A palladium and gold catalytic system enables direct access to O- and S-linked non-natural glyco-conjugates

Article abstract of DOI:10.1039/c6ob02437h

Here we report a straightforward cross-coupling method for the synthesis of non-natural glycoamino acids from alkyne-bearing monosaccharides and p-iodophenylalanine. Pd/Au-catalyzed Sonogashira coupling is tolerant to both O- and S-glycosides without any epimerization. In addition, no racemization of the amino acid was observed allowing direct access to the homogeneous glyco-conjugate in a single step. Notably, this Pd/Au catalytic system presents enhanced catalytic activity than conventional Pd/Cu and Pd-only platforms, and it further enables the convergent synthesis of glycodipeptides.

Full text of DOI:10.1039/c6ob02437h

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DOI: 10.1039/C6OB02437H
Organic & Biomolecular Chemistry
PAPER
Palladium and gold catalytic system enables direct access to O‐
and S‐linked non‐natural glyco‐conjugates
Received 00th January 20xx,
Accepted 00th January 20xx
a
a,b
a,b
b
Min Ho Jeon, Bijoy P. Mathew, Malleswara Rao Kuram, Kyungjae Myung and
a,b
Sung You Hong*
DOI: 10.1039/x0xx00000x
Here we report a straightforward cross‐coupling method for the synthesis of non‐natural glycoamino acids from alkyne‐
bearing monosaccharides and p‐iodophenylalanine. Pd/Au‐catalyzed Sonogashira coupling is tolerant to both O‐ and S‐
glycosides without any epimerization. In addition, no racemization of the amino acid was observed allowing direct access
to the homogeneous glyco‐conjugate in a single step. Notably, this Pd/Au catalytic system presents enhanced catalytic
activity than conventional Pd/Cu and Pd‐only platforms, and it further enables the convergent synthesis of glycodipeptides.
www.rsc.org/
conjugates or complex oligosaccharide structures often include
Introduction
solid‐phase reactions using automated peptide or
oligosaccharide synthesizer. In addition, non‐natural amino
7
acids with reactive functional groups provide chemical handles
Glycosyl moieties covalently conjugated to proteins or lipids
play an essential role in diverse biological events like immune
responses, cell‐cell communications, and endocytosis. Altered
that allow diverse modification of proteins via chemoselective
8
1
ligation processes. For example, the Wong and Schultz groups
prepared neo‐glycoproteins by exploiting the conjugation
between the aminooxy N‐acetylglucosamine (GlcNAc) moiety
glycosylation patterns decorating cell surfaces are often
associated w2ith disease states such as cancer and
inflammation. Unlike the template‐driven production of
nucleic acids or proteins, construction of glycan structures in
nature involves a multi‐step enzyme‐catalyzed reaction
9
and a genetically encoded keto group. The Davis group
reported efficient site‐selective protein modification methods
3
producing heterogeneous structures. The limited availability
of pure glyco‐conjugates is one of the major barriers for their
biological applications. With the significant advances in
proteomics and synthetic organic chemistry, the molecular
functions of specific glycosylation patterns in cellular
physiology have been recognized. For example, the
characteristic oligosaccharide structures associated with
diseases are the primary targets for the development of
2
b,4
carbohydrate‐based vaccines.
Development of facile
synthetic methods to construct homogeneous glycans is thus a
key step towards the progress of carbohydrate chemistry or
glycobiology, which may eventually lead to sugar‐based drug
discovery.
1,5
Along with naturally abundant N‐ and O‐linked glycans,
synthetic neo‐glycans bearing non‐natural glycosidic linkages
have been gaining interest due to their potential biological
activities and stability against chemical and enzymatic
6
hydrolysis. Strategies for the chemical synthesis of glyco‐
a.
School of Energy and Chemical Engineering, Ulsan National Institute of Science
and Technology (UNIST), UNIST‐gil 50, Ulsan 689‐798, Republic of Korea. E‐mail:
syhong@unist.ac.kr
b.
Center for Genomic Integrity (CGI), Institute for Basic Science (IBS), School of Life
Sciences, UNIST, UNIST‐gil 50, Ulsan 689‐798, Republic of Korea
Electronic Supplementary Information (ESI) available: H NMR and C NMR
1
13
†
spectroscopic data. See DOI: 10.1039/x0xx00000x
Scheme 1 Synthesis of non‐natural glycoamino acids.
J. Name., 2013, 00, 1‐3 | 1
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ARTICLE
Journal Name
via transition‐metal catalyzed transformations (e.g. olefin cross Electrophilic activation of alkynes via gold(I) can lower pKa of
View Article Online
1
9
DOI: 10.1039/C6OB02437H
metathesis and Suzuki‐Miyaura cross‐coupling) in an aqueous acetylenic proton, and this renders the
‐gold acetylide to
1
0
20
solution.
Construction of non‐natural glycoamino acids via
transition‐metal‐catalyzed reactions can be classified into catalytic performance (entry 5) because their electron‐rich
form linear geometrical structure.
