Stereoselective Synthesis of C-Vinyl Glycosides via Palladium-Catalyzed C?H Glycosylation of Alkenes

Article abstract of DOI:10.1002/anie.202104430

C-vinyl glycosides are an important class of carbohydrates and pose a unique synthetic challenge. A new strategy has been developed for stereoselective synthesis of C-vinyl glycosides via Pd-catalyzed directed C?H glycosylation of alkenes with glycosyl chloride donors using an easily removable bidentate auxiliary. Both the γ C?H bond of allylamines and the δ C?H bond of homoallyl amine substrates can be glycosylated in high efficiency and with excellent regio- and stereoselectivity. The resulting C-vinyl glycosides can be further converted to a variety of C-alkyl glycosides with high stereospecificity. These reactions offer a broadly applicable method to streamline the synthesis of complex C-vinyl glycosides from easily accessible starting materials.

Full text of DOI:10.1002/anie.202104430

Angewandte
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How to cite:
International Edition: doi.org/10.1002/anie.202104430
German Edition: doi.org/10.1002/ange.202104430
Synthetic Methods Hot Paper
Stereoselective Synthesis of C-Vinyl Glycosides via Palladium-
À
Catalyzed C H Glycosylation of Alkenes
Qikai Sun, Huixing Zhang, Quanquan Wang, Tianjiao Qiao, Gang He,* and Gong Chen*
Dedicated to Professor Christian Bruneau
Abstract: C-vinyl glycosides are an important class of
carbohydrates and pose a unique synthetic challenge. A new
strategy has been developed for stereoselective synthesis of C-
vinyl glycosides via Pd-catalyzed directed CÀH glycosylation
of alkenes with glycosyl chloride donors using an easily
removable bidentate auxiliary. Both the g CÀH bond of
allylamines and the d CÀH bond of homoallyl amine substrates
can be glycosylated in high efficiency and with excellent regio-
and stereoselectivity. The resulting C-vinyl glycosides can be
further converted to a variety of C-alkyl glycosides with high
stereospecificity. These reactions offer a broadly applicable
method to streamline the synthesis of complex C-vinyl glyco-
sides from easily accessible starting materials.
C
-vinyl glycoside motifs are found in many natural products
and frequently used as mimics of O-glycosides in the design of
[1–4]
glyco therapeutic agents (Scheme 1A).
In addition to the
higher metabolic stability over O-glycosides, the alkene
linkages can enable unique structural tuning in the glycomi-
metic design. While considerable progress has been made for
[
3,4]
the synthesis of C-aryl glycosides over the past decade,
synthesis of C-vinyl glycosides is more challenging and
the
[5,6]
remains under-developed. Metal-catalyzed cross coupling
strategies have enjoyed the most success in constructing the
C-vinyl glycosidic bonds (Scheme 1B). Notably, Cossy
[
6]
reported a cobalt-catalyzed coupling of glycosyl bromides
[
6a]
and vinyl Grignard reagents.
catalyzed reductive coupling of glycosyl bromides and vinyl
Gong reported a nickel-
[
6b]
chlorides using zinc reductant.
More recently, Liang
reported a palladium-catalyzed radical-mediated Heck cou-
pling of glycosyl bromides and aryl olefins under visible light
[6c]
irradiated conditions. Glycosyl radical intermediates were
invoked in the all above reaction systems. While useful, the
requirement of pre-functionalized or aryl-activated olefin
coupling partners limits synthetic utility. Recently, we devel-
oped a Pd-catalyzed ortho-directed CÀH glycosylation of
Scheme 1. Structure and synthesis of C-vinyl glycosides.
expand this Pd-catalyzed CÀH glycosylation strategy to
arenes and heteroarenes with glycosyl chloride donors to
construct various C-vinyl glycosides from readily accessible
[
7]
[8–10]
construct C-aryl glycosidic bonds (Scheme 1C). Herein, we
alkene substrates using an easily removable auxiliary.
