Chemoselective Preparation of Clickable Aryl Sulfonyl Fluoride Monomers: A Toolbox of Highly Functionalized Intermediates for Chemical Biology Probe Synthesis

Article abstract of DOI:10.1002/cbic.201600427

Sulfonyl fluoride (SF)-based activity probes have become important tools in chemical biology. Herein, exploiting the relative chemical stability of SF to carry out a number of unprecedented SF-sparing functional group manipulations, we report the chemoselective synthesis of a toolbox of highly functionalized aryl SF monomers that we used to quickly prepare SF chemical biology probes. In addition to SF, the monomers bear an embedded click handle (a terminal alkyne that can perform copper(I)-mediated azide–alkyne cycloaddition). The monomers can be used either as fragments to prepare clickable SF analogues of drugs (biologically active compounds) bearing an aryl ring or, alternatively, attached to drugs as minimalist clickable aryl SF substituents.

Full text of DOI:10.1002/cbic.201600427

Accepted Article
Title: Chemoselective Preparation of ”Clickable” Aryl Sulfonyl Fluoride Monomers:
A Toolbox of Highly Functionalized Intermediates for Chemical Biology Probe
Synthesis
Authors: Olugbeminiyi Fadeyi; Mihir Parikh; Ming Chen; Robert Kyne, Jr.; Alexan-
dria Taylor; Inish O’Doherty; Stephen Kaiser; Sabrina Barbas; Sherry Niessen;
Manli Shi; Scott L Weinrich; John Kath; Lyn Jones; Ralph Pelton Robinson
This manuscript has been accepted after peer review and the authors have elected
to post their 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 pu-
blished to ensure accuracy of information. The authors are responsible for the content
of this Accepted Article.
To be cited as: ChemBioChem 10.1002/cbic.201600427
Link to VoR: http://dx.doi.org/10.1002/cbic.201600427
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ChemBioChem
10.1002/cbic.201600427
COMMUNICATION
Chemoselective Preparation of “Clickable” Aryl Sulfonyl Fluoride
Monomers. A Toolbox of Highly Functionalized Intermediates for
Chemical Biology Probe Synthesis
Olugbeminiyi Fadeyi,[a] Mihir D. Parikh,[a] Ming Z. Chen[a], Robert E. Kyne, Jr.,[a] Alexandria P. Taylor,[a]
Inish O’Doherty,[b] Stephen E. Kaiser,[b] Sabrina Barbas,[b] Sherry Niessen,[b] Manli Shi,[b] Scott L.
Weinrich,[b] John C. Kath,[b] Lyn H. Jones[c] and Ralph P. Robinson* [a]
In memory of Ralph P. Robinson (senior) 1939-1976.
important roles in contemporary drug discovery, quick access
chemical biology probes can be critical for rapid project
progression and decision making.10,11
Abstract: Sulfonyl fluoride (SF)-based activity probes have become
important tools in chemical biology. Herein, exploiting the relative
chemical stability of SF to carry out a number of unprecedented SF-
sparing functional group manipulations, we report the
chemoselective synthesis of a toolbox of highly functionalized aryl
SF monomers that we have used to quickly prepare SF chemical
biology probes. In addition to SF, the monomers bear an embedded
click handle (a terminal alkyne that can perform copper(I)-mediated
azide alkyne cycloaddition). The monomers can be used either as
fragments to prepare clickable SF analogues of drugs (biologically
active compounds) bearing an aryl ring or, alternatively, attached to
drugs as “minimalist” clickable aryl SF substituents.
Scheme 1. Sulfonyl fluoride chemical biology probes containing an imbedded
click handle.
Sulfonyl fluoride (SF)-based activity probes have become
important tools in chemical biology and molecular
pharmacology.1,2 SFs are capable of modifying most amino acid
side chains but, in general, they react with proteins only in a
context-specific manner, i.e., only when bound in an active site
or binding pocket. Aryl SFs are typically slow to hydrolyze under
physiologic conditions and therefore are more commonly
incorporated into chemical biology probes than are aliphatic SFs,
which are typically more prone to hydrolysis.3 Attachment of SF
to a compound of biological interest results only in modest
changes to overall lipophilicity and thus minimal perturbations to
cell permeability and distribution can be anticipated. SF probes
(e.g., 1-3, Scheme 1)4,5,6 that contain an embedded click handle
(a terminal alkyne that can perform copper(I)-mediated azide
alkyne cycloaddition - CuAAC7,8) are of particular interest in
developing technologies for measuring target engagement in
intact cells. Subsequent to probe binding to target, a reporter
group can be attached to the click handle using CuAAC thereby
allowing measurement of protein activity and target occupancy
(Scheme 2).9 In view of the fact that target engagement studies
and related chemical biology technologies play increasingly
Scheme 2.
Employing clickable SF probes in target engagement studies;
X = O (tyrosine, serine, threonine), S (cysteine) or NH (lysine, arginine).
Herein, exploiting the relative chemical stability of SF to carry
out a number of unprecedented SF-sparing functional group
manipulations, we report the chemoselective synthesis of a
toolbox of trifunctional aryl SF monomers (4-8), that we have
used to quickly prepare clickable SF probes in support of drug
discovery projects (Scheme 3). Based on our experience, we
anticipate these compounds will find general utility in chemical
biology research. For ease of synthesis, the click handle and SF
can be simultaneously introduced. As shown in Scheme 4, the
monomers can be used as fragments to prepare clickable SF
analogues of drugs (biologically active compounds) bearing an
aryl ring. Alternatively, the monomers can be attached to drugs
as “minimalist” (irreducibly small) clickable aryl SF substituents,
complementing, for example, the set of minimalist diazirine
photo-crosslinkers described by Yao et al.11 The range of
functionalities (FG1) in the toolbox allows a number of options for
coupling depending on the functionality (FG2) present on the
drug or fragment of interest. Of course the utility of the clickable
SF analogues prepared using the monomer set will be
[a]
O. Fadeyi, M. D. Parikh, M. Z. Chen, R. E. Kyne, Jr, A. P. Taylor,
R. P. Robinson
Medicine Design, Pfizer Inc
Eastern Point Rd., Groton, CT, U.S.A. 06340
E-mail: ralph.p.robinson@pfizer.com
I. O’Doherty, S. E. Kaiser, S. Barbas, S. Niessen, M. Shi, S. L.
Weinrich, J. C. Kath
Oncology RU Medicinal Chemistry, Pfizer Inc
10770 Science Center Drive, San Diego, CA, U.S.A. 92121
L. H. Jones
[b]
[c]
Medicine Design, Pfizer Inc
610 Main Street, Cambridge, MA, U.S.A. 02139
Supporting information for this article is given via a link at the end of
the document.