Phosphine ligands played an essential role in enhancing
13
sequential and convergent approaches (Scheme 1). The Sinou nature and steric bulk activated the oxidative addition step.
III
group introduced the stepwise synthesis of C‐glycosyl The PdCl (PPh ) and HAu Cl systems also effectively
2
3 2
4
analogues of amino acids through OsO ‐mediated catalyzed Sonogashira coupling (entry 6); the progress of the
4
I
III
dihydroxylation, asymmetric hydrogenation, and Heck reaction using gold co‐catalysts (Au vs. Au ) was more
1
1
coupling sequences. However, it requires laborious and time‐ precisely determined by measuring the initial rates (Fig. 1). The
consuming functional group manipulations. modular profiles of these results fitted closely with pseudo‐first order
approach has also been studied to allow direct C–C bond kinetics that gave a higher rate constant (k ) (0.059 min ) for
A
‐
1
obs
‐1
I
III
formation between C‐glycosides and amino acids (Scheme 1b Au compared to that for Au (0.017 min ). Lastly, excellent
1
2
and c). Herein, we report a one‐step synthetic protocol to yield (98%) was also observed even at room temperature (RT)
synthesize O‐ or S‐linked artificial glycoamino acids or (entry 8).
glycodipeptides via Pd/Au‐catalyzed Sonogashira cross‐
coupling. The key features of this study are as follows: first, Table 1 Optimization of reaction conditions
higher catalytic activity of the Pd/Au catalytic duo compared
with those of Pd/Cu and Pd‐only systems; second, mild
reaction conditions without epimerization or racemization;
third, operational simplicity; fourth, good compatibility to both
O‐ and S‐glycosides.
a
Entry
Catalysts
Yield [%]
Results and discussion
2
The Sonogashira is an efficient C(sp )–C(sp) cross‐coupling
1
2
3
4
5
6
PdCl
PdCl
2
(PPh
(PPh
PdCl
AuI (2 mol%)
(1 mol%) and AuI (2 mol%)
(1 mol%) and HAuCl (2 mol%)
(1 mol%) and AuI (2 mol%)
(1 mol%) and AuI (2 mol%)
3
)
2
(1 mol%) and CuI (2 mol%)
100 (>99)
I
method. Cu salts are typically utilized as co‐catalysts to
2
3
)
2
(1 mol%) and AuI (2 mol%)
100 (>99)
accelerate the reaction while generating copper(I) acetylides in
1
3
situ. However, the catalytic system often suffers from the
Glaser‐Hay reaction to form homocoupling side products as
2
3
(PPh )
2
(1 mol%)
83
0
I
II 14
well as Cu oxidation that forms catalytically inefficient Cu . In
addition, a large excess of organic base is often utilized as the
solvent, which is poorly suited to the manufacturing processes
in pharmaceutical firms. Recently, gold‐based co‐catalytic
systems have been gaining attention due to their
PdCl
2
37
100
76
98
PdCl
2
(PPh
3
)
2
4
b
7
PdCl
PdCl
2
2
(PPh
3
)
)
2
2
I
alkynophilicity and the stability of Au complexes in the
c
15
8
(PPh
3
presence of molecular oxygen. Our initial investigation was
performed using protected p‐iodophenylalanine and
a
1
1
Determined by
H
NMR spectroscopic analysis using 1,1,2,2-
b
tetrachloroethane as an internal standard, isolated yield in parentheses. Air
condition. RT.
ethynyltrimethylsilane as model substrates to explore the
catalytic efficiency of the Pd/Au system (Table 1). Gratifyingly,
c
AuI as a co‐catalyst afforded phenylalanine analogue
2 in
excellent yield (>99%), comparable to CuI (entries 1 and 2). In
the absence of the co‐catalyst, PdCl (PPh ) showed
2
3 2
diminished yield (entry 3). Noticeably, AuI alone did not show
any catalytic activity (entry 4).
In 2010, the Echavarren group reported mechanistic study
of the Pd(II)/Au(I) catalyzed Sonogashira reaction
demonstrating that oxidative addition step hardly proceeds
1
6
under Pd(0)‐free conditions. Au(I) complex acts as a
transmetalation agent in the catalytic cycle replacing the
classical Cu(I) complex. Over the last few decades, the
straightforward formation of Au(I)‐alkynyl complexes has been
1
7
well‐established.
acetylene with a weakly basic NaOAc (the pKa of the conjugate
acid: 4.76) to afford a ‐gold acetylide, triphenylphosphine (p‐
tolylethynyl)gold. Au(I) complex is regarded as a soft Lewis
The Echavarren group treated tolyl

1
6
18
Fig. 1 Initial rate analysis to afford compound 2.
acid, which selectively activates carbon–carbon triple bond.
2
| J. Name., 2012, 00, 1‐3
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a
Table 2 Substrate scope
decreased yield (51%). The yield of glycoamino acid increased
to 63% (6a) upon increasing the amount of sugar 5a (2 equiv.).