The
method can glycosylate both g and d CÀH bond of unac-
[
*] Q. Sun, H. Zhang, Q. Wang, T. Qiao, Prof. Dr. G. He,
Prof. Dr. G. Chen
State Key Laboratory and Institute of Elemento-Organic Chemistry,
College of Chemistry, Nankai University
Tianjin 300071 (China)
tivated alkenes in high efficiency and with excellent regio-
and stereoselectivity. Unlike the products from the ortho
CÀH glycosylation of arenes, the resulting C-vinyl glycosides
can be easily converted to a variety of C-alkyl glycosides in
high stereospecificity.
E-mail: hegang@nankai.edu.cn
Metal-catalyzed directed CÀH functionalization of
gongchen@nankai.edu.cn
alkenes has recently emerged as an effective strategy to
synthesize complex alkenes from easily accessible precur-
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202104430.
[
11–14]
sors.
Bidentate directing groups have unique ability to
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harness the reactivity of higher valent metal intermediates to
optimized conditions of 10 mol% of Pd(OAc) , 1.5 equiv of
2
[
15–17]
form challenging chemical bonds.
In comparison to
K CO , and 30 mol% of Boc protected valeric acid (Boc-Ava-
2
3
arenes, the p reactivity of alkene substrates might more
strongly interfere with the CÀH cleavage process, posing
OH, a7) as additive in dioxane at 1108C for 12 hours gave the
desired product 3 in 85% isolated yield and with exclusive
a diastereoselectivity and cis stereoselectivity (entry 1). NMR
analysis showed compound 3 adopts a C1 conformation.
Compounds 4 and 5 were obtained as the byproducts of 2
a challenge to reaction development. Encouraged by the
success of Pd-catalyzed aryl CÀH glycosylation and the recent
advance of Pd-catalyzed directed CÀH functionalization of
4
alkenes, we wondered whether these chemistries could be
which was used in excess. Use of other solvents including 1,2-
merged to provide a useful method to synthesize C-vinyl
dichloroethane (DCE), CH CN and tetrahydrofuran (THF)
3
[
13]
glycosides. As shown in Table 1, we were pleased to find the
reaction of model substrate 3-ethyl vinylamine 1 bearing an
amide linked isoquinolic acid (iQA) auxiliary with tetraben-
zyl protected mannosyl chloride donor 2 (2.0 equiv) under the
gave considerably lower yield (entries 2–4). Replacement of
K CO3 with Na CO3 or Ag CO3 caused lower reactivity
2
2
2
(entries 5, 6). Reaction at 808C gave lower conversion of
1 (entry 8). Notably, the reaction with 5 mol% of Pd catalyst
on 1 mmol scale gave 2 in 92% isolated yield (entry 17). In
comparison with iQA, the use of picolinic acid (PA) and other
structural analogs gave considerably lower yields (entries 12–
14). No product was formed when benzamide was used as the
directing group (entry 15). The choice of carboxylic acid
Table 1: Optimization of the Pd-catalyzed C
ÀH glycosylation of allyl-
amine 1 with mannosyl chloride donor 2.
[18]
additive is also important to the reaction.
Screening of
various alkyl, aryl carboxylic acids and a-amino acids showed
that linear carbamate-protected aliphatic acids with four to
five methylene units gave the optimal results.
We next examined the scope of allylamines using their
reactions with mannosyl chloride 2 under the optimized
reaction conditions A (Scheme 2A). It was worth noting that
excellent diastereoselectivity was observed in all successful
reactions. Allylamines bearing various b-alkyl substituents
worked well, giving the desired tri-substituted C-vinyl glyco-
side (3–9) in good to high yields and with exclusive Z-
[
a]
Entry
Change from standard conditions
Yield of 3 [%]
[
b]
1
2
3
4
5
6
7
8
9
No change
DCE as solvent
91 (85 )
25
[19]
CH CN as solvent
22
56
54
50
79
42
ND
45
62
stereoselectivity.
