A General Approach to O-Sulfation by a Sulfur(VI) Fluoride Exchange Reaction

Article abstract of DOI:10.1002/anie.202007211

O-sulfation is an important chemical code widely existing in bioactive molecules, but the scalable and facile synthesis of complex bioactive molecules carrying O-sulfates remains challenging. Reported here is a general approach to O-sulfation by the sulfur(VI) fluoride exchange (SuFEx) reaction between aryl fluorosulfates and silylated hydroxy groups. Efficient sulfate diester formation was achieved through systematic optimization of the electronic properties of aryl fluorosulfates. The versatility of this O-sulfation strategy was demonstrated in the scalable syntheses of a variety of complex molecules carrying sulfate diesters at various positions, including monosaccharides, disaccharides, an amino acid, and a steroid. Selective hydrolytic and hydrogenolytic removal of the aryl masking groups from sulfate diesters yielded the corresponding O-sulfate products in excellent yields. This strategy provides a powerful tool for the synthesis of O-sulfate bioactive compounds.

Full text of DOI:10.1002/anie.202007211

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Accepted Article
Title: A General Approach to O-Sulfation via Sulfur(VI) Fluoride
Exchange Reaction
Authors: Chao Liu, Cangjie Yang, Seung Hwang, Samantha L. Ferraro,
James P. Flynn, and Jia Niu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202007211
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A General Approach to O-Sulfation via Sulfur(VI) Fluoride
Exchange Reaction
Chao Liu+, Cangjie Yang+, Seung Hwang, Samantha L. Ferraro, James P. Flynn, Jia Niu*
[a]
[+]
Chao Liu, Dr. Cangjie Yang, Seung Hwang, Samantha L. Ferraro, James P. Flynn, Prof. Dr. Jia Niu
Department of Chemistry
Boston College
Chestnut Hill, Massachusetts 02467, United States,
E-mail: jia.niu@bc.edu
These authors contribute equally to this work.
Supporting information for this article is given via a link at the end of the document
Abstract: O-Sulfation is an important chemical code widely existing
in bioactive molecules, but the scalable and facile synthesis of
complex bioactive molecules carrying O-sulfation remains
challenging. Herein, we report a general approach to O-sulfation via
the Sulfur (VI) Fluoride Exchange (SuFEx) reaction between aryl
fluorosulfates and silylated hydroxyl groups. Efficient sulfate diester
formation was achieved through systematic optimization of the
electronic properties of aryl fluorosulfates. The versatility of this O-
sulfation strategy was demonstrated in the scalable syntheses of a
variety of complex molecules carrying sulfate diesters at various
positions, including monosaccharides, disaccharides, amino acid,
and steroid. Selective hydrolytic and hydrogenolytic removal of the
aryl masking groups from sulfate diesters yielded the corresponding
O-sulfated products in excellent yields. This strategy provides a
powerful tool for the synthesis of O-sulfated bioactive compounds.
in the final step (Figure 1B). Penney and Perlin first reported the
phenyl sulfate diester as a precursor of O-sulfation,[8] but their
method necessitated chemically labile reagents, harsh reaction
conditions, and long reaction time. Further optimization of the
reactivity and stability of the phenyl sulfate diester was not
explored, either. Since this seminal work, other sulfate diesters
were employed in early-stage O-sulfation approaches, including
those with neopentyl (nP),[9] isobutyl (iBu),[9] trifluoroethylene
(TFE),[10] and 2, 2, 2-trichloroethylene (TCE)[11] groups. However,
incompatibility with common reaction conditions and the
deactivating effect on the modified carbohydrate substrates in
glycosylation limited their utility in the synthesis of O-sulfated
complex carbohydrates.[12] Recently, enzymatic O-sulfation by
sulfotransferases emerged as
a promising strategy with
excellent yields and regioselectivity (Figure 1C).[13] However, the
stringent specificity of sulfotransferase enzymes has caused the
inflexible reaction sequence in polysulfation[13b] and limited
substrate scope. The highly polar O-sulfated carbohydrates from
enzymatic reactions also required high-resolution purification
techniques.[13d]
O-Sulfation widely exists in polysaccharides, liposaccharides,
peptides, proteins, marine natural products, and drug
metabolites in nature (Figure 1A). The spatiotemporal
distribution of the O-sulfation in these molecules plays important
roles in a variety of biological activities such as telomerase
Reported by Sharpless and coworkers in 2014, the SuFEx
reaction has been employed to prepare a myriad of sulfate
diesters.[14] We envisioned that the SuFEx reaction between an
aliphatic or aromatic silylether and an aryl fluorosulfate could
serve as a general early-stage O-sulfation approach to site-
specifically install sulfate diesters onto carbohydrate and non-
carbohydrate substrates (Figure 1D). Subsequent selective
deprotection of the aryl sulfate monoester would lead to the
desired O-sulfated compounds. Compared to the existing
chemical and enzymatic O-sulfation strategies, advantages of
this approach include the ability to balance stability and reactivity
to accommodate different substrates and achieve efficient
deprotection.
