Synthesis of Azacyclic Nucleoside Analogues via Asymmetric [3 + 2] Cycloaddition of 9-(2-Tosylvinyl)-9H -purines

Article abstract of DOI:10.1021/acs.orglett.6b00108

With 9-(2-tosylvinyl)-9H-purines as the dipolarophiles, a series of chiral azacyclic nucleosides with four continuous stereocenters were obtained in 86-99% yields, >20:1 dr, and 94 → 99% ee via the Cu(I)-catalyzed asymmetric [3 + 2] cycloaddition. Both (E)- and (Z)-9-(2-tosylvinyl)-9H-purines were suitable dipolarophiles, enriching the structure diversity of azacyclic nucleosides. Furthermore, when α-methyl imino ester was explored, the corresponding azacyclic nucleoside with a chiral quaternary stereocenter could also be afforded with excellent results. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.6b00108

Letter
pubs.acs.org/OrgLett
Synthesis of Azacyclic Nucleoside Analogues via Asymmetric [3 + 2]
Cycloaddition of 9‑(2-Tosylvinyl)‑9H‑purines
Dan-Jie Zhang, Ming-Sheng Xie,* Gui-Rong Qu, Yao-Wei Gao, and Hai-Ming Guo*
Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Collaborative Innovation Center of Henan Province
for Green Manufacturing of Fine Chemicals, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang,
Henan 453007, P. R. China
S
* Supporting Information
ABSTRACT: With 9-(2-tosylvinyl)-9H-purines as the dipo-
larophiles, a series of chiral azacyclic nucleosides with four
continuous stereocenters were obtained in 86−99% yields,
>20:1 dr, and 94 → 99% ee via the Cu(I)-catalyzed
asymmetric [3 + 2] cycloaddition. Both (E)- and (Z)-9-(2-
tosylvinyl)-9H-purines were suitable dipolarophiles, enriching
the structure diversity of azacyclic nucleosides. Furthermore,
when α-methyl imino ester was explored, the corresponding
azacyclic nucleoside with a chiral quaternary stereocenter could also be afforded with excellent results.
hiral cyclic nucleosides have displayed significant antivirus
and anticancer activities, making modification of the ribose
much effort has been devoted to modification of the ribose
moiety,8 thestructure diversityofazacyclic nucleosidesisstillvery
limited.9 Therefore, finding an efficient route for the synthesis of
azacyclic nucleosides with different substituent groups on the
pyrrolidine ring would be highly desirable.
Here, we propose that the dipolarophile 9-(2-tosylvinyl)-9H-
purine 3a could be afforded via the addition of 6-chloro-9H-
purine 1atoTs-substituted alkyne2. Through asymmetric[3+2]
cycloaddition of dipolarophile 3a with azomethine ylides 4,10 the
chiral azacyclic nucleoside analogues 5 could be obtained with
four continuous stereocenters and one quaternary stereocenter,
which could be easily reduced to an azacyclic nucleoside with
different substituent groups (Scheme 1).
C
moiety an advanced research hotspot.1 Modification of the ribose
moiety was mainly focused on the following: (1) introducing
different substituent groups or a quaternary stereocenter to the
ribose moiety;2 (2) employing a structurally similar oxathiolanyl,
cyclopentyl, or pyrrolidine ring to replace the furan ring.3 As
illustrated in Figure 1, AZT, an antiretroviral medication for the
Scheme 1. Our Strategy for the Synthesis of Azacyclic
Nucleoside Analogues
Figure 1. Selected chiral cyclic nucleosides with biological activities.
Initially, 9-(2-tosylvinyl)-9H-purine 3a was obtained in a
mixture of E/Z isomers when the addition reaction was carried
out in CH3CN for 4 h (Table S1, entry 1). By prolonging the
reaction time from 4 to 30 h, the Z-3a was transformed to E-3a
totally (entry 2). Meanwhile, by changing the reaction solvent to
DMF, only E-3a could be afforded (entry 3). Comparatively,
when the reaction was performed in CH2Cl2, the Z-3a isomer was
treatment of HIV/AIDS, incorporated an azide group in the
deoxyribose ring;4 EFdA, Trachycladine A, and HF-7, including
an alkynyl group, a sulfate group, or a quaternary carbon center,
also showed outstanding biological activities.5 Meanwhile, 3TC
and Abacavir, an oxathiolanyl or cyclopentyl ring incorporated in
the nucleosides, have been approved by the FDA (Food and Drug
Administration) to treat HIV infections;6 azacyclic nucleosides I
and II could inhibit the growth of BHK (Baby hamster kidney)
cells and exhibit anti-HIV-1TEKI activity, respectively.7 Although
Received: January 12, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00108
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Letter
generated in the dominant form after 6 h. However, the Z-3a
isomer could be transformed to E-3a when the reaction time was
prolonged (entries 4−5).
