Asymmetric Hydrogenation of α-Purine Nucleobase-Substituted Acrylates with Rhodium Diphosphine Complexes: Access to Tenofovir Analogues

Article abstract of DOI:10.1021/acs.orglett.6b00869

The first asymmetric hydrogenation of α-purine nucleobase-substituted α,β-unsaturated esters, catalyzed by a chiral rhodium (R)-Synphos catalyst, has been developed. A wide range of mono- and disubstituted acrylates were successfully hydrogenated under very mild conditions in high yields with good to excellent enantioselectivities (up to 99% ee). This method provides a convenient approach to the synthesis of a new kind of optically pure acyclic nucleoside and Tenofovir analogues.

Full text of DOI:10.1021/acs.orglett.6b00869

Letter
pubs.acs.org/OrgLett
Asymmetric Hydrogenation of α‑Purine Nucleobase-Substituted
Acrylates with Rhodium Diphosphine Complexes: Access to
Tenofovir Analogues
†
‡
†
,†
†
‡
Huan-Li Sun, Fei Chen, Ming-Sheng Xie, Hai-Ming Guo,* Gui-Rong Qu, Yan-Mei He,
,‡
and Qing-Hua Fan*
†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, China
‡
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of
Chemistry, Chinese Academy of Sciences, Beijing 100190, China
*
S Supporting Information
ABSTRACT: The first asymmetric hydrogenation of α-purine nucleobase-substituted α,β-unsaturated esters, catalyzed by a
chiral rhodium (R)-Synphos catalyst, has been developed. A wide range of mono- and disubstituted acrylates were successfully
hydrogenated under very mild conditions in high yields with good to excellent enantioselectivities (up to 99% ee). This method
provides a convenient approach to the synthesis of a new kind of optically pure acyclic nucleoside and Tenofovir analogues.
cyclic nucleosides and their phosphonates possess a broad
chiral acyclic nucleosides and their phosphonates has received
more attention in recent years. Among the various reported
4
A
spectrum of potential antiviral activity, and some of them
1
are currently used in clinics. Representative examples are shown
in Figure 1. The chirality of the aliphatic side chain has proven to
approaches for synthesizing such chiral compounds, including
4
chiral pool and chiral auxiliary strategies, the more efficient and
5
atom-economic asymmetric catalysis is less studied.
Transition-metal-catalyzed asymmetric hydrogenation has
been established as one of the most powerful tools for preparing
6
enantiomerically pure compounds in organic synthesis. Many
efficient chiral rhodium and ruthenium diphosphine catalysts
have been developed for the hydrogenation of CC bonds
bearing an adjacent coordinating functional group (CFG) with
excellent activities and enantioselectivities. However, hydro-
genation of unsaturated substrates bearing a N-containing
heterocyclic group remains a great challenge because of the
strong coordinating ability of the nitrogen moiety, which often
results in catalyst deactivation. Successful examples in the
7
hydrogenation of such types of substrates are rare. For example,
Zhou and co-workers recently reported a highly efficient iridium-
catalyzed asymmetric hydrogenation of pyridyl-containing cyclic
imines using a substituent-controlled strategy. It was found that
Figure 1. Representative acyclic nucleosides and nucleoside phospho-
nates possessing antiviral activities.
7l
the introduction of a substituent at the ortho position of the
pyridyl ring could reduce its coordinating ability. In contrast to
the strategies of preventing coordination of the nitrogen atom to
play a pivotal role in their relevant bioactivities. For example,
introduction of a methyl group into the side chain of Adefovir,
leading to Tenofovir, improved its anti-HBV (hepatitis B virus)
6
,7b−e,l
the metal center,
we envisioned that a suitable N-
containing heterocyclic group may be used to serve as a CFG
2
activity. In addition, the S-enantiomer of Cidofovir shows high
3
antiviral activity, whereas the R-isomer is devoid of effect.
Received: March 29, 2016
Therefore, the development of new methods for the synthesis of
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00869
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
to facilitate the asymmetric hydrogenation. Given the
importance of nucleosides in medicinal chemistry, as described
above, we exemplified this new strategy with the asymmetric
hydrogenation of α-nucleobase-substituted acrylates. To the best
of our knowledge, this is the first highly enantioselective
hydrogenation of nucleobase-containing α,β-unsaturated acid
esters with chiral rhodium diphosphine catalysts at ambient
Table 2. Optimization of Conditions for Asymmetric
Hydrogenation of 1b
a
8
temperature and pressure with excellent enantioselectivity.
