Highly stereoselective synthesis of aryl/heteroaryl-: C -nucleosides via the merger of photoredox and nickel catalysis

Article abstract of DOI:10.1039/c9cc07184a

A photoredox/nickel dual-catalyzed decarboxylative cross-coupling reaction of anomeric ribosyl/deoxyribosyl acids with aryl/heteroaryl bromides has been developed. The reaction proceeds smoothly under visible-light irradiation and features the using of cost-effective and easily handled catalysts and starting materials, which allows the highly stereoselective synthesis of diverse aryl/heteroaryl-C-nucleosides in moderate to high yields.

Full text of DOI:10.1039/c9cc07184a

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Highly stereoselective synthesis of aryl/
heteroaryl-C-nucleosides via the merger
of photoredox and nickel catalysis†
Cite this:DOI: 10.1039/c9cc07184a
Received 13th September 2019,
Accepted 13th November 2019
Yingying Ma,‡a Shihui Liu,‡b Yifan Xi,a Hongrui Li,a Kai Yang,a Zhihao Cheng,a
ac
a
Wei Wang
*
and Yongqiang Zhang
*
DOI: 10.1039/c9cc07184a
rsc.li/chemcomm
A photoredox/nickel dual-catalyzed decarboxylative cross-coupling
reaction of anomeric ribosyl/deoxyribosyl acids with aryl/heteroaryl
bromides has been developed. The reaction proceeds smoothly
under visible-light irradiation and features the using of cost-
effective and easily handled catalysts and starting materials, which
allows the highly stereoselective synthesis of diverse aryl/hetero-
aryl-C-nucleosides in moderate to high yields.
C-Nucleosides with aryl and heteroaryl groups as nucleobase
surrogates represent a class of promising antiviral and anti-
cancer agents and are extensively applied in chemical biology to
extend the genetic alphabet (see representative examples shown
in Fig. S1, ESI†).1,2
Scheme 1 Synthesis of C-nucleosides via nickel, cobalt or iron-catalyzed
radical cross-coupling approach.
The cross-coupling reaction enabled by low-cost and relatively
non-toxic transition-metal catalysts, such as nickel, cobalt or iron
catalyst, offers a powerful tool to access this class of valuable (64–84%, b:a 4 99 : 1).6 Nonetheless, this method suffers from the
targets (Scheme 1a). The transformations typically proceed via use of hazardous organometallic reagents and moisture-sensitive
anomeric radical intermediates and exhibit many advantages anomeric halides as the coupling partners. Moreover, low reaction
over the conventional methods based on the corresponding efficiency was typically observed in the synthesis of the medicinally
anions and cations: the reaction conditions are generally mild valuable electron-deficient aryl/heteroaryl-C-nucleosides.
so that varied functional and protecting groups are tolerated
To overcome these limitations, herein, we wish to report a
and undesired elimination and/or epimerization reactions are novel photoredox/nickel dual-catalyzed cross-coupling approach
suppressed.3 For example, the nickel- and cobalt-catalyzed for the highly stereoselective synthesis of both electron-rich
procedures have been reported for the synthesis of phenyl-C- and -deficient aryl/heteroaryl-C-nucleosides in moderate to high
nucleosides albeit with variable yields (20–88% yields) and yields (Scheme 1b). By utilizing an organic photocatalyst (4CzIPN)
limited substrate scope.4,5 Recently, a highly stereoselective in the presence of visible light, anomeric radicals are in situ
cross-coupling reaction catalyzed by a well-defined iron complex generated via the decarboxylation process and efficiently coupled
has been developed by Nakamura’s group, providing aryl/heteroaryl- with a variety of aryl and heteroaryl bromides. In addition to the
C-nucleosides in moderate to high yields and excellent b-selectivity mild reaction conditions, broad substrate scope and good
functional group compatibility, the most significant advantage
of this transformation is the using of safe, bench-stable and
a State Key Laboratory of Bioengineering Reactor and School of Pharmacy,
East China University of Science and Technology, 130 Meilong Road,
easily handled starting materials. The powerful synthetic capacity
of this method was further demonstrated by its application in the
synthesis of various vinyl-C-nucleosides.
Shanghai 200237, P. R. China. E-mail: yongqiangzhang@ecust.edu.cn
b College of Medicine, Jiaxing University, 56 South Yuexiu Road, Jiaxing 314033,
P. R. China
c Department of Pharmacology and Toxicology and BIO5 Institute, University of
Arizona, Tucson, AZ 85721-0207, USA. E-mail: wwang@pharmacy.arizona.edu
† Electronic supplementary information (ESI) available: Full experimental details
and NMR spectra. See DOI: 10.1039/c9cc07184a
Since the pioneering work by MacMillan group,7 photoredox/
nickel dual-catalyzed decarboxylative cross-coupling reaction
has emerged as a versatile method for the synthesis of valuable
targets.8 Our group has also reported a visible-light-promoted
‡ These two authors contributed equally to this paper.
