Isoquinoline-1-Carboxylate as a Traceless Leaving Group for Chelation-Assisted Glycosylation under Mild and Neutral Reaction Conditions

Article abstract of DOI:10.1002/anie.201708920

Glycosyl isoquinoline-1-carboxylate was developed as a novel benchtop stable and readily available glycosyl donor. The glycosylation reaction was promoted by the inexpensive Cu(OTf)₂ salt under mild reaction conditions. The copper isoquinoline-1-carboxylate salt was precipitated from the solution and thus rendered a traceless leaving group. Surprisingly, the proton from the acceptor was absorbed by the precipitated metal complex and the reaction mixture remained at neutral pH. The copper-promoted glycosylation was also proven to be completely orthogonal to the gold-promoted glycosylation, and an iterative synthesis of oligosaccharides from benchtop stable anomeric ester building blocks becomes possible under mild reaction conditions.

Full text of DOI:10.1002/anie.201708920

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Accepted Article
Title: Isoquinoline-1-carboxylate as a Traceless Leaving Group for
Chelation-Assisted Glycosylation under Mild Neutral Conditions
Authors: Hao-Yuan Wang, CHRISTOPHER J SIMMONS, STEPHANIE
ANN BLASZCZYK, Paul G. Balzer, Renshi Luo, XIYAN
DUAN, and Weiping Tang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201708920
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10.1002/anie.201708920
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Isoquinoline-1-carboxylate as a Traceless Leaving Group for
Chelation-Assisted Glycosylation under Mild Neutral Conditions
Hao-Yuan Wang, Christopher J. Simmons, Stephanie A. Blaszczyk, Paul G. Balzer, Renshi Luo, Xiyan
Duan and Weiping Tang*
Abstract: Glycosyl Isoquinoline-1-carboxylate was developed as a
novel benchtop stable and readily available glycosyl donor. The
glycosylation reaction was promoted by inexpensive Cu(OTf)2 salt
under very mild conditions. The copper isoquinoline-1-carboxylate
salt was precipitated from the solution and rendered it as a traceless
leaving group. Surprisingly, the proton from the acceptor was
absorbed by the precipitated metal complex and the reaction mixture
remained neutral. The copper-promoted glycosylation was also
proven to be completely orthogonal to the gold-promoted
glycosylation and an iterative synthesis of oligosaccharides from
benchtop stable anomeric ester building blocks becomes possible
under mild conditions.
elucidated subsequently.[8] This mild glycosylation reaction avoids
strong acidic, nucleophilic, or electrophilic conditions and is
orthogonal to most other glycosyl donors. It has become one of
the preferred glycosylation methods for the synthesis of complex
oligosaccharides and glycosylated natural products.[9] Other
related anomeric esters or carbonates bearing a remote alkyne
were also developed as glycosyl donors.[10] In all cases,
byproducts associated with the leaving group such as 5 need to
be separated from the desired product 2.
We envisioned that a transition metal complex might be able
to chelate[11] to an appropriately designed anomeric ester 6 to
form salt 7, which could be precipitated from the solution under
mild conditions. If byproducts associated with the leaving group
become undetectable in the solution by NMR, the leaving group
can be considered as a “traceless leaving group”. This strategy
would leave 2 as the major product in the reaction system and
greatly facilitate automated solution phase synthesis of libraries
of oligosaccharides.[12] This new glycosylation reaction is likely
orthogonal to the Au(I)-promoted process.
Carbohydrates are essential in numerous fundamentally
important biological events such as immunological responses,
cancer metastasis, and bacterial or viral infections.[1] Chemical
synthesis of oligosaccharides and glycoconjugates is crucial to
decipher the complex carbohydrate-mediated biological events
and develop novel therapeutics.[2] Numerous efficient and
stereoselective glycosylation methods have been developed in
the past century.[3] However, most of these methods require
strong Lewis acids, Brønsted acids, or reactive electrophiles.