b-Aryl-substituted allylamines (10, 13)
3
THF as solvent
also showed excellent reactivity. In contrast, allylamines
without b-substituents (e.g. 16) gave little desired product
under various reaction conditions. We suspect unsubstituted
alkenes can form stronger p complexes with Pd, hampering
the CÀH palladation process. As seen in 12 (vs. 7), allylamines
K CO replaced with Na CO
2
3
2
3
K CO replaced with Ag CO
2
3
2
3
1.5 equiv of 2
808C
Without Pd
bearing a-substituents showed lower reactivity. The yield of
12 can be improved to 75% using 20 mol% of Pd catalyst
(conditions B). Cyclene substrates (e.g. 11, 14) worked well to
give the tetra-substituted cyclic alkene products. Notably,
acyclic tetra-substituted alkene product 15 can also be
obtained in moderate yield from the corresponding acyclic
tri-substituted allylamines. The yield of 15 was improved
under conditions C in which Boc-Ava-OH additive was
replaced with PivOH. In general, Boc-Ava-OH additive is
10
11
12
13
14
15
16
17
18
No additive added
PdCl as cat
2
iQA is replaced with PA
44
53
38
iQA is replaced with i QA
3
iQA is replaced with QA
iQA is replaced with Bz
5 mol% of Pd (0.1 mmol scale)
5 mol% of Pd, 24 h (1 mmol scale)
2 mol% of Pd, 24 h (1 mmol scale)
ND
78
[
b]
92
70
[
b]
more effective than PivOH in this g CÀH glycosylation. Tetra-
1
substituted alkene products 11, 14, and 15 all adopt a C
4
conformation. As shown in Scheme 2B and C, both furanosyl
and pyranosyl chloride donors can react with allylamine
substrates to give the corresponding C-vinyl glycosides in
good to excellent yields and with excellent stereoselectivity.
Most of the glycosyl chloride donors were prepared in high
a diastereoselectivity (a/b > 20:1), except for a 16:1 selectiv-
ity fora 5:1 selectivity for arabinose (see 23). Notably, ribosyl
chloride (see 18) was obtained in high b selectivity (a/b =
[20]
1
:16). All glycosylation reactions proceeded in a stereo-
retentive fashion, forming predominantly C-a-vinyl glyco-
sides except C-b-vinyl ribosides (see 18, 28). Overall,
mannose (17, 19), rhamnose (22, 24) and ribose (18, 28)
exhibited highest reactivity; glucose (21) and galactose (20)
1
[
a] Yields are based on H NMR analysis of the crude reaction mixture at
a 0.1 mmol scale. [b] Isolated yield. ND: not detected.
2
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were less reactive. Protecting groups such as benzyl, acetyl,
silyl ether and acetonide were well tolerated.
Following the success of g CÀH glycosylation of allyl-
amines, we investigated whether the more remote d CÀH
bond of homoallyamines can also be glycosylated via a 6-
[
13g–i]
membered palladacycle intermediate (Scheme 3).
2
Scheme 3. Pd-catalyzed d C(sp )ÀH glycosylation of homoallylic
amines. Isolated yield at a 0.1 mmol scale. <5% of the other
1
diastereomer was detected by H NMR or chromatographic analysis of
the reaction mixtures.
Gratifyingly, both 3-Me and 3-Ph substituted 3-butenylamines
reacted with mannose donor 2 to give the desired products in
excellent yields and with excellent stereoselectivity (30, 31)
under the standard conditions A. 3-butenylamine was glyco-
[
21]
sylated at the d position to give 32 in moderate yield.
Interestingly, using PivOH additive increased the yield of 32
to 73% (condition C). Overall, PivOH additive was more
effective for d CÀH glycosylation of homoallylamines (e.g.
2
Scheme 2. Pd-catalyzed g C(sp )ÀH glycosylation of allyl amines.
3
3). For unclear reasons, allylglycine bearing an a-CO Me
2
Isolated yield at a 0.1 mmol scale. The above reactions proceeded in
excellent diastereoselectivity; <5% of the other diastereomer was
detected by H NMR or chromatographic analysis of the reaction
mixture. a) An inseparable mixture of Z and E alkene starting material
was used. Z isomer was unconsumed. Yield was based on the E
isomer in starting material. b) The product was not isolated. c) About
0–40% of the alkene starting material was recovered. The stereo-
chemistry of representative C-vinyl glycosides was assigned by NMR
group did not give any desired product 35 under various
conditions (vs. 32). In comparison to mannopyranose donor 2,
other glycosyl donors such as rhamnose (34), arabinose (36),
ribose (37) and mannofuranose (38) showed lower reactivity
in the d CÀH glycosylation reactions.
