Controllable Activation of Pd-G3 Palladacycle Precatalyst in the Presence of Thiosugars: Rapid Access to 1-Aminobiphenyl Thioglycoside Atropoisomers at Room Temperature

Article abstract of DOI:10.1002/asia.201701415

A controllable method for the functionalization of XantPhos Pd-G3 precatalyst with thiosugars and thiols has been established. Under mild and operationally simple reaction conditions through just mixing of precatalyst and thiosugars (α- or β-mono-, di- and poly-thiosugar derivatives) in water at 25 °C for 20 min, a series of 1-aminobiphenyl thioglycosides that are difficult to synthesize by classical methods has been synthesized in very high yields.

Full text of DOI:10.1002/asia.201701415

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Controllable activation of Pd-G3 palladacycle precatalyst in
the presence of thiosugars: rapid access to 1-aminobiphenyl
thioglycoside atropoisomers at room temperature
Authors: Samir Messaoudi, Riyadh Ahmed Atto Al-Shuaeeb, Mouad
Alami, and Camille Dejean
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To be cited as: Chem. Asian J. 10.1002/asia.201701415
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Controllable activation of Pd-G3 palladacycle precatalyst in the
presence of thiosugars: rapid access to 1-aminobiphenyl
thioglycoside atropoisomers at room temperature
Riyadh Ahmed Atto AL-Shuaeeb,[a] Camille Dejean,[a] Mouâd Alami,*[a] and Samir Messaoudi*[a]
Abstract:
A
controllable method for the functionalization of
of functionalized 2-aminobiphenyls is Suzuki–Miyaura cross-
coupling of haloanilines with boronic acid derivatives.
Surprisingly, a thorough literature search revealed a lack of
methods to access substituted 2-aminobiphenyls bearing
polyfunctionnal complex groups such as sugar moieties. Owing
to the significance importance of 2-aminobiphenyls there is a
strong impetus to discover new chemical transformations for
their efficient synthesis and functionalization.
XantPhos Pd-G3 precatalyst with thiosugars and thiols has been
established. Under mild and operationally simple reaction conditions
through just mixing of precatalyst and thiosugars (α- or β-mono-, di-
and poly-thiosugar derivatives) in water at 25 °C for 20 min, a series
of 1-aminobiphenyl thioglycosides that are difficult to synthesize by
classical methods, has been synthesized in very high yields.
We recently reported an efficient protocol for the bioconjugation
of cysteine-containing peptides through the use of the
palladacycle pre-catalyst Xantphos Pd-G3.[11] When the
therapeutic peptide oxytocin was used as a substrate (Scheme
1), the disulfide bridge of the peptide was reduced and the two in
situ generated thiols reacted with iodoarenes, in the presence of
G3-XantPhos (50 mol%). Under these conditions, the diarylated
oxytocin was formed as the major product together with a by-
product, which corresponds to the mixed naphthalene/2-
aminobiphenyl conjugate (m/z = 1302.4), arising from the
reaction of the thiol function of cysteine with the Pd-G3-
precatalyst (Scheme 1). This by-product, although obtained in a
traces amount, pointed to the principal feasibility of this alluring
reaction of Pd-G3-precatalyst with thiols into a 2’-S-linked 2-
aminobiphenyls under mild reaction conditions (Scheme 1).
Thus, we envisioned in the present study whether XantPhos Pd-
G3 precatalyst could be reacted with various thiol derivatives
such as 1-thiosugars to synthesize a range of 2-S-glycosylated-
2’-aminobiphenyls (Scheme 1). If further developed, such a
transformation could provide an easy and very fast access to
substituted 2-aminobiphenyl under mild (25 °C) and
operationally simple reaction conditions. Continuing our efforts
to provide the community of chemists with more efficient ways to
produce high value thioglycosides,[12] we describe herein how
this controlled
The biaryl motif is
a fundamental core component and
constitutes an important class of compounds that find
widespread use as pharmaceuticals,[1] natural products,[2]
ligands[3], catalysts[3] and in material industries.[4] As depicted in
the Figure 1, the biaryl core represents the principle architecture
in various top marketed drugs such as the antihypertensives
valsartan and telmisartan as well as the non-steroidal anti-
inflammatory drug diflunisal. 2-Aminobiphenyls are one of the
most important subdivisions of functionalized biaryls primarily
found
in
biologically
active
natural
products
and
pharmaceuticals[5] such as the agrochemical agent boscalid and
the natural product ambidalmine (Figure 1). Furthermore, a wide
variety of chiral ligands and catalysts based on the biaryl
scaffolds such as 2-aminobinaphtyl NOBIN were utilized in
numerous asymmetric transformations to produce important
chiral compounds in optically enriched form.[6] Besides all these
utilities, 2-aminobiphenyls are used as pivotal key intermediates
to access functionalized heterocycles such as carbazoles,[7]
phenanthridinones,[8] phenanthrenes[9] and dibenzofurans.[10] The
most direct method used for the synthesis
Figure 1. Examples of some useful molecules containing the biaryl core
[a]
Dr.RAA AL Shuaeeb, C. Dejean, Dr. M. Alami, Dr. S. Messaoudi,
BioCIS, Univ. Paris-Sud, CNRS, University Paris-Saclay, Châtenay-
Malabry,
samir.messaoudi@u-psud.fr,
France
Tel:
+
(33)
0146835887;
E-mail:
Scheme 1 previous observations and present work
process can be used as a step-efficient and modular method to
synthesize 2’-glycosyl-2-aminobiaryls.
