Direct N-Glycofunctionalization of Amides with Glycosyl Trichloroacetimidate by Thiourea/Halogen Bond Donor Co-Catalysis

Article abstract of DOI:10.1002/anie.201712726

Using a halogen bond (XB) donor and Schreiner's thiourea as cooperative catalysts, various amides, including the asparagine residues of several peptides, were directly coupled with glycosyl trichloroacetimidates to give unique N-acylorthoamides in good yi

Full text of DOI:10.1002/anie.201712726

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Accepted Article
Title: Direct N-glycofunctionalization of amides with glycosyl
trichloroacetimidate by thiourea/halogen bond donor co-catalysis
Authors: Yusuke Kobayashi, Yuya Nakatsuji, Shanji Li, Seiji Tsuzuki,
and Yoshiji Takemoto
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201712726
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10.1002/anie.201712726
Angewandte Chemie International Edition
COMMUNICATION
Direct N-glycofunctionalization of amides with glycosyl
trichloroacetimidate by thiourea/halogen bond donor co-catalysis
Yusuke Kobayashi,[a] Yuya Nakatsuji,[a] Shanji Li,[a] Seiji Tsuzuki,[b] Yoshiji Takemoto*[a]
glycofunctionalization of amide, impacting on prodrug synthesis. In
fact, during the course of our investigation on the rearrangement of
N-acylorthoamide to N-glycoside (path d), we have developed a new
type of Brønsted-acid-salt catalyst, comprised of Brønsted acid and
2-halogenated azole, which was found to be an efficient catalyst for
the direct N-glycosylation of various amides utilizing the same
glycosyl trichloroacetimidates (path b and/or path a and d).
Abstract: Using a halogen bond (XB) donor and Schreiner’s
thiourea as cooperative catalysts, various amides, including the
asparagine residues of several peptides, were directly coupled with
glycosyl trichloroacetimidates to give unique N-acylorthoamides in
good yields. Synthetic applications of N-acylorthoamides, including
rearrangement to the corresponding -N-glycoside, were also
demonstrated.
N-Glycosides are found in various pharmaceuticals, biologically
active compounds, and natural products.[1] They can be used in
material science as glycolipids for lipid nanotubes. [2] Sugar moieties
are known to impart hydrophilicity to molecules, and alter the higher
order structure and bioavailability of molecules.[3] Several N-
glycosides have been utilized as prodrugs to improve delivery to
target tissues and organs.[4] However, synthetic methodologies for
N-glycosylamides are not as well developed[5 as those for O-
glycosides (Scheme 1a).[9] Among the reported synthetic methods
for N-glycosylamides, [6] direct N-glycosylation of amides is the most
straightforward but challenging approach because of the poor
nucleophilicity of the amides, and only limited catalytic conditions
have been reported to date.[8] However, there still remains to be
improved concerning scope of amides and the accessibility of
Leaving group (LG). In fact, direct introduction of asparagine
residues of peptides have been rarely investigated, and the use of
tripeptide significantly decreased the chemical yield,[8a] as compared
with that of dipeptide.[8a,c] We then focused on the utilization of
glycosyl trichloroacetimidates,[10] which are regarded as one of the
most readily available glycosyl donors and activated under relatively
mild condition.[11a,b] On the other hand, undesired glycosyl
trichloroacetamide was obtained as byproduct, especially when the
glycosyl acceptor (Nu-H) has low nucleophilicity (path c).[8a] Herein,
we report two different catalytic systems, which offers a solution to
these problems (Scheme 1b). We envisaged that the activation of
glycosyl trichloroacetimidates under mildly acidic condition would
afford kinetically favored product by the preferential addition of
employed amides via path a.[10] We thus focused on Schreiner’s
thiourea,[12] whose pKa value was reported to be 8.5 in DMSO.[12c]
Although thiourea have been recently employed for glycosylation[11]
and acetalization[13] of alcohols, its acidity was insufficient to activate
trichloroacetimidate.[11a,b] We envisioned that a soft and mild Lewis
acid, such as 2-iodoazolium salt[14] (R2  H) as halogen bond (XB)
8]
‒
Scheme 1. Summary of this work
We first screened various catalysts for the direct N-
glycofunctionalization of a protected asparagine derivative 2a[8] with
a readily accessible glycosyl donor 1[22a] (Table 1). The use of
Schreiner’s thiourea (5) on its own did not promote the reaction at all
(entry 1). We next investigated several co-catalysts for activation of
thiourea,[19] including metallic Lewis acids (entries 2‒5)[11c] and
Brønsted acids (entries 6‒7).[11a] Interestingly, when a substituted
diarylphosphoric acid was employed, an N-acylorthoamide 4a,
whose structure was fully characterized using spectral data (Figure
S5), was obtained in 22% yield (entry 6). A stronger Brønsted acid
resulted in the production of 3a, albeit in 26% yield (entry 7),
indicating that the acidity of the catalyst affects production of 3a.