1
3
These Pd-catalyzed iQA-directed vinyl CÀH glycosyla-
tion reactions with glycosyl chlorides likely follow a similar
pathway of the ortho-directed aryl CÀH glycosylation via the
sequence of CÀH palladation, oxidative addition (OA) and
analyses, see SI for details.
[
7]
reductive elimination (RE). As shown in Scheme 4A, Pd-
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As shown in Scheme 5, the iQA auxiliary of compound 3
was removed under mild conditions via treatment of Zn
[
22]
powder at rt to give free amine 41 in 77% yield. Treatment
of 3 with excess amount of anhydrous FeCl (8.0 equiv) in
3
Scheme 4. Mechanistic considerations.
catalyzed CÀH deuteration of 39 in CH CO D selectively
3
2
took place at the alkenyl CÀH bond, forming 40 in good yield
after three rounds of reaction. A kinetic isotope effect (KIE =
Scheme 5. Facile removal of iQA auxiliary and stereospecific conver-
sions of C-vinyl glycoside 3 to C-alkyl glycosides.
6
.0) for the reactions of 39 vs. 40 with 2 indicated that the CÀH
palladation is the rate-limiting step. As outlined in Sche-
me 4B, the CÀH glycosylation reaction starts with the iQA-
directed CÀH palladation of the alkene substrate I to form the
[
23]
DCM at rt gave debenzylated product 42 in good yield.
Hydroboration of 3 with BH THF followed by H O oxida-
palladacycle intermediate II. OA of mannosyl chloride donor
3
2
2
IV
2
to II gives the Pd intermediate III, which then gives the
tion gave 44 in 76% yield as a single diastereomer.
Epoxidation with meta-chloroperbenzoic acid (m-CPBA)
gave the epoxide product 45 as a single diastereomer.
Interestingly, treatment of 3 using a modified procedure of
Baranꢀs method with stoichiometric Fe(acac) and PhSiH
II
Pd -bound glycosylated product IV upon RE. The details of
the OA step have not been firmly established. Our previous
computational studies of the related Pd-catalyzed aryl CÀH
mannosylation system supported a concerted OA mechanism
3
3
[7b]
with the a mannosyl chloride donor. However, a stepwise
OA of a glycosyl oxocarbenium intermediate to II cannot be
ruled out. The stereochemical outcome of the glycosylation is
probably controlled by both steric and stereoelectronic effects
as both 1,2-trans (e.g. 3) and 1,2-cis (e.g. 20) configured
products can be formed in high selectivity for different
glycosyl donors. In comparison to aryl CÀH glycosylation, the
under air atmosphere gave the unexpected ketone product 43
[
24]
in high yield. We suspect that a FeÀH species first adds to
the alkene to generate an alkyl radical, which reacts with O
2
to give the ketone product following cleavages of the OÀO
and CÀC bonds.
In summary, we have developed a new method for
stereoselective synthesis of C-vinyl glycosides via Pd-cata-
lyzed CÀH glycosylation of unfunctionalized alkenes with
alkene moiety in both starting material and glycosylated
II
product might be able to form a p complex with Pd . Such
glycosyl chloride donors using an easily removable auxiliary.
The glycosyl groups can be installed on both g CÀH bond of
allylamines and d CÀH bond of homoallylamines in high
complexation could interfere with the CÀH palladation and
hamper the dissociation of Pd catalyst from the glycosylated
product (from IV to V). The role of carboxylic acid additives
is unclear at the moment. While their involvement in the CÀH
efficiency, regio- and stereoselectivity. Moreover, the result-
ing C-vinyl glycosides can be easily converted to various C-
alkyl glycosides with high stereospecificity. Overall, this CÀH
palladation step cannot be ruled out, they could also facilitate
II
the Pd dissociation from the product to speed up catalyst
glycosylation strategy provides a streamlined and versatile
[
18]
turnover.
method to synthesize a variety of C-vinyl and C-alkyl
4
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glycosides that can be difficult to access by other means from
readily available precursors.
