Synthesis of acyclic nucleosides with a chiral amino side Chain by the mitsunobu coupling reaction

Article abstract of DOI:10.1021/jo100397a

Figure presented A novel and efficient synthetic method has been developed for the preparation of chiral acyclic nucleosides with a chiral amino side chain by Mitsunobu reaction between nucleoside bases and protected l-serine. This method suggests a potentially more efficient and complementary process to acquire chiral acyclic nucleosides.

Full text of DOI:10.1021/jo100397a

pubs.acs.org/joc
R-PMPA (Tenofovir),4 S-DHPA,5 et al., have been shown to
Synthesis of Acyclic Nucleosides with a Chiral Amino
Side Chain by the Mitsunobu Coupling Reaction
possess antiviral activities (Figure 1). The biological activity
spectrum of the acyclic nucleoside is markedly influenced not
only by the base moiety, but also by the structure and absolute
configuration of the aliphatic side chain. For example, for
DHPA and HPMPA, only their S-enantiomers exhibit antiviral
activities whereas the R-enantiomers are markedly less active. 5a
Reversely, the R-enantiomers of PMPA and PMPDAP show
10-100-fold higher activity against human immunodeficiency
virus than their S-counterparts.6 It should also be mentioned
that the antiviral activity found for a racemic mixture is not
necessarily half of the activity of the more active enantiomer. The
markedly different activities of respective enantiomers make it
very important to synthesize optically pure compounds for
antiviral evaluation.
Hai-Ming Guo,*,† Yan-Yan Wu,† Hong-Ying Niu,‡
Dong-Chao Wang,† and Gui-Rong Qu*,†
†College of Chemistry and Environmental Science, Key
Laboratory of Green Chemical Media and Reactions of
Ministry of Education, Henan Normal University, Xinxiang
453007, Henan, China, and ‡School of Chemistry and
Chemical Engineering, Henan Institute of Science and
Technology, Xinxiang 453003, China
ghm@htu.cn; quguir@sina.com.cn
Received March 3, 2010
The reported synthesis methods of acyclic nucleoside
analogues involve alkylation of purine or pyrimidine bases
with various alkylating agents. The most frequently used
alkylating agents are halogenated compounds.7 Some alky-
lating agents are mesylate8 or tosylate.9 Another straightfor-
ward method for the synthesis of acyclic nucleoside is
Michael addition, which usually provides racemic or achiral
acyclic nucleosides.10 All these methods suffer serious dis-
advantages because they are multistep and laborious, and are
targeted at the synthesis of the analogues of one type.
Encouraged by the properties of these chiral acyclic
nucleosides and based on the previous work of our studies
on nucleoside analogues,11 herein, we report the synthesis of
novel chiral acyclic nucleoside analogues through the Mit-
sunobu reaction between purine or pyrimidine bases and
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A novel and efficient synthetic method has been developed
for the preparation of chiral acyclic nucleosides with a chiral
amino side chain by Mitsunobu reaction between nucleoside
bases and protected L-serine. This method suggests a poten-
tially more efficient and complementary process to acquire
chiral acyclic nucleosides.
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DOI: 10.1021/jo100397a
r
Published on Web 04/30/2010
J. Org. Chem. 2010, 75, 3863–3866 3863
2010 American Chemical Society

