The synthesis of tenofovir and its analogues via asymmetric transfer hydrogenation

Article abstract of DOI:10.1021/ol500583d

A series of tenofovir analogues with potential antiviral and immunobiologically active compounds were synthesized through an asymmetric transfer hydrogenation reaction from achiral purine derivatives. Up to 97% ee and good to excellent yields were achieved under mild conditions through short reaction steps. The present report suggests an efficient process to acquire tenofovir and its analogues.

Full text of DOI:10.1021/ol500583d

Letter
pubs.acs.org/OrgLett
The Synthesis of Tenofovir and Its Analogues via Asymmetric
Transfer Hydrogenation
Qian Zhang,* Bai-Wei Ma, Qian-Qian Wang, Xing-Xing Wang, Xia Hu, Ming-Sheng Xie, Gui-Rong Qu,
and Hai-Ming Guo*
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical
Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang,
Henan 453007, P. R. China
S
* Supporting Information
ABSTRACT: A series of tenofovir analogues with potential
antiviral and immunobiologically active compounds were
synthesized through an asymmetric transfer hydrogenation
reaction from achiral purine derivatives. Up to 97% ee and
good to excellent yields were achieved under mild conditions
through short reaction steps. The present report suggests an
efficient process to acquire tenofovir and its analogues.
Scheme 1. Reported Methods for the Synthesis of Tenofovir
cyclonucleoside and acyclonucleotide analogues which
Apossess a broad spectrum of antiviral activities are
currently used in clinics. As a typical example, 9-[2-(R)-
(phosphonomethoxy)propyl]adenine (R-PMPA, tenofovir, Fig-
ure 1)1−5showed significant anti-HIV/HBV activity. In 2001,
tenofovir disoproxil fumarate was approved by the FDA for the
treatment of HIV infection. Clinically, this drug can be used by
itself or in combination with other drugs. Tenofovir disoproxil
fumarate was also approved for therapy of hepatitis B in 2008.
The excellent treatment effect has led to significant declines in
HIV/HBV-associated morbidity and mortality.1b,2b,4,6 Surpris-
ingly, some acyclonucleotides owning the same chiral side chain
with tenofovir, such as (R)-PMPDAP,7 6-cypr-(R)-PMPDAP,8
(R)-PMPG,9 and (R)-PMPMAP,2a have been shown to possess
various medicinal activities (Figure 1). Hence, there is
considerable interest in the development of effective methods
for the synthesis of tenofovir and its analogues.
through 5 steps.2a Another route is based on the condensation
of (R)-1-(6-amino-9H-purin-9-yl)propan-2-ol (B) and purchas-
able toslate (C). The latter is used commonly, and four main
approaches have been developed for the preparation of B
(Scheme 2).
As shown in Scheme 2, the reported methods for the
synthesis of (R)-1-(6-amino-9H-purin-9-yl)propan-2-ol (B)
include the following: (1) In 1967, Schaeffer group first
developed a 6 steps route to construct B, in which (R)-2-
hydroxypropanoic acid was used as the chiral starting material
(Scheme 2, Route 1);3 (2) Subsequently, a 5 steps route for the
synthesis of B was realized, which required NaAl-
H2(OCH2CH2OMe)2 for the ester reduction and (R)-isobutyl
2-hydroxypropanoate as the chiral starting material (Scheme 2,
Route 2);10 (3) The commonly used method in production B
was started from chiral (R)-2-hydroxypropanoate or (S)-
glycidol in 3 steps, and the hazardous hydrogen and Pd/C
were used (Scheme 2, Route 3);11 (4) In 1996, Jacobsen group
prepared product B in 5 steps, in which the chiral side chain
was synthesized from the asymmetric ring-opening of
propylene oxide with (salen)CrN3 as the catalyst (Scheme 2,
There were two routes that were mainly employed for the
synthesis of optical tenofovir (Scheme 1). One route is based
on alkylation of adenine with chiral toslate (A) which is
synthesized from (R)-2-(2-tetrahydropyranyloxy)-1-propanol
Figure 1. Structures of tenofovir and its analogues possessing
medicinal activities.
Received: February 24, 2014
Published: March 20, 2014
© 2014 American Chemical Society
2014
dx.doi.org/10.1021/ol500583d | Org. Lett. 2014, 16, 2014−2017