View Article Online
DOI: 10.1039/C6OB02437H
a
Table 3 Synthesis of glycoamino acid
6
a
1
Yield is determined by H NMR spectroscopic analysis using 1,1,2,2-
b
2 3 2
tetrachloroethane as an internal standard. PdCl (PPh ) (1 mol%) and
CuI (2 mol%). RT. Isolated yield.
c
d
With the optimized conditions in hand, the substrate scope
was investigated (Table 2). When the amino acid derivative
1
was treated with various acetylene‐bearing substrates,
excellent yields were achieved with aromatic alkynes with
electron‐donating groups (3a‐3c). Electron‐deficient alkyne
substrates including 1‐fluoro‐4‐ethynylbenzene (3d) and 1‐
nitro‐4‐ethynylbenzene (3e) gave slightly diminished yields
a
b
c
(
86–87%). Aliphatic alkynes (3f and 3g) showed low to
moderate yields (37% and 60%, respectively). Interestingly, AuI
100%) showed a better performance than CuI (72%) for the
Isolated yield. PdCl
2
(PPh
(PPh
3
)
3
2
(1 mol%) and CuI (2 mol%).
1
(1 equiv.)
d
e
and
5
(2 equiv.). PdCl
2
)
2
(1 mol%). RT.
(
formation of 4a. In addition, formation of product 4c was
observed in 95% yield at RT.
After checking the feasibility of the Pd/Au‐catalyzed
Sonogashira coupling for simple substrates, we were now able
to design our synthesis for non‐natural glycoamino acids
(
Table 3). 6a was obtained in moderate yield (54%) from the
corresponding GlcNAc substrate 5a without any epimerization.
The challenge associated with S‐glycosides arises from the
strong coordination of sulfur compounds to transition‐metal
2
1
catalysts, which in turn reduces their catalytic activity. The
tolerance levels of the thiosugars were examined by preparing
GlcNAc, galactose, and mannose derivatives (5b‐d). The
formation of S‐linked glycoamino acids (6b‐d) was successfully
observed in moderate yields (53–55%) and the configurations
of the anomeric positions remained untouched. The sterically
bulky sugar moiety adjacent to the thioether may weaken
coordination to the late‐transition metals. Interestingly, Au
showed higher catalytic activity than Cu for both S‐ and O‐
linked glycoamino acids (6a, 6b). Co‐catalyst‐free Sonogashira
reactions provided diminished yields (6a:37%, 6b 31%). The
catalytic efficiency was further compared by investigating
conversion over time (Fig. 2). This study demonstrated a
promoted catalytic activity of Pd/Au system compared to
Pd/Cu or Pd‐only system. Even though the increased yield is
modest, this small difference could be useful in cases where
rare and valuable cross‐coupling partners are employed.
Consistent with aforementioned examples, the GlcNAc‐
conjugate 6b could be also formed at RT with slightly
I
I
Fig. 2 Conversion vs time profiles for Pd/Au , Pd/Cu and Pd to afford
glycoamino acid 6a.
Next, we extended the synthetic utility of this cross‐
coupling reaction to access glycodipeptides. Synthesis of
glycopeptides is typically classified into two approaches:
stepwise (or so‐called cassette‐based) and convergent
22
strategies. Stepwise method utilizes pre‐formed glycoamino
acids (cassettes) to afford linear glycopeptides requiring
protecting group manipulations. In this study, we chose
convergent method allowing the direct access of glycopeptides.
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DOI: 10.1039/C6OB02437H
Scheme 2 Synthesis of non‐natural glycodipeptide 8.
As shown in Scheme 2, non‐natural glycodipeptides
8
were ABI API‐3000 ESI mass spectrometer. Commercial reagents
prepared by utilizing Pd/Au catalyzed Sonogashira cross‐ were purchased from standard suppliers. Thin layer
coupling. Gratefully, this catalytic system was compatible with chromatography was carried out on Merck Kieselgel 60 F254
O‐/S‐linked GlcNAc (5a/5b) and dipeptide 7 while affording glass plates. Flash column chromatography was carried out
pure glycodipeptide 8a and 8b with 41% and 23% yields, using Merck Silica gel 60 silica.
respectively, without any sign of racemization of amino acids General method for the synthesis of compound 4a‐4g
or epimerization of sugars.
To a solution of compound 1 (500 mg, 1.234 mmol), PdCl
2 3 2
(PPh )
(8.7 mg, 1 mol%), AuI (8.0 mg, 2 mol%) and TEA (0.860 mL, 6.170
mmol) in acetonitrile was added alkynyl derivate 3 (1.481 mmol)
dropwise. The reaction mixture was stirred for 18 h at 80 C under
argon atmosphere, then diluted with water and extracted with
Conclusions
We have developed a one‐step synthesis of non‐natural glyco‐ dichloromethane (DCM) for 3 times. The combined organic layers
conjugates via Pd/Au‐catalyzed Sonogashira cross‐coupling. were washed with brine, dried with Na SO , filtered, and then
2
4
The reaction tolerates various substrates with terminal concentrated in vacuo.
acetylenes bearing electron‐donating or electron‐withdrawing
N‐Boc‐4‐(4‐methoxyphenyl)ethynyl‐L‐phenylalanine methyl ester
I
1
groups. Noticeably higher catalytic activity of Au was observed
(
4a). H NMR (400 MHz, CDCl
3
) δ 7.43 (t, J = 7.0 Hz, 4H), 7.09 (d, J =
III
I
compared to Au and Cu . Both O‐ and S‐linked non‐natural
glycoamino acids were prepared in moderate yields (53–63%).
