Chemical Methods for N- and O-Sulfation of Small Molecules, Amino Acids and Peptides

Article abstract of DOI:10.1002/cbic.201900673

Sulfation of the amino acid residues of proteins is a significant post-translational modification, the functions of which are yet to be fully understood. Current sulfation methods are limited mainly to O-tyrosine (sY), which requires negatively charged species around the desired amino acid residue and a specific sulfotransferase enzyme. Alternatively, for solid-phase peptide synthesis, a de novo protected sY is required. Therefore, synthetic routes that go beyond O-sulfation are required. We have developed a novel route to N-sulfamation and can dial-in/out O-sulfation (without S-sulfurothiolation), mimicking the initiation step of the ping-pong sulfation mechanism identified in structural biology. This rapid, low-temperature and non-racemising method is applicable to a range of amines, amides, amino acids, and peptide sequences.

Full text of DOI:10.1002/cbic.201900673

Accepted Article
Title: Chemical methods for N- and O-sulfation of small molecules,
amino acids and peptides
Authors: Anna Mary Benedetti, Daniel M Gill, Chi W Tsang, and Alan M
Jones
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10.1002/cbic.201900673
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Chemical methods for N- and O-sulfation of small molecules,
amino acids and peptides
Anna Mary Benedetti,[a] Daniel M. Gill,[a] Chi W. Tsang,[b] and Alan M. Jones*[a]
and effects of pre-existing sulfate groups (Scheme 1, previous
work).2,27 A ping-pong mechanism has been discovered to
operate with arylsulfotransferases via the intermediacy of a
histidine N-sulfamate,28 this spurred our interest in developing a
general N-sulfamation strategy to small molecules and peptides.
To the best of our knowledge, limited non-enzymatic,
methods to directly chemically sulfate a peptide have only been
reported at phenolic tyrosine residues.29 Inspired by the role of
sY, we sought to expand the sulfation epigenetic tool box to
other amino acids. To address this, we detail a mild betaine-
mediated method using TBSAB for the novel and rapid
preparation of N-sulfamates. We demonstrate scope on a
diverse array of nitrogen containing substrates and investigate
heteroatom selectivity (N-sulfamation vs O-sulfation vs S-
sulfurothiolation). We surveyed the reactivity on nine canonical
nucleophilic amino acid residues and demonstrate the ability to
chemically modify peptide sequences (Scheme 1, this work).
There are limited reliable methods30 to prepare N-
sulfamates: (i) direct sulfamation with an SO3-amine complex
(amines used include: Me3N, Et3N, Me2Bz, Py, N-
methylmorpholine) or an SO3 source (chlorosulfonic acid); (ii)
sulfuric acid-mediated hydrosulfation of isocyanates; and (iii) (for
N-acyl sulfamates only)31 the reverse addition of a sulfamate
through a carbonate intermediate. Limitations of these methods
include the requirement for extensive chromatography, and ion-
exchange methods, incompatibility with acid sensitive substrates,
and multi-step sequences.
Sulfation of the amino acid residues of proteins is an
emerging post-translational modification, the functions of
which are yet to be fully understood. Current sulfation methods
are limited mainly to O-tyrosine (sY) which requires negatively
charged species around the desired amino acid residue and a
specific sulfotransferase enzyme. Alternatively, for solid phase
peptide synthesis a de novo protected sY is required. Therefore,
synthetic routes are required to go beyond O-sulfation. We
have developed a novel route to N-sulfamation and can dial-
in/out O-sulfation (without S-sulfurothiolation), mimicking the
initiation step of the ping-pong sulfation mechanism identified
in structural biology. This rapid, low temperature and non-
racemizing method is applicable to a range of amines, amides,
amino acids, and peptide sequences.
The sulfate group is
a ubiquitous post-translational
modification, accounting for approximately 1% of all known
epigenetic markers, and plays a vital role in a variety of
biological
processes,
including
protein-protein
and
oligosaccharide interactions.1-9
Yet, sulfoproteins have been overlooked in favour of more
common phosphorylation, limiting our exploration of their
function. Recent developments in ultra-high resolution mass
spectrometry have revealed a m/z difference of 9.5 mDa
between kinase phosphorylation versus sulfation.10-12 Therefore,
many previously assigned phosphorylated proteins have been
miss-assigned.