Indeed, as previously reported, with 10 mol % of trimethylsilyl
trifluoromethanesulfonate (TMSOTf) [8] as a conventional Lewis acid,
the donor 1 was immediately consumed, and 3a was obtained in
25% yield (entry 8), along with several inseparable byproducts. As
the results were not satisfactory, we next investigated several XB
donors as cooperative catalysts (entries 9‒12). We found that
combination of thiourea 5 with 2-iodobenzimidazolium-type XB
donors 7b[14] afforded 4a as a major product in 66% yield (entry 11).
A newly designed XB donor with extended aromatic rings 7c
similarly afforded 4a as the major product (entry 12). We next
performed several control experiments. The addition of 10 mol % of
base (NEt3 or Cs2CO3) to the condition of entry 10 resulted in the
17]
donor, [15
used as a co-catalyst would interact with the soft Lewis
‒
basic moiety of thiourea[18] to increase the HB-donating ability of
thiourea,[19] so that the LG could be activated[20] with wide functional
group tolerance. The produced N-acylorthoamides[21] would serve as
intermediates for thermodynamically favored -N-glycosides[10]
(Scheme 1a, path d, Nu = amide), and offer a unique traceless N-
[a]
[b]
Dr. Y. Kobayashi, Y. Nakatsuji, S. Li, Prof. Dr. Y. Takemoto,
Graduate School of Pharmaceutical Sciences, Kyoto University,
Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Dr. S. Tsuzuki,
Research Initiative of Computational Sciences (RICS), Nanosystem
Research Institute (NRI), National Institute of Advanced Industrial
Science and Technology (AIST), 1-1-1 Umezono, Tsukuba, Ibaraki
305-8568, Japan
E-mail: takemoto@pharm.kyoto-u.ac.jp
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201712726
Angewandte Chemie International Edition
COMMUNICATION
prohibition of the reaction (3a: 0%, 4a: 0%), rather than the
acceleration of the reaction. The XB donor 7b on its own did not
afford the target products (entry 13), which indicated that
combination of thiourea 5 and XB donor 7b was essential for
production of 4a. The yields of 4a greatly decreased when the
squaramide[23] 6, which has superior HB-donating ability[23c] to
thiourea,[12b,c] was employed instead of 5 (entries 14 and 15). In
addition, a control experiment using non-halogenated azolium salt 8
did not afford 4a at all (entry 16). These results suggest that the
reaction was not accelerated by the azoliium cation moiety or triflate
anion by itself,[24] and that XB formation between the sulfur atom of 5
and the iodine atom of XB donor 7[15d,18a,b,d] plays an important role
for the promotion of the reaction, presumably through the activation
of LG (Scheme S1).[25] Although other solvents, such as THF,
toluene, and acetonitrile, can be used for this reaction without
significant decrease of the chemical yields (entries 17‒19), CH2Cl2
was chosen for further investigation in terms of the solubility of
various amides. To gain further support for the XB formation, a 13C
NMR experiment was performed using thiourea (5) and XB donor
(7b) (Figure S2).[25] When 1.0 equivalent of 5 was added, the 13C
NMR peak of the C2 position of 7b broadened and shifted downfield
in accordance with previous reports on XB interaction of the
iodoazolium salts.[14f-i]
(1.0 equiv) was employed (Scheme 2a), presumably due to the
inherent reactivity of the acyloxonium ion intermediate toward
nucleophiles.[10] Encouraged by this result, we then investigated the
efficient catalysts to promote the rearrangement of 4a to 3a (Scheme
2b). Although the chemical yields of 3a were low using TMSOTf[10c]
and TfOH as catalysts, partly because of the degradation of 4a,
Brønsted acid salt 9•TfOH, synthesized from the same intermediate
for 7c, was found to be most suitable.
