Orthogonal One-Pot Synthesis of Oligosaccharides Based on Glycosyl ortho-Alkynylbenzoates

Article abstract of DOI:10.1021/acs.orglett.9b00617

One of the most popular one-pot glycosylation strategies is orthogonal one-pot synthesis, which was mainly based on thioglycosides. Despite its successful application, shortcomings of thioglycosides including aglycon transfers, interference of departing s

Full text of DOI:10.1021/acs.orglett.9b00617

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Orthogonal One-Pot Synthesis of Oligosaccharides Based on
Glycosyl ortho-Alkynylbenzoates
Yunqin Zhang, Guisheng Xiang, Shaojun He, Yikao Hu, Yanjun Liu, Lili Xu, and Guozhi Xiao*
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Kunming 650201, China
S
* Supporting Information
ABSTRACT: One of the most popular one-pot glycosylation strategies is orthogonal one-pot synthesis, which was mainly
based on thioglycosides. Despite its successful application, shortcomings of thioglycosides including aglycon transfers,
interference of departing species and unpleasant odor restrict its application scope. Herein, we report a new and efficient
orthogonal one-pot synthesis of oligosaccahrides based on glycosyl ortho-alkynylbenzoate, which solves the issues of
thioglycoside-based orthogonal one-pot synthesis. Over a dozen of oligosaccharides have been efficiently synthesized by this
method.
arbohydrates are essential biomolecules in living
glycosylation10 and preactivation-based iterative one-pot
Corganisms, which play such important roles in numerous glycosylation,11 among which orthogonal one-pot glycosylation
is particularly noteworthy. Glycosyl trichloroacetimidate
(TCAI) and thioglycoside pair,12 glycosyl N-phenyltrifluor-
oacetimidate (PTFAI) and thioglycoside pair,13 S-benzoxazolyl
(SBox) glycoside and thioglycoside pair,14 glycosyl bromide
and thioglycoside pair,15 together with glycosyl phosphites and
phosphates with thioglycoside pair16 had been utilized for two-
step, orthogonal one-pot synthesis of several oligosaccharides
and natural products.(Scheme 1) Despite its successful
application, the shortcomings inherent to thioglycosides
including the propensity of aglycon transfer,17 the high
electrophilic character of departing species18 and unpleasant
odor restrict its application scope. Furthermore, the number of
leaving groups that could be employed for multistep
orthogonal one-pot synthesis is still limited.19
In 2008, Yu’s group reported that a novel leaving group
ortho-alkynylbenzoate (ABz) could be activated by a catalytic
amount of gold(I) complexes.20a This venerable Yu glyco-
sylation enjoys mild and neutral glycosylation reaction
conditions and has been extensively utilized in the total
synthesis of complex glycosylated natural products as well as
assembly of complex oligosaccharides.20 We envisioned that
orthogonal one-pot synthesis of oligosaccharides based on
glycosyl ABz, with much less nucleophilicity compared with S-
glycosides as donor, stable isocoumarin as the departing
species of the leaving group, and odor-free ortho-alkynylben-
biological processes as immune response, viral and bacterial
infection, and cell growth and proliferation.1 In comparison
with the gene-regulated synthesis of DNA and proteins,
biosynthesis of oligosaccharides is a nontemplate-driven and
stepwise process via post-translational modification in the
Golgi apparatus and endoplasmic reticulum, which results in
highly heterogeneous and extremely diverse carbohydrate
structures.2 It is a formidable task to isolate pure and
homogeneous glycans from natural resources. Chemical
synthesis is an effective means to obtain well-defined glycans
for deciphering their functions and developing new therapeutic
reagents.3 During the past three decades, many novel methods
and strategies have been developed to streamline the chemical
synthesis of oligosaccharides, such as automated chemical
synthesis,4 one-pot glycosylation strategies,5 latent-active
glycosylation,6 and orthogonal glycosylation,7 among which
one-pot glycosylation strategies are particularly attractive.
Unlike traditional glycosylation methods, which require
tedious protection and deprotection manipulations during
assembly of oligosaccharides, one-pot glycosylation strategies
not only omit glycosylation-interval workups and intermediates
purifications but also greatly reduce chemical wastes and highly
accelerate oligosaccharide synthesis. Nevertheless, it is still
highly challenging to perform one-pot synthesis of oligosac-
charides due to the regio- and stereochemical issues during
oligosaccharide synthesis.5,8
In general, one-pot glycosylation strategies mainly include
Received: February 18, 2019
reactivity-based one-pot glycosylation,9 orthogonal one-pot
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00617
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Strategies of Orthogonal One-Pot Synthesis of
Oligosaccharides
Table 1. Selective Activation of Other Leaving Groups over
the ABz Leaving Group
zoic acid as starting material may solve the issues associated
with thioglycoside-based two-step orthogonal one-pot syn-
thesis (Scheme 1).