no better results were obtained (entries 6−7). When other types
of ligands including (R)-SynPhos L4, (R,R)-DIOP L5, and (R,R)-
Trost ligand L6 were tried, the cycloaddition reaction did not
occur (entries 8−10). Subsequently, several ferrocenyl ligands
L7−L9 were investigated carefully (entries 11−13). L9, a phenyl
group at the 5-position of the oxazoline ring, could achieve the
highest enantioselective (>99% ee, entry 13). After utilizing
different solvents including ClCH2CH2Cl (DCE), dioxane, THF,
and CH3CN, CH2Cl2 was still the better solvent (entries 13−17).
Meanwhile, when the reaction was performed at 1 mol % catalyst
loading, the diastereo- and enantioselectivity could still be
maintained, although with a lower yield (entry 18). By reducing
the amount of α-iminoester 4a, the yield of 5aa decreased
significantly (entries 19−20). When the reaction was performed
under air, the cycloadduct 5aa was obtained in 43% yield, >20:1
dr, and 91% ee (entry 21). Thus, the optimal reaction conditions
include 2 mol % Cu(CH3CN)4ClO4−L9 in CH2Cl2 at rt for 10 h
(entry 13).
With (E)-9-(2-tosylvinyl)-9H-purine 3a in hand, the asym-
metric [3 + 2] cycloaddition of E-3a to N-benzylidene glycine
methyl ester 4a was investigated (Table 1). First, in the presence
a
Table 1. Optimization of Reaction Conditions
With the optimized reaction conditions in hand, the α-
iminoesters 4a−4m, azomethine ylide precursors, were subjected
to the asymmetric [3 + 2] cycloaddition reactions (Table 2). By
a
Table 2. Substrate Scope of Azomethine Ylides
a
Unless otherwise noted, the reaction conditions are as follows: metal/
a
Reaction conditions: Cu(CH3CN)4ClO4−L9 (1:1, 2 mol %), 3a
L (1:1, 2 mol %), 3a (0.05 mmol), 4a (0.25 mmol), and K2CO3 (20
b
(0.05 mmol), 4a−4m (0.25 mmol), and K2CO3 (20 mol %) in CH2Cl2
mol %) in solvent (0.7 mL) under N2 at rt for 10 h. Isolated yield.
b
c
c
Determined by the 1H NMR spectra of the crude products.
(0.7 mL) under N2 at rt for 10 h. Isolated yield. Determined by the
d
1H NMR spectra of the crude products. Determined by chiral HPLC
d
e
Determined by chiral HPLC analysis. Catalyst loading: 1 mol %.
f
g
h
analysis. N.R. = No Reaction.
4a (0.15 mmol) was used. 4a (0.075 mmol) was used. Under air.
of (R, RP)-phosferrox L1, several central metals including Cu(I),
Cu(II), and Ag(I) salts were screened (entries 1−5). Cu-
(CH3CN)4ClO4 was superior compared to other central metals,
delivering the chiral azacyclic nucleoside analogue 5aa in 86%
yield, >20:1 dr, and 95% ee (entry 3). Then, 1,2-P,N-ferrocene
ligandsL2−L3withdifferentsterichindrancewereexamined, and
changing the ester group of α-iminoesters, the corresponding
chiral azacyclic nucleoside analogues 5ab and 5ac could still be
obtained in excellent selectivities (97−99% ee, entries 2−3).