Guo et al.
JOCNote
TABLE 1. Optimization of Reaction Conditionsa
concn
(mol/L)
entry
solvent
DCM
DCE
ether
THF
temp (°C)
yieldb (%)
1
2
3
4
5
6
7
8
25
25
25
25
25
25
25
25
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
60
53
64
NR
64
98
35
24
toluene
xylene
dioxane
ether/DCM
(v/v = 1/2)
ether/THF
(v/v = 2/1)
xylene
xylene
xylene
xylene
xylene
9
25
0.1
NR
FIGURE 1. Structures of some acyclonucleosides possessing anti-
viral activities.
10
11
12
13
14
15
16
0
60
80
25
25
25
25
0.1
0.1
0.1
0.025
0.05
0.2
63
82
74
90
96
25
32
SCHEME 1. Preparation of Both Chiral Acyclic Nucleosides
and Nucleotides
xylene
xylene
0.4
aReaction conditions: reaction time, 1.5 h; alcohol (0.3 mmol) was
dissolved in the solvent, then 6-chloropurine (0.45 mmol) and PPh3 (0.48
mmol) were added sequentially, finally DIAD (0.48 mmol) was added
dropwise. bIsolated yields based on alcohol.
mixture of triaryphosphine, alcohol, and the nucleophile.
Disappointingly, the reaction was poor according to the
above typical adding order. A survey of the adding order
showed that the yield can be improved significantly accord-
ing to the following order: alcohol was first dissolved in the
solvent, followed by the addition of nucleophile and triaryl-
phosphine sequentially, then DIAD was added dropwise
last.
Next, the effects of solvent, temperature, and concentra-
tion were examined (Table 1). As shown in Table 1, xylene
was shown to be the best choice for the Mitsunobu reaction
(entries 1-9). In xylene, the reaction proceeded smoothly
and gave the desired product in excellent yield (entry 6).
Temperature also made a difference on the reaction. At 0 °C,
the yield was moderate (entry 10); when the temperature was
increased to 25 °C, the yield was excellent and the reaction
time was shortened to 1 h (entry 6). However, when the
temperature was higher than 25 °C (entries 11 and 12), the
yields decreased obviously. Therefore, 25 °C is the optimized
temperature. The results of the survey of reaction concentra-
tion (entries 6 and 13-16) indicated that the reaction pro-
ceeded well in dilute environment and 0.1 mol/L turned out
to be the best choice.
To evaluate the generality of the reaction, a number of
purines with various substituents were subjected to the
optimized reaction conditions. However, the result came as
a surprise. Some of the substrates gave low yields; for most of
them, no reaction was observed. To extend the application of
the reaction, we decided to try different solvents. To our
delight, each substrate could conduct well in at least one of
the investigated solvents (for details see the Supporting
Information). For most substrates, DCM proved to be the
best solvent. The best solvent for each substrate was listed in
Table 2.
N-protected L-serine methyl ester. These novel chiral acyclic
nucleoside ananogues can be used as key intermediates for
the synthesis not only of naturally occurring S-willardiine
and its analogues, but also of S-DHPA-like nucleoside
analogues. The proposed uniform scheme allows the pre-
paration of both chiral acyclic nucleosides and nucleotides
(Scheme 1).
Initially, we investigated the Mitsunobu reaction between
6-chloropurine and N-tert-butoxycarbonyl (Boc) L-serine
methyl ester. To our disappointment, the primary product
was not the expected coupling product but the elimination
product of N-tert-butoxycarbonyl (Boc) L-serine methyl
ester. A survey of the literature12 demonstrated that when
Cbz or Boc was used as the N-protecting group for serine, the
elimination product was in 73% or 91% yield, respectively,
along with a small amount of the nucleophilic substitution
product. Consistent with the literature, we decided on trityl
(Tr) as the N-protecting group. Gratifyingly the elimination
product was avoided, but the yield was still quite low.
To obtain satisfactory yield, various factors were investi-
gated to optimize the reaction condition. First, the addition
order of the reactants and solvents was studied. The typical
procedure of the Mitsunobu reaction was as follows: diiso-
propyl azodicarboxylate (DIAD) was added dropwise to the
(12) Cherney, R. J.; Wang., L. J. Org. Chem. 1996, 61, 2544.
3864 J. Org. Chem. Vol. 75, No. 11, 2010