We first investigated the model reaction between trimethylsilyl
(TMS)-protected galactopyranose (1)[15] and substituted aryl
fluorosulfates (Figure 2A). Aryl fluorosulfates 2a-j carrying
variable substitutions ranging from strongly electron-withdrawing
groups to electron-donating groups were readily prepared from
corresponding phenols (Table S1).[14c,d] A systematic screening
identified that 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
efficiently catalyzed the coupling of 1 with 2a-f carrying electron-
inhibition,[1]
cell
signaling,[2]
anticoagulation,[3]
drug
detoxification,[4] and cancer metastasis.[5] However, the lack of
synthetic tools for efficient and scalable O-sulfation imposes a
significant constraint on our abilities to access bioactive
molecules carrying complex sulfation patterns and use them to
study the structure-function relationships of the sulfate
modifications in biology.
To date, sulfur trioxide-nitrogen base remains the most
common chemical reagent to introduce O-sulfation to a variety
of substrates (Figure 1B).[6] O-Sulfation using this reagent can
only be performed at the late stage of synthesis due to the
challenging purification of the highly polar O-sulfated products
and their chemical instability. These challenges are frequently
exacerbated in the synthesis of polysulfated compounds of
which O-sulfation at multiple residues are targeted.[7] Efforts to
address these deficiencies have led to the development of the
so-called “early-stage” sulfation strategies, in which targeted
hydroxyl groups were converted to sulfate diesters at the early
stage of synthesis that were deprotected to generate O-sulfate
1
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Figure 1. Significance of O-sulfation and approaches to O-sulfation in carbohydrate and other substrates.
withdrawing substitutions, providing 3a-f in excellent yields
(Figure 2B and Table S2). In contrast, the coupling of 1 with 2g-
j carrying electron-neutral or electron-donating substitutions
were sluggish, affording 3g-j in modest to low yields from 76%
to 29%. These results suggested that the reaction rates
positively correlated with the electron deficiency of the aryl
fluorosulfates. The SuFEx reactivity of the electron-rich aryl
fluorosulfates
could
be
improved
when
1,5,7-
triazabicyclo[4.4.0]dec-5-ene (TBD)[16] was used as the catalyst
(e.g., 2i in Figure 2B and Table S3).
We then sought to generate the desired 6-O-sulfated
galactose (4) through the selective deprotection of the aryl
groups in 3a-j. Previous studies have shown that the fission rate
of the two S–O bonds in a sulfate diester is determined by the
2
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Figure 2. Synthesis of aryl sulfate diesters as protected O-sulfation.
pKa difference between the two leaving groups.[17] Consistently,
we observed that 4 was efficiently generated as the sole product
when 3a-d carrying strongly electron-withdrawing groups were
treated with 5 M sodium methoxide in methanol at room
temperature (Figure 2B and Table S4). In contrast, the hydrolysis
of 3e-j carrying weak electron-withdrawing or electron-neutral
groups was inefficient (Figure 2B and Figures S1-S2. See Figure
S3 for mechanistic analysis).
Concerns over undesired side reactions caused by strong
base treatment[18] prompted us to investigate an alternative
deprotection strategy. Penny and Perlin first reported
hydrogenolysis of phenyl sulfate monoester using PtO2 and
hydrogen gas (H2) in modest yields.[8] Inspired by this work, we
studied the selective hydrogenolysis of the aryl sulfate
monoester in glycosyl aryl sulfate diesters by Pd(OH)2/C/H2, and
observed high deprotection efficiency in an
3
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Figure 3. Compatibility of aryl sulfate diesters to common reagents used in carbohydrate and peptide chemistries.