Herein, we report a new and highly efficient orthogonal one-
pot method for synthesis of oligosaccharides on the basis of
glycosyl ABz, which overcomes the limitations of thioglyco-
side-based orthogonal one-pot synthesis. Over a dozen of
oligosaccharides had been highly efficiently synthesized by this
method, which highly streamlines the chemical synthesis of
oligosaccharides.
Table 2. Selective Activation of Glycosyl ABz over Other
Leaving Groups
As shown in Scheme 1, orthogonal one-pot glycosylation
that involves sequential and selective activation of different
leaving groups LG1, LG2, and LG3 in the same reaction vessel
allows the expeditious synthesis of oligosaccharides, which is
independent of reactivities of the building blocks. We reasoned
that two criteria must be met for this successful orthogonal
one-pot glycosylation: (1) the leaving group LGn+1 must be
stable in the activation of the previous leaving group LGn with
the promoter n; (2) byproducts obtained from the activation
should not interfere with glycosylations.
To this end, we embarked on the investigation of the
orthogonality of glycosyl ABz with the other leaving groups.
First, we fixed glycosyl ABz as the bifunctional acceptor, which
bears the free hydroxyl group and the activatable leaving group
(Table 1). A variety of glycosyl donors were screened,
including glycosyl TCAI,21 glycosyl PTFAI,22 p-toluene
thioglycoside (STol),23 SBox glycoside,24 STaz glycoside,25
and glycosyl isoquinoline-1-carboxylate (IQC).26 The results
showed that the bifunctional acceptor glycosyl ABz 2 was
stable under the activation conditions for TCAI 1a and PTFAI
1b (cat. TMSOTf), SBox 1c (AgOTf), STaz 1d (MeOTf), and
IQC 1e [Cu(OTf)2], providing the ABz disaccharides 3a−3d
in excellent yields. No self-condensation products were
detected. However, coupling of STol thioglycoside with the
glycosyl ABz 2 under the activation conditions such as NIS/
TMSOTf and Ph3Bi(OTf)2 failed to provide the desired
disaccharide.
thioglycosides such as armed thioglycosides were used as the
bifunctional acceptor, unsatisfactory results were obtained
(Supporting Information), which indicated the issues inherent
to thioglycosides such as undesired intermolecular aglycon
transfers.17 Both disarmed n-Pen 5b and armed n-Pen 5c were
glycosylated with glucosyl ABz 4 smoothly under the catalysis
of PPh3AuOTf at room temperature, producing n-Pen
disaccharide 6b and 6c, respectively, in excellent yields (entries
2−3).27
Having examined the orthogonality of glycosyl ABz with the
other leaving groups, we next focused on the orthogonal one-
pot synthesis of oligosaccharides (Scheme 2). For the glycosyl
TCAI and ABz pair, glycosylation of TCAI 1a (1.2 equiv) with
ABz 7 (1.0 equiv) under the activation of TMSOTf afforded
the intermediate, which was further coupled with the acceptor
Next, we investigated whether glycosyl ABz could be
coupled under the catalysis of a gold(I) complex with the
other bifunctional acceptors (Table 2). Glycosylation of
glucosyl ABz 4 with the disarmed thioglycoside 5a under the
activation of PPh3AuOTf at −15 °C afforded thioglycoside 6a
in an excellent yield (85%). However, when the other
B
DOI: 10.1021/acs.orglett.9b00617
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Scheme 2. Orthogonal One-Pot Synthesis of Oligosaccharides Based on Glycosyl ABz
8 (0.9 equiv) under the catalysis of PPh3AuOTf, affording
trisaccharide 21 in 89% yield in one pot. For the glycosyl
PTFAI and ABz pair, using the above similar procedures,
trisaccharide 22 was obtained in 95% yield by successive
coupling of PTFAI 9, ABz 7, and acceptor 10 in one pot.