Guo et al.
JOCNote
TABLE 2. Reaction of Purines with Various Substituentsa
TABLE 3. Reaction of Pyrimidines with Various Substituentsa
entry
R3
R4 product
solvent
DCM
DCM
ether/DCM
(v/v = 1/2)
time (h) yieldb (%)
1
2
3
OH
OH
I
4a
4b
4c
3.5
2
76
35
63
Cl
H
NHCOMe
3
aReaction conditions: alcohol (0.3 mmol) was dissolved in solvent,
then pyrimidine (0.45 mmol) and PPh3 (0.48 mmol) were added sequen-
tially, finally DIAD (0.48 mmol) was added dropwise. bIsolated yields
based on alcohol.
SCHEME 2. Reduction of 2b
aReaction conditions: alcohol (0.3 mmol) was dissolved in solvent,
then purine (0.45 mmol) and PPh3 (0.48 mmol) were added sequentially,
finally DIAD (0.48 mmol) was added dropwise. bIsolated yields based on
alcohol.
The effect of substituents on purine was investigated, too.
When there was no substituent at the C2 position, all the purine
derivatives gave the desired products 2a-e in moderate to good
yields (entries 1-5). Replacement of H by NH2 (entry 6) ledtoa
lower yield after purification; by contrast, replacement of H by
Cl (entry 8) led to higher yields. This indicated that the electron-
donating effects on C2 could lead to a decrease of the yields
whereas the electron-withdrawing effects on C2 could lead to an
increase of the yields. The influence of different substituent
groups at C6 was also studied. When there was no substituent at
the C6 position (entry 2), the yield was moderate. Replacement
of H by Cl (entry 1) led to a higher yield after purification
whereas replacement of H by NH2 (entry 8) led to a lower yield.
The results indicated that the yield was in inverse proportion to
the electron density at C6, which was in agreement with the
effect on C2.
SCHEME 3. Hydrolysis of 4b
chiral amino side chain by the Mitsunobu reaction between
L-serine and a base. Compared to previously known ap-
proaches, the simplicity of this procedure and generally
satisfactory yields make this method particularly attractive.
Since the target molecules could be converted to many other
useful compounds, this method suggests an opportunity to
acquire many other useful derivatives from these chiral
acyclic nucleosides.
When this procedure was applied to pyrimidine deriva-
tives, to our delight, the target molecules were obtained in
moderate to good isolated yields (Table 3)
As indicated in Table 3, the reaction could proceed smoothly
with pyrimidine derivatives, and the yield was moderate, except
for 5-chlorouracil, which might be affected by the chlorine atom.
It is noteworthy that the purine target products would
serve in further functionalizations to produce a molecule that
is similar to S-DHPA5 (Figure 1), a medicinal which is
effective against a variety of RNA viruses. Herein we just
try 2b to do the further transformation (Scheme 2).
Besides, pyrimidine target products would also serve in further
functionalizations to produce [(S)-1-(2-amino-2-carboxyethyl)-
pyrimidine-2,4-dione] (S-Willardiine) derivatives (Figure 1). S-
Willardiine1 is a naturally occurring heterocyclic excitatory
amino acid present in the seeds of Acacia and Mimosa. The
(S)- but not (R)-isomers of willardiine and 5-bromowillardiine
were potent agonists, producing rapidly but incompletely de-
sensitizing responses. Herein we just try 4b to do the further
transformation (Scheme 3).
Experimental Section
Typical Experimental Procedure for the Mitsunobu Reaction
of Purines or Pyrimidines with N-Trityl L-Serine Methyl Ester.
N-Trityl L-serine methyl ester (0.3 mmol) was dissolved in the
solvent, then purine base 1 or pyrimidine 3 (0.45 mmol) and
PPh3 (0.48 mmol) were added sequentially, then DIAD (0.48
mmol) was added dropwise. After completion of the reaction
monitored by thin layer chromatography (TLC), the solvent was
evaporated, then the crude product was purified by column
chromatography over silica gel with ethyl acetate and petroleum
ether as the eluent, to give target product 2 or 4.
Compound 2a: white powder, mp 90-91 °C; 1H NMR (CDCl3,
400 MHz) δ 8.70 (s, 1H), 8.31 (s, 1H), 7.34-7.32 (m, 6H),
7.23-7.15 (m, 9H), 4.55 (dd, J = 5.6, 14.0 Hz. 1H), 4.35 (dd,
J= 4.8, 14.0 Hz, 1H), 3.88-3.82 (m, 1H), 3.22 (s, 3H), 2.89 (s, 1H);
13C NMR (CDCl3, 100 MHz) δ 171.5, 151.2, 151.1, 150.2, 145.1,
144.0, 130.4, 127.5, 127.2, 126.0, 70.2, 55.0, 51.6, 47.0; HRMS calcd
for C28H24ClN5NaO2 [M þ Naþ] 520.1516, found 520.1519.
In conclusion, we have developed a novel and efficient
synthetic method to prepare chiral acyclic nucleosides with a
J. Org. Chem. Vol. 75, No. 11, 2010 3865