Reduced yields were observed for S‐linked sugar substrates
when the co‐catalyst was CuI. The Pd/Au catalytic duo was
more efficient than classical Pd/Cu and Pd‐only catalytic
platforms for the preparation of non‐natural glycoamino acids.
The catalytic system was further applied to synthesize both O‐
and S‐linked glyco‐dipeptides via convergent approach. We
anticipate that this mild and efficient Pd/Au catalytic system
will have broad implications to extend the scope of non‐
natural glyco‐conjugates.
7
=
3
.8 Hz, 2H), 6.84 (d, J = 8.3 Hz, 2H), 5.08 (d, J = 8.3 Hz, 1H), 4.57 (d, J
7.2 Hz, 1H), 3.77 (s, 3H), 3.68 (s, 3H), 3.11 (dd, J = 13.8, 5.9 Hz, 1H),
13
.02 (dd, J = 14.1, 6.3 Hz, 1H), 1.41 (s, 9H); C NMR (101 MHz, CDCl
3
)
δ 172.13, 159.61, 155.04, 136.10, 132.98, 131.53, 129.28, 122.28,
1
2
found: 432.1783.
N‐Boc‐4‐(phenyl)ethynyl‐L‐phenylalanine methyl ester (4b).
NMR (400 MHz, CDCl ) δ 7.55‐7.49 (m, 2H), 7.46 (d, J = 7.7 Hz, 2H),
7
=
=
15.30, 113.99, 89.55, 87.80, 79.90, 55.21, 54.34, 52.19, 38.20,
+
8.27; HRMS (ESI): m/z calcd for C24
H
27NNaO
5
([M+Na ]): 432.1787;
1
H
3
.32 (d, J = 5.5 Hz, 3H), 7.11 (s, 2H), 5.08 (d, J = 8.3 Hz, 1H), 4.59 (q, J
6.8 Hz, 1H), 3.70 (s, 3H), 3.13 (dd, J = 13.8, 5.9 Hz, 1H), 3.04 (dd, J
1
3
3
14.2, 6.2 Hz, 1H), 1.43 (s, 9H); C NMR (101 MHz, CDCl ) δ 172.13,
Experimental
General
155.04, 136.48, 131.71, 131.56, 129.34, 128.34, 128.31, 128.26,
1
23.23, 121.96, 89.55, 89.13, 79.95, 54.34, 52.23, 38.26, 28.29;
+
HRMS (ESI): m/z calcd for C23
02.1678.
N‐Boc‐4‐(p‐tolyl)ethynyl‐L‐phenylalanine methyl ester (4c).
NMR (400 MHz, CDCl
H
25NNaO
4
([M+Na ]): 402.1681; found:
1
13
H and C NMR spectra were recorded on an Agilent 400 MHz
4
spectrometer. Mass spectra were recorded on a Bruker
spectrometry. High resolution mass spectra were recorded on
1
H
3
) δ 7.43 (dd, J = 14.5, 7.8 Hz, 4H), 7.16‐7.07 (m,
4
| J. Name., 2012, 00, 1‐3
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ARTICLE
4
H), 5.11 (d, J = 8.2 Hz, 1H), 4.59 (q, J = 6.8 Hz, 1H), 3.69 (s, 3H), 3.12 Hz, 2H), 5.81 (d, J = 8.9 Hz, 1H), 5.33 (t, J = 9.9 Hz, 1H), 5.07 (d,
View Article Online
(dd, J = 13.8, 5.8 Hz, 1H), 3.03 (dd, J = 13.8, 6.4 Hz, 1H), 2.34 (s, 3H), J = 9.6 Hz, 1H), 5.05 – 4.98 (m, 1H), 4.94 (
DO
d
,
I
J
: 1
=
0.
8
10.439
H
/Cz,6O1HB0),24.57H
4 8
3
1
3
1
1
8
.43 (s, 9H); C NMR (101 MHz, CDCl
) δ 172.14, 155.05, 138.34, – 4.49 (m, 3H), 4.26 (dd, J = 12.3, 4.6 Hz, 1H), 4.12 (dd, J = 12.3,
3
36.30, 131.64, 131.45, 129.31, 129.11, 122.16, 120.16, 89.75, 2.4 Hz, 1H), 3.93 – 3.83 (m, 1H), 3.74 (ddd, J = 10.1, 4.8, 2.4 Hz,
1
1
9
H), 3.67 (s, 3H), 3.09 (dd, J = 13.9, 5.7 Hz, 1H), 3.00 (dd, J =
8.50, 79.90, 54.35, 52.20, 38.21, 28.29, 21.47; HRMS (ESI): m/z
+
4.6, 5.9 Hz, 1H), 2.04 (s, 3H), 1.99 (s, 6H), 1.89 (s, 3H), 1.38 (s,
calcd for C24
H
27NNaO
4
([M+Na ]): 416.1838; found: 416.1840.