acetonitrile/methanol/water solution of phosphate salts (Table
S5). Notably, this condition is insensitive to the electronic
properties of the aryl substitution, yielding 4 from all substrates
3a-j in excellent yields at room temperature (Figure 2B). Gas
chromatography-mass spectrometry (GC-MS) analysis of the
hydrogenolysis reaction revealed a mechanism of oxidative
addition of palladium into the aryl C–O bond followed by the
reductive elimination of arenes (Figures S4-S6), as opposed to
the previously proposed mechanism of hydrogenation of the aryl
group followed by S–O bond fission to release cyclohexanol.[8]
Our observation that hydrogen gas can be replaced by
ammonium formate, a far less potent hydrogenation agent,
without affecting the hydrogenolysis efficiency, further proved
the oxidative addition-reductive elimination mechanism (Figure
S7).[19]
position of methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside by
reacting with 2a generated an ether byproduct methyl 2,3,4-tri-
O-benzyl-6-O-(p-nitrophenyl)-α-D-glucopyranoside along with
the targeted sulfate diester. We attributed this side reaction to
the susceptibility of the electron-deficient sulfate diesters to
nucleophiles. Indeed, O-6 substitution using 2e provided sulfate
diesters 5 and 6 in 70% and 78% yields, respectively, without
ether formation. Furthermore, O-6 substitution of the glucosyl
thiol donor required 2j carrying the strongly electron-donating p-
methoxy group, affording 7 in 72% yield. In these reactions, we
also discovered that aryl fluorosulfates remained stable in the
presence of silylethers before the introduction of organobase
catalysts, making it possible for a one-pot procedure combining
in situ hydroxyl silylation by hexamethyldisilazane (HMDS)[20]
and the subsequent SuFEx reaction. Following the one-pot
procedure, sulfate diesters 8 was prepared in 77% yield. No
major difference in reaction efficiency was found between the
stepwise and one-pot procedures, as shown in the preparation
Our subsequent investigation was focused on the feasibility of
this strategy for a variety of substrates (Figure 2C). Initial
attempts to install p-nitrophenyl sulfate diester onto the O-6
4
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Figure 4. Preparation of O-sulfated complex molecules.
of 9a and 14a. In addition to simplifying the operation, the one-
pot procedure could also circumvent the challenge to isolate
TMS silylethers that are often unstable on silica gel
chromatography. Other silylether protecting groups, such as tert-
butyldimethylsilyl (TBS) in 9a and tert-butyldiphenylsilyl (TBDPS)
in 9b, remained stable in both stepwise and one-pot procedures.
Sulfate diesters at different positions like O-3 and O-4 of glucose
were also successfully obtained, giving products 10, 11, 12a and
12b in 67%, 94%, 60%, and 67% yields, respectively.[21]
Moreover, 13 and 14a, monosaccharides carrying two sulfate
diesters were prepared successfully in 73% and 71% yields,
respectively. The efficiency and scale of disubstitution could be
5
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further improved to 95% in multi-gram quantities when switching
from 2a to 2e. Disubstituted disaccharide 15 was also
synthesized in gram scale from the corresponding dual-TMS-
protected substrate, with 2j being found to enable the highest
SuFEx efficiency of all aryl fluorosulfates tested at 67% yield.
Besides carbohydrates, the SuFEx reaction was further applied
to install sulfate diesters on non-carbohydrate substrates.
Estrone sulfate diester 16 and tyrosine sulfate diester 17 were
efficiently prepared in 89% and 94% yields, respectively. It is
noteworthy that all compounds mentioned above were prepared
in readily scalable procedures and purified by silica gel
chromatography. Taken together, these examples highlight the
broad substrate scope of our method and its versatility in tuning
the electronic properties of the aryl fluorosulfates to optimize
their reactivities.
donor (31), and the phosphate donor (32) all proceeded
efficiently, forming disaccharide 34 in excellent (73-92%) yields
(Figure 4B). Because sulfate diester modifications could
deactivate carbohydrate building blocks in glycosylation
reactions, coupling the glycosyl donor and acceptor became
challenging when both were modified by sulfate diesters in
previous early stage sulfation strategies.[10c,12a] Our initial attempt
to couple the bromide donor and the 1,6-anhydroidosyl acceptor
20 generated the disaccharide product 35 in 51% yield (Figure
4C). The yield of the disaccharide was improved to 79% when
thiol donor 7 was employed (Figure 4C). However, it was found
o
that 7 was partially decomposed after three days at 4 C, likely
attributed to the intramolecular nucleophilic attack at the O-6
sulfate diester by the anomeric thiol group. This challenge was
overcome by oxidizing 7 into the sulfoxide donor 23, which can
be stored in long term without any signs of decomposition.
Glycosylation efficiency was further improved when the sulfoxide
donor 23 was employed, affording 36 in 95% yield even when
both the donor and the acceptor carried sulfate diester
substitutions (Figure 4C).
Because hydrogenolysis was milder and less prone to side
reactions than hydrolysis, it became the method of choice for
sulfate diester deprotection (Figure 4D). Indeed, global
deprotection of multigram amounts of 14b by Pd(OH)2/C/H2
successfully yielded O-2, O-4 disulfated idose 37 in 95% yield.
