacti-
vates the donor is necessary for the stereocontrolled forma-
tion of the anomeric bond. Application of an ether-type
substituent [e.g., I, benzyl (Bn)], which electronically acti-
vates the donor molecule, in many cases leads to a mixture
of two stereoisomers that differ in the configuration of the
anomeric center.
Scheme 1. Application of the ether- and ester-type participating
groups in glycosylation reactions.
The above concept is fundamental for the stereocon-
trolled synthesis of the glycosidic bond, and the use of an
electron-rich ether-type neighboring group (Scheme 1, II)
has been only scantly mentioned in the literature. Examples
of heterocyclic thiophen-2-yl[3] and picolinyl[4] substituents
have been presented, whereas successful examples of substi-
tuted benzyl ethers have never been deeply explored. This
concept, however, seems to have great potential, and the
use of stereocontrolling benzyl-type groups may have many
advantages that include (1) the use of an activated (armed)
donor that allows for milder reaction conditions and
(2) easy one-step deprotection of all benzyl-type groups af-
ter the reaction.
Now, we present our contribution to the field by demon-
strating the successful application of o-nitrobenzyl (oNBn)
as an arming participating group to control glucosidic bond
formation. This concept was initially investigated by using
phenyl thioglucoside (1), which is frequently used as a glyc-
osyl donor in glycoside synthesis.[5] We assumed that neigh-
boring group participation of the 2-O-oNBn protecting
group would give a more stable acetoxonium ion, which
would provide the β-glycosides after alcohol attack from
only one face to afford 1,2-trans-glucosides (Scheme 2).
[a] Faculty of Chemistry, Jagiellonian University
Ingardena 3, 30-060 Krakow, Poland
E-mail: jacek.mlynarski@gmail.com
Homepage: www.jacekmlynarski.pl
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300123.
3988
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 3988–3991

Application of the 2-Nitrobenzyl Group in Glycosylation Reactions
Scheme 3. Synthesis of glycosyl donor 1.
Scheme 2. Proposed arming participating group concept by using
the o-nitrobenzyl group.
reocontrolling effects of the o-nitrobenzyl group were also
accompanied by a great influence on the general reaction
yield (36 vs. 88% in the case of disaccharides 7 and 8).
These two features – stereocontrol and anomeric center ac-
tivation – should allow the o-nitrobenzyl group to be con-
sidered as an arming participating group.
Results and Discussion
The synthesis of the model thioglucoside selectively pro-
tected with 2-O-oNBn (i.e., 1) was achieved starting from
3,4,6-tri-O-benzyl-d-glucal (2) by using a short and efficient
strategy that included stereoselective oxidation of the
double bond by using bis(acetoxy)iodobenzene (BAIB,
Scheme 3). This methods allows the preparation of C2-acet-
yloglycosides directly from glycal donors in a one-pot pro-
cedure by employing an iodine(III) reagent.[6] We demon-
strated that BAIB in combination with a catalytic amount
of Lewis acid (BF3·OEt2) served as an ideal oxidant and
that the diacetyl intermediate could be easily transformed
into thiophenyl glycoside (3) in high yield upon treatment
with thiophenol in a one-pot reaction sequence. The last
reaction step in this transformation, that is, nucleophilic
displacement of the acyl group with a sulfur reagent, could
be significantly enhanced by sonication.[7] Next, a deacetyl-
ation–benzylation sequence afforded 2-O-nitrobenzyl thio-
glucoside (1, Scheme 3). Notably, o-nitrobenzyl ether 1
could be efficiently prepared from alcohol 4 by using the
same methodology (o-nitrobenzyl bromide, NaH) as that
used for the corresponding benzyl ether. The use of aceto-
nitrile allowed more reproducible results to be obtained rel-
ative to those obtained in DMF.[8]
Scheme 4. Glycosylation reactions with donors 1 and 5.
Preliminary experiments with novel glycosyl donor 1
Being satisfied with these results, we decided to evaluate
were performed in direct comparison with standard glycos- how the solvent used for the reaction could further in-
idation of perbenzylated glycosyl donor 5 (Scheme 4). Ini- fluence the reaction yield and selectivity. Table 1 summa-
tial couplings were performed by using two selected and rizes our major findings and confirms that preferential for-
structurally different model glycosyl acceptors, namely, mation of β-glycoside from donor 1 and methanol is also
methyl 2,3,4-tri-O-benzyl-α-d-glucopyranoside (6) and visible in various solvents. The best results in terms of
methanol. Thus, activation of the glucosyl donor by using stereoselectivity were observed when the coupling was car-
Ph2SO/Tf2O/TTBP (Tf = trifluoromethylsulfonyl, TTBP = ried out in diethyl ether (Table 1, entry 5); only the β-an-
2,4,6-tri-tert-butylpyrimidine) in CH2Cl2 afforded disaccha- omer was formed, albeit in lower yield (31%). A similar yet
rides 7–10 as anomeric mixtures. The obtained results unselective reaction performed with donor 5 (phenyl
strongly support our assumptions. The substituted benzyl 2,3,4,6-tetra-O-benzyl-1-thio-β-d-glucopyranoside) in di-
group at the C2 position efficiently shielded the α-face of ethyl ether (Table 1, entry 6) additionally confirmed the
the glycosyl triflate intermediate, which resulted in preferen- sharp difference between the participating effects of the o-
tial formation of 1,2-trans-glycosides 7 and 9. The ste- nitrobenzyl and benzyl groups (Table 1, entries 5 and 6).
Eur. J. Org. Chem. 2013, 3988–3991
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3989

