A rapid and divergent access to chiral azacyclic nucleoside analogues via highly enantioselective 1,3-dipolar cycloaddition of β-nucleobase substituted acrylates

Article abstract of DOI:10.1039/c4cc06632d

A rapid and divergent access to chiral azacyclic nucleoside analogues has been established via highly exo-selective and enantioselective 1,3-dipolar cycloaddition of azomethine ylides with β-nucleobase substituted acrylates. Using 1 mol% of a chiral copper complex, various chiral azacyclic nucleoside analogues were obtained in high yields, excellent exo-selectivities and enantioselectivities (98 to >99% ee). This journal is

Full text of DOI:10.1039/c4cc06632d

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A rapid and divergent access to chiral azacyclic
nucleoside analogues via highly enantioselective
1,3-dipolar cycloaddition of b-nucleobase
substituted acrylates†
Cite this: Chem. Commun., 2014,
50, 14809
Received 27th August 2014,
Accepted 28th September 2014
Qi-Liang Yang, Ming-Sheng Xie, Chao Xia, Huan-Li Sun, Dan-Jie Zhang,
Ke-Xin Huang, Zhen Guo, Gui-Rong Qu* and Hai-Ming Guo*
DOI: 10.1039/c4cc06632d
www.rsc.org/chemcomm
A rapid and divergent access to chiral azacyclic nucleoside analogues
has been established via highly exo-selective and enantioselective
1,3-dipolar cycloaddition of azomethine ylides with b-nucleobase
substituted acrylates. Using 1 mol% of a chiral copper complex, various
chiral azacyclic nucleoside analogues were obtained in high yields,
excellent exo-selectivities and enantioselectivities (98 to 499% ee).
Fig. 1 Selected nucleosides with biological activities.
Nucleoside analogues and their derivatives have displayed
significant antivirus and anticancer activities.1 To date, several
clinically useful nucleosides, such as AZT, 3TC, Abacavir, and
Entecavir, have been approved by the FDA for the treatment of
HIV and HBV infections (Fig. 1).2 Therefore, there is intense interest
in the synthesis of new nucleoside analogues with potential antiviral
activity. The synthesis of nucleoside analogues was focused on the
modification of the heterocyclic base or sugar or both moieties.3
Due to the substantial similarity to the furan and cyclopentyl
structures, the pyrrolidine ring might be a possible functional
moiety that could be incorporated in nucleosides, leading to a
Scheme 1 Different strategies to construct cyclic nucleoside analogues.
new family of biologically significant substances. However, most of azomethine ylides have been discovered, enabling the efficient
the synthetic methods available to build up the skeletons are based synthesis of highly functionalized pyrrolidines.8 However, the
on a linear approach involving the synthesis of a sugar ring dipolarophiles in most of the cases are limited to electron-deficient
analogue followed by introduction of the nucleobase by formation alkenes, in which one terminal is an electron-withdrawing group
of the C–N bond using a substitution reaction (Scheme 1a).4 Thus, (EWG), and the other terminal is usually an EWG or a hydrogen
we anticipated the straightforward preparation of azacyclic nucleo- atom (Scheme 2). Until now, b-heteroaryl acrylates, either racemic
side analogues by 1,3-dipolar cycloaddition of azomethine ylides or asymmetric, have never been used as dipolarophiles in the
with nucleobase substituted acrylates (Scheme 1b).5,6
1,3-dipolar cycloaddition to azomethine ylides.9 Furthermore,
Since the pioneering reports of Grigg and co-workers,7 a large b-heteroaryl acrylates may competitively coordinate to the catalyst,
number of asymmetric variants of activated dipolarophiles with presumably leading to deactivation or inhibition of the catalyst due
to the presence of multi-nitrogen atoms to render the 1,3-dipolar
cycloaddition even more challenging.
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine
Herein, we will describe the first synthesis of chiral azacyclic
Chemicals, Key Laboratory of Green Chemical Media and Reactions,
nucleoside analogues via asymmetric 1,3-dipolar cycloaddition
with b-nucleobase acrylates as dipolarophiles.
Ministry of Education, School of Chemistry and Chemical Engineering,
Henan Normal University, Xinxiang, Henan 453007, China.