Ed. 2012, 51, 11101 – 11104; Angew. Chem. 2012, 124, 11263 –
1266; b) J. Liu, H. Gong, Org. Lett. 2018, 20, 7991 – 7995; c) M.
Li, Y.-F. Qiu, C.-T. Wang, X.-S. Li, W.-X. Wei, Y.-Z. Wang, Q.-F.
1
Bao, Y.-N. Ding, W.-Y. Shi, Y.-M. Liang, Org. Lett. 2020, 22,
6
288 – 6293; d) L. Nicolas, E. Izquierdo, P. Angibaud, I. Stans-
field, L. Meerpoel, S. Reymond, J. Cossy, J. Org. Chem. 2013, 78,
1807 – 11814.
Acknowledgements
1
We thank NSFC-21725204, NSFC-22071119, “111” project
[7] a) Q. Wang, S. An, Z. Deng, W. Zhu, Z. Huang, G. He, G. Chen,
Nat. Catal. 2019, 2, 793 – 800; b) Q. Wang, Y. Fu, W. Zhu, S. An,
Q. Zhou, S.-F. Zhu, G. He, P. Liu, G. Chen, CCS Chem. 2020, 2,
(
B06005) of MOE China, and NCC2020FH02 for financial
support of this work.
1729 – 1736.
[
8] For recent reports on Pd-catalyzed CÀH glycosylation: a) W. Lv,
Y. Chen, S. Wen, D. Ba, G. Cheng, J. Am. Chem. Soc. 2020, 142,
Conflict of Interest
14864 – 14870; b) Y.-N. Ding, W.-Y. Shi, C. Liu, N. Zheng, M. Li,
Y. An, Z. Zhang, C.-T. Wang, B.-S. Zhang, Y.-M. Liang, J. Org.
Chem. 2020, 85, 11280 – 11296; c) J. Ghouilem, C. Tran, N.
Grimblat, P. Retailleau, M. Alami, V. Gandon, S. Messaoudi,
ACS Catal. 2021, 11, 1818 – 1826.
The authors declare no conflict of interest.
Keywords: alkene functionalization · auxiliary · CÀ
H glycosylation · C-vinyl glycoside · palladium
[
9] For reports on Pd-catalyzed CÀH functionalization to install
glycal motifs: a) M. Liu, Y. Niu, Y.-F. Wu, X.-S. Ye, Org. Lett.
2
016, 18, 1836 – 1839; b) Y. Liu, Y. Wang, W. Dai, W. Huang, Y.
Li, H. Liu, Angew. Chem. Int. Ed. 2020, 59, 3491; Angew. Chem.
020, 132, 3519; c) J. Wu, N. Kaplaneris, S. Ni, F. Kaltenhꢃuser, L.
Ackermann, Chem. Sci. 2020, 11, 6521 – 6526.
[
1] a) D. E. Levy, C. Tang, The Chemistry of C-Glycosides, Elsevier,
Oxford, 1995; b) T. Bililign, B. R. Griffith, J. S. Thorson, Nat.
Prod. Rep. 2005, 22, 742 – 760.
2
[
10] For selected examples of CÀH functionalization of carbohydrate
substrates: a) T. G. Frihed, M. Bols, C. M. Pedersen, Eur. J. Org.
Chem. 2016, 2740 – 2756; b) N. Probst, G. Grelier, N. Gherman,
V. Gandon, M. Alami, S. Messaoudi, Org. Lett. 2017, 19, 5038 –
[
2] For selected reviews on synthesis of C-glycosides: a) Y. Yang, B.
Yu, Chem. Rev. 2017, 117, 12281 – 12356; b) K. Kitamura, Y.
Ando, T. Matsumoto, K. Suzuki, Chem. Rev. 2018, 118, 1495 –
1
2
2
598; c) H. Liao, J. Ma, H. Yao, X.-W. Liu, Org. Biomol. Chem.
018, 16, 1791 – 1806; d) M. J. McKay, H. M. Nguyen, ACS Catal.
012, 2, 1563 – 1595; e) L.-Y. Xu, N.-L. Fan, X.-G. Hu, Org.