13
H); C NMR (101 MHz, CDCl ) δ 172.04, 170.85, 170.70,
N‐Boc‐4‐(4‐florophenyl)ethynyl‐L‐phenylalanine methyl ester (4d).
3
1
170.27, 169.36, 154.96, 137.06, 131.93, 129.38, 120.85, 109.99,
H NMR (400 MHz, CDCl
H), 7.01 (t, J = 8.7 Hz, 2H), 5.05 (d, J = 8.2 Hz, 1H), 4.58 (q, J = 6.7
Hz, 1H), 3.69 (s, 3H), 3.12 (dd, J = 13.8, 5.9 Hz, 1H), 3.03 (dd, J = 13.9,
3
) δ 7.51‐7.40 (m, 4H), 7.11 (d, J = 7.8 Hz,
9
5
8.33, 86.78, 83.76, 80.07, 72.34, 71.95, 68.49, 61.96, 56.77,
2
4.57, 54.25, 52.29, 38.29, 28.27, 23.37, 20.72, 20.66, 20.61;
+
1
3
HRMS (ESI): m/z calcd for C32
H
42
N
2
NaO13 ([M+Na ]): 685.2585;
6
1
1
3
4
3
.3 Hz, 1H), 1.41 (s, 9H); C NMR (101 MHz, CDCl ) δ 172.09, 163.67,
found: 685.2583.
Glycoamino acid (6b)
61.19, 155.00, 136.59, 133.45, 133.37, 131.62, 129.35, 121.73,
ꢄꢆ
1
.
ꢀꢁꢂ +147.98 (c, 0.642 in CH
2
Cl
2
); H
ꢃ
19.34, 119.31, 88.78, 88.76, 88.39, 79.92, 54.30, 53.45, 52.20,
8.23, 28.23; HRMS (ESI): m/z calcd for C23
NMR (400 MHz, CDCl ) δ 7.34‐7.30 (m, 2H), 7.06 (d, J = 8.1 Hz,
+
3
H
24FNNaO
4
([M+Na ]):
2H), 5.17‐5.04 (m, 2H), 4.80 (dd, J = 10.5, 1.0 Hz, 1H), 4.52 (t, J
5.9 Hz, 1H), 4.25‐4.08 (m, 3H), 3.77 (d, J = 16.4 Hz, 1H), 3.68
20.1587; found: 420.1585.
=
N‐Boc‐4‐(4‐nitrophenyl)ethynyl‐L‐phenylalanine methyl ester (4e).
(s, 4H), 3.50 (d, J = 16.4 Hz, 1H), 3.12 – 3.05 (m, 1H), 3.01 (d, J =
1
3
H NMR (400 MHz, CDCl ) δ 8.15 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.5
6
.4 Hz, 1H), 2.04 (s, 3H), 1.99 (d, J = 0.7 Hz, 6H), 1.90 (d, J = 0.8
1
3
Hz, 2H), 7.45 (d, J = 7.9 Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H), 5.08 (d, J =
8
5
Hz, 3H), 1.38 (s, 9H); C NMR (101 MHz, CDCl ) δ 172.15,
3
.2 Hz, 1H), 4.57 (d, J = 7.2 Hz, 1H), 3.69 (s, 3H), 3.13 (dd, J = 13.8,
1
70.86, 170.59, 169.40, 155.09, 136.62, 131.79, 129.31, 121.38,
.8 Hz, 1H), 3.03 (dd, J = 14.3, 6.2 Hz, 1H), 1.39 (s, 9H); C NMR 84.48, 83.06, 83.04, 80.13, 75.92, 73.87, 68.43, 62.16, 54.20,
) δ 172.02, 155.00, 146.84, 137.81, 132.15, 131.89, 52.64, 52.28, 38.18, 28.21, 22.90, 20.53, 18.40; HRMS (ESI):
1
3
(101 MHz, CDCl
3
+
1
3
4
30.13, 129.50, 123.54, 120.66, 94.49, 87.68, 79.89, 54.29, 52.24, m/z calcd for C32
H42LiN
2
O
12S ([M+Li ]): 685.2619; found:
+
8.26, 28.22; HRMS (ESI): m/z calcd for C23
24
H N
2
NaO
6
([M+Na ]): 685.2625.
1
Glycoamino acid (6c)
.
ꢇꢀꢁꢂ ꢄꢃ ꢆ ‐98.80 (c, 0.830 in CH
2
Cl
2
); H NMR
47.1532; found: 447.1527.