Guo et al.
JOCNote
Compound 4a: white powder, mp 76-80 °C; 1H NMR
(CDCl3, 400 MHz) δ 9.34 (s, 1H), 7.85 (s, 1H), 7.42-7.40 (m,
6H), 7.31-7.22 (m, 9H), 4.14 (d, J = 8.8 Hz, 1H), 3.70-3.64 (m,
2H), 3.29 (s, 3H), 2.89 (d, J = 9.2 Hz, 1H); 13C NMR (CDCl3,
100 MHz) δ 171.7, 159.3, 149.3, 149.2, 144.1, 127.6, 127.3, 126.0,
70.3, 65.8, 54.2, 51.7, 51.0, 21.0; HRMS calcd for C27H24IN3-
NaO4 [M þ Naþ] 604.0709, found 604.0710.
capacity of 12 mL. Then the THF solution of ester 4b (1 mL) was
added dropwise. The vessel was placed in a thermostated bath
(26 °C) and stirred for 20 h. The reaction mixture was extracted
with CH2Cl2, the aqueous layer was acidified by 2 M HCl to pH
3 and filtered, then the residue was dried in an oven to afford the
target molecular 6.
Compound 6: white powder, mp 118-120 °C; 1H NMR
(CDCl3, 400 MHz) δ 10.50 (s, 1H), 7.51 (s, 1H), 7.50 (m, 6H),
7.23 (m, 10H), 4.13 (d, J = 6.4 Hz, 1H), 3.65 (s, 1H), 3.35 (d, J =
9.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 146.4, 144.6, 143.2,
127.6, 127.0, 126.7, 126.4, 125.7, 125.5, 100.5, 70.0, 51.0.
Typical Experimental Procedure for the Reduction of Methyl
3-(9H-Purin-9-yl)-2-(tritylamino)propanoate. LiAlH4 was sus-
pended in THF and the mixture was stirred at room temperature
for 25 min. To this solution was added 2b and the mixture was
stirred for 4 h. After completion of the reaction, the solvent was
evaporated, then the crude product was purified by column
chromatography over silica gel with dichloromethane and
methanol as the eluent, to give target product 5.
Acknowledgment. We are grateful for financial support
from the National Nature Science Foundation of China
(grants 20772024 and 20802016), the Program for New
Century Excellent Talents in University of Ministry of
Education (NCET-09-0122), the Program for Innovative
Research Team in University of Henan Province
(2008IRTSTHN002), and the Henan National Nature
Science Foundation (092300410226).
Compound 5: white powder, mp 190-193 °C; 1H NMR
(CDCl3, 400 MHz) δ 9.16 (s, 1H), 8.92 (s, 1H), 7.94 (s, 1H),
7.56-7.54 (m, 6H), 7.34-7.30 (m, 6H), 7.27-7.22 (m, 3H), 4.14
(dd, J = 3.2, 14.0 Hz, 1H), 3.73 (dd, J = 6.0, 14.0 Hz, 1H),
3.16-3.14 (m, 1H), 2.98 (dd, J = 4.0, 12.0 Hz, 1H), 2.66 (dd, J =
7.2, 12.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 151.3, 150.9,
148.1, 145.8, 145.2, 133.0, 127.6, 127.3, 126.0, 70.3, 60.2, 53.0,
43.6; HRMS calcd for C27H25N5NaO [M þ Naþ] 458.1957,
found 458.1957.
Typical Experimental Procedure for the Hydrolysis of Methyl
3-(5-Chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-(tritylamino)-
propanoate. The aqueous solution of NaOH (1 M, 1 mL) was
placed in a cylindrical vessel with a cross section of 3 cm2 and a
Supporting Information Available: General information,
experimental procedures, optimization of reaction conditions
for each purine base or pyrimidine, and characterization data
for the products including spectroscopic information. This
material is available free of charge via the Internet at http://
pubs.acs.org.
3866 J. Org. Chem. Vol. 75, No. 11, 2010