Solid Phase Synthesis of Sulfonimidamide Pseudopeptides and Library Generation

Article abstract of DOI:10.1002/ejoc.202000108

Many synthetic routes have been explored to make small molecule sulfonimidamides (SIAs), however, its introduction into larger molecules such as oligopeptides has not been studied before. We herein demonstrate three alternative and complementary methods f

Full text of DOI:10.1002/ejoc.202000108

A Journal of
Accepted Article
Title: Solid Phase Synthesis of Sulfonimidamide Pseudopeptides and
Library Generation
Authors: Praveen K. Chinthakindi, Andrea Benediktsdottir, Per I
Arvidsson, Yantao Chen, and Anja Sandström
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000108
Link to VoR: http://dx.doi.org/10.1002/ejoc.202000108
Supported by

10.1002/ejoc.202000108
European Journal of Organic Chemistry
Full Paper
Solid Phase Synthesis of Sulfonimidamide Pseudopeptides and
Library Generation
Praveen K. Chinthakindi,[a] Andrea Benediktsdottir,[a] Per I Arvidsson,[b, c] Yantao Chen,[d] and Anja
Sandström*[a]
Abstract: Many synthetic routes have been explored to make small
molecule sulfonimidamides (SIAs), however, its introduction into
larger molecules such as oligopeptides has not been studied before.
We herein demonstrate three alternative and complementary
methods for synthesis of SIA based pseudopeptides, on solid phase,
using both on and off-resin SIA-synthesis, via sulfonimidoyl chlorides
from sulfonamides, in high conversion. Beside evaluation of various
resins such as 2-CTC, Wang, and Rink amide-ChemMatrix, the
possibilities to further N-functionalize and cyclize the SIA functionality
on solid support are shown. The diastereomers of SIA containing
pseudopeptides could in most cases be separated using normal
reverse phase preparative HPLC. The solid phase SIA methodology
has many advantages when it comes to handling and purification as
compared to in solution, and will therefore enable exploration of the
SIA group as isosteric substitutions and peptidomimetic building
blocks in the development of drug-like pseudopeptides in many ways.
Of particular note these approaches facilitate combinatorial library
synthesis as demonstrated herein.
in different ways.[6b, 7] Moreover, single atom swapping has shown
to improve biological activity in some cases.[8] All these aspects
make the SIA group interesting from a drug discovery perspective,
beside obvious applications within asymmetric synthesis.[9]
Figure 1. Comparison of sulfonimidamide and isosteres
We have previously studied synthetic routes to sulfonimidamides
and acyl sulfonimidamides as well as their potential use as
bioisosteres to sulfonamides and acyl sulfonamides, respectively,
the latter being an isostere to carboxylic acids.[7b, 10] Moreover, the
Introduction
sulfonimidamide has similar geometry to
a
tetrahedral
intermediate of amide bond hydrolysis. This similarity qualifies the
SIA group as a transition state isostere (Figure 1), of potential use
in inhibitors of hydrolases, such as proteases. Indeed,
sulfonimidamide based carboxypeptidase inhibitors have been
reported by Cathers and Schloss.[11]
Sulfur containing functional groups,[1] such as thioethers, sulfones,
sulfonamides[2], etc., and their construction continue to play an
important role in medicinal chemistry.[3] Synthesis and
biochemical evaluation of compounds based on sulfonimidamides
(SIAs) have gained much attention in recent time as judged by an
increasing number of related publications,[4] patents[5] and
reviews[6]. The sulfonimidamide functionality is an isostere to the
sulfonamide, where one of the oxygens is replaced by an imine
nitrogen (Figure 1). Thus, chirality is introduced and furthermore
the extra "N" handle conveys either an additional hydrogen bond
donor or the possibility of adding various substituents (i.e. =NH,
=NR), which can tune physical-chemical and biological properties
Peptide drug discovery is going through a renaissance[12], partly
driven by their potential use in new drug modalities addressing
challenging undruggable targets like intracellular protein-protein
interactions,[13] and for their use of various purposes in
biomedicine, biotechnology, and bioengineering.[14] The
transformation of peptides into peptidomimetics, mimicking the
structure and conformation of physiologically active peptides,
aims at improving stability against proteolysis, cell membrane
permeability, and oral bioavailability.[4b] Approaches to make
peptidomimetics include replacement of one or more of the
metabolically unstable amide bonds of the backbone with amide
bond isosteres such as sulfoximines[15] and sulfonamides;[16]
incorporation of unnatural amino acids[17] is also a common
practice (Figure 2).[18]
[a]
Assoc. Prof. Anja Sandström.
Dr. Praveen Kumar Chinthakindi
Mrs. Andrea Benediktsdottir
The Beijer Laboratory, Department of Medicinal Chemistry,
Uppsala University,
Box 574, SE-75123 Uppsala, Sweden
E-mail: anja.sandstrom@ilk.uu.se
https://www.ilk.uu.se/research-groups/ldlu_en/
Prof. Per I Arvidsson
[b]
Science for Life Laboratory, Drug Discovery and Development
Platform and Division of Translational Medicine and Chemical
Biology, Department of Medical Biochemistry and Biophysics,
Karolinska Institutet,171 77 Stockholm, Sweden
Catalysis and Peptide Research Unit, University of KwaZulu-
Natal,4000 Durban, South Africa
Medicinal Chemistry, Research and Early Development,
Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D,
AstraZeneca, 43183 Gothenburg, Sweden
[c]
[d]
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000108
European Journal of Organic Chemistry
Full Paper
sulfenamides (R1SNHR2),[26] thionyl tetrafluoride (SOF4)[27] using
multi step and often tedious and harsh conditions, as well as from
commercially available sulfonamides (R1SO2NHR2)[28]
. Our
method was optimized from a convenient one-pot method starting
from TBS-protected sulfonamides, reported by Chen and
Gibson.[28] Moreover, this is a cheap and metal free medicinal
chemistry friendly method. In continuation to our previous work,
we have now explored the possibility to combine the SIA
synthesis with SPPS to make SIA-based pseudopeptides using
alternative methods, which is herein presented.
Figure 2. Peptide backbone modifications using amide bond isosteres.
Aiming at new peptide-based modalities, we felt encouraged to
synthesize SIA-based pseudopeptides where the scissile peptide
bond was replaced with chiral SIAs and to study the
diastereomers forming when it comes to physicochemical
properties, proteolytic stability, conformational preferences and
target binding. Beside these obvious effects we saw great
opportunities with the incorporation of the chiral SIA group to
construct diverse high-quality compound libraries,[19] especially if
the compounds could be synthesized on solid support, such as in
solid phase peptide synthesis (SPPS).[20]
Scheme 1: Solid phase synthesis approaches to SIA based pseudopeptides.
Results and discussion
Our investigation of the synthesis of SIA-based
pseudopeptides on solid phase started by retrosynthetic analysis,
which suggested three alternative methods according to Scheme
1. The first approach includes the synthesis of SIA-based amino
acid building blocks[4b] (Scheme 1) followed by a standard peptide
coupling on solid phase. Alternatively, instead of making SIA
based amino acid building block in solution, we considered
utilization of sulfonimidoyl chloride (SIC) solution made from a
cocktail of TBDPS-protected sulfonamide and PPh3Cl2 directly on
the N-terminal amine on the resin-bound peptide (approach 2,
Scheme 1). Thirdly, a sulfonamide peptide could be made on solid
phase using sulfonyl chloride, which could be further reacted with
PPh3Cl2 to get SIC followed by addition of an amine (approach 3,
Scheme 1).This would, however, require a solid phase reaction at
low temperature (0 °C), which is not commonly explored and
might be challenging to handle. All three approaches would be of
use in library production since diversity is introduced in the last
step, however approach 3 offers extra advantages since it
introduces diversity on solid-phase in the three handles around
chiral “S”. Also, if the SIA synthesis is compatible with solid phase,
advantages in purifications will be obvious. Moreover, the
stoichiometry can be changed to support a higher yielding SIA
synthesis by the allowing to use excess reagents that can be
easily removed. Thus, the on-resin approaches 2 and 3 (Scheme
1) would be particularity advantageous in this regard.
SPPS is considered as the best method for the
manufacturing of peptide drugs.[21] In 1963 Bruce Merrifield
invented the solid phase approach for peptide synthesis, and the
methodology has thereafter been extensively used for
oligonucleotide (DNA, RNA, PNA etc.), oligosaccharide, and
combinatorial libraries synthesis.[22] In general, attaching the
starting material covalently to an insoluble solid support has
several advantages in comparison with solution phase synthesis.
In solid phase synthesis reaction work-up is simplified because of
excess reagents and soluble by-products can be removed by
simple filtration using iterative resin washing steps. Also, it avoids
chromatographic purification of each intermediates which
increases the speed of the synthesis. However, this method
normally requires final HPLC purification of the final peptide
product. Overall, SPPS is a robust method for combinatorial
chemistry applications and can easily be adjusted to
automation.[23]
With the long term goal to combine the sulfonimidamide
functionality and peptides we recently published a method to
synthesize SIAs based amino acid building blocks using a one-
pot method from tert-butyldiphenylsilyl (TBDPS)-protected
sulfonamides as well as orthogonal protection strategies.[4b] In
general, SIAs can be synthesized from non-commercially
available sulfinamides (R1SONHR2),[24] sulfinylamines (RNSO),[25]
Attachment of a SIA-based amino acid building blocks under
SPPS conditions
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000108
European Journal of Organic Chemistry
Full Paper
Initially, approach 1 (Scheme 1) was explored to see if the
TBDPS-protected SIA based amino acids is compatible with
SPPS (Scheme 2). Polystyrene 2-chlorotrityl chloride (2-CTC)-
resin was swelled in DCM and Fmoc-Phe-OH was added and
attached using by addition of diisopropylethylamine (DIPEA).