In our initial attempt, we examined the asymmetric hydro-
genation in methanol using rhodium and ruthenium complexes
of (R)-BINAP as the catalysts. The effect of a substituent on the
6
-position of the purine skeleton and the ester or acid groups on
catalytic performance was investigated. As shown in Table 1, the
Table 1. Asymmetric Hydrogenation of Acrylates 1a−c with
a
Different Chiral Metal Catalysts
b
c
entry
solvent
ligand
H (atm); t (h) conv (%)
2
ee (%)
1
2
3
4
5
6
7
8
9
MeOH
EtOH
IPA
(R)-3a
(R)-3a
(R)-3a
(R)-3a
(R)-3a
(R)-3a
(R)-3a
(R)-3a
(R)-3a
(R)-3a
(R)-3b
(R)-3c
(R)-3d
(R)-3e
(R)-3f
(S)-3g
(R)-3h
(R)-3c
(R)-3c
30; 24
30; 24
30; 24
30; 24
30; 24
30; 24
30; 24
30; 24
10; 5
1; 5
>95
>95
>95
>95
>95
70
93
95
90
89
96
76
90
87
95
95
92
97
94
92
93
−23
28
93
93
t-BuOH
acetone
b
c
entry
R1/R2
metal
conv (%)
ee (%)
1
2
3
4
5
H/Et (1a)
H/Et (1a)
Cl/Et (1b)
Cl/Et (1b)
Cl/H (1c)
[Ru(C H )Cl ]
2 2
<5
43
6
6
CH Cl2
2
[Rh(COD)Cl]2
[Ru(C H )Cl ]
2 2
44
58
93
86
THF
12
>95
>95
>95
6
6
EtOAc
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
38
[Rh(COD)Cl]2
[Rh(COD)Cl]2
>95
>95
94
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
a
Reaction conditions: substrate 1 (0.15 mmol), MeOH (2 mL), chiral
metal catalyst (1 mol %) generated in situ by mixing a metal precursor
with (R)-3a (1.1 equiv), H (30 atm), stirred at rt for 5 h.
Determined by H NMR analysis. Determined by chiral HPLC
1; 5
1; 5
>95
70
2
1; 5
b
1
c
1; 5
38
analysis with a chiral OD-H column.
1; 5
>95
86
1; 5
ruthenium catalyst was found to be inactive in the hydrogenation
of ethyl 2-(6H-9H-purine-9-yl)acrylate 1a (entry 1). Low
conversion and enantioselectivity were observed for the rhodium
catalyst (entry 2). In sharp contrast, introducing a chloro group
on the 6-position of the purine skeleton (1b) improved the
reactivity and enantioselectivity significantly (entries 3 and 4),
and excellent ee value was achieved for the rhodium catalyst.
Particularly, the acid substrate 1c was hydrogenated smoothly,
giving the product with the same configuration, albeit with low
enantioselectivity (entry 5). These results suggested that the
substituent on the purine skeleton could tune the coordination
strength of nitrogen atoms, and consequently, the heterocyclic
purine ring (not the acid group) might act as the CFG (instead of
the poison) to facilitate the hydrogenation process (for a
proposed coordination model, see Scheme S2 in the Supporting
Information).
Encouraged by this exciting result, we then chose the
asymmetric hydrogenation of 1b with chiral rhodium diphos-
phine catalysts as the model reaction for optimizing the reaction
conditions. The solvent effect was first investigated at room
temperature under 30 atm of hydrogen for 24 h. As shown in
Table 2 and Table S1, the reaction was found to be sensitive to
solvent. Hydrogenation proceeded smoothly in alcoholic
solvents and acetone (entries 1−5), and ethanol was the optimal
solvent in terms of both reactivity and enantioselectivity (entry
7
d
1; 5
81
1
8
1; 5
>95
44
e
1
9
1; 5
a
Reaction conditions (unless otherwise noted): substrate 1b (0.15
mmol), solvent (2 mL), Rh catalyst (1 mol %), stirred at rt for 5 h. IPA
b
1
c
=
isopropyl alcohol. Determined by H NMR analysis. Determined
d
by chiral HPLC analysis with a chiral OD-H column. Substrate 1b
e
(
2.5 mmol), EtOH (5 mL), S/C = 1000, 48 h. Substrate 1b (2.5
mmol), EtOH (5 mL), S/C = 2000, 48 h.
hydrogen pressure (Table 1 and Table S2). Remarkably, even if
the reaction proceeded at ambient temperature and pressure, full
conversion and the same ee value were obtained in 5 h (entry
10). Subsequently, some comercially available chiral diphosphine
ligands were screened (entries 10−17), and the best result (97%
ee) was achieved with (R)-Synphos (entry 12). Furthermore, the
reaction proceeded smoothly at a low catalyst loading of 0.1 mol
% in full conversion with a slightly low enantioselectivity (93%
ee) upon prolonged reaction time (entry 18). When the
substrate to catalyst ratio (S/C) was furthered increased to
2000, the excellent enantioselectivity still remained unchanged
(entry 19).