Stable glycosyl donors that can be activated under mild and
neutral conditions are still rare but highly desirable.[4]
Anomeric esters are attractive glycosyl donors as they are
easy to prepare and generally benchtop stable. However, simple
anomeric esters such as glycosyl acetates have not been widely
used as glycosyl donors in the synthesis of oligosaccharides and
glycoconjugates due to their low reactivity. The activation of
anomeric ester donors generally requires harsh conditions that
are not applicable to complex substrates. Practical glycosylation
conditions were developed in the 1990’s for anomeric esters with
a remote alkene and later with alkyne or allene (e.g. 1, Scheme
1), all of which could be activated by electrophiles.[5] In addition to
the desired product 2, byproduct 3 is also generated, and it often
reacts with glycosyl acceptor nucleophiles.[6] In 2008,[7] Yu
Scheme 1. Readily Available and Stable Anomeric Ester Glycosyl Donors
reported that anomeric esters bearing
a
novel ortho-
alkynylbenzoate such as 4 could be activated by gold (I)
complexes. The mechanistic details of this elegant method were
To this end, we examined various anomeric esters with
chelating ability and different types of transition metal complexes
for glycosylation. As early as 1991, glycosyl pyridine-2-
carboxylates or picolinic esters were introduced to armed glycosyl
donors[13] for glycosylations, and they yielded a mixture of α- and
β-isomeric products in low selectivity.[14] However, picolinic esters
have rarely been applied to the synthesis of oligosaccharides as
general glycosyl donors. We found that disarmed donors bearing
an anomeric picolinic ester such as 8a could be activated by 60
mol% of Cu(OTf)2 to afford only β-isomeric product 9a in 81%
yield (Scheme 2A). Interestingly, when the amount of Cu(OTf)2
was decreased to 40 mol% or increased to 240 mol %, lower
conversions were observed. Other anomeric esters such as
[a]
[b]
H.-Y. Wang, P. G. Balzer, Dr. R. Luo, Dr. X. Duan, Prof. Dr. W. Tang
Pharmaceutical Sciences Division, School of Pharmacy
University of Wisconsin-Madison
777 Highland Avenue, Madison, WI 53705 (USA)
E-mail: weiping.tang@wisc.edu
C. J. Simmons, S. A. Blaszczyk, Prof. Dr. W. Tang
Department of Chemistry
University of Wisconsin-Madison
1101 University Avenue, Madison, WI 53706 (USA)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201708920
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glycosyl 3- or 4-pyridinecarboxylates and glycosyl 2-
pyridylacetates could not be activated by various metal
complexes for glycosylation, suggesting that chelation via a five-
membered ring in a conjugated system is critical for the activation.
When we began to examine the scope of glycosyl donors and
acceptors using picolinic ester as the leaving group, we quickly
realized that significant amount of transesterification byproducts
often accompanied the glycosylation products. For example, only
45% yield of the desired product 10b was obtained for disarmed
donor 8b and acceptor 9b. Transesterification byproduct 11 was
isolated in as much as 38% yield.
the attack of alcohol ROH to the carbonyl carbon and minimize
the formation of transesterification byproduct.
After examining various commercially available pyridine-2-
carboyxlic acids with a 3-substituent, isoquinoline-1-carboxylic
acid was identified as the most affordable (e.g. $80/100g from Ark
Pharm, Inc.) reagent with a bulky “3-substituent”. Isoquinoline-1-
carboxylate (IQC) esters 14a and 14b were easily prepared from
the corresponding lactols (Scheme 2C). The desired glycosylation
products 10a and 10b were isolated in high yields by using 60
mol% of Cu(OTf)2. Lower conversions were observed with less
copper salt. We did not observe any transesterification
byproducts in these two cases. No byproduct associated with the
leaving group was observed by NMR after removing the solid
material including molecular sieves by filtration, suggesting that
the IQC copper salt is rather insoluble in DCM and IQC can be
considered a traceless leaving group. We also examined the
corresponding quinoline-2-carboxylate donors and obtained
much lower yields of the glycosylation products.
To better understand the relative reactivity of anomeric
picolinic and IQC esters, we performed a competition experiment
between glycosyl donors 8a and 14a (Scheme 2D). Surprisingly,
only 14a was able to react when both donors were treated with
1.0 equiv. of acceptor 9a. We could isolate disaccharide product
10a in greater than 95% yield and the unreacted 8a in 99% yield.
This indicated that our newly designed IQC glycosyl donor was
far more reactive than picolinic ester. We also stored IQC ester
14a at room temperature under air for months and no
decomposition was observed, indicating excellent stability.
We then explored the general scope of Cu(OTf)2-mediated
glycosylation using IQC glycosyl donors (Table 1). As previously
discussed, high yields and high selectivity were observed for the
formation of products 10a and 10b from mannosyl or glucosyl IQC
donors 14a/14b and primary alcohols 9a/9b. When these
disarmed glycosyl donors reacted with secondary alcohols, lower
yields were obtained in the presence of 60 mol% Cu(OTf)2. The
rate of glycosylation was slower in these cases and hydrolysis
became competitive. By increasing the amount of copper salts to
120 mol %, we were able to improve the yields of products 10c
and 10d by nearly 20%.
Product 10e could be obtained in high yield by using phenol
as the glycosyl acceptor. Other pyranose IQC donors, such as
those derived from L-fucose (e.g. donor of 10f and 10g), galactose
(e.g. donor of 10h, 10i and 10j), xylose (e.g. donor of 10k), and
furanose IQC donors, such as those derived from ribose (e.g.
donor of 10l) could all react with diverse range of glycosyl
acceptors to yield β-isomeric products exclusively, through the
participation of a neighbouring group. The 6-OH of GlcNAc is
generally considered as a poor glycosyl acceptor.[15] Using our
method, we prepared 10h in 77% yield. For comparison, products
10i and 10h were prepared in 89% and 64% yields, respectively,
using the corresponding trichloroacetimidate glycosyl donor.
