Palladium-Catalysed C(sp3)?H Glycosylation for the Synthesis of C-Alkyl Glycoamino Acids

Article abstract of DOI:10.1002/anie.201914184

We have developed a highly efficient and practical approach for palladium-catalyzed trifluoroacetate-promoted N-quinolylcarboxamide-directed glycosylation of inert β-C(sp³)?H bonds of N-phthaloyl α-amino acids with glycals under mild conditions. For the first time, C(sp³)?H activation for glycosylation was achieved to build C-alkyl glycosides. This method facilitates the synthesis of various β-substituted C-alkyl glycoamino acids and offers a tool for glycopeptide synthesis.

Full text of DOI:10.1002/anie.201914184

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Accepted Article
Title: Palladium-Catalysed C(sp3)-H Glycosylation for Synthesis of C-
Alkyl Glycoamino Acids
Authors: Hong Liu, Yichu Liu, Yibing Wang, Wenhao Dai, Wei huang,
and Yingxia Li
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201914184
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http://dx.doi.org/10.1002/ange.201914184

Angewandte Chemie International Edition
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3
Palladium-Catalysed C(sp )-H Glycosylation for Synthesis of C-
Alkyl Glycoamino Acids
Yichu Liu,[a,b,c] Yibing Wang,[b,c] Wenhao Dai,[b,c] Wei Huang,[b,c] Yingxia Li* and Hong Liu*
[a]
[b,c]
Abstract: In this work, we developed a highly efficient and practical
approach for the palladium-catalyzed trifluoroacetate-promoted N-
catalyzed activation of aryl C-H bond and avoided preactivation
of the acceptors in glycosylation. These methods offer a mild,
straightforward, efficient and general strategy for the synthesis
of a series of C-aryl glycosides. Nevertheless, these approaches
3
quinolylcarboxamide-directed glycosylation of inert -C(sp )-H bonds
of N-phthaloyl -amino acids with glycals under mild conditions. For
3
2
3
the first time, the C(sp )-H activation for glycosylation was achieved
are highly useful for C(sp )-H but not for the less active C(sp )-H.
3
to build C-alkyl glycosides. This method facilitates the synthesis of
various -substituted C-alkyl glycoamino acids and offers a tool for
glycopeptide synthesis.
Therefore, developing C(sp )-H activation for the synthesis of C-
alkyl glycosides would be highly valuable.
Here, we report a simple and powerful strategy for the regio-
and diastereoselective synthesis of C-alkyl glycoamino acids via
3
Pd-catalysed,
N-quinolyl-group-directed
-C(sp )-H
C-glycosides exhibit enhanced in vitro and in vivo stability
compared with O- or N-glycosides and therefore become an
attractive strategy for structural optimization in carbohydrate-
functionalization of natural and unnatural -amino acids with
readily accessible 1-iodoglycals (Scheme 1c). This work
facilitates the synthesis of various C-glycoamino acids with
structural diversity, and more importantly, it presents a general
strategy for C-alkyl glycosides synthesis via C(sp )-H activation
which will advance the state-of-the-art technique in carbohydrate
chemistry.
[1]
based drugs development . For instance, the design of SGLT2
inhibitors, replacement of O-glycoside with C-glycoside can
dramatically improve the pharmacokinetic profiles and drug-like
3
[2]
property . Glycoamino acids, as mimic moieties of protein
glycosylation, represent a featured scaffold and building block
[3]
for regulating carbohydrate-mediated biological events .
Table 1. Optimization of the reaction conditions[a]
Scheme 1. Approaches to access C-glycosides via C-H functionalization.