(
2
400 MHz, CDCl ) δ 7.33 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 7.8 Hz,
H), 5.45‐5.42 (m, 1H), 5.30‐5.25 (m, 1H), 5.07 (dd, J = 10.0, 3.4
N‐Boc‐4‐(1‐dodecynyl)ethynyl‐L‐phenylalanine methyl ester (4f).
H NMR (400 MHz, CDCl ) δ 7.31 (d, J = 7.9 Hz, 2H), 7.03 (d, J = 7.8
3
3
1
Hz, 1H), 5.02‐4.97 (m, 1H), 4.76 (d, J = 10.0 Hz, 1H), 4.56 (q, J =
7
=
= 13.7, 5.8 Hz, 1H), 3.01 (dd, J = 13.8, 6.2 Hz, 1H), 2.13 (s, 3H),
2
Hz, 2H), 4.96 (d, J = 8.3 Hz, 1H), 4.55 (q, J = 6.7 Hz, 1H), 3.69 (s, 3H),
.08 (dd, J = 13.8, 5.8 Hz, 1H), 3.01 (dd, J = 13.8, 6.1 Hz, 1H), 2.38 (t,
J = 7.1 Hz, 2H), 1.58 (p, J = 7.1 Hz, 2H), 1.45 (s, 11H), 1.28 (d, J = 9.3
.2, 6.6 Hz, 1H), 4.21‐4.06 (m, 3H), 3.98‐3.92 (m, 1H), 3.78 (d, J
16.4 Hz, 1H), 3.69 (s, 3H), 3.54 (d, J = 16.4 Hz, 1H), 3.10 (dd, J
3
1
3
3
Hz, 12H), 0.87 (t, J = 6.8 Hz, 3H); C NMR (101 MHz, CDCl ) δ 172.15,
.05 (s, 3H), 2.01 (d, J = 2.7 Hz, 3H), 1.97 (s, 3H), 1.40 (s, 9H);
C NMR (101 MHz, CDCl ) δ 172.06, 170.34, 170.20, 170.00,
3
69.65, 154.98, 136.60, 131.82, 129.33, 121.41, 84.14, 83.40,
2.74, 80.03, 74.57, 71.85, 67.21, 67.17, 61.37, 54.25, 52.27,
1
5
2
55.00, 135.38, 131.64, 129.12, 122.83, 90.62, 80.21, 79.93, 54.29, 13
2.19, 38.16, 31.88, 29.57, 29.53, 29.30, 29.15, 28.90, 28.75, 28.26,
1
8
3
2.66, 19.39, 14.09; HRMS (ESI): m/z calcd for C27
H
41NNaO
4
+
([M+Na ]): 466.2933; found: 466.2928.
8.24, 28.26, 20.78, 20.63, 18.65; HRMS (ESI): m/z calcd for
N‐Boc‐4‐(6‐chloro‐1‐hexynl)ethynyl‐L‐phenylalanine methyl ester
+
C H NNaO S ([M+Na ]): 702.21908; found: 702.22033.
Glycoamino acid (6d). ꢀꢁꢂ +121.11 (c, 0.870 in CH Cl ); H
ꢃ
2 2
NMR (400 MHz, CDCl ) δ 7.34 (d, J = 7.8 Hz, 2H), 7.06 (d, J = 7.9
3
2
41
13
1
1
(
4g). H NMR (400 MHz, CDCl
3
) δ 7.35‐7.27 (m, 2H), 7.04 (d, J = 7.8
ꢄꢈ
Hz, 2H), 4.96 (d, J = 8.3 Hz, 1H), 4.56 (q, J = 7.3, 6.8 Hz, 1H), 3.70 (s,
3
3
6
9
1
2
H), 3.60 (t, J = 6.6 Hz, 2H), 3.06 (qd, J = 13.8, 5.9 Hz, 2H), 2.45 (t, J =
Hz, 2H), 5.54 (s, 1H), 5.41 (d, J = 3.1 Hz, 1H), 5.33 (d, J = 9.8 Hz,
.9 Hz, 2H), 1.96 (tt, J = 8.2, 6.4 Hz, 2H), 1.80‐1.69 (m, 2H), 1.41 (s, 1H), 5.25 (dd, J = 10.0, 3.4 Hz, 1H), 4.96 (d, J = 8.4 Hz, 1H), 4.56
1
3
H); C NMR (101 MHz, CDCl
3
) δ 172.15, 155.00, 135.64, 131.66, (s, 1H), 4.42‐4.29 (m, 2H), 4.10 (d, J = 11.1 Hz, 1H), 3.75‐3.60
29.18, 122.47, 89.40, 79.99, 54.27, 52.23, 44.54, 38.17, 31.59, (m, 4H), 3.48 (d, J = 16.7 Hz, 1H), 3.09 (d, J = 5.4 Hz, 1H), 3.05
8.27, 25.86, 18.70; HRMS (ESI): m/z calcd for C21
H
28ClNNaO
4
(d, J = 6.3 Hz, 1H), 2.16 (d, J = 7.9 Hz, 3H), 2.08 (d, J = 10.2 Hz,
1
3
+
3
H), 2.05 (d, J = 3.1 Hz, 3H), 1.99 (s, 3H), 1.41 (s, 9H); C NMR
([M+Na ]): 416.1605; found: 416.1599.