Furthermore, disulfated 38, trisulfated 39, and disulfated 40 were
also efficiently prepared in quantitative, 83%, and 90% yields,
respectively. The deprotection of non-carbohydrate sulfate
diesters was also efficient. Hydrogenolysis of 16 and 17
exclusively furnished sulfoestrone 41 and sulfotyrosine 42 in
high yields, without any desulfated byproducts being observed.
The excellent selectivity of hydrogenolysis is attributed to the
strong electron-withdrawing p- or m-NO2 substitution that
weakens the nearby aryl C–O bond and makes it susceptible to
oxidative addition by palladium.
In summary, a facile and scalable approach for early stage O-
sulfation via SuFEx reaction was developed for both
carbohydrates and non-carbohydrate compounds. The SuFEx
coupling reactions were optimized to efficiently generate sulfate
diesters. The sulfate diesters demonstrated excellent
compatibility with a broad range of reaction conditions and can
be efficiently deprotected to yield O-sulfated products. This
strategy provides a powerful tool for the synthesis of complex O-
sulfated small molecules and macromolecules including
carbohydrates, glycomimetic polymers, and peptides.
Next, the compatibility of our approach with frequently used
reagents and reaction conditions in carbohydrate and peptide
chemistries was examined (Figure 3). First, the aryl sulfate
diesters as the protected sulfates could overcome the acid
sensitivity of the nonprotected sulfates (Figure 3A). The
anomeric O-methyl group of 5 was converted to the O-acetyl
group in 18 by sulfuric acid in 85% yield. Disulfated 1,6-
anhydroidose 14b was readily converted into the ring-opening
product 19 in 81% yield by strong Lewis acid scandium triflate.[22]
Basic conditions were tolerated (Figure 3B). From 9c and 21,
removal of the TBS and acetyl protecting groups by
tetrabutylammonium fluoride (TBAF) and sodium methoxide
afforded 20 in excellent yields. Notably, TBAF compatibility was
a challenge for the state-of-the-art TCE sulfate diesters due to
the tendency of the undesired fluorination.[12a] While tyrosine p-
nitrophenylsulfate diester demonstrated limited stability in 20%
piperidine in DMF (Table S6), the m-nitrophenyl sulfate diester
17 was perfectly stable under the same condition. Oxidizing
conditions were also well tolerated (Figure 3C). The anomeric p-
methoxyphenyl group of 6 was removed to form 22 in 92% yield
by cerium ammonium nitrate (CAN). Oxidation of the thiol donor
7 by m-chloroperoxybenzoic acid (m-CPBA) afforded sulfoxide
23 in 79% yield. Oxidative debenzylation of 14a by sodium
bromate and sodium dithionite quantitatively yielded glycosyl
acceptors 24. Reducing conditions were tolerated (Figure 3D).
Acid-promoted reductive benzylidene opening of 8 exposed O-6
or O-4 positions as free hydroxyls to afford 25 and 26 in
quantitative and 95% yields, respectively. Zinc-catalyzed azide
reduction of 15 afforded the free amine 27 in 78% yield. Finally,
the sulfate diesters are also compatible with the sulfur trioxide-
nitrogen base reagent (Figure 3E). N-Sulfation of 27 by
SO3∙pyridine generated 28 in 72% yield. Overall, these results
indicated excellent compatibilities of the aryl sulfate diesters with
acidic, basic, oxidizing, and reducing conditions commonly used
in carbohydrate and peptide chemistries.
We then examined the glycosylation reactions of both donors
and acceptors modified by glycosyl aryl sulfate diesters (Figure
4). First, the disubstituted acceptor 24 was coupled with imidate
donor 29, successfully yielding disaccharides 30 in 65% yield
(Figure 4A). Next, glycosylation of acceptor 33 using O-6 sulfate
diester-substituted glucosyl donors including the bromide donor
(in situ generated from 1-O-acetyl-glucopyranoside 18), fluoride
6
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Sharpless, L. Kwisnek, J. S. Oakdale, V. V. Fokin, Angew.
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Acknowledgements
We thank Marek Domin for assistance in mass spectrometry
characterizations and Professor James Morken for helpful
comments. The research is supported by a startup fund from
Boston College to J.N. and the NIH Director’s New Innovator
Award (1DP2HG011027-01) to J.N.
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Keywords: O-sulfation • SuFEx • early-stage sulfation •
glycosylation • carbohydrate chemistry
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7

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Table of Contents
-O
HO
X
O
O
O
S
O
O
S
O
O
O
O
O
S
Sugar
O
Hydrogenolysis
or
Hydrolysis
O
F
X
O
-O
O
O
O
O
O
S
SuFEx
S
HO
O
O
X
Steroid/Amino acid
This Communication describes an efficient and broadly compatible early-stage O-sulfation approach based on the SuFEx chemistry.
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