Entry
Silver salt
AgOAc
Additive
Solvent
Yield (%) [b]
1
2
3
4
5
6
7
8
9
-
-
-
-
-
-
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCE
10
18
0
0
0
Ag
AgOTf
Ag
AgBF
2
CO
3
2
O
4
AgTFA
AgOAc
Ag CO
2 3
AgTFA
AgOAc
45
23
48
56
30
61
52
88
43
68
39
58[
(BnO)
(BnO)
(BnO)
TFA
2
PO
2
PO
2
PO
2
H
2
H
2
H
10
11
12
13
Ag
2
Ag
2
Ag
2
Ag
2
Ag
2
Ag
2
Ag
2
Ag
2
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
Over the past few decades, the synthesis of complex C-
glycosides has achieved significant progress. However, many
existing methods resort to pre-functionalized coupling partners
of high reactivity (such as metallation arenes/alkanes for
THF
14
15
t-AmylOH
1,4-dioxane
Acetone
THF
16
17
18
c]
[4]
nucleophilic substitution and metal-catalysed cross-coupling) ,
lack the general regiochemical control (such as the Friedel-
[d]
THF
76
[
5]
Crafts-type glycosylation) , and often require
a multi-step
[
a] Reaction conditions: 1a (0.04 mmol), 2a (0.08 mmol), Pd(OAc)
silver salt (0.12 mmol), and an additive (0.08 mmol) were stirred in a solvent
2 mL) at 75 °C for 24 h. [b] Yield of isolated products. [c] Reaction
2
(5 mol%),
[6]
reaction sequence and delicate operating conditions . Recently,
several groups reported elegant methods for the synthesis of C-
aryl glycosides via C-H functionalization[6-7], which applied metal-
(
temperature 60 °C . [d] Reaction temperature 90 °C .
Initially, N-phthaloyl Alanine 1a and triisopropylsilyl-protected
1
-iodoglucal 2a were used as the glycosylation acceptor and
[
[
a]
b]
Department of Medicinal Chemistry, School of Pharmacy, Fudan
University, Shanghai 201203, China.
donor substrates respectively for the optimization of reaction
conditions. Although aminoquinoline (AQ) is extensively used
as the directing group in C-H activation, great challenge still
remains for its application in glycosylation which is extremely
sensitive to moisture and oxygen. We focused on screening
Key Laboratory of Receptor Research, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road,
Shanghai 201203, China. E-mail: hliu@simm.ac.cn
University of Chinese Academy of Sciences, No.19A Yuquan Road,
Beijing 100049, China.
[c]
2
various silver salts as the additive by employing Pd(OAc) (5
Supporting information for this article is given via a link at the end of
the document.
mol%) as a catalyst at 75 °C stirred in toluene for 24 h. The
results are summarized in Table 1. As shown in Table 1, the
reaction occurred when in the presence of AgOAc, Ag
2 3
CO or
AgTFA, affording the desired product 3aa in low yield (entry 1, 2,
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and 6). Previously, Chen’s work showed that using TFA or
phthaloyl Alanine 1a and N-phthaloyl Phenylalanine 1b also
worked well (Scheme 2, 3ab-3bc).
Finally, the scope of the present procedure with regard to
different types of N-phthaloyl Phenylalanine derivatives 4 has
also been established systematically (Scheme 3). A variety of
functional groups, either electron-donating groups (Me, t-Bu, Ph,
(
BnO)
products . To our delight, the results demonstrated that
employing combination of Ag CO and TFA could moderately
2 2
PO H as additive could increase the yield of the
[
8]
2
3
increase the yield of 3aa to 61% (Table 1, compare entries 7-10
with 11). Subsequently, we continued to evaluate various
solvent to further improve the reaction conversion of 1a (Table 1,
entries 12-16). Among the investigated solvents, THF was
identified as the optimal solvent that could significantly improve
the yield of 3aa from 61% to 88%. It should be noted that
lowering or increasing the reaction temperature led to worse
results (Table 1, compare entries 17-18 with 13).
BnO, and MeO) or electron-withdrawing groups (F, Cl, Br, CF
3
,
COOMe, and NO ), were well tolerated. In addition, most
2
reactions using substrate 4 bearing different substituents at
either ortho- or meta-positions of the phenyl ring had good
diastereoselectivity (dr = 20:1 ~ 6:1). In contrast, excellent
diastereoselectivity was achieved when the substituents were at
para-positions (5aa-5fa, dr > 20:1), possibly because of less
steric hindrance between R group and iodine atom.