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dependent on structure-activity relationships for the target
protein in question.
We first established routes to the 1,3,4-trisubstituted (“ortho”)
monomers 4-o, 5-o, 6-o and 7-o (Scheme 5). We were
concerned about the stability of the alkyne under conditions
typically employed for introduction of SF, e.g., thiobenzyl ether
chlorination/dealkylation. Thus, hoping to capitalize on the
relative stability of SF, we elected to introduce SF at an early
stage and investigate chemoselective functional group
manipulations in its presence.
Treatment of commercially available ethyl 3-bromo-4-
(chlorosulfonyl)benzoate (9) with KF in acetonitrile gave SF 10 in
good yield (82%). Although subsequent Sonogashira coupling12
with ethynyltrimethylsilane cleanly afforded 11 (82%), exposure
of 11 to standard aqueous hydrolysis conditions (aq.
LiOH/MeOH/THF, 0°C) led to rapid and selective hydrolysis of
the SF group. This result was consistent with observations
suggesting that SF reactivity is increased when a hydrogen bond
donor (in this case H2O) is available to assist fluoride as a
leaving group. Therefore, switching to an aprotic system was
expected to reverse the chemoselectivity in favor of ester
hydrolysis. Indeed this was the case, carboxylic acid monomer
4-o being isolated in good yield (86%) upon exposure of 11 to
trimethyltin hydroxide in 1,2-dichloroethane at 80°C.13 Also to
our satisfaction, the SF function remained intact after Curtius
rearrangement (diphenylphosphoryl azide, Et3N, 80°C) and
cleavage of the resulting tert-butyl carbamate to give amino
monomer 6-o (41% over 2 steps).
Scheme 3. Clickable SF monomer toolbox (4-8).
Reflecting the high degree of stability of SF under reductive
conditions,
11
underwent
smooth
reduction
with
diisobutylaluminum hydride (DIBAL) to yield intermediate alcohol
12 (89%). This was then converted to bromomethyl monomer
7-o (74%) and aldehyde monomer 5-o (81%).
Scheme 4. a: clickable SF monomer is used as an aryl fragment for
combination with another functionalized drug fragment; the product is a close
analogue of the parent drug bearing an aryl side chain; b: clickable SF
monomer is attached to a drug bearing functionality suitable for derivatization.
In planning the synthesis of the monomers, we needed to
consider potential challenges associated with chemoselectively
introducing three potentially reactive functionalities onto the
aromatic ring, for example introducing FG1 in the presence of SF
and alkyne or attaching alkyne in the presence of FG1 and SF.
Fortunately, as recently reviewed by Sharpless et al.,2 the
relative chemical stability of SF in comparison to other sulfonyl
halides can be exploited in synthesis. For example, SFs are
particularly stable to reduction, which allows chemoselective
reduction of other functional groups in the same molecule. As
described herein, the routes to 4-8 significantly expand the
scope of known functional group manipulations that can be
carried out in the presence of SF.
Scheme 5. Synthesis of monomers 4-7, highlighting key orthogonal reactions
leaving SF intact (blue): a) KF, MeCN; b) DBI, H2SO4; c)
ethynyltrimethylsilane, Et3N, CuI (cat.), PdCl2(PPh3)2 (cat.); d) Me3SnOH, DCE,