Supporting information for this article are available on the www
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To verify the proposed strategy, our initial investigation focused
on identifying optimal conditions for the functionalization of
XantPhos Pd-G3 palladacycle precatalyst with the tetra-O-
acetylated 1-thio-β-D-glucopyranose 1a in the presence of Et3N
(1.2 equiv), in H2O/THF combination ([0.1 M]). Thus, reaction of
1a with XantPhos Pd-G3 in the presence of Et3N (1.2 equiv) in
H2O:THF (8:2, v/v) for 2 h at room temperature led to complete
conversion of the precatalyst into the carbazole 3 together with
sugar disulfide 4 but the desired compound 2a was not detected
(Table 1, entry 1). This result is not surprising since the
activation of the precatalyst in the presence of Et3N is well
known.[13] To overcome the formation of this undesired
carbazole 3, we conducted the model reaction in the presence of
0.5 equivalents of Et3N. Under these conditions compound 2a
was isolated in an acceptable 56% yield together with the
carbazole 3 and the disulfide 4 (entry 2). Delightfully, when the
reaction was performed in the absence of the base, using
otherwise identical conditions, the conversion rate of the
precatalyst is total and the activation is selective toward the
desired aminobiphenyl thioglycoside 2a (99% yield, entry 3).
Shortening the reaction time until 20 min led to same yield (entry
4). Thus, the best conditions were found to require 1a (2 equiv)
and XantPhos Pd-G3 (1 equiv) in H2O:THF (8:2) stirring for 20
min at 25 °C. Under these conditions, 2a was isolated in a 99%
yield.
temperature is lowered, the signal broadens and ultimately splits
into two peaks around the critical coalescence temperature of
280 K. These data confirmed the hypothesis that the doubling of
1
signals in the H- and 13C-NMR spectra at 280 K (coalescence
temperature) was due to the presence of two atropoisomers of
2-aminobiphenyl 2a in 1:1 ratio separated by a relative energy
barrier of DG#(280 K) = 14.49 kcal/mol.[14]
Table 1: Survey of reaction conditions for the coupling of XantPhos Pd-G3
with the tetra-O-acetylated 1-thio-b-D-glucopyranose 1aa
1
1
Figure 2. (A) H-NMR of 2a. (B) Variable-temperature (VT) H-
entry
Et3N
(equiv)
1.2
0.5
equiv
of 1a
1.5
1.5
2
t (h)
% yield (2a)b
NMR studies
1
2
3
4
5
1
1
1
0.3
0.3
0c
56d
99
Motivated by these results, we next explored the scope of the
coupling of structurally diverse α- or β-mono-, di- and poly-
thiosugar derivatives with XantPhos Pd-G3 (Scheme 2).
Gratifyingly, all the couplings proceeded in excellent yields and
tolerate a large variety of thiosugars 1a-i with a perfect retention
of the anomeric configuration. O-acetylated 1-thio- β-D-
glycopyranose 1a, O-acetylated N-Ac-1-thio- β-D-glucopyranose
1b, O-acetylated 1-thio- β-D-galactopyranose 1c and O-
acetylated 1-thio- β-D-mannocopyranose 1d were reacted
selectively with XantPhos Pd-G3 to furnish saccharides 2a-d
without any loss of reactivity. Importantly, this procedure is not
limited to only β-glycosyl thiols, but it also worked successfully
with 1-thioglucose 1e, which had an anomeric α-configuration. In
this case, the corresponding α-saccharide product 2e was
-
-
-
2
2
99
99e
[a] 1a (x equiv), XantPhos Pd-G3 (1 equiv), in H2O: THF (8:2, v/v) [0.1M]) at
25 °C. b Yield of the isolated product 2a. c Compound 2a was not detected and
only the formation of carbazole 3 together with sugar disulfide
4
were
d
e
observed. Carbazole 3 together with sugar disulfide 4 were also isolated.
Reaction was performed in only THF
The structure of the product 2a was unambiguously determined
by 1H and 13C NMR as well as 2D experiments. Interestingly, 1H-
and 13C-NMR analysis showed the presence of doubling signals
in the whole spectrum. As we can see in Figure 2A, the signals
of the acetate groups at 2.1-1.8 Hz are doubled to eight singlets
(8 x CH3) with identical integrals length. This result demonstrates
the presence of two diastereoisomers in a 1:1 ratio (Figure2A).