Unreacted sites on the resin were capped through addition of
MeOH, after which Fmoc was removed by 20% piperidine in DMF
according to standard procedure. TBDPS-SIA-Phe-OH 1[4b] was
coupled with activation using HBTU and DIPEA. Mini-cleavage
performed at this point using 20% hexafluoroisopropanol (HFIP)
in DCM confirmed consumption of the starting material showing
full conversion into the TBDPS-protected SIA-peptide. The
TBDPS-group was successfully removed with 1M TBAF in THF,
after which the product (SIA-Phe-Phe-OH, 2) was released from
the resin using 50% TFA in DCM. Analysis of the crude product
after cleavage shows the SIA-Phe-Phe-OH product as a single
major peak (according to LC-MS conversion at 254 nm), which
after HPLC purification yielded 2 as a diastereomeric mixture
chemistry. Thus, the synthesis started with the transformation of
TBDPS-p-toluenesulfonamide into the SIC derivative at 0 °C
degree in DCM instead of chloroform as previously described; this
is partially due to resin swelling purpose and in order to avoid
unwanted reaction with phosgene.[4b] Although, for SPPS
convenience, we modified Chen’s one pot protocol somewhat
with respect to solvents and bases as will be described below.[4b]
The SIC solution was thereafter transferred with a needle into the
solid phase chamber containing the resin-bound dipeptide
premixed with DIPEA in DMF under N2-atmosphere and left
shaking for 3-5 h. Thereafter, the resins were washed with DCM
and DMF repeatedly. The TBDPS group was removed using 1M
TBAF in THF. Finally, the sulfonimidamide based peptide was
released from the ChemMatrix-Rink amide resin with TFA-TES
(95:5), the Wang resin with TFA-TIS-H2O (95:2.5:2.5) for 3 h, and
from the 2-CTC resin with 50% TFA in DCM or 20% HFIP in DCM
for 60 min (Scheme 3). Gratifyingly, according to analysis of the
crude products by LC-MS the sulfonimidamide-dipeptides were
formed as diastereomeric mixtures (3a, 60:40 and 3b, 57:43) with
full conversion on all three resins without any unreacted starting
material left. It is also worth noting that, with this solid phase
method, unreacted sulfonamide from the presynthesis of SIC,
triphenyl phosphine oxide, and peptide coupling byproducts were
easily washed off by the simple washing steps. Removing
triphenyl phosphine oxide is normally relatively tedious in solution
phase synthesis.[29] Moreover, it should be mentioned that
conditions were initially screened and slightly modified for
coupling of SIC to the N-terminal amine of the resin bound peptide.
For example different bases (triethylamine, DIPEA) and different
solvents (DCM, DMF) were evaluated. The usage of triethylamine
in DCM in the solid-phase SIA synthesis at room temperature led
to decomposition of SIC over the coupling to the amine residue of
peptide. Thus, the reaction temperature of the peptide reactor was
lowered from r.t. to 0-5⁰C. Still, only modest conversion was
achieved. We believe this could be due to sparingly soluble
reaction mixture in DCM, which disfavored completion of the
coupling. Therefore, the solvent was changed from DCM to DMF
for better solubility of SIC, resulting in higher, although not
satisfactory, partial (65-75%) conversion. After changing the base
triethylamine to DIPEA almost full conversion was achieved. Also,
various equivalents of the SIC mixture were evaluated showing
that two equivalents were sufficient to get full conversion (for
movie, see supporting information). Further, the synthesis of SIA
peptide proved that the coupling of SIC to an amine on the solid
support occurs similarly to in solution, without losing
stereochemical integrity. Overall, in comparison with solution
phase synthesis, the solid phase synthesis is robust with respect
to conversion, purification and yields.
(around ̴60:40) in 82% isolated yield. This proves that protected
SIA-based amino acids could be used in SPPS and that the
protection using TBDPS is advantageous since it allows a high
yielding synthesis of SIA-based amino acids[4b] and since the
protecting group can be removed selectively using TBAF also on
resin.
Scheme 2. Approach 1. Attaching a SIA-based amino acid building block using
SPPS conditions.
Scheme 3. Approach 2. On-resin SIA based pseudopeptides synthesis using
addition of SIC.
Having optimized conditions in hand, scope and limitations
of the reaction (Scheme 3) were explored in the syntheses of
other sequences and larger peptides (tetra) using either TBDPS
protected toluene- and methane- SICs for the synthesis of N-
terminal SIA peptides. We chose 2-CTC-resin for this study since
this resin has many advantages related to handling and synthetic
options.[30] For example, swelling, attachment of the first amino
acid, and final cleavage from the 2-CTC resin are fast and
performed under mild conditions. The coupling of TBDPS
protected toluene-SIC to a resin bound Phe-Phe peptide
On-resin SIA synthesis by addition of TBDPS protected SIC to a
resin-bound peptide.
Next, the on-resin SIA synthesis using approach 2 (Scheme 1)
was explored (Scheme 3). In this case we decided also to
evaluate different resins, i.e. the 2-CTC, Wang and Rink-amide
ChemMatrix resins. A model dipeptide (Pro-Phe) on each resin
was chosen as starting material for the one pot sulfonimidamide
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000108
European Journal of Organic Chemistry
Full Paper
sequence was successful, giving compound 2 in an alternative
way, as compared to in Scheme 2, although with less conversion
in comparison to in the synthesis of proline based compound 3a
due to formation of side-products. It seems as e.g. a reactive
iminophosphorane can form with the primary amine of
phenylalanine under conditions with excess of the PPh3Cl2
solution. However, the product could easily be purified using
HPLC giving a diastereomeric mixture of 2 in reasonable yields
(70%). Next, we introduced SIA into two different tetrapeptides as
outlined in Scheme 4, one with an N-terminal alanine and one with
an N-terminal proline using either methane- or toluene-SIC,
respectively. To our satisfaction, the reactions yielded desired
diastereomeric products (4, dr 55:45 and 5, dr 45:65) that easily
could be isolated from each other using normal reversed-phase
HPLC purification. Our gained experience indicate that sterically
crowded or larger sequences may well give SIA-diastereomers,
which can be easily separated from each other, which is greatly
advantageous. Again, we observed a clean and full conversion
reaction for the proline (secondary amine) sequence and a slightly
lower yielding reaction for the alanine sequence (primary amine)
due to side-product formation, although the latter can be easily
purified using HPLC (Scheme 4). Furthermore, it was
demonstrated that the peptides can be cleaved from the 2-CTC-
resin with the TBDPS protection still intact as shown for the
TBDPS-protected SIA peptide 4 using mild 10% HFIP in DCM for
cleavage. These results demonstrate that SIA formation works
equally well for longer peptides.
inhibitor design, e.g. in simeprevir[31] and ACE-inhibitor[32]. Also, it
mimics peptide urea analogs.[33]
Scheme 5. Approach 2. On-resin SIA based (tetra) pseudopeptides synthesis
using addition of functionalized SIC amino acid.
Another way of making N-functionalized SIA-peptides is to
functionalize the N-terminal imine of the SIA-group after its
incorporation to peptides. We further investigated this possibility
in acylation, arylation and alkylation reactions as outlined in
Scheme 6.
On-resin N-Acylation of SIA-peptides: N-acylation is the easiest
and most common method to grow a peptide, so we performed
acylation at imine “N” of the sulfonimidamide using standard
peptide coupling of Fmoc-Gly-Gly-OH with HBTU and DIPEA
(Scheme 6). The reaction worked giving the acyl-SIA peptide 7,
although with 50% unreacted starting material left (Scheme 6). To
improve the yield we opted double couplings, tried optimization by
changing coupling reagents and reaction conditions (microwave,
classical heating). Unfortunately, none of them improved the
yields. This could be due to steric hindrance of proline groups
flanked by SIA. Nevertheless, the product 7 could be isolated as
diastereomers (28%, dr 86:14).
Scheme 4. Approach 2. On-resin SIA based (tetra) pseudopeptides synthesis
using addition of SIC.
On-resin, protecting group free, SIA synthesis by addition of a
functionalized SIC amino acid to a resin-bound peptide.
Our further investigations of the scope of the on-resin SIA-
formation (approach 2) included the novel procedure to use a
preformed amino acid based SIC-derivative, meaning formation
of SIC from an amino acid toluene sulfonamide (instead of a
TBDPS-protected toluene/methane sulfonamide), which gives us
a bidirectional SIA-peptide with two C-terminal ends, as outlined
in Scheme 5. To our satisfaction, the reaction worked with full
conversion on a resin-bound tetrapeptide with an N-terminal
proline, giving the peptidomimetic diastereomers (6, dr 60:40),
which could be separated. Note that bidirectional peptides have
in several cases shown useful in peptidomimetic protease
Scheme 6. On-resin N-functionalization of SIA based (tetra) pseudopeptides.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000108
European Journal of Organic Chemistry
Full Paper
On-resin N-arylation of SIA-peptides: With the inspiration of
N-arylation of sulfonamides[34] and amines[35] on solid support, we
selectively carried out N-arylation of sulfonimidamide using Chan-
Lam coupling conditions without affecting other functional groups
like amides. To our delight, product 8 was successfully formed
and isolated as pure diastereomers in moderate yields (21%, dr
72:28) (Scheme 6).
On-resin N-alkylation of SIA-peptides: Various alkylation
methods were tried with e.g. propargyl bromide and methyl iodide,
however, only low conversion were observed. Alkylation with
iodomethane worked with heating, however resulting in multiple
methylations. Finally, using Chan-Lam conditions with
methylboronic acid and copper acetate at 50 °C, the methylated
SIA-peptides 9 was formed according to LC-MS, but unfortunately
the compound could not be isolated during HPLC purification,
possibly due to degradation (Scheme 6).
cocktail was added to the resin at 0-5 °C yielding the TBDPS-
protected SIA peptide. Interestingly, at room temperature and in
presence of TBAF, selective TBDPS deprotection took place
(83% conversion as per LC-MS), while at 50-60 °C using
conventional (95% crude yield as per LC-MS) or microwave
heating (94% crude yield as per LC-MS), the simultaneous
deprotection-cyclization was the predominated route (Scheme 7),
yielding the desired product 10 (78%, dr 60:40 ). However,
separation of the diastereomers was difficult using either
preparative HPLC or SFC. We hypothesise that cyclic
sulfonimidamide like 10, i.e. having a shorter peptide sequence,
might be difficult to separate. Possibly, increasing the peptide
length might be helpful to separate the diastereomers. Based on
our previous experience with solution-phase SIA synthesis,
having bulkier functional groups around the sulfur atom is most
often helpful for the separation of the diastereomers.