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80°C; e) DPPA, Et3N, t-BuOH, 90°; f) HCl, 1,4-dioxane or EtOAc; g) DIBAL,
DCM, -40°C; h) CBr4, PPh3, DCM; i) Dess-Martin periodinane, DCM.
alkylation conditions. Notably, we did not see evidence of
competing reaction of the phenolate with the SF group under the
reaction conditions.
We also prepared the corresponding 1,3,5-trisubstituted
(“meta”) monomers 4-m, 5-m, 6-m,14 and 7-m in to order
minimize the potential for interference between the SF and
alkyne groups, i.e., steric hindrance of covalent protein labelling
by the SF or subsequent reporter attachment via 1,3-dipolar
cycloaddition to the alkyne. These monomers were prepared in
a similar way to the synthesis of the “ortho” monomers, except
that
bromide
14
was
obtained
from
methyl
3-
(fluorosulfonyl)benzoate (13) by selective bromination at the 5-
position using dibromoisocyanuric acid (DBI) in H2SO4 (99%)
(Scheme 5).
Aryl bromide monomer 8-m was accessed from
commercially available 3-bromo-5-iodobenzenesulfonyl chloride
(17) via reaction with KF (to yield 18) followed by selective
Sonogashira coupling (Scheme 6). However, because of the
high cost of commercial 17 (~$1000/g), we explored alternative
approaches including Hartwig-Miyaura CH borylation15 of 3-
bromobenzenesulfonyl fluoride (19). Although we were pleased
that borylation of 19 took place efficiently to provide 20, attempts
to obtain 8-m by subsequent Sonogashira coupling were not
successful. 3,5-Dibromobenzenesulfonyl fluoride (21) could be
used as the Sonogashira coupling partner, but, due to
competing formation of the bis-coupling product, isolated yields
of 8-m were quite low.
Scheme 7. Coupling of monomers to drug fragments. a) 7-o, K2CO3, acetone;
b) HCl, dioxane; c) 4-o, (COCl)2, DCM, then 25, Et3N, DCM; d) KF, acetone,
MeCN, H2O; e) 5-o, NaHB(OAc)3, AcOH, DCM; f) TBAF, THF; g) 8-m, 10
mol% RuPhos-G3, Cs2CO3, 1,4-dioxane, 70°C; h) KF, acetone, H2O; i) 8-m,
MeCN, 82°C.
To demonstrate an ability to use other coupling chemistries
for monomer attachment without the occurrence of significant
side-reactions involving the SF or alkyne, drug analogues 26, 28,
30, 32 and 33 representing different target classes, were
prepared from drug fragment precursors 25, 27, 29 and 31
(Scheme 7). Based on literature pertaining to the relative
stability of aryl SF in the presence of amines and considering the
mild (room temperature) conditions employed, we did not
anticipate problems with SF reactivity during amide bond
formation and reductive amination. Indeed this was the case as
exemplified by smooth formation of vismodegib analogue 26 via
acid 4-o (63%, 2 steps including TMS removal) and donepezil
analogue 28 from aldehyde 5-o (72%, 2 steps). On the other
hand, given the elevated temperatures often required, we were
concerned whether conditions for SNAr and Buchwald-Hartwig17
couplings would be compatible with SF monomers. However, as
shown by the preparation of trazodone analogue 30 from aryl
bromide monomer 8-m (26%, 2 steps) and erlotinib analogues
32 (89%, 2 steps) and 33 (73%) from amine monomers 6-o and
6-m respectively, useful yields of the drug analogues could be
obtained.
Scheme 6. Synthesis monomer 8-m, highlighting key orthogonal reactions
leaving SF intact (blue): a) KF, MeCN; b) ethynyltrimethylsilane, Et3N, CuI
(cat.), PdCl2(PPh3)2 (cat.); c) B2pin2, 2 mol% [Ir(cod)(OMe)]2, 4 mol% dtpby,
heptane, CPME, 140°C.
Our first application of one of the monomers to an ongoing
project was for an improved synthesis of 23, a chemical biology
probe based on D153249 (24), an inhibitor of the mRNA
decapping scavenger enzyme DcpS (Scheme 7).16 As
previously disclosed, we used 23 to quantify in-cell target
occupancy by DcpS inhibitors. In the original route to 23, the
alkyne was installed late in the synthesis by way of a low-
yielding (~5%) Stille coupling on
a
fully elaborated
diaminoquinazoline template. In the new convergent route using
monomer 7-o, chemoselective alkylation of phenol 22 with 7-o
took place to provide 23 after Boc deprotection (41% overall).
Cleavage of the TMS group conveniently took place under the
As a second demonstration of the utility of the monomer set
and derived drug analogues in a chemical biology setting we