With the optimal reaction conditions in hand, a series of α-
purine nucleobase-containing monosubstituted acrylates were
then hydrogenated, and the data are collected in Scheme 1. In
most cases, the reaction proceeded smoothly at ambient
1
5 vs 16 in Table S1). Interestingly, in contrast to other
functional olefins, the enantioselectivity was insensitive to
9
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DOI: 10.1021/acs.orglett.6b00869
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Letter
a
Scheme 1. Asymmetric Hydrogenation of Acrylates 1b−p
position (1m) was carried out under higher hydrogen pressure
for longer reaction time with good enantioselectivity. Notably,
substrates bearing two substituents on the purine skeleton (1n−
p) could also be hydrogenated but gave low reactivity or
enantioselectivity.
Intrigued by the results described above, we extended this
catalyst system to the hydrogenation of the more challenging α-
purine nucleobase-containing disubstituted acrylates (Scheme
2
). After reaction condition optimization (Table S4), all
a
Scheme 2. Asymmetric Hydrogenation of Acrylates 1q−u
a
Reaction conditions: substrates 1q−u (0.15 mmol), MeOH (2 mL),
5
mol % of Rh catalyst, H (30 atm), stirred at rt for 24 h. Yield of
2
isolated product was given. The enantiomeric excesses were
determined by chiral HPLC analysis.
a
disubstituted acrylates 1q−t bearing an aryl group were
Reaction conditions (unless otherwise noted): substrates 1b−p (0.15
successfully hydrogenated with 5 mol % of Rh catalyst under
mmol), EtOH (2 mL), 1 mol % of Rh catalyst, H (1 atm), stirred at rt
2
3
0 atm of hydrogen pressure to give the chiral acyclic nucleosides
for 5 h. Yield of isolated product was given. The ee values were
determined by chiral HPLC analysis. The absolute configuration of 2b
was determined to be R based on single-crystal X-ray analysis of its
corresponding alcohol 2ba (Scheme S1). The configurations of the
other products are proposed by analogy. Reaction for 24 h. With 5
mol % of Rh catalyst, H (30 atm), 24 h. H (30 atm), 24 h.
in high yields with very good enantioselectivities regardless of
different substituents on the aryl group. Notably, excellent
enantioselectivity (97% ee) and reactivity were observed in the
hydrogenation of substrate 1u bearing a methyl group.
b
c
d
2
2
To demonstrate the synthetic utility of the current method-
8b
ology, the Tenofovir analogue 2bc was synthesized as shown in
Scheme 3. The asymmetric hydrogenation of 1b was carried out
temperature and pressure to give the chiral acyclic nucleosides in
high yields with excellent enantioselectivities (up to 99% ee). It
was found that the substrates bearing small ester groups (1b and
Scheme 3. Asymmetric Synthesis of Tenofovir Analogue (R)-
1
1
d) gave excellent enantioselectivity. Hydrogenation of substrate
f bearing bulky ester also proceeded smoothly with excellent ee
2bc
value, albeit with low reactivity. Notably, hydrogenation of the
corresponding acid 1c gave very good enantioselectivity (91%
ee). Moreover, introducing different substituents onto the
skeleton of purine (1h−1p) was found to influence the reaction.