E-mail: quguir@sina.com, guohm518@hotmail.com
Initially, we investigated the 1,3-dipolar reaction of (E)-b-
nucleobase acrylate 1a with N-benzylidene glycine methyl ester
2a using K2CO3 as the base in CH2Cl2 catalyzed by a chiral silver
catalyst generated in situ from AgOAc and different chiral
ligands (Table 1). To our delight, when (R,R)-DIOP L1 was used
† Electronic supplementary information (ESI) available: Experimental details, the
preparation of the starting b-heteroaryl acrylates, and analytical data of the
products (NMR, HPLC, ESI-HRMS, and optical rotation). CCDC 1016261. For
ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4cc06632d
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Table 1 Optimization of the reaction conditionsa
Scheme 2 Dipolarophiles in the 1,3-dipolar cycloaddition to azomethine
ylides.
as the ligand, the 1,3-dipolar cycloaddition proceeded and
yielded endo-3aa as the major product, but with poor yield and
stereocontrol (entry 1). After screening different ligands including
(R)-synPhos L2 and (S,Sp)-phosferrox L3, gratifyingly the
1,3-dipolar cycloaddition proceeded well with a chiral phosferrox
complex (entries 2 and 3). Encouraged by the results, the steric
hindrance and electronic effect of phosferrox ligands were
investigated, but no better results were obtained (entries 3–6).
Ligand L3, one of the best ligands in the previously reported
1,3-dipolar cycloaddition of azomethine ylide, was less effective
in this reaction (entry 3).8g Next, a phenyl group at the 5-position
of the oxazoline ring of phosferrox was introduced; however, the
enantioselectivity significantly decreased and the exo-3aa isomer
was the major product (entry 7), indicating the mismatched
nature of the (S)-planar chirality with the (R,R)-central chirality
on the oxazolinyl ring. Thus, (R,R,Rp)-ligand L8 was examined;
the enantioselectivity of exo-3aa sharply increased to 91% ee
(entry 8).10 By changing the solvent from CH2Cl2 to HC(OCH3)3,
the yield was improved from 83% to quantitative yield (entries 8
and 9). After varying the central metal including Ag(I) and Cu(I),
Cu(CH3CN)4ClO4 afforded the best results, with complete
enantiocontrol (499% ee, entries 9–12). By changing the
solvent to CH2Cl2 again, the diastereoselectivity increased from
83 : 17 to 90 : 10 (entries 12–15). When the reaction temperature
Yieldb endo/ eed (%)
(%) (endo/exo)
exoc
Entry MXn
L
Solvent
1
2
3
4
5
6
7
8
AgOAc
L1 CH2Cl2
L2 CH2Cl2
L3 CH2Cl2
L4 CH2Cl2
L5 CH2Cl2
L6 CH2Cl2
L7 CH2Cl2
L8 CH2Cl2
47 66 : 34 53/19
95 60 : 40 11/14
95 60 : 40 67/89
81 65 : 35 55/38
77 54 : 46 71/85
85 35 : 65 36/75
86 20 : 80 5/9
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgSbF6
CuI
83 20 : 80 78/91
9
L8 HC(OCH3)3 499 30 : 70 72/93
10
11
12
13
14
15
16e
17
18
L8 HC(OCH3)3
L8 HC(OCH3)3
56 30 : 70 56/72
86 18 : 82 —/499
Cu(CH3CN)4ClO4 L8 HC(OCH3)3 499 17 : 83 85/499
Cu(CH3CN)4ClO4 L8 THF 499 25 : 75 87/499
Cu(CH3CN)4ClO4 L8 1,4-Dioxane 499 20 : 80 —/499
Cu(CH3CN)4ClO4 L8 CH2Cl2
Cu(CH3CN)4ClO4 L8 CH2Cl2
Cu(CH3CN)4ClO4 L9 CH2Cl2
Cu(CH3CN)4ClO4 L10 CH2Cl2
499 10 : 90 —/499
499 7 : 93 —/499
85 80 : 20 71/95
499 50 : 50 97/98
19e, f Cu(CH3CN)4ClO4 L8 CH2Cl2
20e,g Cu(CH3CN)4ClO4 L8 CH2Cl2
499
61
7 : 93 —/499
7 : 93 —/499
a
Unless otherwise noted, the reaction conditions were as follows: metal
L
À1 (1 : 1), 1a (0.05 mmol), 2a (0.2 mmol), and K2CO3 (2.0 mg) in solvent
(1.0 mL) at 0 1C for 8 h. Isolated yield. Determined by the 1H NMR
b
c
d
spectra of the crude products. Determined by chiral HPLC analysis.
e
f
g
Reaction temperature: À25 1C. Catalyst loading: 1 mol%. Catalyst
loading: 0.5 mol% and reaction time: 72 h.
was lowered to À25 1C, the diastereoselectivity increased to adduct was obtained without any loss ofthe yield, diastereo-, or
93 : 7 (entry 16). Surprisingly, the diastereoselectivity could be enantioselectivity (entry 3). To our delight, regardless of either
switched when other ligands, L9 and L10, were used (entries 17 the electronic properties or steric hindrance of the substituents
and 18). Remarkably, 1 mol% catalyst loading showed satisfactory on the aromatic ring of a-iminoesters, the corresponding
catalytic efficiency; the product was obtained in a quantitative yield azacyclic nucleoside analogues 3af–3ap were obtained in high
and with excellent exo-selectivity and enantioselectivity (499% ee, diastereoselectivities (up to 96 : 4 dr) and enantioselectivities
entry 19 vs. 16). Significantly, even 0.5 mol% of the catalyst still gave (499% ee) (entries 7–17), but a lower yield was afforded for the
excellent exo-selectivity and enantioselectivity and moderate yield a-iminoester 2p with a strong electron-donating group (entry 17).