Protein sulfation may be more abundant and important
than previously recognised. Similarly to phosphorylation,
proteins have been discovered to be sulfated at tyrosine (sY),
serine (sS), threonine (sT) and histidine (sH).13 Opening up the
We have previously developed a new class of sulfating
agent, tributyl sulfoammonium betaine (TBSAB) that overcomes
the purification challenges,15 and considered whether TBSAB
would provide a solution to these issues associated with
possibility of further sulfation motifs that are yet to be discovered. accessing an under-exploited but important functional group.
Methods to access sulfated proteins to date have focussed
on the sulfated amino acid sY,2-5 with very limited examples of
sS and sT.14-15 The pre-installation of a sulfate group onto Y is
possible via alternative protecting group methods,14,16-26 with the
added complication of the instability of sY to solid phase peptide
cleavage. These chemical methods have various merits and
drawbacks, but do allow for pinpoint accuracy in installing a
sulfate group. Alternatively, the use of SULT, TPST, ASST
sulfotransferases with PAPS cofactor allows for selectivity
between tyrosine groups, due to the ±5 amino acids around Y
Using benzylamine (1) as a model system to study N-
sulfamation, the reaction progress was readily monitored by 1H
NMR spectroscopy (Table 1). Subtle changes in the shielding of
the benzylic methylene group gave insight into the variety of
reaction pathways that could operate, including the dynamic
interplay between protonation, sulfamation, counterion exchange
and imidosulfamation.
[a]
[b]
A. M. Benedetti, D. M. Gill, Dr A. M. Jones
School of Pharmacy
University of Birmingham
United Kingdom
E-mail: a.m.jones.2@bham.ac.uk
Dr C. W. Tsang
School of Chemistry
University of Birmingham
United Kingdom
Supporting information for this article is given via a link at the end of
the document.
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Scheme 1. Previous approaches to sulfating tyrosine and sulfated peptides. This work: a new route to sulfating nitrogen, sulfation of a range of amino acids
including tyrosine, and the non-enzymatic in situ sulfation of a peptide.
substrate), avoiding this and obtaining 2a exclusively. Although
2b is an impurity, exchange to the sodium salt (3) delivers the
identical product. The structures of 2a and 2b were confirmed by
single crystal X-ray crystallography.32
We next considered
a comparison of entry 3 with
commercial sulfating agents Me3N-SO3 and Py-SO3 (Table 1,
entries 10 and 11, respectively). The opposite reactivity trend to
O-sulfation15 was observed with Me3N-SO3, affording a near-
quantitative conversion (>99%) compared with Py-SO3 (47%).
Due to decreased lipophilicity of the trimethylammonium
counterion (c.f. tributylammonium) an isolated yield of only 23%
was obtained in the control experiments. These control
experiments highlighted the challenging purification cascades to
obtain analytically pure N-sulfated molecules with known
strategies.
No deleterious effect of moisture was found (Table 1, entry
12). The use of additional base e.g. tributylamine was
unnecessary (Table 1, entry 13). The effect of hydrochloride salt
additives, at 10-50 mol% (Table 1, entries 14 and 15), showed
none to modest (21%) decreases in conversion, respectively. In
summary, robust optimised reaction conditions were identified
using 2.0 equivalents of TBSAB at 30 °C afforded quantitative
conversion and 98% isolated yield of 3 and in less than 30 min.
Importantly, the formation of imidosulfates were not observed
under these conditions.33
Table 1. Optimization of benzylamine N-sulfamation. [a] formation of the
benzylammonium salt (2b) observed; [b] miscellaneous side products
observed. Reaction conversions reported as measured by 1H NMR
spectroscopy. Selected isolated yields are reported in parentheses.
Survey of reaction temperature (Table 1, entries 1-5)
demonstrated that 30 °C was optimal with 2.0 equivalents of
TBSAB. Varying the equivalents of TBSAB (Table 1, entry 3 vs
6-9) showed that 2.0 equivalents afforded high conversions.
Unexpectedly, it was observed that the conversion for entry 6,
with 0.5 eq. TBSAB, was quantitative. It was revealed that the
tributylammonium counterion can exchange with unreacted
benzylamine in situ to afford 2b. We identified that longer
reaction times gave rise to increased conversion to 2b, with
shorter reaction times, generally <30 min (depending on
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Chart 2. Reaction scope on diverse amines, amides and aminoalcohols. [a] t =
60 min; [b] isolated as NBu3H salt; [c] t = 24 h. (Parentheses indicate reaction
conversion as measured by 1H NMR spectroscopy.)