On-resin peptido five membered cyclic SIA formation (Scheme 7):
A variant of the acylation reaction is intramolecular cyclization
between the SIA-nitrogen and an amino acid carboxylic acid as
we previously demonstrated in solution phase.[4b] Initially, we tried
to synthesize the cyclic SIA-Asp-(Phe-Phe-OH), where the
sidechain of Asp was coupled to the peptide, thus facilitating
utilization of the -carboxylic acid in formation of a five membered
ring. This sequence was however accompanied by competing
aspartimide[36] formation.
On-resin SIA synthesis, via on-resin SIC formation followed by
addition of an amino acid.
Finally, we studied the possibility to make a peptide SIC-derivate
on solid phase at 0 °C, followed by addition of an amino acid ester,
as the amine, according to approach 3 (Scheme 1). To be able to
get a simultaneous shaking and cooling in the solid phase reactor
we considered using ultrasonication[38] in an ice bath. Thus, H-
Phe-Phe-O-2-CTC-resin was synthesized using the standard
procedure. An N-terminal sulfonamide was thereafter prepared by
addition of toluene sulfonyl chloride at room temperature, as
outlined in Scheme 8. After completion of the coupling, the resin
was washed thoroughly and dried carefully. Thereafter, dry DCM
was added to the resin under nitrogen atmosphere and the solid
phase reactor cooled to 0 °C by adjusting the sonicator bath
temperature with dry ice. Pre-dissolved PPh3Cl2 and triethylamine
in DCM was then added dropwise to the solid phase reactor,
which was further sonicated for 30 min at 0 °C forming the SIC.
Subsequently, proline methyl ester and DIPEA were added and
the reactor sonicated for another 30 min at 0 °C. Final cleavage
using 20% HFIP in DCM successfully delivered the final products
11 as single products in an isolated yield of 90 %. The two
diastereomers of 11 (dr 63:34) could be separated and isolated
after standard HPLC (0.1% TFA-water-acetonitrile).
Scheme 7. On resin synthesis of 5-membered cyclic SIA based pseudopeptides.
In order to avoid the aspartimide formation we started our
sequence with Fmoc-Pro-OH[37] and carried out Fmoc removal
with 20% piperidine in DMF with 0.1 equiv. formic acid[36] instead
of the standard 20% piperidine in DMF. Then, Fmoc-Asp-OMe
was coupled followed by Fmoc deprotection. Thereafter, the SIC
Scheme 8. Approach 3. On-resin SIC formation by followed SIA synthesis.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000108
European Journal of Organic Chemistry
Full Paper
atom in the last steps on solid-phase using different commercially
available sulfonyl chlorides instead of sulfonamides. Taken
together, the solid-phase SIA reactions are convenient and user
friendly one-pot methods, with a wide scope that could be adapted
to generate combinatorial libraries using automation. In this work
we furthermore show the possibility to further functionalize and
cyclize the SIA functionality on solid support, as well as to perform
protection group free preparation of bidirectional SIA peptides.
Overall, this study offers a critical basic foundation to flourish
sulfonimidamide based pseudopeptides as a new modalities for
various applications in medicinal chemistry and chemical biology,
and constitute a valuable addition to peptide chemistry tool box.
Figure 3. On-resin parallel combinatorial library synthesis.
The synthetic approach 3 was tried in a small parallel library
format (for movie, see supporting information). Hence, cold SIC
resin (as in Scheme 8) was dispensed into eight sealed syringes
prepared with a filter and excess amount of different amine
nucleophiles. The syringes were placed on a fitting plate to hold
the syringes in the water bath and placed in a sonicator for 30 min
at 0 °C (illustrated in Figure 3), followed by washing by filtration.
Finally, a cleavage solution was added to each syringe, delivering
desired products as major peaks according to LC-MS analysis at
254 nm (SerOEt 99% conversion, PhgOEt 100% conversion,
ValOEt 100% conversion, AlaOEt 91% conversion, TyrOMe
60% conversion, MeNH2 96% conversion, aniline 99%
conversion and propargylamine 50% conversion). In case of the
reaction with tyrosine methyl ester we observed several peaks in
the LC-MS diagram. This could be due to presence of free phenol
reacting with SIC on either the hydroxyl group of phenol or the
activated aromatic ring. A similar situation was observed for
serine methyl ester, where two major peaks with the same mass
was observed, probably as a result of the free hydroxyl group
reacting with SIC. These results suggest that protection of all
other reactive functional groups in the starting material is needed
in order to get good yields. In case of the propargyl amine, several
other peaks were observed along with desired SIA with propargyl
handle. This could be due to polymerization of the propargyl
amine and chlorination of the triple bond with SIC under these
conditions.
Experimental Section
General Information:
Anhydrous solvents were collected from Innovative Technology
(Model No. PS-MICRO) dry solvent system and other organic
reagents in Sure-SealTM bottles from various vendors and dried
prior to use using standard drying procedures. Commercially
available starting materials were used without purification unless
otherwise stated. All amino acids are of L-configuration unless
otherwise
stated.
N-(tert-butyl
diphenyl
silyl)-4-methyl
benzenesulfonamide was prepared following previously
described literature procedure.[4b] All solution phase reactions
(sulfonimidoyl chloride solution preparation) were carried out in
microwave vials (Biotage®) under nitrogen atmosphere. All solid
phase reactions were carried out in manual solid phase syringe
reactor (Biotage ISOLUTE® SPE reservoir) or on Biotage®
Initiator+ Alstra™ Microwave Peptide Synthesizer. Thin layer
chromatography was performed on pre-coated Silicagel 60 F254
,
visualised by UV 254 nm. Nuclear magnetic resonance (NMR)
spectra were recorded on Bruker Avance III (400 MHz)
spectrometer. Chemical shifts (δ) are reported in parts per million
(ppm) relative to the solvent residual peaks (CDCl3 δH: 7.26 ppm,
δC: 77.16 ppm; CD3CN δH: 1.94 ppm, δC: 1.32, 118.26 ppm;
CD3OD δH: 3.31 ppm, δC: 49.00 ppm; DMSO-d6 δH: 2.50 ppm,
δC 39.52 ppm). Coupling constants (J) are reported in hertz (Hz).
Splitting patterns are abbreviated as follows: singlet (s), doublet
(d), triplet (t), quartet (q), multiplet (m), broad (br), or combination
of these. Low-resolution mass spectra were recorded on Thermo
Scientific Dionex UltiMate 3000 HPLC system with the MSQ™
Plus single quadrupol LCMS instrument. High-resolution mass
spectra were recorded using a LC TOF (ES) ultra‐spectrometer.
Analytical HPLC/ESI‐MS was performed using electrospray
ionization (ESI) and a C18 column (50ꢀ× 3.0 mm, 2.6 µm particle
size, 100 Å pore size) with CH3CN/H2O in 0.05ꢀ% aqueous
HCOOH as mobile phase at a flow rate of 1.5 mL/min. LC
analyses were run using a gradient of 5–100ꢀ% CH3CN/H2O in
0.05ꢀ% aqueous HCOOH as mobile phase at a flow rate of 1.5
mL/min for 2 min on a C18 column unless otherwise stated.
Preparative RP‐HPLC was performed on a system equipped with
a Macherey–Nagel Nucleodur C18 HTec (21 mmꢀ× 125 mm,
particle size 5 µm), with a H2O/MeCN gradient with 0.1ꢀ% TFA as
mobile phase at a flow rate of 10 mL/min for 20 min and with UV
detection at 254/214 nm. IR was recorded on Agilent FTIR model
Cary 630.
Conclusion
In summary, we have for the first time demonstrated three
alternative methods for the introduction of the SIA group into a
peptide backbone on solid phase using various resins. The first
approach, using SIA-based amino acids as building blocks in
SPPS, is suitable for construction of complex SIA based
pseudopeptides with many reactive functional groups since the
complex SIA synthesis is made beforehand in solution. The
second approach where SIC is premade in solution and then
added to a resin-bound peptide, is a faster option, since the SIA
is made on solid-phase, which simply purification. This route
works well for different peptides and with full conversion for
secondary amines, such as proline at the N-terminal of the resin-
bound peptide. Finally, the third approach is highly advantageous
since the SIA-synthesis is made fully on solid-phase, making
handling and purification easy. Moreover, this approach allows
introduction of diversity at three handles around the chiral “S”
Note: PPh3Cl2 and sulfonimidoyl chloride (SIC) solutions are
highly moisture sensitive thus trace amount of water presence
seriously affects the outcome of the reaction conversion and yield.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000108
European Journal of Organic Chemistry
Full Paper
General procedures:
To a stirred suspension of PPh3Cl2 (1.2 equiv, ca. 0.3M) in dry
DCM under a N2 atmosphere at room temperature, TEA (1.6
equiv.) was added dropwise. The reaction mixture was stirred for
20 min at room temperature where after it was cooled to -5 to 0 °C.
A solution of the silyl protected sulfonamide (1 equiv.) in minimum
amount of dry DCM was added, instantly resulting in a clear light‐
yellow coloured precipitate. The reaction mixture was stirred for
ca. 20 min at -5 to 0 °C to get SIC.
Solid phase synthesis of peptide nucleophiles (Peptidyl
resin):
All
carried
polypropylene
syringes fitted
reactions
out
were
in
plastic
with
The resulting reaction mixture was transferred with syringe to a
solid phase reactor containing peptidyl-resin under nitrogen
atmosphere.
polypropylene frits. Syntheses were performed manually or by
automation. Amino acids were coupled using a 3-fold excess. 2-
Cl-Trt (2-CTC) resin (1 g, 1.69 mmol/g) was activated using
SOCl2- DCM (1:9) (60 mL) overnight. ChemMatrix-rink amide, and
Wang resin were used as received without any pre-activation. In
case of 2-CTC, to load the first amino acid, Fmoc-L-AA−OH (1
equiv.) and DIEA (25 equiv.) were dissolved in DCM (3.5 mL) and
shaken for 1 h. Then, MeOH (700 μL) was added and the mixture
was shaken for 30 min to ensure full capping of the resin. The
resin was washed with DMF (2 × 14 mL, 1 min), DCM (2 × 14 mL,
1 min), MeOH (2 × 14 mL, 1 min), DCM (2 × 14 mL, 1 min) and
DMF (2 × 14 mL, 1 min). Fmoc removal was achieved with 20%
piperidine in DMF (2 × 14 mL, 5 min) and the subsequent amino
acids were added using the following coupling conditions: A
solution of HBTU (3 equiv.), and DIEA (6 equiv.) in DMF, was
added to the Fmoc-AA-OH (3 equiv.) and the amino acid was
activated for 30 sec prior to addition to the resin. Fmoc-
AA−OH/HBTU/DIEA (3:3:6) in DMF (3.5 mL) mixed for 30 min.