Scheme 2. Scope of 1-iodoglycals and -amino acids.
Scheme 3. Scope of N-phthaloyl Phenylalanine derivatives.
The excellent yield after successful condition optimization
encouraged us to further examine the substrate scope of this
method, using 2a with various N-phthaloyl -amino acid
2 3
substrates 1 under the general conditions using Ag CO (2
equiv)/TFA (3 equiv). The results are shown in Scheme 2. As
expected, N-phthaloyl Phenylalanine 1b with a secondary C-H
bond successfully generated the product 3ba with 84% yield and
excellent diastereoselectivity (dr
> 20:1) (the dr value is
1
estimated by H NMR, see Supporting Information). Moreover,
the reactions of -substituted -amino acids tolerating functional
groups such as aryl (3ba-3ea), cycloalkyl (3fa and 3ga), linear
alkyl (3ha and 3ia), and branched alkyl (3ja) proceeded
smoothly, furnishing the desired products 3ba-3ja in moderate to
good yields and with acceptable diastereoselectivity (dr = 20:1 ~
To highlight the synthetic utility of this procedure, further
transformations of the products were performed (Scheme 4). As
shown in Scheme 4a, the directing group can be smoothly
removed under mild reaction conditions. Amide-linked AQ group
was cleanly cleaved via a two-step sequence of Boc activation
and LiOH cleavage to give a free carboxylic acid 6 in excellent
yield. As the hydroxyl protecting group, TIPS group can be
3
:1). Notably, the lower diastereoselectivity of 3ha is presumably
due to the less steric hindrance between methyl and phthalimide.
Besides the glucal 2a, the reactions of glycals 2b and 2c,
respectively derived from galactose and rhamnose, with N-
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removed by TBAF in tetrahydrofuran (details see Supporting
Information Scheme S5). Furthermore, the glucal can be
successfully converted to glucose by hydroboration-oxidation
reaction (Scheme 4b).
Scheme 4. Further transformations of the product.
In summary, we have developed a highly efficient and
practical protocol for the palladium-catalyzed trifluoroacetate-
promoted N-quinolylcarboxamide-directed glycosylation of
3
unactivated -C(sp )-H bonds of N-phthaloyl amino acids with
As shown in Scheme 5a, a small deuterium kinetic isotope
glycals under mild conditions. To the best of our knowledge, this
is the first time to build C-alkyl glycoamino acids by C-H
activation. Glycals can be regio- and stereoselectively installed
onto the -position of a broad range of AQ-coupled N-phthaloyl
amino acids to provide various natural and unnatural C-alkyl
glycoamino acid compounds. From an operational perspective,
these glycosylation reactions are compatible with sensitive
functional groups, tolerant of air and water, and suitable for gram
scale synthesis (see Supporting Information 3.1 Scale-up
Reaction). Moreover, a palladacycle has been successfully
effect (KIE) experiments with N-phthaloyl Alanine 1a and 9 (1a
3
with deuterated methyl) (k
H
/k
D
:1.2) indicated that the sp C-H
bond cleavage may be not the rate-limiting step in this Pd
catalytic cycle[8a]
To get better understanding of the
.
a
glycosylation process, a palladacycle 11 was prepared from
3
substrate 1a via C(sp )-H activation (Scheme 5b). We found this
palladacycle is a fully competent catalyst for reaction of N-
phthaloyl Alanine 1a with 1-iodoglucal 2a under standard
conditions. Reaction of 11 with 2a in THF at 75 °C gave product
3
aa in high yield (Scheme 5b).
3
prepared to elucidate the mechanism of this -C(sp )-H
glycosylation process. We anticipate that this protocol will
provide an opportunity to access various -substituted C-alkyl
glycoamino acids, difficult to be obtained by other means, in a
diastereoselective and programmable manner.
Scheme 5. Mechanistic investigation.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China
(Nos.