(
101 MHz, CDCl ) δ 172.06, 170.55, 169.80, 169.75, 169.63,
General method for the synthesis of glycoamino acids
Compound (0.373 mmol) and sugar (0.373 mmol) were
treated with PdCl (PPh ) (2.6 mg, 1 mol%) and AuI (2.4 mg, 2
mol%) in acetonitrile and TEA (0.260 mL, 1.864 mmol). The
solution was bubbled with Ar for few mins and stirred for 18 h
3
1
7
2
54.99, 136.60, 131.91, 129.26, 121.26, 83.86, 83.53, 81.54,
0.57, 69.60, 69.36, 66.21, 62.30, 54.24, 52.25, 38.25, 28.26,
1
5
2
3 2
0.89, 20.71, 20.67, 20.58, 19.24; HRMS (ESI): m/z calcd for
+
C H LiNO S ([M+Li ]): 686.2459; found: 686.2489.
3
2
41
13
General method for the synthesis of glycodipeptides
at 80 C. The mixture was diluted with water and extracted
2
3
Dipeptide
with PdCl
TEA (5 equiv.). The solution was bubbled with Ar for few mins
and stirred for 18 h at 80 C. The mixture was diluted with
NMR (400 MHz, CDCl ) δ 7.34 (d, J = 7.8 Hz, 2H), 7.06 (d, J = 7.8 water and extracted with diethyl ether for 3 times. The
7
(1 equiv.) and sugar
5 (1 equiv.) were treated
with diethyl ether for 3 times. The combined organic layers
were washed with brine, dried with Na SO , filtered, and then
2
(PPh (1 mol%) and AuI (2 mol%) in acetonitrile and
3 2
)
2
4
concentrated in vacuo.
Glycoamino acid (6a). ꢀꢁꢂ +100.53 (c, 1.120 in CH
ꢄꢅ
1

2
2
Cl ); H
ꢃ
3
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 5
Please do not adjust margins

Org aP nl ei ca s &e dB oi on mo to al ed cj uu sl at rm Ca hr ge imn si stry
Page 6 of 7
ARTICLE
Journal Name
combined organic layers were washed with brine, dried with
6
7
8
(a) B. G. Davis, Chem. Rev., 2002, 102, 579Vi‐e6w0A2rt;icle(bO)nlinKe.
Pachamuthu and R. R. Schmidt, Chem. Rev., 2006, 106, 160‐
Na SO , filtered, and then concentrated in vacuo.
DOI: 10.1039/C6OB02437H
2
4
1
87.
ꢄꢅ
1
2 2
Glycodipeptide (8a).ꢇꢀꢁꢂꢃ +64.48 (c, 0.977 in CH Cl ); H NMR
(a) M. Hurevich and P. H. Seeberger, Chem. Commun., 2014,
50, 1851‐1853; (b) O. J. Plante, E. R. Palmacci and P. H.
Seeberger, Science, 2001, 291, 1523‐1527.
(
400 MHz, CDCl ) δ 7.34 (d, J = 6.8 Hz, 2H), 7.26 – 7.20 (m, 3H),
3
7
.13 (d, J = 7.3 Hz, 2H), 7.00 (d, J = 7.2 Hz, 2H), 6.39 (d, J = 7.4
(a) K. Tanaka, Org. Biomol. Chem., 2016, 14, Advance article;
Hz, 1H), 5.74 (d, J = 8.7 Hz, 1H), 5.30 (dd, J = 14.7, 5.5 Hz, 1H),
(b) J. M. Chalker, G. J. Bernardes and B. G. Davis, Acc. Chem.
5.07 (dd, J = 13.9, 5.3 Hz, 1H), 4.99 (s, 1H), 4.96 – 4.89 (m, 1H),
4.76 (d, J = 6.1 Hz, 1H), 4.57 (d, J = 2.3 Hz, 2H), 4.35 – 4.23 (m,
2H), 4.13 – 4.08 (m, 1H), 3.92 (dd, J = 17.7, 8.8 Hz, 1H), 3.77 –
3.71 (m, 1H), 3.67 (s, 3H), 3.10 – 2.96 (m, 4H), 2.06 (d, J = 1.5
Res., 2011, 44, 730‐741; (c) J. Xie and P. G. Schultz, Nat. Rev.
Mol. Cell. Biol., 2006, , 775‐782; (d) J. A. Johnson, Y. Y. Lu, J.