Between the different steps, the resin was washed with DMF (2 ×
35 mL), DCM (2 × 35 mL), and DMF (2 × 35 mL) for swelling.
Every coupling was monitored by LC-MS after a mini-cleavage
from the resin.
Approach 1: Attachment of a SIA-based amino acid building
blocks[4b] under SPPS conditions
Synthesis of (4-methylphenylsulfonimidoyl)-L-phenylalanyl-
L-phenylalanine (diastereomeric mixture) (2):
The peptide was synthesized using standard Fmoc-SPPS from 2-
CTC polystyrene (PS) resin (1 mmol/g) on a 0.5 mmol scale and
the SIA amino acid building block (1) prepared in solution phase
as described previously.[4b] 1 (834 mg, 1.5 mmol) was coupled
using HBTU (568 mg, 1.5 mmol), DIPEA (521 µl, 3.0 mmol) in
DMF under agitation at room temperature for 1 h. The title peptide
(190 mg, 82%) was obtained as a diastereomeric mixture as a
white fluffy powder after RP-HPLC purification and lyophilization.
Gradient 0.1% TFA in acetonitrile and 0.1% TFA in water, with a
linear gradient of 45% to 85% for 30 min at 10 ml min-1 and UV
detection at 220 nm and 254 nm.
1H NMR (400 MHz, CDCl3) major isomer reported: δ 7.84 (br, 1H),
7.52 – 7.37 (m, 2H), 7.25 – 7.18 (m, 3H), 7.17 – 7.09 (m, 5H),
7.05 - 7.03 (m, 2H), 7.01 – 6.92 (m, 2H), 6.89 – 6.49 (br, 3H), 4.82
– 4.70 (m, 1H), 4.12-4.09 (m, 1H), 3.13-3.09 (m, 1H), 2.9-2.83 (m,
2H), 2.69 (dd, J = 13.9, 9.2 Hz, 1H), 2.37 (s, 3H). 13C NMR (101
MHz, CDCl3) δ 175.0, 172.8, 136.4, 130.0, 129.6, 129.5, 128.8,
128.7, 128.6, 128.5, 127.5, 127.1, 127.1, 126.9, 58.6, 53.2, 39.0,
37.1, 21.7. IR (ATR): ν = 1718, 1653, 1522, 1496, 1453, 1254,
1190, 1138, 1004, 810 cm-1. HRMS (ESI‐TOF) m/z [M+H]+ calcd.
for C25H28N3O4S: 466.1801, found 466.1790.
Note: The synthesis of peptide nucleophile was also carried out
on Biotage® Initiator+ Alstra™ Microwave Peptide Synthesizer.
Before coupling to sulfonimidoyl chloride (SIC), the peptide
nucleophile was dried in a desiccator and purged with N2.
Synthesis of tert-butyl tosyl-L-phenylalaninate:
To
a
mixture of tert-butyl 2-amino-3-phenyl-propanoate
hydrochloride (4.83 mmol) DMAP (0.525 mmol) and triethylamine
(21 mmol.) in DCM (30 mL), at 0 ⁰C and under nitrogen
atmosphere was added 4-methylbenzene-1-sulfonyl chloride
(5.25 mmol) in small portions. The reaction was allowed to stir
overnight at room temperature before being quenched by water
(30 mL). The organic and aqueous layer were separated, and the
aqueous layer extracted with 3 x 50 mL DCM. The organic layers
were pooled and washed with brine solution and, dried over
anhydrous sodium sulfate. The solvent was removed under
reduced pressure to afford crude compound which was purified
by column chromatography using 10-40% EtOAc in pentane as a
mobile phase.
Approach 2: On-resin SIA synthesis by addition of TBDPS
protected SIC to a resin-bound peptide
The peptidyl-resin was dried under vacuum, bubbled with N2 for
10 min and dry DMF was added for further N-capping with
sulfonimidoyl chloride using DIPEA as a base under nitrogen
atmosphere at 0 °C. The resulting solid phase reaction shook for
3-5 h on shaker. After completion of the reaction, the resin was
washed with sufficient amount of DCM and DMF to wash off un-
reacted starting materials (TBDPS-sulfonamide) and by-products
(PPh3O, DIPEA salt etc.). Thereafter, 1M TBAF in THF was added
to remove TBDPS protecting group for 9 h to overnight. Finally,
sulfonimidoyl peptidyl-resin was dried under vacuum and cleaved
from the resin with the reagent cocktail: 20% HFIP in DCM (25
mL/1 g peptidyl-resin (or) 90% TFA, 5% DCM, 2.5% TIS and 2.5%
H2O) for 1 h and repeated with fresh cleavage cocktail to ensure
full cleavage from the resin. The cleavage solution filtrates
containing the peptide were collected and concentrated. The
resulting crude peptide was purified on a semi preparative column
to obtain the desired peptide. Recovered yields for the purified
peptides were calculated based on the original resin loading (2-
CTC resin 1mmol/g; Wang resin 0.67 mmol/g; ChemMatrix-Rink
amide 0.4 mmol) and the amount of peptidyl-resin cleaved.
1H NMR (400 MHz, CDCl3) δ 7.69 – 7.64 (m, 2H), 7.26 – 7.21 (m,
5H), 7.16 – 7.11 (m, 2H), 5.05 (d, J = 9.2 Hz, 1H), 4.11-4.05 (m,
1H), 3.04 (dd, J = 13.6, 5.8 Hz, 1H), 2.99 (dd, J = 13.6, 6.1 Hz,
1H), 2.38 (s, 3H), 1.18 (s, 9H). 13C NMR (101 MHz, CDCl3) δ
169.9, 143.6, 137.0, 135.4, 129.8, 129.7, 128.5, 127.4, 127.2,
82.8, 57.0, 39.8, 27.7, 21.6. IR (ATR): ν = 3293, 2916, 1712, 1455,
1433, 1347, 1224, 1153, 922, 903 cm-1. LCMS (ESI‐TOF) m/z
[M+CH3CN+Na]+ calcd. for C22H28N2O4NaS: 439.1664, found
439.1667.
Synthesis of sulfonimidoyl chloride (SIC) from TBDPS-
toluene sulfonamide:
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000108
European Journal of Organic Chemistry
Full Paper
For demonstration of approach 2 - see movie in supporting
information.
Synthesis of ((2S)-3-(4-(tert-butoxy) phenyl)-2-((2S)-2-((((tert-
butyldiphenylsilyl)
amino)
(methyl)(oxo)-l6-
sulfanylidene)amino)propanamido)propanoyl)-L-
phenylalanylglycine (4):
Synthesis
of
(4-methylphenylsulfonimidoyl)-L-prolyl-L-
phenylalanine (diastereomeric mixture) (3a):
The peptide was synthesized using standard Fmoc-SPPS from 2-
CTC resin (1 mmol/g) on a 0.5 mmol scale and SIC prepared and
coupled according to the general procedure described above. The
title peptide (103 mg, 25%) was obtained as a white fluffy powder
after RP-HPLC purification and lyophilization. Gradient 0.05%
formic acid in acetonitrile and 0.05% formic acid in water, with a
linear gradient of 35% to 85% for 30 min at 10 ml min-1 and UV
detection at 220 nm and 254 nm.
The peptide was synthesized using standard Fmoc-SPPS from 2-
CTC resin (1 mmol/g) on a 0.5 mmol scale and SIC prepared and
coupled according to the general procedure described above. The
title peptide (190 mg, 92%) was obtained as a white fluffy powder
after RP-HPLC purification and lyophilization. Gradient 0.1% TFA
in acetonitrile and 0.1% TFA in water, with a linear gradient of
50% to 75% for 30 min at 10 ml min-1 and UV detection at 220
nm and 254 nm
Isomer 1 (4a): 1H NMR (400 MHz, CDCl3) δ 7.78 – 7.66 (m, 4H),
7.64 – 7.27 (m, 6H), 7.25 – 7.12 (m, 3H), 7.11 – 7.05 (m, 2H),
6.96-6.94 (m, 2H), 6.81-6.78 (m, 2H), 4.86-4.81 (m, 1H), 4.68-
4.64 (m, 1H), 4.10 (dd, J = 18.2, 5.6 Hz, 1H), 3.93-3.91 (m, 1H),
3.80 (dd, J = 18.2, 4.6 Hz, 1H), 3.17 (dd, J = 13.9, 5.6 Hz, 1H),
2.96 – 2.76 (m, 3H), 2.62 (s, 3H), 1.28 (s, 9H), 1.06 (s, 9H), 1.00
(d, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 172.9, 171.9,
171.3, 170.9, 154.6, 136.6, 135.6, 135.6, 134.9, 130.6, 129.9,
129.8, 129.5, 129.4, 128.5, 127.8, 127.8, 127.8, 127.0, 124.3,
78.7, 54.5, 54.1, 52.6, 46.3, 41.5, 38.3, 28.9, 27.1, 26.7, 19.8,
19.3. Isomer 2 (4b): 1H NMR (400 MHz, CDCl3) δ 7.76 – 7.70 (m,
4H), 7.49 – 7.32 (m, 4H), 7.28 – 7.25 (m, 6H), 7.20 – 7.13 (m, 1H),
6.84 – 6.78 (m, 2H), 6.68 – 6.66 (m, 2H), 6.58-6.56 (m, 1H), 4.85-
4.79 (m, 1H), 4.25-4.22 (m, 2H), 3.81 – 3.72 (m, 2H), 3.46 (dd, J
= 14.5, 4.4 Hz, 1H), 3.03-3.01 (m, 1H), 2.98 (s, 3H), 2.88 – 2.82
(m, 1H), 2.15 (dd, J = 14.5, 9.9 Hz, 1H), 1.31 (s, 9H), 1.11 (s, 9H),
0.78 (d, J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 174.5,
172.5, 171.4, 171.2, 154.5, 137.6, 135.5, 135.4, 134.9, 130.9,
130.0, 129.8, 129.2, 129.1, 128.7, 128.3, 128.2, 127.8, 126.8,
124.5, 78.7, 56.3, 54.5, 53.7, 43.4, 41.8, 36.9, 28.9, 27.0, 26.7,
19.3, 18.7. IR (ATR): ν = 2956, 1686, 1654, 1559, 1541, 1522,
1459, 1177, 1136, 924 cm-1. HRMS (ESI‐TOF) m/z [M+H]+ calcd.
for C44H58N5O7SSi: 828.3826, found 828.3840.