21632008,
21672231,
21877118,
and
On the basis of the above results and previous reports[7-9], a
plausible C-H activation mechanism was proposed. As shown in
81620108027) and the Strategic Priority Research Program of
the Chinese Academy of Sciences (XDA12040107 and
XDA12040201) for financial support.
Scheme 6, the palladacycle
I was firstly generated via
cyclometallation. This palladacycle intermediate provided us a
reliable model to predict the diastereoselectivity of the -
3
Keywords: C-alkyl glycosides • C(sp )-H activation • -amino
glycosylations[
8b,10]
. Then the oxidative addition of I with 1-
acids • palladium • diastereoselectivity
iodoglycal afforded the intermediate II, which underwent
reductive elimination to afford intermediate III. Subsequently, III
underwent disassociation to generate the desired product IV and
release Pd catalyst. The exact role of a carboxylic acid additive
such as TFA is unclear at the moment. To account for the
unusual reactivity, trifluoroacetate may serve as a unique ligand
to stabilize the Pd(II) palladacycle intermediate I or even
[
1] a) A. Dondoni, A. Marra, Chem. Rev. 2001, 100, 4395-4422; b) D. C.
Koester, A. Holkenbrink, D. B. Werz, Synthesis 2011, 42, 3217-3242; c)
E. Leclerc, X. Pannecoucke, M. Ethève-Quelquejeu, M. Sollogoub,
Chem. Soc. Rev. 2013, 42, 4270-4283; d) Z. Wei, Curr. Top. Med. Chem.
2
005, 5, 1363-1391; e) P. Compain, O. R. Martin, Bioorg. Med. Chem.
001, 9, 3077-3092; f) G. Yang, J. Schmieg, M. Tsuji, R. W. Franck,
2
Angew. Chem., Int. Ed. 2004, 43, 3818-3822; g) R. W. Franck, M. Tsuji,
Acc. Chem. Res. 2006, 39, 692-701; h) Y. Yang, B. Yu, Chem. Rev.
facilitate the oxidative addition[6, 8a]
.
2
017, 117, 12281-12356.
Scheme 6. Proposed mechanism.
[
2] a) E. C. Chao, R. R. Henry, Nat. Rev. Drug Discovery 2010, 9, 551-559;
b) X. J. Wang, L. Zhang, D. Byrne, L. Nummy, D. Weber, D.
Krishnamurthy, N. Yee, C. H. Senanayake, Org. Lett. 2014, 16, 4090-
4093; c) J. P. Henschke, C. W. Lin, P. Y. Wu, W. S. Tsao, J. H. Liao, P.
C. Chiang, J. Org. Chem. 2015, 80, 5189-5195; d) C. Guo, M. Hu, R. J.
Deorazio, A. Usyatinsky, K. Fitzpatrick, Z.; Zhang, J. H. Maeng, D. B.
Kitchen, S. Tom, M. Luche, Bioorg. Med. Chem. 2014, 22, 3414-3422; e)
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.

Angewandte Chemie International Edition
10.1002/anie.201914184
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W. Cai, L. Jiang, Y. Xie, Y. Liu, W. Liu, G. Zhao, Med. Chem. 2015, 11,
Isozaki, H. Takaya, A. Orita, H. C. Li, S. Tkm, J. Am. Chem. Soc. 2017,
139, 10693-10701.
317-328.
[
3] a) A. Helenius, Mol. Biol. Cell 1994, 5, 253-265; b) E. S. Trombetta, A.
Helenius, Curr. Opin. Struct. Biol. 1998, 8, 587-592; c) A. Helenius, M.
Aebi, Science 2001, 291, 2364-2369; d) T. Prudence, B. D. Shur, D. G.
Myles, Bio. Reprod. 2003, 68, 1-9; e) A. Varki, Glycobiology 1993, 3, 97-
[5] a) K. Kitamura, Y. Ando, T. Matsumoto, K. Suzuki, Chem. Rev. 2018,
118, 1495-1598; b) Z. Wu, G. Wei, G. Lian, B. Yu, J. Org. Chem. 2010,
75, 5725-5728; c) B. Yu, J. Sun, Chem. Commun. 2010, 46, 4668-4679.