5041; c) N. Probst, G. Grelier, S. Dahaoui, M. Alami, V. Gandon,
S. Messaoudi, ACS Catal. 2018, 8, 7781 – 7786; d) W. Wang, P.
Subramanian, O. Martinazzoli, J. Wu, L. Ackermann, Chem.
Eur. J. 2019, 25, 10585 – 10589.
Biomol. Chem. 2020, 18, 5095 – 5109.
[
3] For selected examples of synthesis of C-aryl glycosides: a) H.
Gong, M. R. Gagne, J. Am. Chem. Soc. 2008, 130, 12177 – 12183;
b) F. Zhu, M. J. Rourke, T. Yang, J. Rodriguez, M. A. Walczak, J.
Am. Chem. Soc. 2016, 138, 12049 – 12052; c) F. Zhu, J. Rodri-
guez, T. Yang, I. Kevlishvili, E. Miller, D. Yi, S. OꢀNeill, M. J.
Rourke, P. Liu, M. A. Walczak, J. Am. Chem. Soc. 2017, 139,
[
11] For selected reviews on Pd-catalyzed directed CÀH functional-
ization: a) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110,
1
147 – 1169; b) X. Chen, K. M. Engle, D.-H. Wang, J.-Q. Yu,
Angew. Chem. Int. Ed. 2009, 48, 5094 – 5115; Angew. Chem.
009, 121, 5196 – 5217.
2
[
12] For selected reviews on directed CÀH functionalization of
17908 – 17922; d) L. Adak, S. Kawamura, G. Toma, T. Takenaka,
alkenes: a) K. Wang, F. Hu, Y. Zhang, J. Wang, Sci. China Chem.
K. Isozaki, H. Takaya, A. Orita, H. C. Li, T. K. M. Shing, M.
Nakamura, J. Am. Chem. Soc. 2017, 139, 10693 – 10701; e) C.
Zhao, X. Jia, X. Wang, H. Gong, J. Am. Chem. Soc. 2014, 136,
2
2
015, 58, 1252 – 1265; b) M. Maraswami, T.-P. Loh, Synthesis
019, 51, 1049 – 1062; c) B. Liu, L. Yang, P. Li, F. Wang, X. Li,
Org. Chem. Front. 2021, 8, 1085 – 1101; d) J. Zhang, X. Lu, C.
Shen, L. Xu, L. Ding, G. Zhong, Chem. Soc. Rev. 2021, 50, 3263 –
17645 – 17651; f) Y. Dai, B. Tian, H. Chen, Q. Zhang, ACS Catal.
2019, 9, 2909 – 2915; g) Q. Wang, J. Duan, P. Tang, G. Chen, G.
3314.
He, Sci. China Chem. 2020, 63, 1613 – 1618; h) Y. Wei, B. Ben-
zvi, T. Diao, Angew. Chem. Int. Ed. 2021, 60, 9433 – 9438; Angew.
Chem. 2021, 133, 9519 – 9524.
[
13] For selected examples of bidentate auxiliary directed CÀH
functionalization of alkenes: a) C. Wang, L. Zhang, C. Chen, J.
Han, Y. Yao, Y. Zhao, Chem. Sci. 2015, 6, 4610 – 4614; b) Z.-L.
Zang, S. Zhao, S. Karnakanti, C.-L. Liu, P.-L. Shao, Y. He, Org.
Lett. 2016, 18, 5014 – 5017; c) H. M.-F. Viart, A. Bachmann, W.
Kayitare, R. Sarpong, J. Am. Chem. Soc. 2017, 139, 1325 – 1329;
d) R. Parella, S. A. Babu, J. Org. Chem. 2017, 82, 6550 – 6567;
e) M. Liu, P. Yang, M. K. Karunananda, Y. Wang, P. Liu, K. M.
Engle, J. Am. Chem. Soc. 2018, 140, 5805 – 5813; f) Y.-C. Luo, C.
Yang, S.-Q. Qiu, Q.-J. Liang, Y.-H. Xu, T.-P. Loh, ACS Catal.