Alternatively, the same procedure was applied on Wang resin
(0.67 mmol/g) on a 0.33 mmol scale to get desired compound 3a
(111 mg, 81%).
1H NMR (400 MHz, CDCl3) major isomer reported: δ 7.93-7.89 (m,
2H), 7.45 – 7.35 (m, 2H), 7.27 – 7.23 (m, 5H), 6.90-5.93 (br, 3H),
4.93 (dt, J = 9.7, 4.7 Hz, 1H), 4.09 (dd, J = 9.2, 3.1 Hz, 1H), 3.61-
3.56 (m, 1H), 3.39 – 3.28 (m, 2H), 3.14-3.10 (m, 2H), 2.44 (s, 3H),
1.79-1.77 (m, 1H), 1.68-1.58 (m, 1H), 1.43 – 1.39 (m, 1H). 13C
NMR (101 MHz, CDCl3) δ 173.9, 171.5, 147.2, 136.7, 130.9,
129.7, 129.3, 128.8, 128.7, 127.1, 63.0, 53.1, 50.0, 36.9, 31.4,
24.1, 21.8. IR (ATR): ν = 2965, 2877, 1727, 1654, 1595, 1526,
1455, 1259, 1177, 1131cm-1.HRMS (ESI‐TOF) m/z [M+H]+ calcd.
for C21H26N3O4S: 416.1644, found 416.1632.
Alternatively, compound 2 was prepared using this approach 2 on
2-CTC resin (1 mmol/g) on a 0.5 mmol scale to get the desired
product (145 mg, 70%).
Synthesis of N-((S)-1-amino-1-oxo-3-phenylpropan-2-yl)-1-(4-
methylphenylsulfonimidoyl) pyrrolidine-2-carboxamide (3b):
The peptide was synthesized using standard Fmoc-SPPS from
Chem-Matrix rink amide resin (0.4 mmol/g) on a 0.2 mmol scale
and SIC prepared and coupled according to general procedure
described above. The title peptide (68 mg, 84%) was obtained as
a white fluffy powder after RP-HPLC purification and lyophilization.
Gradient 0.1% TFA in acetonitrile and 0.1% TFA in water, with a
linear gradient of 43% to 46% for 10 min at 10 ml min-1 and UV
detection at 220 nm and 254 nm.
Synthesis of (4-methylphenylsulfonimidoyl)-L-prolylglycyl-
L-phenylalanyl-L-phenylalanine (5):
The peptide was synthesized using standard Fmoc-SPPS from 2-
CTC resin (1 mmol/g) on a 1 mmol scale and SIC was prepared
and coupled according to general procedure described above.
The title peptide (396 mg, 64%) was obtained as a white fluffy
powder as enriched isomers after RP-HPLC purification and
lyophilization. Gradient 0.1% TFA in acetonitrile and 0.1% TFA in
water, with a linear gradient of 37% to 85% for 30 min at 10 ml
min-1 and UV detection at 220 nm and 254 nm
1
Isomer 1 (3b1): H NMR (400 MHz, CDCl3) δ 7.78-7.75 (m, 2H),
7.40-7.38 (m, 2H), 7.27-7.21 (m, 5H), 6.86-6.73 (m, 1H), 6.43-
6.23 (br, 1H), 5.77-5.49 (br, 2H) 4.91-4.89 (m, 1H), 3.90-3.88 (m,
1H), 3.59-3.55 (m, 1H), 3.42-3.39 (m, 1H), 3.2-3.17 (m, 2H), 2.47
(s, 3H), 1.79-1.73 (m, 1H), 1.52-1.49 (m, 3H). 13C NMR (101 MHz,
CDCl3) δ 176.2, 171.9, 146.6, 137.0, 130.8, 129.4, 129.1, 128.8,
128.6, 127.2, 62.1, 53.4, 51.7, 36.7, 31.2, 24.5, 21.8. Isomer 2
(3b2): 1H NMR (400 MHz, CDCl3) δ 7.80-7.74 (m, 2H), 7.38-7.34
(m, 2H), 7.32-7.28 (m, 2H), 7.25 (s, 1H), 7.24-7.20 (m, 2H), 6.97-
6.93 (br, 1H), 4.92-4.85 (m, 1H), 4.21-4.18 (m, 3H), 4.02-3.98 (m,
1H), 3.42-3.40 (m, 2H), 3.08-3.02 (m, 2H), 2.45 (s, 3H), 1.78-1.73
(m, 1H), 1.68-1.63 (m, 1H), 1.53-1.46 (m, 1H), 1.39-1.31 (m, 1H).
13C NMR (101 MHz, CDCl3) δ 176.7, 171.8, 146.4, 136.4, 130.7,
129.2, 129.1, 128.9, 128.6, 127.3, 63.3, 53.8, 49.5, 37.3, 31.4,
24.2, 21.8. IR (ATR): ν = 3060, 2968, 1662, 1559, 1425, 1304,
1179, 1133, 1097, 814 cm-1. HRMS (ESI‐TOF) m/z [M+H]+ calcd.
for C21H27N4O3S: 415.1804, found 415.1814.
Isomer 1 (5a): 1H NMR (400 MHz, CDCl3) δ 8.21 (br, 1H), 7.83 (d,
J = 8.1 Hz, 2H), 7.53 (d, J = 7.2 Hz, 1H), 7.41 – 7.29 (m, 3H), 7.23
– 7.20 (m, 2H), 7.19-7.15 (m, 4H), 7.12 (d, J = 7.5 Hz, 2H), 6.70-
5.86 (br, 4H), 4.74-4.66 (m, 1H), 4.56-4.49 (m, 1H), 4.12-4.06
(m,1H), 3.94-3.89 (m,1H), 3.80-3.71 (m, 1H), 3.56-3.46 (m, 1H),
3.26 (dd, J = 14.0, 5.1 Hz, 1H), 3.19-3.11 (m, 1H), 3.02-2.99 (m,
2H), 2.82 (dd, J = 14.2, 9.0 Hz, 1H), 2.45 (s, 3H), 2.01-1.95 (m,
1H), 1.84-1.82 (m, 2H), 1.56-1.53 (m, 1H). 13C NMR (101 MHz,
CDCl3) δ 174.3, 173.4, 171.9, 170.6, 151.5, 145.9, 136.9, 136.8,
131.2, 130.5, 129.4, 129.3, 128.7, 128.6, 128.5, 126.9, 62.4, 56.0,
54.2, 50.9, 43.4, 37.3, 37.2, 30.9, 24.9, 21.8. Isomer 2 (5b, major
isomer reported): 1H NMR (400 MHz, CDCl3) δ 9.04 (br, 4H), 7.85-
7.70 (m, 2H), 7.41-7.39 (m, 2H), 7.24 – 6.98 (m, 11H), 4.66-4.63
(m, 2H), 4.56-4.48 (m, 1H), 3.97-3.88 (m, 1H), 3.79-3.69 (m, 1H),
3.54-3.44 (m, 1H), 3.28 – 3.11 (m, 2H), 3.01 – 2.98 (m, 2H), 2.90-
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000108
European Journal of Organic Chemistry
Full Paper
2.81 (m, 1H), 2.46 (s, 3H), 2.10 – 1.89 (m, 3H), 1.79-1.70 (m, 1H).
13C NMR (101 MHz, CDCl3) δ 173.8, 172.8, 172.2, 170.4, 147.3,
136.5, 136.1, 130.8, 130.3, 129.4, 129.3, 128.8, 128.6, 127.7,
127.2, 127.1, 70.64, 63.4, 49.8, 48.0, 37.8, 36.8, 29.9, 27.5, 24.8,
21.8. IR (ATR): ν = 2868, 1779, 1751, 1636, 1528, 1444, 1420,
1340, 1205, 1120 cm-1. HRMS (ESI‐TOF) m/z [M+H]+ calcd. for
C32H38N5O6S: 620.2543, found 620.2549.
washed thoroughly with DMF, DCM and dried under vacuum
before cleavage of peptide with 20% HFIP in DCM. The title
peptide (102 mg, 28%) was obtained as a white fluffy powder after
RP-HPLC purification and lyophilization. Gradient 0.1% TFA in
acetonitrile and 0.1% TFA in water, with a linear gradient of 25%
to 75% for 30 min at 10 ml min-1 and UV detection at 220 nm and
254 nm.
