Efficient glycosylation with glycosyl ortho-allylbenzoates as donors

Article abstract of DOI:10.1016/j.tetlet.2018.11.061

Glycosylation reactions are significant as they provide access to model compounds that are useful for elucidating biochemical pathways. Herein, we describe the development of glycosyl ortho-alkynylbenzoates as novel, bench-top stable, and readily availabl

Full text of DOI:10.1016/j.tetlet.2018.11.061

Accepted Manuscript
Efficient glycosylation with glycosyl ortho-allylbenzoates as donors
Haijing Liang, Lixia Ma, Changwei Li, Qiang Peng, Zhaoyan Wang, Zhan-xin
Zhang, Lan Yu, Huanxiang Liu, Fengli An, Weihua Xue
PII:
S0040-4039(18)31408-4
https://doi.org/10.1016/j.tetlet.2018.11.061
TETL 50446
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 September 2018
21 November 2018
24 November 2018
Please cite this article as: Liang, H., Ma, L., Li, C., Peng, Q., Wang, Z., Zhang, Z-x., Yu, L., Liu, H., An, F., Xue,
W., Efficient glycosylation with glycosyl ortho-allylbenzoates as donors, Tetrahedron Letters (2018), doi: https://
doi.org/10.1016/j.tetlet.2018.11.061
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Efficient glycosylation with
Leave this area blank for abstract info.
glycosyl ortho-allylbenzoates as donors
Haijing Liang, Lixia Ma, Changwei Li, Qiang Peng, Zhaoyan Wang, Zhan-xin Zhang, Lan Yu, Huanxiang Liu, Fengli An,
Weihua Xue

1
Tetrahedron Letters
Efficient glycosylation with glycosyl ortho-allylbenzoates as donors
Haijing Liang, Lixia Ma, Changwei Li, Qiang Peng, Zhaoyan Wang, Zhan-xin Zhang, Lan Yu, Huanxiang
Liu, Fengli An, Weihua Xue 
a School of Pharmacy, Lanzhou University, Lanzhou, 730000, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Glycosylation reactions are significant as they provide access to model compounds that are
useful for elucidating biochemical pathways. Herein, we describe the development of glycosyl
ortho-alkynylbenzoates as novel, bench-top stable, and readily available glycosyl donors.
Glycosylation is promoted by inexpensive trimethylsilyl triflate (TMSOTf) in combination with
N-iodosuccinimide (NIS) under mild reaction conditions; hence, the novel glycosyl donors are
promising reagents for the synthesis of glycosides.
Available online
Keywords:
Glycosylation
Glycosyl ortho-allylbenzoates
NIS
2009 Elsevier Ltd. All rights reserved.
Lactonisation
Glycosylation reactions are necessary as they afford chemical
access to model glycoconjugates that provide detailed insight into
biochemical pathways [1]. The development of efficient and
stereoselective glycosylation methodologies has attracted
significant research attention over the past decade owing to the
varied and important biological functions of complex
oligosaccharides and glycoconjugates [2]. Anomeric esters form
part of a common family of glycosyl donors because they are
easy to prepare and are generally bench-top stable, and the
glycosyl ortho-alkynylbenzoates reported by Yu et al. are
attractive representative anomeric esters [3]. These donors are
effectively activated for glycosylation by catalytic Au(I)
complexes. The transition-metal-catalysed reaction avoids strong
nucleophilic, or electrophilic conditions, and is orthogonal to
most other glycosyl donor systems [4]. Especially in the past
decade, glycosylations using glycosyl ortho-alkynylbenzoates as
donors have been well documented in the literature as
convenient methods for the synthesis of challenging β-
mannosides [5] and natural glyconjugates [6-7] of medicinal
relevance. In our laboratory the glycosylation protocols based on
activating of alkyne-functionalities [8] have also received great
attention. During the preparation of these donors, we found that
o-hexynylbenzoic acid was unstable because intramolecular
cycloaddition occurs at room temperature leading to
contamination. Recently, Tang and co-workers developed
isoquinoline-1-carboxylate as a traceless leaving group for
chelation-assisted glycosylation under mild and neutral reaction
conditions [9]; this conceptually novel and efficient glycosylation
method is very appealing. Unfortunately, our market survey
acid is very expensive, costing almost as much per gram as gold;
this high cost is bound to restrict its applications. Other related
anomeric esters [10] or carbonates [11] bearing remote alkynes
have also been developed as glycosyl donors; however, they have
not been widely used for the total synthesis of complex
glycoconjugates because of their low reactivities or the need for
catalysts that are inaccessible. Under such circumstances, the
development of alternative glycosyl donors is desirable because
these donors can effectively deliver the desired electrophilic
sugar residue through improving reactivity or alternative modes
of action. The cyclofunctionalisation of an unsaturated acid is a
very popular approach that provides easy access to lactones [12].
These electrophile-induced lactonisations are also effective for
activating donors in carbohydrate chemistry [10c, 13];
halolactonization of o-allylbenzoic acid was observed to proceed
exclusively in an exo manner to produce a six-membered lactone
ring [14]. Based on the above-mentioned reports, we surmised
that o-allylbenzoic acid is an easily accessible ω-unsaturated acid
that provides an anomeric blocking group; this group becomes a
potential anomeric leaving group upon activation by a halonium
species. Herein, we describe a facile and efficient approach for
the construction of glycosides using glycosyl o-allylbenzoates as
donors and N-iodosuccinimide (NIS) as the stoichiometric
halogen source.
o-Allylbenzoic acid is readily prepared according to a literature
protocol [14]; the synthesis was also found to be scalable, as
demonstrated by the multigram preparation of the ortho-
substituted aromatic acid. This carboxylic acid is prepared in an
excellent yield as an air-stable, white crystalline solid and that
can be stored at room temperature for months without any
r—eve—ale—d that commercially available isoquinoline-1-carboxylic
 Corresponding author. Tel.: +86-536-8915682; e-mail: xuewh@lzu.edu.cn