Scheme 2. Identification of General and Highly Reactive Benchtop Stable
Glycosyl Donors with a Traceless Leaving Group
Clearly, the chelation of Cu2+ to picolinic ester 12 not only
weakens the anomeric C-O bond towards glycosylation via path
a, but also activates the carbonyl group towards nucleophilic
attack via path b (Scheme 2B). We envisioned that a bulky RL
substituent on the 3-position of the picolinic ester 13 might block
Both armed and superarmed glucosyl donors[16] are also
viable substrates, and products 10m and 10n were isolated in
high yields. As expected, while only β-product 10n was observed
in the latter case, a mixture of isomeric products was obtained in
the former case. A serine derivative can also be glucosylated
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smoothly to yield product 10o. Product 10p was prepared in
nearly a quantitative yield from a 2-deoxy sugar glycosyl donor.
free TfOH was not formed during the glycosylation. It has been
reported that copper bispicolinic carboxylate can form 1:1 or 1:2
adducts with water, KSCN, or thiourea in different crystal forms.[17]
We propose that IQC-copper complexes co-precipitate with TfOH
from the solution after glycosylation under conditions a) or b) in
Table 1, respectively (See Scheme S1 in SI).
Table 1. Scope of Cu(OTf)2-Mediated Glycosylation
Glycosylation using orthogonal leaving groups is one of the
most efficient strategies for the assembly of oligosaccharides in
solution.[18] However, it remains underdeveloped with limited
known examples that are completely orthogonal.[19] There are
even less examples of stable orthogonal glycosyl donors that can
be activated under mild neutral conditions.
Both our IQC and Yu’s esters are stable glycosyl donors that
can be activated under mild and neutral conditions. These two
donors may become an ideal pair if they are orthogonal to each
other. We then tested this strategy in the synthesis of
tetrasaccharide 18, whose sulfated derivatives possessed potent
proangiogenic activity (Scheme 3).[20] Yu’s donor 15 and our
donor 14a were mixed together with acceptor 9a and treated with
Au(I) and Cu(II) complexes under Yu’s and our conditions,
respectively. Under our conditions, we obtained product 10a in a
78% yield and 15 was recovered. Under Yu’s condition, we
isolated product 10b in a 75% yield and 14a was recovered.
Based on the complete orthogonality of the two anomeric esters,
we accomplished an iterative synthesis of tetrasaccharide 18 in
three steps from four different building blocks. Two of the three
glycosylations were promoted by Cu(II) and one of them was
mediated by Au(I). Only 21% or 63% yields were obtained for the
corresponding trisaccharide with 10 mol% or 50 mol% of Au(I)
complex, respectively. The loading of Au(I) complex needs to be
increased to 1.0 equivalent to achieve the 69% yield.
If the proton on the acceptor is in the free TfOH form after the
formation of copper-IQC complex during glycosylation, the
resuling solution should be relatively acidic. We were surprised to
find that the pH value of the solution after glycosylation was
between 6 and 7. To exclude the effect of molecular sieves, we
also mixed IQC acid with Cu(OTf)2 in either 2:1 or 1:1 ratios in
DCM under the same concentration as the reaction conditions,
and the pH values of the resulting solutions were both close to
neutral. Under the same conditions, the pH value of IQC acid
alone in DCM was between 2 and 3. The details of these
experiments are summarized in SI. These results indicated that
Scheme 3. Iterative Synthesis Based on Orthogonal Glycosyl Esters
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b) E. A. Mensah, F. Yu, H. M. Nguyen, J. Am. Chem. Soc. 2010, 132,
14288.
In summary, we have developed a novel stable glycosyl donor
with a traceless IQC leaving group that can be activated by
Cu(OTf)2 for glycosylation under neutral and extremely mild
conditions. Mechanistic studies revealed that TfOH was co-
precipitated with copper-IQC salts. We also demonstrated the
broad scope of the glycosylation donor in over a dozen examples
and its orthogonality with Yu’s donor in a streamlined iterative
synthesis of oligosaccharides.
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Keywords: glycosylation • carbohydrate • transition metal •
traceless • orthogonal
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Hao-Yuan Wang, Christopher J.
Simmons, Stephanie A. Blaszczyk, Paul
G. Balzer, Renshi Luo, Xiyan Duan and
Weiping Tang*
Page No. – Page No.
Title: Isoquinoline-1-carboxylate as a
Traceless Leaving Group for
Chelation-Assisted Glycosylation
under Mild Neutral Conditions
A new glycosyl ester donor was developed with many advantages: readily
available, benchtop stable, very reactive upon chelation to inexpensive copper salts
under mild and neutral conditions, orthogonal to other glycosyl esters, with a
traceless leaving group and broad substrate scope.
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