Synthesis of (N-((S)-1-(tert-butoxy)-1-oxo-3-phenyl propan-2-
yl) -4-methyl phenyl sulfonimidoyl) -L-prolyl-L-phenyl alanyl-
L-phenyl alanyl glycine (6):
Isomer 1 (7a): 1H NMR (400 MHz, DMSO-d6) δ 8.7-8.67 (m, 1H),
8.34 – 8.25 (m, 2H), 8.08 - 8.05 (m, 3H), 7.98-7.95 (m, 1H), 7.87
– 7.81 (m, 2H), 7.44 – 7.42 (m, 2H), 7.29 – 7.26 (m, 4H), 7.25-
7.22 (m, 4H), 7.20 – 7.13 (m, 2H), 4.62-4.56 (m, 1H), 4.49 (ddd,
J = 10.5, 8.4, 4.2 Hz, 1H), 4.28 (dd, J = 8.5, 2.8 Hz, 1H), 3.98 (dd,
J = 17.88, 5.93 Hz, 1H), 3.88 (dd, J = 17.88, 5.66 Hz, 1H), 3.79
(d, J = 5.8 Hz, 2H), 3.64 - 3.60 (m, 2H), 3.10 – 2.99 (m, 4H), 2.83
– 2.75 (m, 2H), 2.41 (s, 3H), 1.67-1.62 (m, 1H), 1.59 – 1.45 (m,
2H), 1.21 – 1.14 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 176.2,
171.1, 171.0, 170.7, 170.4, 166.2, 144.5, 137.8, 137.5, 132.5,
130.0, 129.2, 129.1, 128.0, 128.0, 127.8, 126.3, 126.2, 60.9, 54.2,
53.7, 48.6, 45.7, 45.0, 40.6, 37.8, 37.2, 30.2, 23.6, 21.0. Isomer 2
(7b): 1H NMR (400 MHz, CD3CN) δ 8.42 (d, J = 8.5 Hz, 1H), 7.93
– 7.88 (m, 2H), 7.48-7.45 (m, 3H), 7.28-7.24 (m, 15H), 4.55 – 4.47
(m, 2H), 4.23 (dd, J = 9.0, 3.1 Hz, 1H), 3.99 - 3.90 (dd, J = 18.1,
6.5 Hz, 3H), 3.9 - 3.74 (dd, J = 18.1, 5.7 Hz, 2H), 3.27-3.24 (m,
3H), 3.17-3.12 (m, 1H), 2.95 – 2.89 (m, 3H), 2.44 (s, 3H), 1.74-
1.69 (m, 1H), 1.64-1.60 (m, 1H), 1.49-1.45 (m, 1H), 1.24-1.19 (m,
1H). 13C NMR (101 MHz, CD3CN) δ 175.6, 172.8, 172.66, 172.3,
172.2, 172.1, 166.9, 147.2, 138.7, 138.6, 131.7, 131.3, 130.3,
130.2, 129.3, 129.3, 128.7, 127.5, 127.5, 63.0, 56.5, 55.7, 50.2,
45.1, 41.9, 37.9, 37.8, 31.4, 26.0, 24.8, 21.6. IR (ATR): ν = 2958,
2916, 2849, 1718, 1653, 1522, 1457, 1377, 1202, 1181 cm-1.
HRMS (ESI‐TOF) m/z [M+H]+ calcd. for C36H44N7O8S: 734.2972,
found 734.2972.
The peptide was synthesized using standard Fmoc-SPPS from 2-
CTC resin (1 mmol/g) on a 1 mmol scale and SIC prepared and
coupled according to the general procedure described above. The
title peptide (255 mg, 31%) was obtained as a white fluffy powder
after RP-HPLC purification and lyophilization. Gradient 0.1% TFA
in acetonitrile and 0.1% TFA in water, with a linear gradient of
45% to 90% for 30 min at 10 ml min-1 and UV detection at 220
nm and 254 nm
1
Isomer 1 (6a): H NMR (400 MHz, CDCl3) δ 9.48 (br, 3H), 8.27-
8.20 (m, 1H), 7.56-7.49 (m, 1H), 7.42 – 7.33 (m, 6H), 7.32-7.28
(m, 3H), 7.27 – 7.25 (m, 7H), 7.14 – 7.08 (m, 2H), 5.12 – 5.10 (m,
2H), 4.87-4.82 (m, 1H), 4.08 (dd, J = 18.7, 5.4 Hz, 1H), 3.91 –
3.74 (m, 2H), 3.68-3.60 (m, 1H), 3.32 – 3.06 (m, 7H), 2.51 (s, 3H),
2.35-2.22 (m, 1H), 2.03 – 2.0 (m, 2H), 1.83-1.72 (m, 1H), 1.62 (s,
9H). 13C NMR (101 MHz, CDCl3) δ 171.6, 171.0, 170.7, 170.2,
169.6, 161.3 (TFA), 160.9 (TFA), 147.2, 136.6, 136.1, 135.9,
130.7, 130.0, 129.7, 129.5, 129.5, 129.3, 128.8, 128.4, 128.3,
127.3, 127.1, 127.0, 116 (TFA), 114 (TFA), 83.3, 63.7, 59.5, 54.7,
53.8, 50.3, 41.8, 39.0, 38.9, 38.2, 31.6, 27.9, 24.7, 21.8. Isomer 2
(6b): 1H NMR (400 MHz, CDCl3) δ 10.55 (br, 3H), 8.01 - 7.98 (m,
2H), 7.41 – 7.27 (m, 7H), 7.20-7.17 (m, 7H), 7.11 – 7.07 (m, 2H),
7.0 – 6.98 (m, 2H), 4.88-4.81 (m, 1H), 4.69-4.61 (m, 1H), 4.39-
4.28 (m, 1H), 4.20 – 4.13 (m, 1H), 3.99-3.89 (m, 2H), 3.26 (dd, J
= 13.8, 6.4 Hz, 1H), 3.14-3.10 (m, 3H), 2.99-2.97 (m, 2H), 2.91-
2.88 (m, 2H), 2.38 (s, 3H), 2.04-1.95 (m, 1H), 1.79-1.76 (m, 1H),
1.65 – 1.55 (m, 2H), 1.31 (s, 9H). 13C NMR (101 MHz, CDCl3) δ
172.1, 171.7, 171.6, 171.2, 170.3, 147.0, 136.6, 136.4, 136.2,
130.4, 129.8, 129.7, 129.5, 129.3, 129.1, 128.8, 128.6, 128.5,
127.2, 127.1, 127.0, 82.9, 63.9, 59.4, 55.2, 54.4, 49.4, 41.7, 39.7,
38.2, 37.7, 31.8, 27.7, 24.4, 21.7. IR (ATR): ν = 3267, 2935, 1733,
1664, 1638, 1546, 1280, 1172, 1131, 1064 cm-1. HRMS (ESI‐
TOF) m/z [M+H]+ calcd. for C45H54N5O8S: 824.3693, found
824.3704.
N-Arylation of imine “NH” of Sulfonimidoyl peptide:
Synthesis
of
(N-(4-methoxyphenyl)-4-
methylphenylsulfonimidoyl)-L-prolyl-L-phenylalanyl-L-
phenylalanylglycine (8):
The peptide was synthesized using standard Fmoc-SPPS from 2-
CTC resin (1 mmol/g) in a 1.0 mmol scale. Then SIC was
prepared and coupled according to the general procedure
described above.
Initially, sulfonimidamide resin (1 g, loading 1 mmol/g) was
vacuum dried and swelled in dry THF (7 mL) and the following
reagents were added in a sequential order: aryl boronic acid (5
equiv., 760 mg), anhydrous copper acetate (2.0 equiv., 362 mg),
4 Å powdered molecular sieves (100 mg), TEA (2.0 equiv., 300
µL) and dry THF (3 mL).[34] The heterogeneous mixture was mixed
for 3 h. The resin was filtered off and washed with THF (×4), DCM
(×4), followed by THF (×4) and charged with fresh reagents. The
reaction mixture was again mixed for 3 h. The washing procedure
was repeated, and the resin was charged again with fresh
reagents and then shaken overnight. The washing procedure was
repeated as above. The product was cleaved from the solid
support by treatment with 50% TFA in DCM for 1 h. The cleavage
solution was filtered off and washed with DCM. The combined
filtrates were passed through celite and evaporated to dryness.
The light green residue was re-dissolved in HPLC buffer and
lyophilized. The resulting product was purified on a preparative
column to obtain the desired peptide. The title peptide (153 mg,
21%) was obtained as a white fluffy powder after RP-HPLC
purification and lyophilization. Gradient 0.1% TFA in acetonitrile
N-Acylation of imine “NH” of Sulfonimidoyl peptide:
Synthesis of (N-(glycylglycyl)-4-methylphenylsulfonimidoyl)-
L-prolyl-L-phenylalanyl-L-phenylalanylglycine (7):
The peptide was synthesized using standard Fmoc-SPPS from 2-
CTC resin (1 mmol/g) on a 0.5 mmol scale and SIC prepared and
coupled according to the general procedure described above.
Resin of attached toluene sulfonimidamide containing tetra-
peptide (tol-SIA-Pro-Phe-Phe-Gly-2CTC) was made as per above
mentioned by the SPPS protocol. Further, it was subjected to
simple amide coupling using Fmoc-Gly-Gly-OH (5.0 equiv., 885
mg) as an acylating agent in presence of HBTU (5.0 equiv., 947
mg), DIPEA (10 equiv., 870 µL) in dry DMF (7 mL) at room
temperature overnight, followed by a double coupling the next day.
After completion of the reaction, the resin was washed thoroughly
with DCM-DMF and the Fmoc group was deprotected using 20%
piperidine in DMF. After completion of deprotection, the resin was
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000108
European Journal of Organic Chemistry
Full Paper
and 0.1% TFA in water, with a linear gradient of 45% to 95% for
25 min at 10 ml min-1 and UV detection at 220 nm and 254 nm.