Then, the steric hindrance of the substituted group on the
aromatic ring was explored, and the cycloadducts could be
afforded in excellent yields as well as diastereo- and
B
DOI: 10.1021/acs.orglett.6b00108
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Letter
a
enantioselectivities (entries 4−6). Subsequently, several α-
iminoesters with different electron-withdrawing groups on the
phenyl ring were investigated, and the desired cycloadducts were
generated in 98−99% yields, >20:1 dr, and 99 → 99% ee (entries
7−9). Furthermore, when α-iminoesters with electron-donating
groups on the phenyl ring were examined, excellent results could
still be achieved (entries 10−11, 90−95% yields, > 20:1 dr, 98−
99% ee). Meanwhile, 2-naphthaldehyde-derived α-iminoester 4l
also was a suitable substrate, undergoing the cycloaddition well
(entry 13). In the case of 2-thienyl α-iminoester 4m, the desired
azacyclic product 5am was afforded in 90% yield, >20:1 dr, and
97%ee(entry13). Inaddition, cyclohexylandtert-butylaldehyde-
derivedα-iminoesters4n−4owerealsoexamined. Unfortunately,
the asymmetric [3 + 2] cycloaddition reactions did not occur
(entries 14−15).
Scheme 3. Substrate Scope of the Dipolarophiles
Encouraged by the excellent results obtained using α-
iminoesters, we then examined the asymmetric [3 + 2]
cycloaddition with α-methyl imino ester 4p (Scheme 2). In the
Scheme 2. Synthesis of Chiral Azacyclic Nucleoside Analogue
5an with a Quaternary Stereocenter
a
Reaction conditions: Cu(CH3CN)4ClO4−L9 (1:1, 2 mol %), 3a−3j
(0.05 mmol), 4a (0.25 mmol), and K2CO3 (20 mol %) in CH2Cl2 (0.7
mL) under N2 at rt for 10 h. And the yields were referred to isolated
yields. The dr values were determined by the 1H NMR analysis of the
crude products, and the ee values were determined by chiral HPLC
analysis.
presence of 2 mol % of Cu(I)−L9, the cycloaddition of α-methyl
imino ester 4p to 9-(2-tosylvinyl)-9H-purine 3a proceeded well,
affording the corresponding chiral azacyclic nucleoside analogue
5ap with a chiral quaternary stereocenter in 87% yield, >20:1 dr,
and 97% ee.
Scheme 4. Asymmetric [3 + 2] Cycloaddition of Z-9-(2-
Tosylvinyl)-9H-purine 3a
Subsequently, the substrate scope of the dipolarophiles was
investigated (Scheme 3). A series of 9-(2-tosylvinyl)-9H-purines
with different substituents at the C6 or C2 position were
synthesized. As for the dipolarophiles 3b−3e with amino
substituentsattheC6positionofpurine, the[3+2]cycloaddition
reactions proceeded well, delivering the desired azacyclic
nucleoside analogues 5ba−5ea in 93−96% yields, >20:1 dr, and
90 → 99% ee. With 6-methoxyl purine derived dipolarophile 3f as
the reactant, the corresponding cycloadduct 5fa was obtained in
excellent yield. In the case of 6-phenyl-purine derived
dipolarophile 3g, the corresponding azacyclic product 5ga was
given in 95% yield, >20:1 dr, and 99% ee. Then, the [3 + 2]
cycloaddition of 9-(2-tosylvinyl)-9H-purine 3h with the amino
group at the C2 position was performed, affording the desired
adduct 5ha in 90% yield, >20:1 dr, and 99% ee. Furthermore,
benzoimidazole derived dipolarophiles 3i and 3j also were
suitable reactants, giving the cycloadducts 5ia and 5ja with
excellent results (97 → 99% ee).
To our delight, when Z-3a was used as the dipolarophile, the
corresponding [3 + 2] cycloaddition proceeded well under air,
affording the desired adduct 6aa in 86% yield, >20:1 dr, and 94%
ee (Scheme 4), which enriched the structure diversity of azacyclic
nucleosides.
To further evaluate the prospect of the methodology in
synthesis, a gram-scale synthesis of chiral azacyclic nucleoside
analogue5aawasperformed. AsshowninScheme 5, bytreatment
of 2 mmol of 9-(2-tosylvinyl)-9H-purine 3a in the Cu(I)−L9
catalytic system, chiral azacyclic nucleoside analogue 5aa was
afforded in 93% yield (0.95 g) with >20:1 dr and 97% ee.