A. Van Deventer and D. A. Tirrell, Curr. Opin. Chem. Biol.,
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7
2
R. Bertozzi, Proc. Natl. Acad. Sci. U. S. A., 2002, 99, 19‐24; (f)
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Hz, 3H), 2.02 (dd, J = 6.7, 1.5 Hz, 7H), 1.89 (d, J = 1.3 Hz, 3H),
1
3
1
1
1
7
3
.39 (s, 9H); C NMR (101 MHz, CDCl
3
) δ 171.37, 170.81,
9
1
70.56, 170.37, 169.36, 137.54, 135.57, 131.96, 129.43, 129.21,
29.18, 128.59, 128.56, 127.14, 120.79, 98.44, 86.71, 83.81,
2.40, 71.88, 68.57, 61.99, 56.73, 54.45, 53.28, 52.31, 38.16,
7.90, 37.07, 29.67, 28.23, 23.29, 20.71, 20.65, 20.60; HRMS
ESI): m/z calcd for C41
0 (a) J. M. Chalker, C. S. C. Wood and B. G. Davis, J. Am. Chem.
Soc., 2009, 131, 16346‐16347; (b) Z. Gao, V. Gouverneur and
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Bhushan, R. S. Paton and B. G. Davis, J. Am. Chem. Soc., 2013,
+
(
H
51
N
3
NaO14 ([M+Na ]): 833.3269; found:
8
33.3260.
1
35, 12156‐12159.
ꢄꢉ
1
Glyco‐dipeptide (8b)
.
ꢀꢁꢂ ‐6.76 (c, 1.035 in CH
2
Cl
2
); H NMR 11 X. Xu, G. Fakha and D. Sinou, Tetrahedron, 2002, 58, 7539‐
ꢃ
(
400 MHz, CDCl ) δ 7.33 (d, J = 6.6 Hz, 2H), 7.27 – 7.22 (m, 3H),
7544.
3
1
2 (a) T. Lowary, M. Meldal, A. Helmboldt, A. Vasella and K.
Bock, J. Org. Chem., 1998, 63, 9657‐9668; (b) M. Ousmer, V.
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Chem., 2006, 2006, 1216‐1221.
7
.14 (d, J = 6.7 Hz, 2H), 7.01 (d, J = 2.2 Hz, 2H), 6.28 (d, J = 7.3
Hz, 1H), 5.62 (d, J = 9.2 Hz, 1H), 5.13 (dq, J = 19.5, 9.7 Hz, 2H),
4
5
.94 (d, J = 18.2 Hz, 1H), 4.82 (d, J = 10.5 Hz, 1H), 4.77 (d, J =
.8 Hz, 1H), 4.36 – 4.08 (m, 5H), 3.79 (d, J = 16.3 Hz, 1H), 3.69
1
3 (a) R. Chinchilla and C. Nájera, Chem. Rev., 2007, 107, 874‐
9
5
22; (b) R. Chinchilla and C. Najera, Chem. Soc. Rev., 2011, 40
,
(
d, J = 10.0 Hz, 3H), 3.53 (d, J = 16.4 Hz, 1H), 3.04 (dd, J = 15.4,
084‐5121.
7
1
.2 Hz, 4H), 2.06 (d, J = 1.8 Hz, 3H), 2.03 (dd, J = 5.0, 1.7 Hz, 6H),
1
1
4 J. Jover, P. Spuhler, L. Zhao, C. McArdle and F. Maseras, Catal.
Sci. Technol., 2014, , 4200‐4209.
5 (a) B. Panda, T. K. Sarkar, Chem. Commun., 2010, 46, 3131‐
1
3
.93 (d, J = 1.8 Hz, 3H), 1.41 (s, 9H); C NMR (101 MHz, CDCl
3
)
4
δ 170.97, 170.47, 170.12, 135.54, 132.22, 131.92, 129.42,
3
3
133; (b) B. Panda, T. K. Sarkar, Tetrahedron Lett. 2010, 51
,
1
5
2
1
29.18, 128.57, 127.16, 83.15, 73.81, 68.32, 62.13, 55.36,
3.29, 53.03, 52.39, 52.36, 37.93, 37.08, 32.73, 31.91, 30.02,
9.68, 29.34, 28.23, 27.07, 23.15, 22.68, 20.66, 20.59, 20.54,
01‐305.
1
1
6 T. Lauterbach, M. Livendahl, A. Rosellón, P. Espinet and A. M.
Echavarren, Org. Lett., 2010, 12, 3006‐3009.
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Luzung, K. N. Houk and F. D. Toste, J. Am. Chem. Soc., 2008,
51 3
9.71, 18.45; HRMS (ESI): m/z calcd for C41H N NaO13S
+
(
[M+Na ]): 848.3040; found: 848.3030.
1
30, 4517‐4526; (c) R.‐Y. Liau, A. Schier and H. Schmidbaur,
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Acknowledgements
This work was supported by UNIST research fund (No.
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| J. Name., 2012, 00, 1‐3
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Page 7 of 7
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C6OB02437H
Ulsan National Institute of Science and Technology
School of Energy and Chemical Engineering
Organic & Biomolecular Chemistry - OB-ART-11-2016-002437
Title: Palladium and gold catalytic system enables direct access to O- and S-linked non-natural
glyco-conjugates
A table of contents entry:
Pd/Au-catalyzed Sonogashira reaction allows direct synthesis of O- and S-linked non-natural glyco-
conjugates.