(NH2-Phe-Phe-O-Resin) dipeptide nucleophile was synthesized
as per above mentioned standard Fmoc-SPPS method on 0.5
mmol scale using 2-CTC resin. Next, toluene sulfonyl chloride (5.0
equiv., 476 mg) was coupled
Isomer 1 (8a):1H NMR (400 MHz, CDCl3) δ 11.86 (br, 1H), 7.64
(d, J = 8.0 Hz, 2H), 7.25-7.19 (m, 13H), 7.08 – 7.01 (m, 2H), 6.97
(d, J = 8.7 Hz, 2H), 6.75 – 6.61 (m, 2H), 4.76-4.74 (m, 1H), 4.50-
4.46 (m, 1H), 4.36 (dd, J = 9.2, 3.0 Hz, 1H), 4.21 (dd, J = 18.0,
6.1 Hz, 1H), 3.87 (dd, J = 17.7, 4.6 Hz, 1H), 3.64 (s, 3H), 3.18-
3.12 (m, 4H), 2.97-2.89 (m, 1H), 2.32 (s, 3H), 2.24 (dd, J = 14.2,
10.6 Hz, 1H), 2.14 (dd, J = 14.3, 10.8 Hz, 1H), 1.77 – 1.64 (m,
1H), 1.62 – 1.51 (m, 1H), 1.14 – 1.05 (m, 1H). 13C NMR (101 MHz,
CDCl3) δ 173.9, 173.7, 171.7, 171.5, 155.6, 144.4, 137.7, 136.6,
136.4, 131.8, 130.3, 129.5, 129.4, 129.0, 128.9, 128.5, 127.2,
126.7, 125.1, 115.0, 63.9, 55.6, 54.8, 48.4, 45.8, 41.7, 36.9, 36.3,
30.2, 24.2, 21.6. Isomer 2 (8b): 1H NMR (400 MHz, CDCl3) δ 9.65
(br, 3H), 7.88 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 8.2 Hz, 1H), 7.38-
7.34 (m, 3H), 7.25 – 7.16 (m, 3H), 7.11 – 7.06 (m, 3H), 7.01 –
6.92 (m, 3H), 6.66-6.62 (m, 4H), 5.10 – 4.96 (m, 1H), 4.44 – 4.32
(m, 1H), 4.26 (dd, J = 18.0, 6.3 Hz, 1H), 3.99 – 3.85 (m, 2H), 3.64
(s, 3H), 3.53 (dd, J = 15.2, 4.2 Hz, 1H), 3.29 – 3.17 (m, 2H), 3.10
– 2.99 (m, 2H), 2.39 (s, 3H), 2.27-2.20 (m, 1H), 1.78-1.70 (m, 1H),
1.40 – 1.27 (m, 2H), 1.12-1.02 (m, 1H). 13C NMR (101 MHz,
CDCl3) δ 175.0, 172.8, 172.4, 172.3, 156.5, 145.5, 136.7, 136.2,
134.8, 130.5, 129.6, 128.9, 128.8, 128.8, 128.7, 128.6, 127.2,
127.0, 125.5, 115.1, 62.6, 56.1, 55.6, 54.0, 50.1, 41.6, 36.7, 36.5,
30.6, 24.4, 21.7. IR (ATR): ν = 2980, 1735, 1654, 1522, 1500,
1440, 1272, 1235, 1179, 1105 cm-1.HRMS (ESI‐TOF) m/z [M+H]+
calcd. for C39H44N5O7S: 726.2961, found 726.2973.
(N-capping) to the resin
attached peptide in dry DCM, in
presence of base and DIPEA
(10 equiv., 900 µL). The resulting solid phase reaction shook for
6 h on shaker. Later, the resin was washed thoroughly with DCM,
DMF and reaction was monitored by LC-MS after mini-cleavage.
After successful completion of coupling, the resin was dried and
purged with nitrogen gas. Dry DCM was added to the resin under
nitrogen atmosphere and the solid phase reactor was cooled to
0 °C by adding dry ice to the sonicator bath.[38a] Pre-dissolved
PPh3Cl2 (4.0 equiv., 600 mg), TEA (10 equiv., 850 µL) in dry DCM
(6 mL) was added dropwise to solid phase reactor and further
sonicated for 30 min at 0 °C to get SIC.
Later, proline methyl ester (5.0 equiv., 414 mg), DIPEA (10 equiv.,
900 µL) in DCM (4 mL) was added and sonicated for 30 minutes.
After completion of the reaction, the reactor was washed
thoroughly with DMF and DCM. The resin attached peptide was
cleaved from the resin using 20% HFIP in DCM (10 mL).
Synthesis of ((2S)-2-((((S)-2-(methoxycarbonyl) pyrrolidin-1-
yl)
(oxo)(p-tolyl)-l6-sulfaneylidene)
amino)-3-
phenylpropanoyl)-L-phenylalanine (11):
The title peptide (257 mg, 90%) was obtained as a white fluffy
powder after RP-HPLC purification and lyophilization. Gradient
0.1% TFA in acetonitrile and 0.1% TFA in water, with a linear
gradient of 60% to 65% for 15 min at 10 ml min-1 and UV
detection at 220 nm and 254 nm.
Synthesis of (2-((3S)-1-oxido-4-oxo-1-(p-tolyl)-3, 4-dihydro-
2H-1l6,2,5-thiadiazol-3-yl) acetyl)-L-proline (10):
The peptide was synthesized using standard Fmoc-SPPS from 2-
CTC resin (1 mmol/g) on a 0.5 mmol scale and SIC prepared and
coupled according to the general procedure described above.
Further, the resin attached SIA peptide was treated with 1.0 M
TBAF in THF (10 mL) at 50 °C to get desired compound 10.[4b]
The title peptide (141 mg, 78%) was obtained as a white fluffy
powder after RP-HPLC purification and lyophilization. Gradient
0.1% TFA in acetonitrile and 0.1% TFA in water, with a linear
gradient of 25% to 67% for 30 min at 10 ml min-1 and UV
detection at 220 nm and 254 nm. Further, to separate the
diastereomers, the HPLC purified fraction were subjected for SFC
purification resulted in enriching of the isomers.
Isomer 1 (11a): 1H NMR (400 MHz, CDCl3) δ 8.13 (br, 1H), 7.45
– 7.28 (m, 2H), 7.25 – 7.07 (m, 10H), 6.97-6.95 (m, 2H), 6.57-6.32
(br, 1H), 5.0-4.83 (m, 1H), 4.36-4.28 (m, 1H), 4.26-4.11 (m, 1H),
3.62 (s, 3H), 3.31-3.28 (m, 2H), 3.06-2.97 (m, 4H), 2.48 (s, 3H),
1.84-1.82 (m, 2H)1.80-1.78 (m, 2H). 13C NMR (101 MHz, CDCl3)
δ 176.6, 174.9, 172.0, 146.0, 136.4, 130.7, 130.6, 130.3, 129.1,
129.1, 129.0, 128.9, 128.5, 127.7, 127.4, 63.3, 54.8, 53.6, 52.2,
1
49.5, 37.3, 31.3, 30.9, 24.2, 21.7. Isomer 2 (11b): H NMR (400
MHz, CDCl3) δ 7.66 (d, J = 7.4 Hz, 2H), 7.51 (m, 1H), 7.37 – 7.28
(m, 6H), 7.23 (m, 1H), 7.14 – 7.06 (m, 3H), 7.06 – 7.00 (m, 2H),
4.85-4.79 (m, 1H), 4.40 (dd, J = 9.3, 3.4 Hz, 2H), 4.07-4.02 (m,
1H), 3.67 (s, 3H), 3.16 (dd, J = 13.3, 3.4 Hz, 1H), 3.10-3.06 (m,
1H), 2.80 (dd, J = 13.2, 9.3 Hz, 1H), 2.45 (s, 3H), 2.35-2.45 (m,
1H), 2.25-2.35 (m, 1H), 1.88-1.86 (m, 2H), 1.58-1.65 (m, 1H),
1.32-1.38 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 174.1, 172.9,
172.1, 145.7, 136.6, 135.8, 130.3, 130.2, 129.5, 128.8, 128.6,
128.4, 128.3, 127.1, 127.0, 61.6, 59.0, 53.1, 52.8, 49.3, 40.2, 37.4,
30.6, 24.6, 21.8. IR (ATR): ν = 1735, 1623, 1522, 1453, 1436,
1271, 1190, 1149, 1008, 805 cm-1. HRMS (ESI‐TOF) m/z [M+H]+
calcd. for C31H36N3O6S : 578.2325, found 578.2328.
Isomer1 (10a, major isomer reported) : 1H NMR (400 MHz,
CD3OD) δ 7.82 – 7.79 (m, 2H), 7.51 – 7.45 (m, 2H), 4.68-4.65 (m,
1H), 4.45 (dd, J = 8.6, 3.1 Hz, 1H), 3.68-3.55 (m, 2H), 3.36-3.33
(m, 1H), 3.24 – 3.12 (m, 1H), 2.80 (dd, J = 16.9, 10.4 Hz, 1H),
2.47 (s, 3H), 2.27-2.23 (m, 1H), 2.12 – 1.85 (m, 3H). 13C NMR
(101 MHz, CD3OD) δ 181.4, 175.6, 170.5, 147.2, 136.6, 131.4,
128.8, 62.0, 60.3, 48.3, 40.3, 30.4, 25.5, 21.5. Isomer 2 (10b,
major isomer reported): 1H NMR (400 MHz, CD3OD) δ 7.90-7.86
(m, 2H), 7.47 – 7.45 (m, 2H), 4.65 (dd, J = 9.4, 2.5 Hz, 1H), 4.41
(dd, J = 8.6, 3.2 Hz, 1H), 3.65-3.62 (m, 1H), 3.57 – 3.53 (m, 1H),
3.13 (dd, J = 17.0, 2.5 Hz, 1H), 2.80 (dd, J = 17.0, 9.5 Hz, 1H),
2.46 (s, 3H), 2.27-2.21 (m, 1H), 2.03-1.98 (m, 3H). 13C NMR (101
MHz, CD3OD) δ 181.9, 175.7, 170.2, 147.1, 136.3, 131.2, 129.4,
60.2, 59.9, 47.6, 38.5, 30.3, 25.6, 21.5. IR (ATR): ν = 2143, 1716,
1636, 1453, 1405, 1261, 1190, 1142, 1097, 998 cm-1.HRMS (ESI‐
TOF) m/z [M+H]+ calcd. for C16H20N3O5S: 366.1124, found
366.1128.
A
combinatorial library synthesis was also demonstrated
according to approach 3. On 0.5 mmol scale using 2-CTC resin.
For demonstration of approach 3 in library format - see movie and
LC-MS chromatograms in supporting information.
Acknowledgements
Approach 3: On-resin SIA synthesis, via on-resin SIC formation
followed by addition of an amino acid
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000108
European Journal of Organic Chemistry
Full Paper
[22] a) R. B. Merrifield, J. M. Stewart, Nature. 1965, 207, 522-523; b) R. B.
Merrifield, J. M. Stewart, N. Jernberg, Anal. Chem. 1966, 38, 1905-1914.
[23] O. J. Plante, E. R. Palmacci, P. H. Seeberger, Science. 2001, 291, 1523.
[24] M. Funes Maldonado, F. Sehgelmeble, F. Bjarnemark, M. Svensson, J.
Åhman, P. I. Arvidsson, Tetrahedron. 2012, 68, 7456-7462.