(entry 20). Meanwhile, the Z isomer of b-nucleobase acrylate 1a was Moreover, both ring-fused and heteroaromatic a-iminoesters
also investigated, but the conversion was too low, along with poor furnished the cycloaddition to afford the corresponding products
enantioselectivity.
3ar–3at in high yields and with 499% ee (entries 18–20). In
Under the optimized reaction conditions, the substrate addition, a-iminoester 2t with an alkenyl substituent and
scope of azomethine ylide precursors, a-iminoesters 2a–2u, a-iminoester 2u derived from an aliphatic aldehyde were also
was investigated (Table 2). The ester group of a-iminoesters suitable substrates for the reaction, delivering the targeted
slightly affected the diastereoselectivities, while it had no nucleoside analogues 3at and 3au in excellent diastereo- and
influence on the enantioselectivities (entries 1–6). To further enantioselectivities (entries 21 and 22).
evaluate the synthetic potential of the catalytic system, the
Subsequently, the substrate scope of b-nucleobase acrylates
reaction was carried out on the 1.0 mmol scale, and the desired was investigated (Table 3). Various nucleobase acrylates derived
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Table 2 Substrate scope of azomethine ylidesa
Table 3 Substrate scope of b-nucleobase acrylatesa
eed (%)
exo/
R5 T (h) Product Yieldb (%) endoc (exo)
eed (%)
exo/
T (h) Product Yieldb (%) endoc (exo)
Entry R1
Entry R6
R7/R8
1
Ph
Ph
Ph
Ph
Ph
Ph
Me 12
Et 12
Et 24
iPr 16
tBu 16
Bn 16
Me 16
Me 16
Me 16
Me 16
Me 16
Me 16
3aa
3ab
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
3ao
99
98
97
96
95
98
96
95
98
90
95
97
94
97
95
93
93 : 7 499
94 : 6 499
94 : 6 499
95 : 5 499
91 : 9 499
96 : 4 499
92 : 8 499
92 : 8 499
93 : 7 499
90 : 10 499
89 : 11 499
93 : 7 499
94 : 6 499
86 : 14 499
92 : 8 499
90 : 10 499
1
2
Cl
Br
I
H
OMe
OEt
H/Et
H/Et
H/Et
H/Et
H/Et
H/Et
12
16
16
24
14
14
3aa
3ba
3ca
3da
3ea
3fa
99
95
96
92
98
98
93 : 7 499
92 : 8 99
92 : 8 499
93 : 7 499
95 : 5 499
95 : 5 499
2
3e
4
3
4e
5
5
6
7
8
6
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-CH3OC6H4 Me 16
4-FC6H4
4-BrC6H4
4-CF3C6H4
7
8
H/Et
H/Et
16
16
3ga
3ha
97
96
95 : 5 499
93 : 7 499
9
10
11
12
13
14
15
16
Me 18
Me 18
Me 16
9
H/Et
H/Et
18
16
3ia
3ja
93
96
93 : 7 499
94 : 6 499
10
17 f
Me 18
3ap
56
96 : 4 499
11
Ph
H/Et
16
3ka
95
93 : 7 499
18
19
20
2-Naphthyl
2-Thienyl
2-Furyl
Me 36
Me 18
Me 16
3aq
3ar
3as
93
95
96
94 : 6 499
93 : 7 499
92 : 8 499
12
H/Et
20
3la
95
92 : 8 499
13
14
Cl
Cl
NH2/Et 20
H/Me 12
3ma
3na
91
98
92 : 8
99
91 : 9 499
21 f
22
a
Me 18
Me 18
3at
90
98
95 : 5
98 : 2
99
98
a
Reaction conditions: Cu(CH3CN)4ClO4/L8 (1 : 1,
1
mol%), 1a–1n
tBu
3au
(0.05 mmol), 2a (0.2 mmol), and K2CO3 (2.0 mg) in CH2Cl2 (1.0 mL)
at À25 1C. b Isolated yield. c Determined by the 1H NMR spectra of the crude
products. d Determined by chiral HPLC analysis. e The ratio of exo/endo was
determined by chiral HPLC analysis.