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applied erlotinib SF analogue 32 to assessing drug-target
engagement in live cells (Figure 1). A crystal structure of
erlotinib with its primary target, epidermal growth factor receptor
(EGFR, PDB 1M17),18 highlighted the proximity of the conserved
lysine to the 4-position of the erlotinib aniline ring (Figure 1a).
We thus anticipated that, of the two isomeric SF erlotinib
analogues prepared, the 1,3,4-substituted isomer 32 would best
position the SF for chemical labelling of the conserved lysine
residue in the ATP-binding site of the EGFR protein, in a manner
similar to other SF-containing kinase inhibitors (e.g., 1).4,19 As
expected, intact mass spectrometry studies showed that 32
labelled EGFR (Figure 1b), and the extent of labelling was
significantly higher than that seen for the 1,3,5-substituted
isomer 33. Peptide mapping experiments confirmed the site of
labelling as the conserved Lys745 (Supporting Information). Also,
as determined by ELISA in non-small cell lung cancer H3255
cells, both 32 and 33 exhibited significant inhibition of EGFR
cellular autophosphorylation at Tyr1068 (IC50 = 116 and 74 nM
respectively). With these encouraging results, we next explored
the ability of 32 to report on live cell target engagement.
Treatment of H3255 cells with 32, followed by cell lysis,
subsequent attachment of biotin azide, and streptavidin-
mediated enrichment followed by Western blot, showed that the
probe labelled EGFR in live cells (Figure 1c). Specificity was
confirmed by competing the labelling with parent erlotinib in a
concentration-dependent manner, thus confirming the utility of
32 as an in-cell target occupancy probe.
transformations that can be carried out in the presence of SF.18
We used representative compounds from the monomer set to
prepare clickable SF analogues of known drugs or drug
candidates, thus illustrating their potential for application in “real
world” situations. Further showing utility, as previously disclosed,
D153259 analogue 23 (prepared in improved overall yield from
monomer 7-o), and, as presented here, erlotinib analogue 32
(prepared from amine monomer 6-o) have been employed as
chemical probes for measuring target occupancy in live cells.
We continue to define the scope of sulfonyl fluoride-sparing
chemical transformations as applied to a range of substrates
and to develop new monomers and chemistries for SF chemical
biology probe synthesis. Assessment of the broader proteome
reactivity of 32 is a subject of ongoing work in our group.
Experimental Section
See Supporting Information.
Acknowledgements
The authors thank Christopher AmEnde and Paramita
Mukherjee for their support and helpful dicussions.
Keywords: chemical biology • click chemistry • medicinal
chemistry • proteomics • sulfonyl fluoride
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monomers that may be used as fragments or minimalist
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Text for Table of Contents
Olugbeminiyi Fadeyi, Mihir D. Parikh,
Ming Z. Chen, Robert E. Kyne, Jr.,
Alexandria P. Taylor, Inish O’Doherty,
Stephen E. Kaiser, Sabrina Barbas,
Sherry Niessen, Manli Shi, Scott L.
Weinrich, John C. Kath, Lyn H. Jones
and Ralph P. Robinson*
((Insert TOC Graphic here))
Page No. – Page No.
Chemoselective Preparation of
“Clickable” Aryl Sulfonyl Fluoride
Monomers. A Toolbox of Highly
Functionalized Intermediates for
Layout 2:
COMMUNICATION
Olugbeminiyi Fadeyi, Mihir D. Parikh,
Ming Z. Chen, Robert E. Kyne, Jr.,
Alexandria P. Taylor, Inish O’Doherty,
Stephen E. Kaiser, Sabrina Barbas,
Sherry Niessen, Manli Shi, Scott L.
Weinrich, John C. Kath, Lyn H. Jones
and Ralph P. Robinson*
Expanding the scope of known synthetic transformations that can be carried out in
the presence of sulfonyl fluoride (SF), a toolbox of trifunctional aryl SF monomers is
now available that can be used to quickly prepare “clickable” SF chemical biology
probes. The monomers can be used either as fragments to prepare clickable SF
analogues of drugs bearing an aryl ring or, alternatively, attached to drugs as
“minimalist” clickable aryl SF substituents.
Page No. – Page No.
Chemoselective Preparation of
“Clickable” Aryl Sulfonyl Fluoride
Monomers. A Toolbox of Highly
Functionalized Intermediates for
Chemical Biology Probe Synthesis