Ligand-Controlled Monoselective C-Aryl Glycoside Synthesis via Palladium-Catalyzed C-H Functionalization of N-Quinolyl Benzamides with 1-Iodoglycals

Article abstract of DOI:10.1021/acs.orglett.6b00566

A monoselective synthesis of aryl-C-Δ^1,2-glycosides from 1-iodoglycals via palladium-catalyzed ortho-C-H activation of N-quinolyl benzamides has been developed. An amino acid derivative was used as a crucial ligand to improve the yield and mono

Full text of DOI:10.1021/acs.orglett.6b00566

Letter
pubs.acs.org/OrgLett
Ligand-Controlled Monoselective C‑Aryl Glycoside Synthesis via
Palladium-Catalyzed C−H Functionalization of N‑Quinolyl
Benzamides with 1‑Iodoglycals
Minglong Liu,† Youhong Niu,† Yan-Fen Wu,* and Xin-Shan Ye*
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Road No.
38, Beijing 100191, China
S
* Supporting Information
ABSTRACT: A monoselective synthesis of aryl-C-Δ1,2-glycosides from 1-iodoglycals
via palladium-catalyzed ortho-C−H activation of N-quinolyl benzamides has been
developed. An amino acid derivative was used as a crucial ligand to improve the yield
and monoselectivity of the coupling reaction. The utility of this protocol was
demonstrated by a concise synthesis of key moieties of some natural products.
-Glycosides are important carbohydrate congeners of O-
glycosides that are stable to hydrolytic or enzymatic
cleavage. C-Aryl glycosides belong to a subclass of C-glycosides.
This subclass of sugar derivatives contains vital motifs of a
number of biologically active natural products and medicinally
valuable compounds with antidiabetic, antibacterial, and
antitumor activities (Figure 1).1 C-Aryl glycals are particularly
Scheme 1. Synthesis of Glycals and C-Glycosides
C
Figure 1. Some bioactive natural products and drugs.
methods for the synthesis of C-aryl glycosides is still of great
significance.
Transition-metal-catalyzed, directing-group-mediated C−H
functionalization has emerged as a powerful method for the
construction of organic molecules in the last two decades.7
Among these transformations, Pd-catalyzed C(sp2)−H activa-
tion, in combination with its subsequent cross-coupling reaction
with simple alkynes, alkenes, allenes, arenes, and heteroatoms,7e,8
has generated many aromatic compounds with different
scaffolds. In particular, C−H activation of aromatic acids and
their derivatives followed by modification with aryl iodides9 or
alkenyl iodides10 provides a reliable approach to synthesizing
biphenyl or vinylbenzene derivatives. Given these reports, we
useful synthons for the construction of different sugar moieties
because the 1,2-double bond can be further transformed into
various functionalities.
Various cross-coupling reactions are employed for the
synthesis of C-aryl glycals and glycosides. General methods
include the use of coupling of glycals with aryl halides,2 coupling
of C1-stannylated or boronated glycals with aryl halides,3
coupling of glycals with boronic acids or carboxylic acids,4
coupling reactions between glycal derivatives and organometallic
reagents,5 and Negishi coupling reactions between glycosyl
halides and organozinc reagents (Scheme 1).6 In most cases,
both reactants have to be preactivated, and one of them has to be
an organometallic reagent. Therefore, the development of more
straightforward, atom-economic, and environmentally benign
Received: February 29, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00566
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Letter
envisioned that a direct C−H functionalization of benzoic acid
derivatives might be possible with 1-iodoglycals, though 1-
iodoglycals are much more complicated substrates than simple
aryl and alkenyl iodides. Herein, we report the synthesis of aryl-
C-Δ1,2-glycosides by Pd-catalyzed, N-quinolyl-group-directed
ortho-C−H functionalization of benzoic acid derivatives with 1-
iodoglycals.11
product in high yield and with good selectivity, the effect of base
was investigated. Some inorganic bases such as K2CO3, Na2CO3,
and NaHCO3 (entries 2−4) were tried, and it was found that the
addition of NaHCO3 increased the ratio of 4a to 4aa despite the
low yield of 4a, which might result from the poor solubility of
NaHCO3 in toluene. After testing several solvents, we found that
when the reaction was conducted in the mixed solvent t-
AmylOH/H2O (10:1), the yield of desired product 4a was
doubled and the ratio of 4a to 4aa was maintained at 4:1.