[25] T. Q. Davies, A. Hall, M. C. Willis, Angew. Chem. Int. Ed. 2017, 56,
14937-14941.
A. Sandström gratefully acknowledges Kjell and Märta Beijer
Foundation for financial support. P. K. Chinthakindi acknowledges
the Department of Medicinal Chemistry, Uppsala University,
Sweden, for a postdoc fellowship. The authors wish to thank
master student Anna Joo for her contribution.
[26] E. L. Briggs, A. Tota, M. Colella, L. Degennaro, R. Luisi, J. A. Bull, Angew.
Chem. Int. Ed. 2019, 58, 14303-14310.
Keywords: peptides • solid-phase synthesis • sulfonimidoyl
chloride • sulfonimidamide • new modalities
[27] B. Gao, S. Li, P. Wu, J. E. Moses, K. B. Sharpless, Angew. Chem. Int.
Ed. 2018, 57, 1939-1943.
[28] Y. Chen, J. Gibson, RSC Adv. 2015, 5, 4171-4174.
[29] D. C. Batesky, M. J. Goldfogel, D. J. Weix, J. Org. Chem. 2017, 82, 9931-
9936.
References:
[30] a) P. Cherkupally, G. A. Acosta, S. Ramesh, B. G. De la Torre, T.
Govender, H. G. Kruger, F. Albericio, Amino Acids. 2014, 46, 1827-1838;
b) A. Bernhardt, M. Drewello, M. Schutkowski, J. Pept. Res. 1997, 50,
143-152; c) N. Bayó-Puxan, A. Fernández, J. Tulla-Puche, E. Riego, C.
Cuevas, M. Álvarez, F. Albericio, Chem. Eur. J 2006, 12, 9001-9009; d)
J.-S. Zheng, S. Tang, Y.-K. Qi, Z.-P. Wang, L. Liu, Nat. Protoc. 2013, 8,
2483.
[1]
Sulfur Chemistry (Eds.: X. Jiang), Topics in Current Chemistry
Collections, Springer International Publishing, 2019.
[2]
[3]
M. Wang, Q. Fan, X. Jiang, Green Chem. 2018, 20, 5469-5473.
M. Feng, B. Tang, S. H. Liang, X. Jiang, Curr. Top. Med. Chem. 2016,
16, 1200-1216.
[4]
a) N. Thota, P. Makam, K. K. Rajbongshi, S. Nagiah, N. S. Abdul, A. A.
Chuturgoon, A. Kaushik, G. Lamichhane, A. M. Somboro, H. G. Kruger,
T. Govender, T. Naicker, P. I. Arvidsson, ACS Med. Chem. Lett. 2019,
10, 1457-1461; b) P. K. Chinthakindi, A. Benediktsdottir, A. Ibrahim, A.
Wared, C.-J. Aurell, A. Pettersen, E. Zamaratski, P. I. Arvidsson, Y. Chen,
A. Sandström, Eur. J. Org. Chem. 2019, 2019, 1045-1057; c) E. L. Briggs,
A. Tota, M. Colella, L. Degennaro, R. Luisi, J. A. Bull, Angew. Chem. Int.
Ed. 2019, 58, 14303-14310; d) M. Bremerich, C. M. Conrads, T. Langletz,
C. Bolm, Angew. Chem. Int. Ed. 2019, 58, 19014-19020.
[31] Å. Rosenquist, B. Samuelsson, P.-O. Johansson, M. D. Cummings, O.
Lenz, P. Raboisson, K. Simmen, S. Vendeville, H. de Kock, M. Nilsson,
A. Horvath, R. Kalmeijer, G. de la Rosa, M. Beumont-Mauviel, J. Med.
Chem. 2014, 57, 1673-1693.
[32] P. Arora, A. Chauhan, Int. J. Pharm. Sci. Res. 2013, 4, 532-548.
[33] a) L.-Q. Han, X. Yuan, X.-Y. Wu, R.-D. Li, B. Xu, Q. Cheng, Z.-M. Liu, T.-
Y. Zhou, H.-Y. An, X. Wang, T.-M. Cheng, Z.-M. Ge, J.-R. Cui, R.-T. Li,
Eur. J. Med. Chem 2017, 125, 925-939; b) P. Bakshi, M. S. Wolfe, J. Med.
Chem. 2004, 47, 6485-6489; c) P. Claudon, A. Violette, K. Lamour, M.
Decossas, S. Fournel, B. Heurtault, J. Godet, Y. Mély, B. Jamart-
Grégoire, M.-C. Averlant-Petit, J.-P. Briand, G. Duportail, H. Monteil, G.
Guichard, Angew. Chem. Int. Ed. 2010, 49, 333-336.
[5]
[6]
a) H. A. M. Mucke, Pharm. Pat. Anal. 2019, 8, 73-80; b) E. D. Pressly, C.
J. Hawker, Google Patents. 2016.
a) U. Lücking, Org. Chem. Front. 2019, 6, 1319-1324; b) P. K.
Chinthakindi, T. Naicker, N. Thota, T. Govender, H. G. Kruger, P. I.
Arvidsson, Angew. Chem. Int. Ed. 2017, 56, 4100-4109.
[34] A. P. Combs, M. Rafalski, J. Comb. Chem. 2000, 2, 29-32.
[35] A. P. Combs, S. Tadesse, M. Rafalski, T. S. Haque, P. Y. S. Lam, J.
Comb. Chem. 2002, 4, 179-182.
[7]
a) F. Izzo, M. Schäfer, P. Lienau, U. Ganzer, R. Stockman, U. Lücking,
Chem. Eur. J. 2018, 24, 9295-9304; b) S. R. Borhade, R. Svensson, P.
Brandt, P. Artursson, P. I. Arvidsson, A. Sandström, Chem. Med. Chem.
2015, 10, 455-460.
[36] T. Michels, R. Dölling, U. Haberkorn, W. Mier, Org. Lett. 2012, 14, 5218-
5221.
[8]
[9]
a) D. L. Boger, J. Org. Chem. 2017, 82, 11961-11980; b) D. S. Cooper,
N. Engl. J. Med. 2005, 352, 905-917.
[37] a)T. Wöhr, M. Mutter, Tet. Lett. 1995, 36, 3847-3848; b) A.-B. M. Abdel-
Aal, G. Papageorgiou, R. Raz, M. Quibell, F. Burlina, J. Offer, J. Pept Sci
2016, 22, 360-367.
G. C. Nandi, P. I. Arvidsson, Adv. Synth. Catal. 2018, 360, 2976-3001.
[10] a) S. R. Borhade, A. Sandström, P. I. Arvidsson, Org. Lett. 2013, 15,
1056-1059; b) P. B. Wakchaure, S. R. Borhade, A. Sandström, P. I.
Arvidsson, Eur. J. Org. Chem. 2015, 2015, 213-219.
[38] a) F. Merlino, S. Tomassi, A. M. Yousif, A. Messere, L. Marinelli, P.
Grieco, E. Novellino, S. Cosconati, S. Di Maro, Org. Lett. 2019, 21, 6378-
6382; b) G. Wołczański, H. Płóciennik, M. Lisowski, P. Stefanowicz,
Tetrahedron Lett . 2019, 60, 1814-1818.
[11] B. E. Cathers, J. V. Schloss, Bioorg. Med. Chem. Lett. 1999, 9, 1527-
1532.
[12] A. Henninot, J. C. Collins, J. M. Nuss, J. Med. Chem. 2018, 61, 1382-
1414.
[13] a) A. M. Davis, A. T. Plowright, E. Valeur, Nat. Rev. Drug. Discov. 2017,
16, 681; b) E. Valeur, S. M. Guéret, H. Adihou, R. Gopalakrishnan, M.
Lemurell, H. Waldmann, T. N. Grossmann, A. T. Plowright, Angew.
Chem. Int. Ed. 2017, 56, 10294-10323.
[14] in Peptide Applications in Biomedicine, Biotechnology and
Bioengineering (Ed.: S. Koutsopoulos), Woodhead Publishing, 2018,
623-639.
[15] C. Bolm, D. Müller, C. Dalhoff, C. P. R. Hackenberger, E. Weinhold,
Bioorg. Med. Chem. Lett. 2003, 13, 3207-3211.
[16] I. Avan, C. D. Hall, A. R. Katritzky, Chem. Soc. Rev. 2014, 43, 3575-3594.
[17] M. A. T. Blaskovich, J. Med. Chem. 2016, 59, 10807-10836.
[18] A. Stevenazzi, M. Marchini, G. Sandrone, B. Vergani, M. Lattanzio,
Bioorg. Med. Chem. Lett. 2014, 24, 5349-5356.
[19] F. W. Goldberg, J. G. Kettle, T. Kogej, M. W. D. Perry, N. P. Tomkinson,
Drug. Discov. Today. 2015, 20, 11-17.
[20] J. M. Palomo, RSC. Adv. 2014, 4, 32658-32672.
[21] a) D. M. M. Jaradat, Amino Acids. 2018, 50, 39-68; b) V. Mäde, S. Els-
Heindl, A. G. Beck-Sickinger, Beilstein J. Org. Chem. 2014, 10, 1197-
1212.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000108
European Journal of Organic Chemistry
Full Paper
Entry for the Table of Contents (Please choose one layout)
Layout 2:
Full Paper
Sulfonimidamide Pseudopeptides
Praveen K. Chinthakindi, [a] Andrea
Benediktsdottir, [a] Per I Arvidsson [b, c]
,
Yantao Chen [d] and Anja Sandström*[a]
Page No. – Page No.
Text for Table of Contents
Title: Solid Phase Synthesis of
Sulfonimidamide Pseudopeptides and
Library Generation
In this work the sulfonimidamide functionality has been combined with peptides forming sulfonimidamide pseudopeptides as potential
new modalities in drug discovery. Three alternative synthetic methods to generate the pseudopeptides have been developed, all
harmonized with classical solid-phase peptide synthesis (SPPS), including both on- and off-resin sulfonimidamide synthesis. The
methods allow late stage modifications and parallel syntheses.
Institute and/or researcher Twitter usernames: ((optional))
This article is protected by copyright. All rights reserved.
[a]
Assoc. Prof. Anja Sandström.