Reaction conditions: Cu(CH3CN)4ClO4/L8 (1 : 1,
1 mol%), 1a
(0.05 mmol), 2a–2u (0.2 mmol), and K2CO3 (2.0 mg) in CH2Cl2
(1.0 mL) at À25 1C. Isolated yield. Determined by the 1H NMR spectra
b
c
d
e
of the crude products. Determined by chiral HPLC analysis. The
f
reaction was carried out on a 1.0 mmol scale. The ratio of endo/exo
was determined by chiral HPLC analysis.
3-benzoyl-thymine-substituted acrylate 1p was employed, the
adduct 3pa was formed with high yield and high enantioselectivity,
albeit with lower diastereoselectivity.
from purines with different substituents at the C6 or C2 position
Then, different types of b-heteroaryl acrylates were investi-
were synthesized. To our delight, in the presence of 1 mol% of gated as the dipolarophiles in the 1,3-dipolar cycloaddition to
Cu(I)-L8, these nucleobase acrylates with halogen, hydrogen, alkoxy, a-iminoester 2a (Scheme 3). When a benzimidazole-substituted
amino, and alkyl sulfide substituents at the C6 position of purine acrylate 1q was used, the desired cycloadduct 3qa was obtained in
participated well in the reaction, generating the corresponding 499% ee. Next, 2-chlorobenzimidazole-, 5-chlorobenzimidazole-,
azacyclic nucleoside analogues in excellent yields and with excellent 6-chlorobenzimidazole-, and 5,6-dimethylbenzimidazole-substituted
diastereo- and enantioselectivities (99 to 499% ee) (entries 1–10). acrylates 1r–1u were investigated, and the corresponding pyrrolidine
In the cases of nucleobase acrylates 1k and 1l, with phenyl or derivatives 3ra–3ua were identified in high yields and with excellent
2-naphthyl groups at the C6 position of purine, the 1,3-dipolar diastereo- and enantioselectivities. When 2-phenylimidazole-,
cycloaddition also proceeded well, delivering the desired cyclo- 4,5-diphenylimidazole-, and 4-nitroimidazole-substituted acry-
adducts 3ka–3la with excellent stereocontrol (entries 11 and 12). lates 1v–1x were used, the 1,3-dipolar cycloaddition smoothly
When an NH2 group was introduced at the C2 position of the purine afforded the corresponding cycloadducts 3va–3xa with excellent
part in nucleobase acrylate 1m, the desired azacyclic nucleoside results. Moreover, the benzotriazole-substituted acrylate 1y was
analogue 3ma could be obtained with excellent enantioselectivity also a suitable substrate for the reaction. In the case of indole-
(99% ee, entry 13). Furthermore, methyl ester-derived nucleobase substituted acrylate 1z, the cycloadduct 3za was obtained in a
acrylate 1n also underwent a clean reaction (entry 14).
low yield but with excellent enantioselectivity.
Encouraged by the excellent results with purine-substituted
The absolute configuration of azacyclic nucleoside analogue 3an
acrylates, we then investigated the 1,3-dipolar cycloaddition was determined to be (2R,3S,4R,5S) by the single-crystal X-ray
with pyrimidine-substituted acrylates (Scheme S5, ESI†). When diffraction analysis of the p-tosylprotected azacyclic nucleoside
the 5-F-cytosine-substituted acrylate 1o was examined, the analogue 4an.11 Then, the azacyclic nucleoside analogue 3aa was
1,3-dipolar cycloaddition did not occur. Gratifyingly, when the reduced to afford azacyclic nucleoside 5aa, with two hydroxymethyl
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Scheme 3 Substrate scope of other b-heteroaryl acrylates. a Unless other-
wise noted, the reaction conditions are as follows: Cu(CH3CN)4ClO4/L8
(1: 1, 1 mol%), 1q–1z (0.05 mmol), 2a (0.2 mmol), and K2CO3 (2.0 mg) in
CH2Cl2 (1.0 mL) at À25 1C. Isolated yields are reported. The dr values were
determined by the 1H NMR analysis of the crude products, and the ee values
´
10778–10779; (e) S. Cabrera, R. G. Arrayas and J. C. Carretero, J. Am.
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adenine-derived azacyclic nucleoside.12
In summary, various chiral azacyclic nucleoside analogues
were synthesized through asymmetric 1,3-dipolar cycloaddition
of b-nucleobase acrylates to azomethine ylides for the first time.
In the presence of 1 mol% of the Cu–N–P complex, the
corresponding azacyclic nucleoside analogues were obtained
in high yields and with excellent exo-selectivities and enantio-
selectivities (98 to 499% ee). Moreover, other b-heteroaryl
acrylates including pyrimidine-, benzimidazole-, imidazole-,
benzotriazole-, and indole-substituted acrylates are also suitable
dipolarophiles for the reaction, affording the desired pyrrolidine
derivatives with excellent results. Further study of the reaction
mechanism is currently underway.
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We are grateful for the financial support from the National
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21372066, 21472037, and 21402041), the Program for the
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