Substrates bearing ethylamino, pyrrolidinyl, and 6-phenyl groups
on the 6-position of the purine skeleton were smoothly
hydrogenated at ambient temperature and pressure in high
yield and excellent enantioselectivity. Low yield and ee value
were observed in the hydrogenation of 1k bearing a small methyl
group. The substrate bearing electron-rich methoxyl group (1l)
led to very low reactivity and enantioselectivity, and full
conversion could be achieved with 5 mol % of Rh catalyst
under 30 atm of hydrogen. Unlike the 6-chloro derivative, the
hydrogenation of a substrate bearing a bromo group on the 6-
C
DOI: 10.1021/acs.orglett.6b00869
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Organic Letters
Letter
on a gram scale (1.31 g) in the presence of 1 mol % of Rh catalyst
(5) Studies of the synthesis of the chiral acyclic nucleosides by
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2
h, producing (R)-2b in 97% yield with 93% ee. Then, further
2
009, 131, 8971. (c) Guo, H.-M.; Yuan, T.-F.; Niu, H.-Y.; Liu, J.-Y.;
reduction of 2b with NaBH in MeOH afforded (R)-2ba in 90%
4
Mao, R.-Z.; Li, D.-Y.; Qu, G.-R. Chem. - Eur. J. 2011, 17, 4095. (d) Wu,
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TfOCH P(O)(OEt) in THF at −20 °C to produce 2bb, which
2
2
3
54, 2977. (e) Zhang, Q.; Ma, B.-W.; Wang, Q.-Q.; Wang, X.-X.; Hu, X.;
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underwent aminolysis, giving (R)-2bc in 46% yield in two steps
without any loss of ee.
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In conclusion, we have developed the first highly effective
asymmetric hydrogenation of α-purine nucleobase-substituted
α,β-unsaturated acid esters using chiral rhodium (R)-Synphos
catalyst. A wide range of mono- and disubstituted acrylates were
successfully hydrogenated under very mild conditions in high
yields and good to excellent enantioselectivities (up to 99% ee).
This new method thus provides a practical and facile approach to
the synthesis of a new kind of optically pure acyclic nucleoside
and Tenofovir analogues. In addition, a N-containing hetero-
cyclic purine ring was proposed as the CFG to facilitate the
asymmetric hydrogenation process. We believe that this new
strategy will stimulate future work on the asymmetric hydro-
genation of other more challenging unsaturated substrates
bearing heterocyclic groups.
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ASSOCIATED CONTENT
■
*
S
Supporting Information
́
C.; Scott, J. P.; Shevlin, M.; Wise, C.; Menard, A.; Gibb, A.; Junker, E. M.;
Lieberman, D. J. Am. Chem. Soc. 2015, 137, 999. (g) Grasa, G. A.;
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X.; Li, X.; Fan, W.; Xie, X.; Ayad, T.; Ratovelomanana-Vidal, V.; Zhang,
Z. J. Org. Chem. 2012, 77, 612. (j) Yang, H.; Huo, N.; Yang, P.; Pei, H.;
Lv, H.; Zhang, X. Org. Lett. 2015, 17, 4144. (k) Hu, Q.; Zhang, Z.; Liu,
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(l) Guo, C.; Sun, D.-W.; Yang, S.; Mao, S.-J.; Xu, X.-H.; Zhu, S.-F.; Zhou,
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00869.
Experimental procedures, synthesis method of the starting
materials, and compound characterization data (PDF)
X-ray data for compound 2ba (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
(8) (a) Overberger, C. G.; Chang, J. Y. Tetrahedron Lett. 1989, 30, 51.
*
E-mail: ghm@htu.edu.cn.
E-mail: fanqh@iccas.ac.cn.
(
(
b) Jeffery, A. L.; Kim, J.-H.; Wiemer, D. F. Tetrahedron 2000, 56, 5077.
c) Bambuch, V.; Pohl, R.; Hocek, M. Eur. J. Org. Chem. 2008, 2008,
*
Notes
2
783. (d) Lemaire, S.; Houpis, I.; Wechselberger, R.; Langens, J.;
The authors declare no competing financial interest.
Vermeulen, W. A. A.; Smets, N.; Nettekoven, U.; Wang, Y.; Xiao, T.; Qu,
H.; Liu, R.; Jonckers, T. H. M.; Raboisson, P.; Vandyck, K.; Nilsson, K.
M.; Farina, V. J. Org. Chem. 2011, 76, 297.
ACKNOWLEDGMENTS
We are grateful for the financial support from the National
Natural Science Foundation of China (Nos. 21472037,
■
(
9) (a) Uemura, T.; Zhang, X.; Matsumura, K.; Sayo, N.;
Kumobayashi, H.; Ohta, T.; Nozaki, K.; Takaya, H. J. Org. Chem.
996, 61, 5510. (b) Alame, M.; Pestre, N.; De Bellefon, C. Adv. Synth.
Catal. 2008, 350, 898.
1
21402041, and 21232008), the National Basic Research Program
of China (973 Program, No. 2014CB560713), and the Plan for
Scientific Innovation Talent of Henan Province
(164200510008).
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DOI: 10.1021/acs.orglett.6b00869
Org. Lett. XXXX, XXX, XXX−XXX