Scheme 2: (a) Control experiment using trichloroacetamide (b) Catalytic
rearrangement of 4a to 3a
Table 1: Screening of reaction conditions for orthoamide 4
Scheme 3: Substrate scope for the synthesis of N-acylorthoamides 4. Isolated
yields were indicated. Rib = ribose.
entry
1
catalyst
solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
3a (%)a 4a (%)a
5
0 b
7
0 b
0 b
0 b
0 b
0 b
5 + BF3•OEt2
2
3
4
5
6
0 b
trace
trace
0 b
26
25
0 b
5
5 + Sc(OTf)3
5 + AuCl3
5 + PPh3AuOTf
5 + (4-NO2C6H4O)2P(O)OH
5 + TfOH
TMSOTf
5 + C6F5I
5 + 7a
5 + 7b
5 + 7c
7b
6 + 7b
6
5 + 8
5 + 7b
5 + 7b
5 + 7b
22
7
0 b
0 b
0 b
8c
9
Scheme 4: Substrate scope for the synthesis of N-acylorthoamides 9.
Isolated yields were indicated. Glc = glucose. N.d. = not detected.
10
11
12
13
14
15
16
17
18
19
32
Having established the synthetic utilities of N-acrylorthoamide 4, we
next investigated the substrate scope for glycosyl donors and
amides (Scheme 3, 4). Using 10 mol % of catalysts 5 and 7b, N-
Cbz-glycineamide (2b) could be directly converted into 4b in 67%
yield. Oleamide (2c), which is an important amide towards the
synthesis of lipid nanotubes,[2] was effectively conjugated with sugar
to afford 4c in 41% yield. Notably, the asparagine residues of
dipeptide and tripeptide were glycosylated by the present co-
catalytic system to afford 4e and 4f in unprecedented good yields
(Scheme 3). The same amides were also coupled with the glucose
surrogate utilizing 3,4,6-tri-O-benzyl-2-O-acetyl--D-glucopyranosyl
trichloroacetimidate (10)[22b] to yield N-acylorthoamides 11a‒f in 56‒
71% yields (Scheme 4).
7
66
63
8
0 b
2
0 b
19
0 b
0 b
64
0 b
0 b
3
toluene
CH3CN
15
4
66
53
[a] Isolated yields. [b] Not detected. [c] 58% of 2a was recovered.
It is worth noting that under the optimized condition (Table 1, entry
11), neither N-trichloroacetylorthoamide nor glycosyl
trichloroacetamide were obtained, even additional trichloroacetamide
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10.1002/anie.201712726
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COMMUNICATION
We next focused on the direct N-glycosylation utilizing Brønsted acid
salt 9•TfOH (Scheme 5), as the acidity of the catalyst was supposed
to be important to obtain N-glycoside 3a in Table 1 (entry 7, 8). To
our delight, N-glycoside 12 was obtained in 72% yield, when glycosyl
donor 10 and amide 2a were reacted. A slight improvement of the
yield was observed when thiourea 5 was employed as co-catalyst.
amides, and offer a new tool for the traceless modification of
pharmaceuticals. Further investigation on the details of the reaction
mechanism, including complexation of amides, and substrate scope
is now underway in our laboratory.