2019, 9, 4271 – 4276; g) C. Shen, X. Lu, J. Zhang, L. Ding, Y. Sun,
G. Zhong, Chem. Commun. 2019, 55, 13582 – 13585; h) B. S.
Schreib, E. M. Carreira, J. Am. Chem. Soc. 2019, 141, 8758 –
8763; i) B. S. Schreib, M. Fadel, E. M. Carreira, Angew. Chem.
Int. Ed. 2020, 59, 7818 – 7822; Angew. Chem. 2020, 132, 7892 –
7896.
[14] For other selected reports on vinyl CÀH functionalization:
a) D. A. Colby, R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc.
2008, 130, 3645 – 3651; b) H. Zhou, Y.-H. Xu, W.-J. Chung, T.-P.
Loh, Angew. Chem. Int. Ed. 2009, 48, 5355 – 5357; Angew. Chem.
2009, 121, 5459 – 5461; c) I. S. Hassan, A. N. Ta, M. W. Danne-
man, N. Semakul, M. Burns, C. H. Basch, V. N. Dippon, B. R.
McNaughton, T. Rovis, J. Am. Chem. Soc. 2019, 141, 4815 – 4819;
[
4] For selected recent reports on synthesis of C-alkyl glycosides:
a) J. Zeng, J. Ma, S. Xiang, S. Cai, X.-W. Liu, Angew. Chem. Int.
Ed. 2013, 52, 5134 – 5137; Angew. Chem. 2013, 125, 5238 – 5241;
b) W. Shang, S.-N. Su, R. Shi, Z.-D. Mou, G.-Q. Yu, X. Zhang, D.
Niu, Angew. Chem. Int. Ed. 2021, 60, 385 – 390; Angew. Chem.
2021, 133, 389 – 394.
[
5] For selected reports on synthesis of C-vinyl glycosides: a) G.
Stork, H. S. Suh, G. Kim, J. Am. Chem. Soc. 1991, 113, 7054 –
7056; b) D. Mazꢁas, T. Skrydstrup, O. Doumeix, J.-M. Beau,
Angew. Chem. Int. Ed. Engl. 1994, 33, 1383 – 1386; Angew.
Chem. 1994, 106, 1457 – 1459; c) P. Wipf, J. G. Pierce, N. Zhuang,
Org. Lett. 2005, 7, 483 – 485; d) D. C. Koester, E. Kriemen, D. B.
Werz, Angew. Chem. Int. Ed. 2013, 52, 2985 – 2989; Angew.
Chem. 2013, 125, 3059 – 3063; e) J. Ling, C. S. Bennett, Angew.
Chem. Int. Ed. 2020, 59, 4304 – 4308; Angew. Chem. 2020, 132,
4
334 – 4338; f) G. J. Boehlich, N. Schꢂtzenmeister, Angew.
Chem. Int. Ed. 2019, 58, 5110 – 5113; Angew. Chem. 2019, 131,
164 – 5167.
5
[
6] For selected reports on cross-coupling enabled synthesis of C-
vinyl glycosides: a) L. Nicolas, P. Angibaud, I. Stansfield, P.
Bonnet, L. Meerpoel, S. Reymond, J. Cossy, Angew. Chem. Int.
Angew. Chem. Int. Ed. 2021, 60, 1 – 7
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Angewandte
Communications
Chemie
d) Z. Wu, N. Fatuzzo, G. Dong, J. Am. Chem. Soc. 2020, 142,
715 – 2720.
in Pd-catalyzed CÀH reactions: K. M. Engle, D.-H. Wang, J.-Q.
2
Yu, J. Am. Chem. Soc. 2010, 132, 14137 – 14151.
[
15] For selected reviews on bidentate auxiliaries for metal-catalyzed
[19] We suspect that non-productive CÀH palladation of the g allylic
CÀH functionalization: a) O. Daugulis, H.-Q. Do, D. Shabashov,
methyl group of the alkene substrate of 6 might interfere with
the desired g vinyl CÀH glycosylation process.
Acc. Chem. Res. 2009, 42, 1074 – 1086; b) G. Rouquet, N.