Organic Letters
Letter
a
Scheme 2. Reported Methods of Preparing (R)-1-(6-Amino-
9H-purin-9-yl)propan-2-ol (B) and Our Proposal
Table 1. Optimization of the Reaction Conditions
b
c
entry
x
ligand
y
solvent
yield (%)
ee (%)
1
5
5
5
5
5
5
5
5
5
5
5
1
3
4
5
5
5
5
4
3
L1
L2
L3
L4
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
L5
6
H2O
70
65
80
62
40
97
78
65
50
35
NR
23
60
81
94
97
97
90
86
75
58
8
2
6
H2O
3
6
H2O
15
13
75
96
90
84
95
94
−
4
6
H2O
5
6
H2O
6
6
CH3CN
i-PrOH
EtOH
7
6
8
6
9
6
DMF
10
11
12
13
14
15
16
17
18
19
20
6
THF
6
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
1.2
3.6
4.8
5
96
96
96
95
96
96
7.5
10
12
8
d
96
96
96
6
a
Reaction conditions: The metal [RuCl2(C6H6)]2 and the ligands
(L1−L5) were added to the solvent (1.5 mL), and the mixture was
stirred for 1 h at ambient temperature (20−30 °C). Then HCOONa
(3.0 mmol) was added; after stirring for 10 min, 1a (0.3 mmol) was
b
c
added. Yield of isolated product based on 1a. Determined by chiral
d
HPLC. The reaction time was 52 h, and some byproducts were
detected. N.R. = No Reaction.
tenofovir analogues from achiral purine derivatives for the first
time.
Route 4).12 Although great efforts have been devoted to the
synthesis of product B and remarkable progress has been made,
there are still some problems unsolved. The current methods all
need chiral side chains, and suffer from either multiple-steps
procedure, expensive reagents or harsh reaction conditions.
Thus, developing a catalytic asymmetric route to construct
product B with short steps, mild reaction conditions is
challenging and desirable.
Asymmetric transfer hydrogen processes are attracting
increasing interest from people in recent years in view of
their operational simplicity and stereoselectivity.13 The catalytic
asymmetric transfer hydrogen of ketones by use of metal
complexes is an important process for the synthesis of optically
pure alcohols.14,15 Considering the distinguished advantages of
asymmetric transfer hydrogen and our research experiences on
the synthesis of purine derivatives,16 we envisioned that optical
B could be synthesized by asymmetric transfer hydrogenation
of 1-(9H-purin-9-yl)propan-2-one (Scheme 2, our proposal). In
the present work, we present a method for the synthesis of
First, we researched the enantiomeric excess (ee) of 1-(6-
chloro-9H-purin-9-yl)propan-2-ol (2a) by asymmetric transfer
hydrogenation of 1-(6-chloro-9H-purin-9-yl)propan-2-one (1a)
with [RuCl2(C6H6)]2 and the ligands (L1−L5) in water at
ambient temperature (Table 1). We found that 2a had a better
ee with (S)-diphenyl(pyrrolidin-2-yl)methanol (L5) as the
ligand than other ligands (Table 1, entries 1−5). Hence, we
began to screen the solvents, and the experimental results
showed that the reaction gave the highest yield (97%) and ee
(96%) in CH3CN than other solvents (Table 1, entries 5−11).
Though the reaction gave a high ee in DMF and THF, the yield
was low. In addition, surprisingly the reaction cannot proceed
in DMSO (Table 1, entry 11). The catalyst loading of
[RuCl2(C6H6)]2 had a significant influence on the reaction. As
can be seen in Table 1, the yields decreased from 97% to 23%
with the catalyst loading of [RuCl2(C6H6)]2 changed from 5 to
1 mol % (Table 1, entries 12−14). The ratio of
[RuCl2(C6H6)]2 to ligand also had some effect on the reaction
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dx.doi.org/10.1021/ol500583d | Org. Lett. 2014, 16, 2014−2017