[26]
Under the optimized reaction conditions, a series of N-glycoside
12a‒f were obtained in 62‒82% yields as single -isomers. In
addition to the glucose-derived donor 10, a ribose-derived donor 1
could be directly incorporated into amides to afford the
corresponding adducts in 45‒80% yields. Again, the conjugation with
tripeptide proceeded with unprecedented good yields. Notably, the
catalyst 9•TfOH could be readily prepared from the commercial
source in three steps with high yields, and found to be air- and
moisture-stable for several months.
Scheme 6: Application of the present N-glycofunctionalization
Experimental Section
To a stirred solution of glycosyl donor 1 (36.4 mg, 0.06 mmol) and amide
2a (1.0 equiv, 0.05 mmol) in DCM (1.0 mL) was added activated MS 4Å
(50 mg), and the reaction mixture was stirred at the ambient temperature
for 10 min. Then, the catalysts 5 (2.5 mg, 10 mol %) and 7b (3.5 mg, 10
mol %) were added, and the resulting mixture was stirred at the ambient
temperature for 24 hours. After the MS 4Å was filtered off and washed
with chloroform, the filtrate was concentrated under reduced pressure to
give crude N-acylorthoamide, which was purified by silica gel column
chromatography to afford 4a (24.8 mg, 66%), along with 3a (2.6 mg, 7%).
Scheme 5: Substrate scope for direct N-glycosylation using catalyst 9•TfOH.
[a] With 10 mol % of 5. [b] Without 5. Glc = glucose, Rib = ribose.
The utilities of the present reactions have been clearly demonstrated
by their application to the syntheses of natural products[27] (Scheme
6a), and the modification of pharmaceuticals to prodrugs (Scheme
6b). The direct N-glycosylation of a substituted 2-phenylacetamide
2g with glycosyl donor 10 proceeded very smoothly to obtain the
desired adduct 12g in excellent yield. The successive deprotection
of acetyl and benzyl groups afforded the product in almost
quantitative yield (Scheme 6a). The methodologies developed in this
paper are particularly useful when the compound to be
functionalized has only an amide group for a traceless modification,
and this strategy is especially true for pharmaceuticals. For example,
the anticancer drug temozolomide (2h) can be transformed into the
corresponding N-acylorthoamide 11h using glycosyl donor 10 with
10 mol % of 5 and 7b in THF. After deprotection of the benzyl group
of 11h, the product 15h was found to be soluble in protic solvents,
such as methanol, while temozolomide itself is almost insoluble.[28]
Practically, commercially available glycosyl donor 16 can be
converted into the corresponding adduct 17h in 61% yield. It was
noted that hydrolysis of the N-adduct 17h under mildly acidic
conditions afforded temozolomide (Scheme 6c).
Acknowledgements
This work was partly supported by JSPS KAKENHI (Grant
Number 16H06384 and 17K15423). We also acknowledge
funding from the Society of Iodine Science (SIS). We thank Dr.
Hiroyasu Sato (Rigaku Corporation) for the assistance of X-ray
analysis.
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COMMUNICATION
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This article is protected by copyright. All rights reserved.

10.1002/anie.201712726
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Yusuke Kobayashi, Yuya Nakatsuji,
Shanji Li, Seiji Tsuzuki, Yoshiji
Takemoto*
Page No. – Page No.
Direct N-glycofunctionalization of
amides with glycosyl
trichloroacetimidate by
thiourea/halogen bond donor co-
catalysis
Using a halogen bond (XB) donor and Schreiner’s thiourea as cooperative catalysts,
various amides, including the asparagine residues of several peptides, were directly
coupled with glycosyl trichloroacetimidates to give unique N-acylorthoamides in
good yields. Synthetic applications of N-acylorthoamides, including rearrangement
to the corresponding -N-glycoside, were also demonstrated.
Keywords: glycosylation • organocatalyst • XB donor
This article is protected by copyright. All rights reserved.