[6] Q. Wang, S. An, Z. Deng, W. Zhu, Z. Huang, G. He, G. Chen, Nature
Catal. 2019, 2, 793-800.
1
30; f) R. A. Dwek, Chem. Rev. 1996, 96, 683-720; g) P. M. Rudd, T.
Elliott, P. Cresswell, I. A. Wilson, R. A. Dwek, J. Protein Chem. 2001,
91, 2370-2376; h) B. G. Davis, Chem. Rev. 2002, 102, 579-602; i) D. P.
[7] M. Liu, Y. Niu, Y. F. Wu, X. S. Ye, Org. Lett. 2016, 18, 1836-1839.
[8] a) B. Wang, W. A. Nack, G. He, S. Y. Zhang, G. Chen, Chem. Sci. 2014,
5, 3952-3957; b) S. Y. Zhang, Q. Li, G. He, W. A. Nack, G. Chen, J. Am.
Chem. Soc. 2013, 135, 12135-12141. c) Z. X. Zhou, W. H. Rao, M. H.
Zeng, Y. J. Liu, Chem. Commun. 2018, 54, 14136-14139.
2
Gamblin, E. M. Scanlan, B. G. Davis, Chem. Rev. 2009, 109, 131-163; j)
C. R. Bertozzi, L. L. Kiessling, Science 2001, 291, 2357-2364; k) G. J.
Mcgarvey, T. E. Benedum, F. W. Schmidtmann, Org. Lett. 2002, 4,
3
591-3594; l) O. Seitz, Chembiochem 2000, 1, 214-246. m) H. Herzner,
[9] a) K. Yang, Q. Li, Y. B. Liu, G. G. Li, H. B. Ge, J. Am. Chem. Soc. 2016,
138, 12775-12778. b) B. Wang, C. X. Lu, S. Y. Zhang, G. He, W. A.
Nack, G. Chen, Org. Lett. 2014, 16, 6260-6263.
T. Reipen, M. Schultz, H. Kunz, Chem. Rev. 2000, 100, 4495-4538.
[
4] a) H. G. Gong, R. Sinisi, M. R. Gagne, J. Am. Chem. Soc. 2007, 38,
1
908-1909; b) H. G. Gong, M. R. Gagne, J. Am. Chem. Soc. 2010, 40,
[10] a) B. V. S. Reddy, L. R. Reddy, E. J. Corey, Org. Lett. 2006, 8, 3391-
3394. b) L. D. Tran, O. Daugulis, Angew. Chem. Int. Ed. 2012, 51, 5188-
5191. c) X. S. Wu, K. Yang, Y. Zhao, H. Sun, G. G. Li, H. B. Ge, Nature
Comm., 2015, 6, 6462-6472.
12177-12183; c) L. Nicolas, P. Angibaud, I. Stansfield, P. Bonnet, L.
Meerpoel, S. Reymond, Angew. Chem. Int. Ed. 2012, 51, 11101-11104;
d) F. Zhu, M. J. Rourke, T. Yang, J. Rodriguez, J. Am. Chem. Soc. 2016,
1
38, 12049-12052; e) F. Zhu, J. Rodriguez, T. Yang, I. Kevlishvili, E.
Miller, D. Yi, S. O'Neill, M. Rourke, P. Liu, J. Am. Chem. Soc. 2017, 139,
7908-17922; f) L. Adak, S. Kawamura, G. Toma, T. Takenaka, K.
1
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[
a,b,c]
[b,c]
Yichu Liu,
Yibing Wang, Wenhao
Dai,[ Wei Huang,
b,c]
[b,c]
Yingxia Li* and
[a]
Hong Liu*[
b,c]
Page No. – Page No.
3
Palladium-Catalysed C(sp )-H
Glycosylation for Synthesis of C-
Alkyl Glycoamino Acids
3
This work initially presents a general strategy for C-alkyl glycosides synthesis via C(sp )-H
activation which will advance the state-of-the-art technique in carbohydrate chemistry.
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.