2
Tetrahedron Letters
detectable loss of purity. Representative acetyl-, benzoyl-, and
benzyl- protected glycosyl ortho-allylbenzoatesD1-6 were
conveniently obtained by simple condensation of the
corresponding lactols with o-allylbenzoic acid (Figure 1). To our
Figure 1. Glycosyl donors in iodium-promoted glycosylation
delight, these donors were isolated as single anomers in their α or
β-configurations. Notably, these glycosyl esters were stable when
stored at room temperature for three months.
We began our investigation by studying glycosylation induced by
NIS as the electrophilic halogen source. Model glycosidic-
couplings are listed in Table 1, employing D1 as a typical
glycosyl donor and epiandrosterone as the acceptor. The
beneficial effect of the promoter was demonstrated by the
observation that no product was obtained when the reaction was
performed in the presence of NIS alone, even after 24 h (Table 1,
entry 1), while the use of trimethylsilyl triflate (TMSOTf, 0.1
equiv.) together with NIS gave the desired product G1 in 93%
yield as the single β-anomer, along with the concomitant
formation of B as a by-product after stirring for only 10 min
(Table 1, entry 2). Other commercially available promoters were
screened, the results of which are listed in Table 1. Cu(OTf)2,
Bi(OTf)3, In(OTf)3, Sc(OTf)3 , and BF3OEt2 were found to be
less effective promoters (Table 1, entries 3-7) because the
reactions were sluggish and lower conversions were obtained
even after 24 h. Reducing the amount of TMSOTf to 0.05 equiv.
also resulted in a small decrease in yield (Table 1, entry 8).
Poorer yields of G1 were also obtained in THF(Table1, entry9),
toluene(Table 1, entry 10), and CH3CN(Table 1, entry 11) instead
of CH2Cl2 as the solvent.
Table 1. Optimizing the iodonium-promoted glycosylation reactiona
Entry
Promoter(equiv.)
None
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
Isolated yield (%)b
1
0
2
TMSOTf (0.1)
Cu(OTf)2 (0.1 )
Bi(OTf)3 (0.1 )
In(OTf)3 (0.1 )
Sc(OTf)3(0.1 )
BF3OEt2(0.1 )
TMSOTf (0.05)
TMSOTf (0.1)
TMSOTf (0.1)
TMSOTf (0.1)
93
32
47
40
28
64
72
66
59
81
3
4
5
6
7
8
9
10
CH3CN
11
Toluene
aReaction conditions: D1 (74 mg, 0.1 mmol), epiandrosterone (29 mg, 0.12mmol), a promoter, NIS
(27mg, 0.12mmol) and 4Å molecular sieves in solvent (2 mL) at -20 °C. Isolated yield based on D1.
Having established optimal reaction conditions, we turned our
attention to the scope of the reaction. Figure 2 reveals that fully
protected donors D1–6 react smoothly with a variety of acceptors
in consistently good yields (77–95%); these reactions proceeded