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Table 1 The optimization and validation of the reaction conditionsa
nickel- and organic-dye-cocatalyzed formylation reaction of aryl
halides using diethoxyacetic acid as a formyl equivalent.9 We
envisaged that this state-of-the-art coupling technology might
be extended for the synthesis of aryl/heteroaryl-C-nucleosides.
The initial investigation of the proposed reaction started
with subjecting the readily accessible O-benzyl protected b-ribosyl
acid 1a and 1-(4-bromophenyl)ethan-1-one 2a to the standard
reaction conditions established in our previous study using
4CzIPN and NiCl2ꢀ6H2O as the catalysts and 34 W blue-light-
emitting diodes (LEDs) as the light source.9 To our delight the
desired product 3a was obtained in a tractable yield and excellent
diastereoselectivity (32% yield, b:a 4 99 : 1, entry 1, Table S1,
ESI†). This outcome inspired us to systematically investigate the
interesting reaction. Extensive reaction condition screening
(Tables S1–S5, ESI†) identified the optimal conditions as follow:
in the presence of 34W LEDs, 5 mol% of 4CzIPN, 10 mol% of
NiBr2, 12 mol% of 2,20-bipyridine (bpy) and 2 equiv. of K2CO3, the
reaction of 1a with 2 equiv. of 2a is conducted in DMF for 24 h at
30 1C. Under this reaction conditions, the O-benzyl protected
C-nucleoside 3a was produced in high yield and excellent
b-selectivity (82%, b : a 4 99 : 1, entry 1, Table 1). The variation
of the standard reaction conditions by using Ir[dF(CF3)ppy]2-
(dtbbpy)PF6 as an alternative photocatalyst resulted in slightly
diminished yield, while the diastereoselectivity remained unaffected
(71% yield, b:a 4 99 : 1, entry 2, Table 1).7 The use of reduced
amount of NiBr2 (5 mol%) and bpy (6 mol%) in the reaction also led
to a decreased reaction efficiency (entry 3, Table 1). Interestingly, the
use of O-benzyl protected a-ribosyl acid 1a0 as the substrate has little
effect on the reaction outcome (80% yield, b:a 4 99 : 1, entry 4,
Table 1). However, switching the protecting group of 1a from benzyl
(Bn) to benzoyl (Bz) completely suppressed the reaction (entry 5,
Table 1). The extra coordination interaction induced by the Bz group
at C2 position might interfere with the nickel catalysis (Scheme S1,
Entry
Reaction conditions
Yieldb
1
2
3
4
5
6
7
8
Standard conditions
P1 instead of 4CzIPN
Using reduced amount of NiBr2 and bpy
1a0 instead of 1a
1a000 instead of 1a
2a instead of 2a
2a00 instead of 2a
2a0 0 0 instead of 2a
In darkness
No photocatalyst
No Ni catalyst
No ligand
No base
Under air
82%
71%d
57%e
80%
Trace f
65%
23%
70%
n.dg
9
10
11
12
13
14
15
n.dg
n.dg
n.dg
n.dg
25%
In the presence of TEMPO
23%h
a
Standard reaction conditions:
a mixture of 1a (0.2 mmol), 2a
(0.4 mmol), NiBr2 (0.02 mmol), bpy (0.024 mmol), 4CzIPN (0.01 mmol),
and K2CO3 (0.4 mmol) in DMF (10 mL) was irradiated with 34 W blue
b
LEDs at 30 1C under N2 for 24 h, unless otherwise noted. Isolated
c
yields were reported. Determined using 1H NMR spectroscopy.
d
e
1 mol% of P1 was used. 5 mol% of NiBr2 and 6 mol% of bpy were
f
used. The target product should be O-benzoyl protected C-nucleoside.
g
h
Not detected. 1.0 equiv. of TEMPO was employed in the reaction.
ESI†), which is expected to explain these results. With respect to the substituents at the meta-position of aryl bromides has little
electrophilic coupling partner, we found that aryl bromides were effect on the reaction outcome (3h–3k, 61–86% yields), while
preferred (entries 6–8, Table 1). Control experiments established the inferior reaction efficiency was typically observed for the aryl
importance of visible light, photocatalyst, nickel catalyst, ligand, and bromides with ortho-substituents (3l–3m, 52–63% yields). Notably,
base, as no formation of the desired cross-coupled product was a number of C-nucleosides bearing large p-stacking moieties,
observed in the absence of these reaction promoters (entries 9–13, which serve as artificial nucleobases to extend the genetic
Table 1). Furthermore, the inhibition of the reactivity was also alphabet,2 could also be readily accessible with our method
observed by the presence of molecular oxygen and TEMPO (3n–3q, 34–75% yields). Furthermore, low diastereoselectivity
(23–25% yields, entries 14 and 15, Table 1), again suggesting was observed in the reaction of O-benzyl protected b-deoxyribosyl
the radical nature of the reaction.