N-sulfamation of secondary benzylamines with an N-
methyl (14) or N-benzyl (15) group was well tolerated (Chart 2).
The incorporation of a N-phenyl (16) group, which changed the
amine from an sp3 to an sp2 centre led to a noticeable drop in
isolated yield and increased instability of the product. To
investigate the N(sp2) effect the sulfamation of aniline was
attempted with an extended reaction time. This led to an
excellent yield of anti-pyretic 17.34 Finally, the sp2 amide nitrogen
reactivity of an Fsp3-rich scaffold (vince lactam) was
investigated; a modest conversion to the N-sulfamate 18 was
observed after 30 min but improved upon extended reaction time
to afford the desired compound in an excellent 80% yield.
Chart 1. Reaction scope on benzylamines. [a] t = 60 min; [b] isolated as
NBu3H salt. (Parentheses indicate reaction conversion as measured by 1H
NMR spectroscopy.)
We then surveyed the generality of the developed
conditions on
a
variety of benzylamines with varying
stereoelectronic parameters (Chart 1). The parent benzylamine
could be isolated as either the sodium (3) or tributylammonium
salt (2a), in excellent isolated yields (both 98%). The
incorporation of a strongly electron donating methoxy group (4-
6) was tolerated in all positions (quantitative conversions) but a
slight reduction in isolated yield for the ortho substituent (4)
which is likely due to the isolation method (recrystallisation)
rather than the effect of intramolecular hydrogen bonding. The
incorporation of a strongly electron withdrawing nitro group (7-9)
was tolerated, with good conversions in all cases (72-86%).
Isolation as either the amine or sodium salt was complicated by
the presence of the nitro group. However, the meta position (7)
was isolated as the tributylammonium salt (10%). Next, we
investigated the effect of medicinal chemistry relevant
functionality, e.g. chloro (10 and 11) and trifluoromethyl (12)
groups which proceeded in quantitative conversion and between
61-97% isolated yields. Finally, it was considered whether a
steric block on the α-benzylic position (13) would impede the
reaction. The reaction proceeded in high conversion (>99%) and
excellent isolated yield (90%).
The methodology is also readily applicable to alkyl amines
(linear 19, 53% and cyclic 20, 57%) and amino alcohols (21,
89%) with exclusive selectivity for N-sulfation over oxygen. A
control experiment was performed to determine the stability of
this dual heteroatom containing molecule (21) for possible N to
O sulfate transfer.35-37 Warming the sample led to the partial
conversion of the N-SO3 containing 21 to the O-SO3 containing
molecule, presumably via a six-membered transition state,
driven by the stability of the O-S bond over N-S.38
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The ability to sulfate the phenolic oxygen of tyrosine (sY) is
also possible with TBSAB but under different conditions which
afforded the N-Fmoc protected tyrosine O-sulfate 24 in 62%
isolated yield. 24 was found to be unstable in solution and
desulfated to the starting material with time.39
We found that the amino acid serine led to no-detectable
1
reaction via H NMR spectroscopic studies at either the oxygen
or nitrogen position (25, sulfation or sulfamation, respectively).
The close proximity of an adjacent nucleophile shuts down the
N-sulfamation reaction due to the steric bulk of TBSAB.
Considering the result with tyrosine, the possibility of amino acid
functional group selectivity is possible. We have shown a single
example of serine O-sulfation is possible with TBSAB under
markedly different reaction conditions (4.0 eq. of TBSAB, 38 °C
for 52 h in DMF)15 demonstrating the potential to dial-in different
reaction outcomes with careful selection of conditions.
Next we considered the ability to obtain heteroatom
selectivity in cysteine analogues, beginning with the fully
protected S-benzyl analogue, gave exclusive N-terminal
sulfamation in excellent conversion and isolated yield for 26
(98%). When the protecting group is transposed to the nitrogen
(as an acyl amide), under mild condition no S-sulfurothiolation
was observed in 27, demonstrating the N-selectivity profile of
TBSAB under these conditions. Using a molecule with an amine
and thiol group, N-sulfamation was the exclusive product over S-
sulfurothiolation with quantitative conversion and a modest
isolated yield of 28 (50%). Next we considered nitrogen
containing side chains in lysine and arginine. Lysine was
partially sulfamated at the alkylamine position (29, 50%
conversion) and arginine due to its poor guanidine N-
nucleophilicity did not react with TBSAB (30) again
demonstrating selectivity within the canonical amino acids. We
also demonstrated that TBSAB does not racemise amino acids
Chart 3. Canonical amino acid reactivity survey. [a] Isolated as NBu3H salt; [b]
4.0 eq. TBSAB, reflux, 6 h; [c] An analytically pure, stable sample could not be
obtained (Parentheses indicate reaction conversion as measured by 1H NMR
spectroscopy.)