Previously, Yu’s and Chen’s work13,14 showed that the use of
ligands could increase the monoselectivity of the reactions.
Inspired by these results, we turned our attention to ligand
screening. 2,2′-Dipyridyl (L1) as a ligand was tested. However,
the addition of L1 hindered the reaction, and no products were
detected. Following a literature report,14 when phosphonic acids
(L2, L3, entries 7 and 8, Table 1) were used, both the overall yield
and the monoselectivity of desired product were improved.
These results indicated that the use of ligands would truly benefit
the reaction. So, we next screened several protected amino acid
ligands (L4−L10, entries 9−15). It was found that the L-proline
derivative L5 was the most effective ligand, leading to the
formation of product 4a in 83% yield and with more than 8:1
selectivity of 4a/4aa.
Initially, the reaction of N-quinolyl benzamide (4)12 and
triisopropylsilyl-protected 1-iodoglucal 111 was chosen as the
model reaction to optimize the reaction conditions; the results
are summarized in Table 1. When a mixture of compounds 1 and
4 was treated with Pd(OAc)2 (10 mol %) and AgOAc (2 equiv)
in toluene at 100 °C, the monoglycosylated product 4a and
diglycosylated product 4aa were produced in 14 and 47% yields,
respectively (entry 1). To obtain the desired monoglycosylated
a
Table 1. Optimization of the Reaction Conditions
Having the optimized reaction conditions in hand, we
evaluated the generality of our method for synthesizing C-aryl
glycosides by using various substrates, including different glycals
and N-quinolyl benzamides. The results are shown in Chart 1.
When the glucal derivative 1 was used, the reaction of the
unsubstituted N-quinolyl benzamide (4) worked well and the
reactions of substituted N-quinolyl benzamides bearing either
electron-donating groups such as Me, t-Bu, MeO, and di-MeO
functionalities or electron-withdrawing groups such as F, Cl, Br,
CF3, and NO2 functionalities proceeded smoothly, furnishing the
desired products 4a−17a in moderate to excellent yields and
with good selectivity. Halo groups, especially the bromo group,
were compatible with the reaction conditions. In addition,
different substituents at the ortho-, meta-, or para-positions of the
quinolyl benzamides had little influence on the reaction
outcomes. 1-Naphthalene-derived amide and other heterocyclic
amides as substrates also worked well (the formation of 18a−
21a). Besides the glucal 1, the reactions of glycals 2 and 3 from
galactose and rhamnose with different quinolyl benzamides were
examined. The coupling reactions of these two glycals with
benzamides provided the corresponding products in good yields
and with high mono/di ratios (the formation of 4b, 5b, 16b, 4c,
9c, 11c). To further investigate the practical utility of this
protocol, the gram-scale preparation of 16a from 1 was realized
in yields up to 93% under the optimized reaction conditions.
After validating this method, we tried to deprotect the N-quinolyl
directing group and synthesize the C-aryl glycoside derivatives
through modifications of the double bond on the sugar ring and
the amide bond of the N-quinolyl benzamide moiety. Because of
the instability of the silyl group under strong basic and acidic
conditions and poor solubility of aryl-C-Δ1,2-glycosides in the
protic solvents, we failed to convert the amide products to the
corresponding acids or esters by using various conditions such as
acids and bases in different solvent systems.
The N-quinolyl benzamide was then transformed into the
hydroxymethyl group by sequential reductions with Schwartz’s
reagent15 and NaCNBH3. The amide was first reduced to the
aldehyde which was prone to degradation during the purification
process. So the aldehyde was either directly treated with
triphenylphosphonium benzylide to furnish the stilbene-
a
Unless specified, a solution of 4 (0.04 mmol), 1 (0.08 mmol), and the
catalyst (0.004 mmol) in t-AmylOH/H2O (0.20 M) was heated at 100
°C for 10 h. Yields are based on 1H NMR analysis of the crude
reaction mixture, using dibromomethane as an internal standard. A = t-
AmylOH, H = H2O.