Organic Letters
Letter
Table 2. Reaction of Purin-9-yl propan-2-ones with Various
Substituents on Purine Rings
Scheme 3. Synthesis of (R)-Diethyl (((1-(6-Amino-9H-
purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (T)
a
to the optimized reaction conditions and the results are shown
in Table 2. As can be seen in Table 2, all of the purine
substrates can give high ee values (92−97%), but the different
substituents of the purine ring have a certain influence on the
yields of the products and a very tiny influence on the ee of the
products. Though some substrates afforded high yields (Table
2, entries 1, 7−12, 15, 16), others only resulted in moderate
yields and high ee’s. Some alkyl ketones and aryl ketones were
also subjected to the optimized reaction conditions. Unfortu-
nately, one of the substrates gave low yields and ee’s while the
others did not participate in the reaction.17 The absolute
configuration of 2a and 2c was determined as S by comparison
with the reported optical rotations (see Supporting Information
for details). In order to obtain B and its analogues, we used L6
in place of L5 to carry out some of the reaction. To our delight,
the desired products 3a and B having an R configuration were
synthesized with up to 97% ee. It is noteworthy that 3a and B18
could be converted into (R)-diethyl (((1-(6-amino-9H-purin-9-
yl)propan-2-yl)oxy)methyl)phosphonate (Scheme 3, T), the
final intermediate for tenofovir.19 Compared with the reported
methods3,10−12 which used chiral side chains principally, our
method is more simple and efficient.
a
Reaction conditions: [RuCl2(C6H6)]2 (5 mol %) and L5 (6 mol %)
were added to CH3CN (1.5 mL), and the mixture was stirred for 1 h at
ambient temperature (20−30 °C). Then HCOONa (3.0 mmol) was
added; after stirring for 10 min, purine (0.3 mmol) was added. The
reaction was conducted for 48 h at ambient temperature. Yield of
isolated product based on 1a−1p. Determined by chiral HPLC. The
ligand was L6. The ee of the product was determined by its
b
c
d
e
trimethylsilyl ether.
For the purpose of examining the synthetic potential of the
present approach, gram-scaled 1a was used for the synthesis of
2a under the optimal conditions, affording an 85% yield and
96% ee.
(entries 15−20). Experimental results showed that the reaction
can be finished within 48 h. When the reaction was carried out
below 20 °C, a low yield resulted with a prolonged reaction
time to 56 h. When the reaction temperature rose to above 35
°C, byproducts and a lower ee were detected. In addition, we
found that 10 equiv of HCOONa were the most suitable in the
experiment; reducing the amount of HCOONa resulted in a
low conversion rate or long reaction time. From these
observations, the best result was achieved with 5 mol % of
[RuCl2(C6H6)]2 and 6 mol % of L5 in the presence of 10 equiv
of HCOONa in CH3CN at ambient temperature (Table 1,
entry 6).
In conclusion, we have developed a mild, new synthetic
method to attain chiral acyclonucleosides from achiral purine
derivatives. It is the first report for the synthesis of chiral
acyclonucleosides by asymmetric transfer hydrogenation. A
wide range of 1-(9H-purin-9-yl)propan-2-one compounds are
useful substrates. Good to excellent yields (up to 97%) and
satisfactory enantioselectivities (up to 97% ee) were obtained.
The reaction can be amplified to gram scales. Since the target
molecules could be further modified conveniently, this method
suggests an opportunity for preparing tenofovir and its
analogues efficiently.
To evaluate the general applicability and versatility of the
method, a group of different purine derivatives were subjected
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Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
Experimental details and full spectroscopic data for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Authors
■
(12) Larrow, J. F.; Schaus, S. E.; Jacobsen, E. N. J. Am. Chem. Soc.
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*E-mail: zhangqian1980@gmail.com.
*E-mail: guohm518@hotmail.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Science Foundation of China
(No. 21102038), The Program for Changjiang Scholars and
Innovative Research Team in University (IRT1061), and The
Program for Innovative Research Team in University of Henan
Province (2012IRTSTHN006).
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