We next sought to apply the methodology to amino acids
(Chart 3). If the reaction is to have wide appeal, the N-
sulfamation chemistry needs to be performed at
a non-
denaturing temperature. Therefore, we used low temperature
and longer reaction times. In all cases the formation of a
protonated amino acid counterion (c.f. 2b) was not identified in
1
the crude H NMR spectra. We sought to explore the generality
of the optimised one-pot sulfamation methodology and the
potential for heteroatom selectivity (nitrogen, oxygen and sulfur).
Our survey began with phenylalanine which under non-
denaturing reaction conditions led to a quantitative conversion
and a good isolated yield of 22 (60%) at the N-terminal position.
The use of tyrosine raised the possibility of phenolic sulfation
versus amine sulfamation. Under the optimised conditions a
quantitative conversion of 23 was observed at the N-terminal
position. However, a low isolated yield of the sulfamation
product was obtained (11%). Importantly, no-detection of
phenolic sulfation in the crude 1H NMR was observed.
25
even under more forcing conditions.15 Measurement of the [α]D
of the sulfamates (22-24, 26 and 28) indicated that racemisation
did not occur in these examples.
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Scheme 2. In situ sulfation of glutathione and bradykinin. (inset. PDB: 6f3v crystal structure of Bradykinin with a 7.9 Å distance between Ser(OH) and Arg(NH2).)
chemically sulfating and sulfamating a peptide in situ. This holds
promise as a method to perform site-selective sulfamation of
To test the hypothesis for site-selective sulfamation, a 3-
mer (glutathione, 31) and 9-mer (bradykinin, 33) peptide
sequence were selected (Scheme 2).40 In particular, bradykinin,
is a representative member of the vasoactive kinin class of
cardioprotective peptides, and known to be secreted as sulfates
in mammals.41 Treatment of glutathione gave rise to a single
mono-sulfate containing product, 32 at the N-terminal amine of
glutamic acid. As a test of the methodology, it was envisioned
that the sulfation of the 9-mer peptide, bradykinin should afford
N-terminal sulfation (34). LCMS analysis revealed two mono-
sulfated bradykinin derivatives (34 and 35). MS fragmentation
patterns combined with the sulfation/sulfamation survey of
canonical amino acids (Chart 3) indicated that Bradykinin
contains two potential nucleophilic sites. The major product (34)
being the expected N-terminal sulfamation product. The minor
product (35) was shown to be serine O-sulfate. Analysis of the
crystal structrure of 33 (PDB: 6f3v) revealed a 7.8 Å distance
between the i and i+5 residues (Arg and Ser) due to the
presence of multiple proline residues in Bradykinin, this
compresses the distance (approx. -20% per Pro) of the α-helix.
This gives further credence to the previously reported N to O-
sulfate shutttle in nature28 and a rationalisation for the observed
sS product.
amino acid residues. The ability to modify post-translational
protein sequences opens the door to future applications in
structure sensing and understanding the underlying biology of
sulfated proteins.
Acknowledgements
A.M.B. thanks the Erasmus+ UniPharma programme (University
of Sapienza, Italy) for sponsorship. D.M.G. thanks the University
of Birmingham for a PhD scholarship. The authors thank Dr
Louise Male, Dr Cécile Le Duff, and the Centre for Chemical and
Materials Analysis in the School of Chemistry, University of
Birmingham for analytical support.
Keywords: Sulfation • Sulfamation • Sulfurothiolation • amino
acid • sulfopeptide
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Anna Mary Benedetti,[a] Daniel M. Gill,[a]
Chi W. Tsang,[b] and Alan M. Jones*[a]
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Chemical methods for N- and
O-sulfation of small molecules,
amino acids and peptides
A general sulfation/sulfamation strategy: A new method to selectively N-
sulfamate or O-sulfate molecules is reported. A rapid, low temperature, non-
racemizing approach to functionalise amino acids and peptides is demonstrated.
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