Trisaccharide 24 is the glycosphingolipid analogue of isoGb3,
which was discovered as a key endogenous human NKT cell’s
antigen.28 Sequential glycosylation of PTFAI 1b, ABz 11, and
4-OH acceptor 12 in the same pot generated 24 in 70% yield
with excellent stereoselectivity. Replacing the above acceptor
12 with the poor 4-OH glucosaminyl acceptor 13 generated
trisaccharide 25 in one pot with a 63% yield, which was
identified as an α-Gal epitope that could induce acute
rejections during xenotransplantations.29 For the SBox glyco-
side and glycosyl ABz pair, AgOTf was used to activate SBox
1c (1.2 equiv) over ABz 2 (1.0 equiv), followed by the
addition of acceptor 14 (0.9 equiv) and the catalyst
PPh3AuOTf, affording trisaccharide 26 efficiently in one pot
in 86% yield. The above procedure was employed to
sequentially assemble building blocks 15, 7, and 5b, generating
trisaccharide 27 in one pot with an 84% yield. The key
intermediate of S. pneumonia type 3 trisaccharide 2830 was
obtained in 62% yield in one pot by exchanging the above
acceptor 5b for 4-OH acceptor 12. For the STaz glycoside and
glycosyl ABz pair, coupling of STaz 1d (1.2 equiv) with ABz 2
(1.0 equiv) under the activation of MeOTf, followed by Yu
glycosylation with the acceptor 16 (0.9 equiv) in the same pot,
produced trisacchairde 29 in 70% yield. For the glycosyl IQC
and ABz pair, although ABz 2 was stable in the activation of
IQC 1e with Cu(OTf)2, one-pot synthesis was unsuccessful
due to the interference of the departing species IQC copper
salt in the gold-catalyzed glycosylation reaction. For the
C
DOI: 10.1021/acs.orglett.9b00617
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glycosyl ABz and n-Pen glycoside pair, Yu glycosylation
between ABz 4 (1.2 equiv) and n-Pen 5b (1.0 equiv) provided
the intermediate, which was further coupled with acceptor 17
(0.9 equiv) under the promotion of NIS and TMSOTf,
generating trisaccharide 30 in one pot with an 83% yield.
Trisaccharide motif 31 occurs in complex N-glycoprotein
structures with two challenging Gal-β1,4-GlcNAc and GlcNAc-
β1,2-Man linkages. Following the above similar procedure,
successive glycosylation of ABz 18, 4-OH n-Pen 13, and 2-OH
mannosyl acceptor 19 in the same pot afforded trisaccharide
31 in excellent 80% yield, which had been synthesized
previously in moderate 54% overall yield by a preactivation-
based one-pot method requiring low reaction temperature
(−60 °C to rt) conditions.11
protein structures, and a hexa-β-glucoside motif in phytoalexin
elicitor β-glucan structures had been highly efficiently
synthesized by this method, which highly streamlines the
chemical synthesis of oligosaccharides.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00617.
Experimental procedures and characterization data
(PDF)
Finally, we investigated the multistep orthogonal one-pot
synthesis of oligosaccharides (Scheme 2). Sulfated derivatives
of tetrasaccharide 32 show significant proangiogenic activity.31
Selective activation of TCAI 1a (1.3 equiv) over ABz 2 (1.0
equiv) under the catalysis of TMSOTf provided the
disaccharide intermediate, which was further coupled with
disarmed STol 5a (0.9 equiv) under the catalytic amount of
PPh3AuOTf, affording the trisaccharide intermediate. The
above intermediate was further coupled with the acceptor 17
(0.9 equiv) under the promotion of NIS and TMSOTf to
generate tetrasaccharide 32 in one pot with an excellent 82%
yield, which had been synthesized previously in only 39%
overall yield by stepwise glycosylation.26 For the SBox
glycoside, glycosyl ABz, and n-Pen glycoside triplet, orthogonal
glycosylation between SBox 15 (1.2 equiv) and ABz 20 (1.0
equiv) under the activation of AgOTf produced the
disaccharide intermediate, which was followed by Yu
glycosylation with n-pen 5b (0.9 equiv), providing the
trisaccharide intermediate. The above trisaccharide was further
assembled with acceptor 17 (0.9 equiv) under the promotion
of NIS/TMSOTf, generating tetrasaccharide 33 in 75% yield
in one pot, which was comparable to the previous one-pot
synthesis of 33 with a 73% overall yield.19b Hexasaccharide
motif 34 occurs in fungal β-glucan oligosaccharide structures,
which could induce antibiotic phytoalexins in the soybean
plant.32 Selective coupling of PTFAI 9 (1.3 equiv) with ABz 7
(1.0 equiv) in the presence of TMSOTf afforded the
disaccharide intermediate, which was further glycosylated
with n-Pen 5b (0.9 equiv) under Yu glycosylation conditions
to generate a trisaccharide intermediate. Acceptor 23 (0.9
equiv) obtained from trisaccharide 22 was further coupled with
the above trisaccharide intermediate under the activation of
NIS and TMSOTf, producing hexasaccharide 34 in 67% yield
in a one-pot manner. The analogue of hexasaccharide 34 had
been synthesized previously by an automated solid-phase
method, which required an excess of each building block (15
equiv) for glycosylation reactions.4c
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xiaoguozhi@mail.kib.ac.cn.
ORCID
Guozhi Xiao: 0000-0002-4724-4390
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are thankful for financial support from the CAS Pioneer
Hundred Talents Program (No. 2017-128) and the Start-up
funding of Kunming Institute of Botany. This paper is
dedicated to Professor Yongzheng Hui (Shanghai Institute of
Organic Chemistry) on the occasion of his 80th birthday. We
thank Professor Biao Yu (Shanghai Institute of Organic
Chemistry) and Professor Weiping Tang (University of
WisconsinMadison) for helpful discussions.
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