The origin of signal doubling was investigated and the
coalescence temperature of 2a has been determined using
obtained with
a slightly lower yield of 90% and 1.1:1
atropodiastereomeric ratio. Thus, the activation of XantPhos Pd-
G3 by α-thioglucose 1e induces atropo diastereoselectivity
during the activation process. Additionally, the coupling also
works with the challenging 1-thio β-D-ribose partner, furnishing
2f in an excellent 90% yield. Moreover, the reaction is not limited
1
variable-temperature (VT) H-NMR studies (Figure 2B). A single
sharp signal was detectable at around 5.05 ppm, however as the
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to only monosaccharides, but can be applied in the cases of
more complex di- and trisaccharide derivatives. Thus, 1-thio- β-
D-cellobiose 1g as well as 1-thio- β-D-maltotriose 1h were
efficiently reacted with Pd-G3 precatalyst to give the
corresponding 2-aminobiphenyl β-thioglycosides 2g-i in
quantitative yields. Importantly, the stereochemistry of the β-1,4’-
O-glycosidic bond in the tri-saccharides 2g,h and the α-1,4’ in β-
tri- saccharide 2h remained intact. Importantly, there is no
significant impact of protecting groups on the reactivity of the
glycosyl thiols derivatives since unprotected thiosugars 1i,j react
similarly as their O-acetated congeners furnishing the 2-
aminobiphenyl β-thioglycoside atropodiastereomers 2i and 2j
in excellent yields and an atropodiastereomeric ratios of 1.1:1
and 1.6:1, respectively.
Buchwald group who has disclosed that palladium(II) complexes
could be used as a reagent (2-10 equiv) for selective cysteine
conjugation.[15]
Table 2: Scope of the coupling of XantPhos Pd-G3 with various 1-thiosugars
1a-ja
Scheme 3. Scope of the coupling of other thiols.
Finally, to illustrate the key advantage of this methodology, post-
modifications of 2a were undertaken through its residual aniline,
which was exploited as a platform for molecular diversity
(Scheme 4). Cross-coupling of the aniline of 2a with
haloheterocycles such as 3-bromocoumarin or 3-bromoquinolin-
2H-one by using again Pd-G3 XantPhos as a catalyst in the
presence of Cs2CO3 in dioxane at 100 °C, provided the desired
2,2’-biaryls in high yields and atropodistereomeric ratio 1.4:1 and
1.1.1, respectively (Scheme 2, substrates 7a,b). The 3-
aminoquinolin-2H-one 7a may be regarded as analogues of
6BrCaQ, a potent hsp90 inhibitor developed in our laboratory.[16]
Scheme 4. Scope of the coupling of other thiols
In conclusion, we have developed an unprecedented method
toward the synthesis 1-aminobiphenyl thioglycosides through a
controllable activation of
a
Pd-G3-catalyst with various
[a] Reactions of 1a-j (2 equiv), XantPhos Pd-G3 (0.021 mmol, 1 equiv), in
H2O: THF (8:2, v/v) ([0.1M]) at 25 °C. [b] Yield of isolated product. [c] Ratio
was determined by 1H NMR analysis. [d] Compound 2f is not enough stable
for full characterization (please see SI).
glycosylthiols. The reaction takes place rapidly (20 min) at room
temperature with high selectivity. We expect this simple and
general protocol to be of broad utility for the synthesis and
development of new medicinal agents.
Having demonstrated the large scope of this procedure in regard
of thiosugars, we examined in a further set of experiments,
whether this reaction could be extended to other aryl and
alkylthiol derivatives (Scheme 3). Thus, the coupling proceeds
well with thiophenol 5a within 20 min at room temperature,
giving the coupled product 6a in a 99% yield. In addition, we
were pleased to find that non-aromatic thiols such as 2-
(trimethylsilyl)ethane-1-thiol 5b and N-Boc cysteine derivative 5c
could be reacted efficiently with the precatalyst XantPhos Pd-G3
furnishing 6b,c in excellent yields. This last finding can be
compared favorably to the recently reported procedure from
Experimental Section
Typical procedure for the coupling of thiosugars with Xantphos
Pd-G3 pre-catalyst to synthesize compound (2a-j and 6a-c).
A flame dried sealable tube (5 ml) was charged with Xantphos Pd-
G3 (20 mg, 0.021 mmol, 1.0 equiv) and 1-thiosugars or others thiols
(15 mg, 0.042 mmol, 2 equiv). A solution of H2O: THF (8:2; 168 µL,
0.25 mM) was added and the tube was sealed with a teflon
screwcap, and the mixture was stirred at room temperature for 20
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residue was purified by silica gel column chromatography to afford
the desired product.
Acknowledgements
Authors acknowledge support of this project by CNRS, University
Paris Sud, ANR (ANR-15-CE29-0002) and by la Ligue Contre le
Cancer through an Equipe Labellisée 2014 grant. We also thank
the Iraqi Embassy for a doctoral fellow-ship to R.A.A.S. Our
laboratory is a member of the Laborato-ry of Excellence LERMIT
supported by a grant (ANR-10-LABX-33).
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thiosugars.
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Layout 2:
COMMUNICATION
Riyadh Ahmed Atto AL-Shuaeeb]
Camille Dejean, Mouâd Alami,* and
Samir Messaoudi*
Page No. – Page No.
Controllable activation of Pd-G3
palladacycle precatalyst in the
presence of thiosugars: rapid access
to 1-aminobiphenyl thioglycoside
atropoisomers at room temperature
Text for Table of Contents
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