acid 1b with 2a (3a1, 61% yield, b:a = 1 : 4), suggesting that the
Having established the optimal reaction conditions (entry 1, substituent at the C2 position of anomeric acids plays a crucial role
Table 1), the scope of the transformation with respect to the in controlling the anomeric configuration.
aryl/heteroaryl bromides was explored (Scheme 2). The aryl and
The C-nucleosides bearing electron-deficient heteroaryl
electron-rich heteroaryl bromides were found to readily couple groups exhibit attractive pharmaceutical profiles and have become
with 1a, providing the desired products in moderate to high an important target of synthetic efforts in recent decades.1 There-
yields and excellent b-selectivity (34–86%, b : a 4 99 : 1). The fore, we next turned our attention to the scope of electron-deficient
reactions of the aryl bromides bearing electron-withdrawing heteroaryl bromides. Various pyridyl bromides were proved
groups at the para-position proceeded well (3b–3f, 61–85% competent substrates (5a–5f, 44–67% yields). As expected,
yields), while the introduction of strong electron-donating b-C-nucleoside products were mainly detected in the reaction
group at this position was detrimental to the reaction efficiency of 3-Br- and 4-Br-pyridines with 1a (5a–5c, b : a 4 99 : 1).
(3g, 51% yield). A variety of functional groups, such as ester, Surprisingly, varying the position of Br at pyridine from C3 or
cyano, sulphonate and alkynyl, were well tolerated, providing C4 to C2 resulted in completely opposite diastereoselectivity
handles for further synthetic elaboration. The introduction of (5d–5f, b : a o 1 : 99). Further investigation of this abnormal
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Scheme 2 Photoredox/Ni dual-catalyzed decarboxylative cross-coupling reactions of anomeric ribosyl/deoxyribosyl acids with aryl/heteroaryl
bromides. For the experimental details, see general procedure in ESI† for the experimental details unless otherwise noted, isolated yields were reported.
aStereomeric ratio was determined using 1H NMR spectroscopy. bStereomeric ratio: 3a1, b : a = 1 : 4; 5d–5f, b : a o 1 : 99.
control of anomeric configuration is still ongoing in our laboratory.
Based on the established mechanism of photoredox/nickel
Remarkably, it was found that pyrimidyl, quinolyl, isoquinolyl and dual-catalyzed decarboxylative coupling reaction,7–9 as well as
benzopyrimidyl bromides could also readily undergo the coupling the observation that the formation of 3a was inhibited by the
reaction with 1a (5j–5k, 66–78%, b:a 4 99 : 1). Interestingly, this presence of TEMPO (entry 15, Table 1), a plausible mechanism
metallaphotoredox protocol is also suitable for cyan-substituted is proposed (Scheme 4). Initial excitation of the 4CzIPN (PS)
thiazolyl bromide (5l, 41% yield, b:a 4 99 : 1), providing a potential would produce photoexcited state of 4CzIPN (PS*). The high
alternative approach for the synthesis of the anti-tumor C-nucleo- reduction potential of the photoexcited state of 4CzIPN (PS*)
side tiazofurin1a in combination with the following hydrolysis of (E*red = +1.35 V vs. SCE, CH3CN)11 enables the following
cyan group and debenzylation reaction (Scheme S3, ESI†).
photooxidative decarboxylation reactions of 1a (Eox = +1.15 V
Recently, the impressive compatibility of photoredox/nickel vs. SCE, CH3CN; Fig. S2, ESI†) and the formation of a sp2-
dual-catalysis with non-anomeric glycosyl 1,4-dihydropyridine hybridrized anomeric radical I. Concurrent with this photoredox
derivatives (DHPs) has been demonstrated in the synthesis
of reversed aryl C-glycosides.10 Inspired by this work, non-
anomeric glycosyl acids were investigated. To our delight, the
non-anomeric furanosyl acids 1c was proved effective reactant
(3a2, 79% yield, dr 499 : 1, Scheme 3), while the non-anomeric
pyranosyl acid failed to give the desired product.
Scheme 3 Photoredox/Ni dual-catalyzed decarboxylative cross-coupling
reactions of non-anomeric furanosyl acid.
Scheme 4 Proposed mechanism.
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21572055, 21738002, W. W.) and the Chinese Fundamental
Research Funds for the Central Universities (ECUST: WY1714033) is
gratefully acknowledged.
Conflicts of interest
There are no conflicts to declare.
Scheme 5 Photoredox/Ni dual-catalyzed decarboxylative cross-coupling
of anomeric ribosyl acid with vinyl bromides. For the experimental details,
see general procedure in ESI† unless otherwise noted, isolated yields were Notes and references
reported. aStereomeric ratio was determined using H NMR spectroscopy.
1
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