B
DOI: 10.1021/acs.orglett.6b00566
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a
Chart 1. Scope of the Coupling Reactions
Scheme 2. Further Transformations of the Coupled Product
24 was obtained in 80% yield. (2) The epoxidation of 22 using
oxone in acetone and subsequent in situ ring opening of the
epoxide by the hydroxyl group provided the spiro-cyclization
product 25 of the papulacandin skeleton in good yield. (3)
Treatment of 22 with p-TsOH·H2O in CH2Cl2 at room
temperature furnished two spirocyclic isomers 26 and 27 in
one step (Scheme 2).3d,17 It should be mentioned that the
stereochemistry of products 25, 26, and 27 was confirmed by
NMR analysis (NOESY studies, Figure 2).18
Figure 2. NOESY correlations (red arrows) of compounds 25, 26, and
27.
On the basis of our results and previous reports,8a,14,19
a
plausible C−H activation mechanism is proposed in Scheme 3. 1-
Scheme 3. Proposed Mechanism
a
All reactions were carried out on a 0.04 mmol scale, unless specified;
isolated yields were given; ratios (mono- versus diglycosylation) were
b
1
determined by H NMR. Reaction was conducted in 0.10 mmol.
c
d
e
CH2Cl2 as solvent. Reaction was conducted in 1.0 mmol. K2CO3 (2
equiv) was used. CH2Cl2 as solvent and 20 mol % of Pd(OAc)2 as
catalyst.
f
Iodoglycal undergoes oxidative addition (OA), which is
supposed to be the rate-determining step of C−H functionaliza-
tion,20 to give a palladacycle intermediate, generated from the Pd
coordination with AQ and insertion between carbon and
hydrogen atoms. In our method, amino acid ligands probably
coordinate to the palladacycle, which decreases the reaction rate
of the first OA and makes the second OA more difficult (time
course, Figure S1 in the Supporting Information), leading to the
high monoselectivity and good yields of the coupled products.
Limiting the amount of NaHCO3 was also important for
achieving high monoselectivity and high yield.
containing C-glycoside 2316 in 70% yield or further reduced in
situ to the hydroxymethyl-containing compound 22 in 68%
overall yield (Scheme 2).
Starting from compound 22, three transformations were
effected as follows: (1) When the unsaturated compound 22 was
subjected to hydrogenation under a H2 atmosphere in the
presence of Pd/C, the corresponding 2-deoxy-β-C-aryl glycoside
C
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Letter
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In summary, we have developed a method for the
monoselective synthesis of aryl-C-Δ1,2-glycosides via Pd-
catalyzed C−H functionalization of N-quinolyl benzamides
with different types of 1-iodoglycals in a straightforward, atom-
economic, and environmentally friendly manner. The mono-
selectivity of the glycosylation products can be controlled by the
addition of amino acid ligands. The reaction can be scaled up, and
the protocol can be applied to synthesize natural product
derivatives of potential biological importance by simple trans-
formations. The preparation of new compounds with the
therapeutic potential by this protocol is currently underway in
our group.
ASSOCIATED CONTENT
■
S
* Supporting Information
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(12) We screened several other directing groups such as N-
(pivaloyloxy)benzamide, N-phenylpivalamide, N-methoxy benzamide,
benzoic acid derivative, picolinic acid derivative, and N-quinolyl
benzamide, and N-quinolyl benzamide was found to be the most
efficient directing group for the C−H activation and subsequent
glycosylation by TLC detection.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00566.
Experimental procedures and characterization data for all
new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wuyanfen@bjmu.edu.cn.
*E-mail: xinshan@bjmu.edu.cn.
Author Contributions
†M.L. and Y.N. contributed equally.
Notes
The authors declare no competing financial interest.
(13) Chan, K. S. L.; Wasa, M.; Chu, L.; Laforteza, B. N.; Miura, M.; Yu,
J. Q. Nat. Chem. 2014, 6, 146−150.
ACKNOWLEDGMENTS
■
This work was financially supported by grants (2012CB822100
and 2013CB910700) from the Ministry of Science and
Technology of China, and the National Natural Science
Foundation of China (Grant No. 21232002).
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