Chatani, Angew. Chem. Int. Ed. 2013, 52, 11726 – 11743;
Angew. Chem. 2013, 125, 11942 – 11959; c) G. He, B. Wang,
W. A. Nack, G. Chen, Acc. Chem. Res. 2016, 49, 635 – 645; d) C.
Sambiagio, D. Schçnbauer, R. Blieck, T. Dao-Huy, G. Pototsch-
nig, P. Schaaf, T. Wiesinger, M. F. Zia, J. Wencel-Delord, T.
Besset, B. U. W. Maes, M. Schnꢂrch, Chem. Soc. Rev. 2018, 47,
[20] We greatly appreciated that one of the reviewers pointed out the
unique stereochemical properties of ribosyl chloride donor. Also
see: C. S. Wilcox, R. Otoski, Tetrahedron Lett. 1986, 27, 1011 –
1014. All chloride donors were purified by silica gel chromatog-
raphy before use. The two diastereomers were not separated.
[21] Both the g and d vinyl CÀH bonds of homoallyl starting material
6
603 – 6743.
16] a) V. G. Zaitsev, D. Shabashov, O. Daugulis, J. Am. Chem. Soc.
005, 127, 13154 – 13155; b) D. Shabashov, O. Daugulis, J. Am.
of 32 can be deuterated with CH CO D under Pd-catalyzed
3
2
[
conditions. We suspect a g palladacycle intermediate of the
homoallyl substrate can be generated under our glycosylation
conditions. However, it reverses back to starting material as its
subsequent functionalization with glycosyl partner might be
more difficult.
2
Chem. Soc. 2010, 132, 3965 – 3972.
[
17] For selected studies of bidentate auxiliaries for Pd-catalyzed CÀ
H functionalization: a) Y. Feng, G. Chen, Angew. Chem. Int. Ed.
2
010, 49, 958 – 961; Angew. Chem. 2010, 122, 970 – 973; b) G. He,
[22] D. H. OꢀDonovan, C. D. Fusco, D. R. Spring, Tetrahedron Lett.
2016, 57, 2962 – 2964.
[23] R. Rodebaugh, J. S. Debenham, B. Fraser-Reid, Tetrahedron
Lett. 1996, 37, 5477 – 5478.
[24] J. C. Lo, J. Gui, Y. Yabe, C.-M. Pan, P. S. Baran, Nature 2014, 516,
343 – 348.
G. Chen, Angew. Chem. Int. Ed. 2011, 50, 5192 – 5196; Angew.
Chem. 2011, 123, 5298 – 5302; c) B. Li, X. Li, B. Han, Z. Chen, X.
Zhang, G. He, G. Chen, J. Am. Chem. Soc. 2019, 141, 9401 – 9407;
d) B.-B. Zhan, Y. Li, J.-W. Xu, X.-L. Nie, J. Fan, L. Jin, B.-F. Shi,
Angew. Chem. Int. Ed. 2018, 57, 5858 – 5862; Angew. Chem.
2018, 130, 5960 – 5964; e) J.-W. Xu, Z.-Z. Zhang, W.-H. Rao, B.-
F. Shi, J. Am. Chem. Soc. 2016, 138, 10750 – 10753; f) L. Ju, J.
Yao, Z. Wu, Z. Liu, Y. Zhang, J. Org. Chem. Soc. 2013, 78,
10821 – 10831.
Manuscript received: March 30, 2021
[
18] Chelation of Pd via both BocNH and CO H groups might be
Revised manuscript received: May 22, 2021
Accepted manuscript online: July 6, 2021
Version of record online: && &&, &&&&
2
important to achieve the optimal promoting effect of this amino
acid additive. For a representative example of amino acid ligands
6
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Angewandte
Communications
Chemie
Communications
Synthetic Methods
Q. Sun, H. Zhang, Q. Wang, T. Qiao,
G. He,* G. Chen*
&&&& — &&&&
Stereoselective Synthesis of C-Vinyl
Glycosides via Palladium-Catalyzed CÀH
A new strategy has been developed for
stereoselective synthesis of C-vinyl gly-
cosides via Pd-catalyzed directed CÀH
glycosylation of alkenes with glycosyl
chloride donors using an easily remov-
able bidentate auxiliary.
Glycosylation of Alkenes
Angew. Chem. Int. Ed. 2021, 60, 1 – 7
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7
These are not the final page numbers!