3
efficiently within 30 min at -20 °C. Acetals, alkenes, nitriles,
esters, azides, and carbamates were found to tolerate the
promoter. As expected, donors bearing directing substituents at
C2, such as acetyl or phthalimido groups, gave exclusively the 1,
2-trans-glycosides G2–14 due to the well-known neighbouring-
group effect. Glycosylation with donors bearing non-
participating substituents at C2 was also investigated. β-
Configured D6 reacted with cholesterol to predominately give the
α-glycoside G15 [15], which accounted for 80% of the anomeric
mixture. Among these synthesised glycosides, long-chain
glycosides bearing cyano (G2), halo (G6 and G7), and azido
(G8) groups are functional building blocks that are potentially
applicable to bioconjugation chemistry [16-19]. All coupling
reactions that formed disaccharides G9–14 were high yielding
(80–93%), irrespective of the position of the hydroxyl moiety and
the nature of the protecting group on the nucleophilic acceptor. In
particular, we also found that thioglycosides can be employed as
glycosyl acceptors, which led to the clean formation of
disaccharides G11 and G12. The latter type of glycosylation is
attractive because thioglycosyl products are expected to be
employed as donors in subsequent glycosylations using
appropriate thiophilic reagents, which offers a rapid strategy for
the assembly of oligosaccharides.
Figure 2. Glycosides accessed by the iodonium-promoted glycosylation of common alcohols with donor D1-6. Reagents and
conditions: donor (0.1 mmol), acceptor (0.12 mmol), TMSOTf (0.01 mmol), NIS(0.12 mmol)CH2Cl2 (2 mL) at -20 °C under Ar.
Isolated yields are based on the donor molar equivalent and the anomeric linkage as determined by NMR spectroscopy.