Scheme 5. Gram-Scaled Asymmetric Synthesis of 5aa
The absolute configuration of the chiral azacyclic nucleoside
analogue 5aa was unambiguously determined to be
(2R,3R,4R,5R) by single crystal X-ray diffraction analysis of the
tosyl group protected azacyclic nucleoside analogue 7aa (Scheme
6).11 In the presence of NaBH4, the hydrogenation of the product
5aa proceeded well, affording the desired chiral azacyclic
nucleoside 8aa in excellent yield (Scheme 6).
In conclusion, we have developed an efficient method for the
synthesis of chiral azacyclic nucleoside analogues via asymmetric
[3 + 2] cycloaddition of 9-(2-tosylvinyl)-9H-purines with
azomethine ylides. With 2 mol % of Cu(I)−L9 as the catalyst, a
variety of chiral azacyclic nucleosides with four continuous
C
DOI: 10.1021/acs.orglett.6b00108
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Letter
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stereocenters were obtained in 86−99% yields, >20:1 dr, and 94
→ 99% ee. Both (E)- and (Z)-9-(2-tosylvinyl)-9H-purines were
suitable dipolarophiles, enriching the structure diversity of
azacyclic nucleosides. Furthermore, when α-methyl imino ester
was investigated, the desired azacyclic nucleoside with a chiral
quaternary stereocenter could also be afforded with excellent
results. Moreover, a chiral azacyclic nucleoside could be easily
obtained from the cycloadduct via a simple reduction reaction.
ASSOCIATED CONTENT
* Supporting Information
■
S
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X-ray data for compound 7aa (CIF)
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xiemingsheng@htu.edu.cn.
*E-mail: ghm@htu.edu.cn.
Notes
́ ́
(g)Lopez-Perez,A.;Adrio, J.;Carretero, J. C. J. Am.Chem. Soc.2008,130,
10084. (h) Wang, C.-J.; Liang, G.; Xue, Z.-Y.; Gao, F. J. Am. Chem. Soc.
2008, 130, 17250. (i) Chen, X.-H.; Zhang, W.-Q.; Gong, L.-Z. J. Am.
Chem. Soc. 2008, 130, 5652. (j) Chen, X.-H.; Wei, Q.; Luo, S.-W.; Xiao,
H.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 13819. (k) Xue, Z.-Y.; Liu,
T.-L.; Lu, Z.; Huang, H.; Tao, H.-Y.; Wang, C.-J. Chem. Commun. 2010,
46, 1727. (l) Antonchick, A. P.; Gerding-Reimers, C.; Catarinella, M.;
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the financial support from the National
Natural Science Foundation of China (Nos. 21272059,
21372066, 21472037, and 21402041), the National Basic
Research Program of China (973 Program, No.
2014CB560713), the Plan for Scientific Innovation Talent of
Henan Province (164200510008), and Henan Normal Uni-
versityNationalOutstandingYouthCultivationFund(14JR003).
Schurmann, M.; Preut, H.; Ziegler, S.; Rauh, D.; Waldmann, H. Nat.
̈
Chem. 2010, 2, 735. (m) Wang, M.; Wang, Z.; Shi, Y.-H.; Shi, X.-X.;
Fossey, J. S.; Deng, W.-P. Angew. Chem., Int. Ed. 2011, 50, 4897. (n) He,
L.; Chen, X.-H.; Wang, D.-N.; Luo, S.-W.; Zhang, W.-Q.; Yu, J.; Ren, L.;
́
Gong, L.-Z. J. Am. Chem. Soc. 2011, 133, 13504. (o) Hernandez-Toribio,
J.; Padilla, S.; Adrio, J.; Carretero, J. C. Angew. Chem., Int. Ed. 2012, 51,
8854. (p) Li, Q.-H.; Wei, L.; Chen, X.; Wang, C.-J. Chem. Commun. 2013,
49, 6277. (q) Li, Q.-H.; Liu, T.-L.; Wei, L.; Zhou, X.; Tao, H.-Y.; Wang,
C.-J. Chem. Commun. 2013, 49, 9642. (r) Adrio, J.; Carretero, J. C. Chem.
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D
DOI: 10.1021/acs.orglett.6b00108
Org. Lett. XXXX, XXX, XXX−XXX