S. Buda, P. Gołebiowska, J. Mlynarski
˛
SHORT COMMUNICATION
Notably, if the reaction was carried out on a larger scale in (77%), and cholesteryl (77%) alcohols clearly demonstrates
dichloromethane, the same high level of stereoselectivity proof of concept of the application of ether-type arming
was observed (Table 1, entries 3 and 4).
participating groups.
Lastly, to prove the applicability of the new methodology
in organic synthesis we examined the mild deprotection of
the o-benzyl ether from product 9. This ether was easily
cleaved under standard debenzylation conditions (H2, Pd/
C). This methodology can be used for the convenient depro-
tection of all benzyl substituents (Scheme 6). Interestingly,
this substituent can be also selectively cleaved in the pres-
ence of other benzyl groups by light irradiation[9] to afford
methyl 3,4,6-tri-O-benzyl-β-d-glucopyranoside (16) in high
yield. This mild deprotection method can further open up
new areas of application of the o-nitrobenzyl ether group.
Table 1. Solvent studies.[a]
Entry Solvent
β
Yield [%][b]
24
1
2
3
4
5
6
acetonitrile
toluene
dichloromethane
dichloromethane
diethyl ether
diethyl ether
1:10
1:10
1:12
1:12
β only
1:1
59
90
96[c]
31
40[d]
[a] Reactions were performed with donor 1 (0.074 mmol), MeOH
(0.11 mmol), Ph2SO (0.081 mmol), Tf2O (0.081 mmol), TTBP
(0.185 mmol), solvent (5 mL) at –40 °C to r.t. [b] Isolated yield.
[c] Reaction was performed with donor 1 (0.30 mmol), MeOH
(0.45 mmol), Ph2SO (0.325 mmol), Tf2O (0.325 mmol), TTBP
(0.75 mmol), solvent (20 mL) at –40 °C to r.t. [d] Reaction was per-
formed with donor 5 (phenyl 2,3,4,6-tetra-O-benzyl-1-thio-β-d-
glucopyranoside).
Next, we decided to exam further the influence of the
oNBn group by expanding the scope of the stereoselective
glycosylation to a broader range of alcohols. Thus, the reac-
tion performed in CH2Cl2 was again adopted as our stan-
dard. The results supporting the synthesis of the 1,2-trans
linkage are listed in Scheme 5. In all cases, the synthesis of
the β-glycosides was observed predominantly. This ten-
dency was maintained for both primary (i.e., 7, 9, 11, 12)
and secondary (i.e., 13, 14) alcohols. The synthesis of β-
glycosides from benzyl (86%), pentyl (81%), isopropyl
Scheme 6. Deprotection methods of o-nitrobenzyl group.
Conclusions
In summary, a new method for stereocontrolled glycosyl-
ation by using an elusive type of arming participating group
was developed. We demonstrated that 1,2-trans stereoselec-
tivity can be achieved by using 2-O-(o-nitrobenzyl) ethers,
which can act as a neighboring glycosylation support. This
ether group can also enhance the reaction yield by activa-
ting (arming) glycosyl donors, in contrast to broadly used
deactivating esters. Easy protection and selective deprotec-
tion of the o-nitrobenzyl group further confirms its useful-
ness in synthesis. It is also important that both protection
and deprotection of the o-nitrobenzyl ether does not require
special techniques, and the high stability of this group al-
lows it to be treated as a routine protecting group, which
can be used on a daily basis.
Experimental Section
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures and copies of the 1H NMR
and 13C NMR spectra of all key intermediates and products.
Acknowledgments
Scheme 5. Scope of the glycosylation with armed donor 1. Reac-
tions were performed with donor
1 (0.074 mmol), acceptor
This project was operated within the Foundation for Polish Science
TEAM Programmes co-financed by the EU European Regional
(0.11 mmol), Ph2SO (0.081 mmol), Tf2O (0.081 mmol), TTBP
(0.185 mmol), CH2Cl2 (5 mL) at –40 °C to r.t.
3990
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 3988–3991

Application of the 2-Nitrobenzyl Group in Glycosylation Reactions
2008, 73, 8838–8850; c) J. P. Yasomanee, A. V. Demchenko, J.
Am. Chem. Soc. 2012, 134, 20097–20102.
[5] S. Oscarson, in: Carbohydrates in Chemistry and Biology (Eds.:
B. Ernst, G. W. Hart, P. Sinay), Wiley-VCH, Weinheim, Ger-
many, 2000, vol. 1, p. 93–116.
[6] L. Shi, Y.-J. Kim, D. Y. Gin, J. Am. Chem. Soc. 2001, 123,
6939–6940.
Development Fund. Financial support from the Polish National
Science Centre (grant number 2012/05/B/ST5/0027) is gratefully ac-
knowledged.
[1] S. Hanessian (Ed.), Preparative Carbohydrate Chemistry, Mar-
cel Dekker, New York, 1997.
[2] X. Zhu, R. R. Schmidt, Angew. Chem. 2009, 121, 1932–1967;
Angew. Chem. Int. Ed. 2009, 48, 1900–1934.
[3] D. J. Cox, A. J. Fairbanks, Tetrahedron: Asymmetry 2009, 20,
773–780.
[4] a) J. T. Smoot, P. Pornsuriyasak, A. V. Demchenko, Angew.
Chem. 2005, 117, 7285–7288; Angew. Chem. Int. Ed. 2005, 44,
7123–7126; b) J. T. Smoot, A. V. Demchenko, J. Org. Chem.
[7] S. Deng, U. Gangadharmath, Ch.-W. T. Chang, J. Org. Chem.
2006, 71, 5179–5185.
[8] For a detailed procedure, see the Supporting Information.
[9] U. Zehavi, B. Amit, A. Patchornik, J. Org. Chem. 1972, 37,
2281–2285.
Received: January 23, 2013
Published Online: May 13, 2013
Eur. J. Org. Chem. 2013, 3988–3991
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3991