4
Tetrahedron
1576.
Based on the above results and previous reports [20], we propose
a plausible catalytic cycle (Scheme 1) that describes our
observations. TMSOTf, as a strong Lewis acid, interacts rapidly
with NIS at low temperature to provide an iodonium species,
which regioselectively adds in an electrophilic manner to the
olefinic bond in donor D to generate the intermediate A, which
then undergoes intermolecular nucleophilic attack by the
anomeric oxygen atom in an exo-trig manner to produce the
oxocarbenium ion C, with concomitant expulsion of the six-
membered by-product B. The oxocarbenium ion is a well-known
active species in glycosylations, and reacts with the nucleophilic
alcohol to deliver the product and H+, which is trapped by the
silylated succinimide to yield succimide and regenerate the
catalytically viable TMSOTf. It is notable that iodine smoothly
activates the glycosyl ortho-alkynylbenzoates without the aid of a
Lewis acid [13b], which demonstrates that they are much more
reactive donors for glycosylation than their ortho-allylbenzoate
counterparts.
[2] (a) Boltje, T. J.; Buskas, T.; Boons, G.-J. Nat. Chem. 2009, 1, 611;
(b) Bertozzi C. R.; Kiessling, L. L. Science, 2001, 291, 2357;(c)
Galonić, D. P.; Gin, D. Y. Nature, 2007, 446, 1000;(d) Seeberger,
P. H.and Werz, D. B. Nature, 2007, 446, 1046.
[3] For a representative review, see: Yu, B. Acc. Chem. Res. 2018, 51,
507.
[4] Li, Y.; Yang, Y.; Yu, B. Tetrahedron Lett. 2008, 49, 3604.
[5] Zhu, Y.; Yu, B.Chem. Eur. J. 2015, 21, 8771.
[6] For selected references on natural glycosides synthesis using
glycosyl ortho-alkynylbenzoates as donors, see: (a) Li, Y.; Yang,
X.; Liu, Y.; Zhu, C.; Yang, Y.; Yu, B. Chem. Eur. J. 2010, 16,
1871; (b) Zhu, Y.; Yu, B. Angew. Chem., Int. Ed. 2011, 50, 8329;
(c) Zhang, Q. ; Sun, J.; Zhu, Y.; Zhang, F. ; Yu, B. Angew. Chem.
Int. Ed. 2011, 50, 4933; (d) Yang, X.; Fu, B.; Yu, B. J. Am. Chem.
Soc. 2011, 133, 12433; (e) Nie, S.; Li, W.; Yu, B. J. Am. Chem.
Soc. 2014, 136, 4157; (f) Zhu, D.; Yu, B. J. Am. Chem. Soc. 2015,
137, 15098.
[7] For the synthesis of naturally occurring oligosaccharide using
glycosyl ortho-alkynylbenzoates as donors, see: Yang, Y; Yu, B.
J. Am. Chem.Soc.2009, 131, 12076.
[8] For selective references on other glycosylation protocols based on
the activation of alkyne-functionalities, see: (a)Hotha, S. and
Kashyap, S. J. Am. Chem. Soc. 2006, 128, 9620;(b) Kayastha, A.
K.; Hotha, S. Chem. Commun. 2012, 48, 7161;(c) Adhikari, S. ;
Baryal, K. N.; Zhu, D.; Li, X.; Zhu, J. ACS Catal. 2013, 3, 57;(d)
Mishra, B.; Neralkar, M.; Hotha, S. Angew. Chem., Int. Ed. 2016,
55, 7786.
[9] Wang, H.Y.; Simmons, C.J.; Blaszczyk, S.A.; Balzer, P.G.; Luo,
R.; Duan, X.; Tang, W. Angew. Chem., Int. Ed. 2017, 56, 15698.
[10] Imagawa, H.; Kinoshita, A.; Fukuyama, T.; Yamamoto, H.;
Nishizawa, M. Tetrahedron Lett.2006, 47, 4729; (b) Choi, T.J.;
Ju, Y.B.; Jeon, H.B.; Kim, K.S. Tetrahedron lett.2006, 47, 9191;
(c) Koppolu, S.R.; Niddana, R.; Balamurugan, R. Org. Biomol.
Chem. 2015, 13, 5094.
[11] Mishra, B.; Neralkar, M.; Hotha, S. Angew. Chem. Int. Ed. 2016,
55, 7786.
[12] Dowle, M. D.; Davies, D. I. Chem. Soc. Rev. 1979, 8,171.
[13] (a)Kunz, H.; Wernig, P.; Schultz, M. Synlett, 1991, 22, 631.
(b)Dutta, S.; Sarkar, S.; Gupta, S.J.; Sen, A.K. Tetrahedron
Lett.2013, 54, 865.
[14] Roux, M.C.; Paugam, R.; Rousseau, G. J. Org. Chem. 2001, 66,
4304.
[15] Schmidt, R. R.; Michel, J. J. Carbohydr. Chem. 1985, 4, 141.
[16] For a reference on nitrile-mediated bioconjugations, see: Jo,
H.; Culik, R.M.; Korendovych, I.V.; Degrado, W.F.; Gai, F.
Biochemistry, 2010, 49,10354.
[17] For selected reference on the chloride-mediated bioconjugation,
see: (a)Wu, L.; Sampson, N.S. ACS Chem Biol. 2014, 9, 468;
(b)Thiebault, N.; Lesur, D.; Godé, P.; Moreau, V.; Djedaïni-
Pilard, F. Carbohyd Res.2008, 343, 2719.
Scheme 1. Proposed glycosylation mechanism involving a
glycosyl o-allylbenzoates donor
Our preliminary study demonstrated that o-allylbenzoic acid is a
good anomeric ester precursor. The ortho-substituted aromatic
acid and the corresponding glycosyl ortho-allybenzoates are
easily accessible and bench-stable; these glycosyl esters are
highly reactive glycosylation donors. Herein, we demonstrated
the successful coupling, through iodonium-induced cyclisation of
glycosyl ortho-allylbenzoates, with a wide range of alcohols,
which offers a pathway for the synthesis of diverse glycosides in
high yields. Studies that investigate the generality of this protocol
and further evaluate the synthetic utility of the new anomeric
esters described herein are underway in our laboratory.
[18] For selected references on the bromide-mediated bioconjugation,
see: (a)Dahmén, J.; Frejd, T.; Grönberg,
G.; Lave,
T.; Magnusson, G. Carbohyd Res. 1983, 116, 303; (b) Dahmén,
J.; Frejd, T.; Grönberg, G.; Lave, T.; Magnusson, G.
Carbohydr. Res. 1982, 111, C1.
[19] For a review on the azide-mediated bioconjugation, see: Schilling,
C.I.; Jung, N.; Biskup, M.; Schepers, U.; Bräse, S. Chem. Soc.
Rev. 2011, 40, 4840.
[20] Hu, Y.; Yu, K.; Shi, L.-L.; Liu, L.; Sui, J.-J.; Liu, D.-Y.; Xiong,
B.; Sun, J.-S. J. Am. Chem. Soc. 2017, 139, 12736.
Acknowledgments
The work was supported by the National Science Foundation of
China (51501080, 21675070, 21405067 and 31670350), the
Natural Science Foundation of Gansu Province (18JR3RA282),
and the Fundamental Research Funds for the Central
Universities, Lanzhou University (lzujbky-2017-207, lzujbky-
2017-k24, lzujbky-2017-k25, and lzujbky-2018-134).
Supplementary Material
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
References and notes
[1] For seminal reviews on glycochemistry, see: (a) Danishefsky, S.
J.; Bilodeau, M. T. Angew. Chem. Int. Ed. Engl. 1996, 35, 1380;
(b) Davis, B. G. J. Chem. Soc. Perkin Trans. 1 2000, 2137; (c)
Seeberger, P. H.; Haase, W.-C. Chem. Rev. 2000, 100, 4349; (d)
Nicolaou, K. C.; Mitchell, H. Angew. Chem. Int. Ed. 2001, 40,

5
Click here to remove instruction text...

6
Tetrahedron
Highlights

Glycosyl ortho-allybenzoates functioning as novel
donors for glycosylation are easily accessible and
bench-stable.
NIS/TMSOTf-promoted

glycosylations
smoothly
proceed to afford the expected products in good
yields.
Good stereoselectivity was observed.
Method shows broad functional group compatability.

