Synthesis of Chiral Acyclic Nucleosides by Sharpless Asymmetric Dihydroxylation: Access to Cidofovir and Buciclovir

Article abstract of DOI:10.1021/acs.joc.8b02442

An efficient method to construct chiral acyclic nucleosides via Sharpless asymmetric dihydroxylation of N-allylpyrimidines or N-alkenylpurines is reported. A range of chiral acyclic nucleosides with two adjacent hydroxyl groups present on the side chains could be produced in good yields (up to 97% yield) and excellent enantioselectivities (90-99% ee). The synthetic utility of the reaction was demonstrated by the catalytic asymmetric synthesis of (S)-Cidofovir and (R)-Buciclovir.

Full text of DOI:10.1021/acs.joc.8b02442

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Note
Synthesis of Chiral Acyclic Nucleosides by Sharpless
Asymmetric Dihydroxylation: Access to Cidofovir and Buciclovir
Tao Qin, Jian-Ping Li, Ming-Sheng Xie, Gui-Rong Qu, and Hai-Ming Guo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02442 • Publication Date (Web): 23 Nov 2018
Downloaded from http://pubs.acs.org on November 24, 2018
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Synthesis of Chiral Acyclic Nucleosides by Sharpless
Asymmetric Dihydroxylation: Access to Cidofovir and
Buciclovir
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Tao Qin, Jian-Ping Li, Ming-Sheng Xie*, Gui-Rong Qu, and Hai-Ming Guo*
Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, 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.
ABSTRACT
An efficient method to construct chiral acyclic nucleosides via Sharpless asymmetric
dihydroxylation of N-allylpyrimidines or N-alkenylpurines is reported. A range of chiral acyclic
nucleosides with two adjacent hydroxyl groups present on the side chains could be produced in
good yields (up to 97% yield) and excellent enantioselectivities (90-99% ee). The synthetic utility
of the reaction was demonstrated by the catalytic asymmetric synthesis of (S)-Cidofovir and
(R)-Buciclovir.
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Acyclic nucleosides and their phosphonates have emerged as a key class of antiviral nucleoside
analogues.1 Representative examples are shown in Figure 1. (S)-Cidofovir has been approved by
the FDA in 1996 for the clinical use to treat cytomegalovirus retinitis in AIDS patients.2
(S)-Cidofovir exhibits broad-spectrum activities against virtually all DNA viruses.2b
(R)-Buciclovir is an anti-herpesvirus drug.3 (S)-HPMPA is a potent and selective antiviral agent
with activities against a broad-spectrum of DNA viruses.4 D-Eritadenine is an inhibitor of
S-adenosyl-L-homocysteine hydrolase.5 For this list of chiral acyclic nucleosides and nucleotides
exhibiting biological activities, one characteristic property is that two adjacent hydroxyl groups
can always be found in the corresponding side chains. Therefore, developing an efficient method
to construct chiral acyclic nucleosides and nucleotides with two adjacent hydroxyl groups
connected to the side chains, is highly desirable.
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Figure 1. Selected biologically active chiral acyclic nucleosides and nucleotides
Conventional routes to synthesize chiral acyclic nucleosides and nucleotides, which contain two
adjacent hydroxyl groups in the side chains, are based on a chiral pool strategy.6 Take
(S)-Cidofovir as the example, different synthetic routes are shown in Scheme 1. Webb II and
co-workers first reported the synthesis of (S)-Cidofovir involving alkylation of cytosine with a
chiral pre-assembled glycerol-phosphonate as the key step (Route a).6a Later, Bronson and
co-workers developed an approach to produce (S)-Cidofovir based on coupling of
(S)-2,3-O-isopropylideneglycerol with Bz-protected cytosine (Route b).6b Afterwards, Vemishetti
and co-workers reported a practical route to synthesize (S)-Cidofovir starting from a ring-opening
reaction of Bz-protected cytosine to (S)-tritylglycidol (Route c).6c Although remarkable progress
has been achieved using the chiral pool strategy, the generation of chiral key starting materials
often requires multiple steps from a chiral pool with necessary stereochemistry.7 In 2014, our
group reported an efficient route to synthesize chiral acyclic nucleoside Tenofovir through
asymmetric transfer hydrogenation of α-purine-substituted acetone.8-9 Considering that the
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Sharpless asymmetric dihydroxylation (SAD) reaction represents a powerful strategy to construct
optically active vicinal diols,10-12 herein we report a catalytic asymmetric synthesis of chiral
acyclic nucleosides, containing two adjacent hydroxyl groups in the side chains, via SAD of
N1-allylcytosine (Route d).
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Route a
P(O)(OEt)2
NH2
N
NH2
N
O
OBn
NH2
N
N
i) Pd(OH)2
ii) TMSBr
OMs
N
O
O
O
O
P
OH
Cs2CO3
O
O
P(OEt)2
O
N
H
OH
OH
OBn
Route b
(S)-Cidofovir
OMs
NHBz
N
NHBz
N
i) TrCl
O
NHBz
ii) (EtO)2POCH2OTs
iii) HOAc
N
O
N
HCl
O
N
(S)-Cidofovir
O
t-BuOK
iv) TMSBr
v) NH4OH
OH
O
N
O
H
O
OH
Route c
NHBz
NHBz
N
O
N
i) (EtO)2POCH2OTs
ii) HCl
OTr
N
(S)-Cidofovir
O
iii) TMSBr
iv) NH4OH
NaH
OH
O
N
H
OTr
Route d (this work)
NHBz
NH2
NHBz
N
Asymmetric
Dihydroxylation
N
N
O
N
O
N
O
P
O
N
OH
OH
OH
O
OH
OH
(S)-Cidofovir
Scheme 1. Different strategies to construct (S)-Cidofovir
Initially, Bz-protected N1-allylcytosine 1a was selected as a model reactant in the asymmetric
dihydroxylation reaction with K2OsO2(OH)4 as the catalyst (Table 1). When (DHQD)2PYR L1
was employed as the chiral ligand, the dihydroxylation proceeded well, affording the desired
Bz-protected N1-(2,3-dihydroxypropyl)cytosine 2a in 95% yield and 29% ee (entry 1). Several
known SAD ligands were screened (entries 2-5) and (DHQD)2PHAL L2 proved to be the better
choice, providing the diol 2a in 97% yield and 55% ee (entries 2). The pseudoenantiomer
(DHQ)2PHAL L3 provided nearly identical results, along with an opposite enantiomer (entries 2).
o
Upon lowering the reaction temperature from rt to 0 C, the ee value of 2a increased to 67% ee
(entries 6). Optimization of reaction conditions demonstrated that the equivalents of K3Fe(CN)6
and K2CO3 could be decreased, and the ratio and concentration of t-BuOH/H2O slightly influenced
yield or ee value (entries 7-9). Several solvent mixtures were examined, and t-BuOH/H2O proved
to be better (entries 9). When the catalyst loading was reduced to 1 mol %, the ee value of 2a
decreased to 66% (entries 12).
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Table 1. Optimization of reaction conditionsa
NHBz
NHBz
N
K2OsO2(OH)4 (2 mol %)
N
N
L (10 mol %)
O
N
O
K3Fe(CN)6, K2CO3
OH
MeSO2NH2, t-BuOH/H2O
OH
8
1a
2a
9
Ph
Ph
DQHD
O
DHQD
O
DQHD
DHQD
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N
N
DHQD
DHQ
DQHD
QHD
N
N
N
N
(DHQD)2PYR
L1
(DHQ)2PHAL
L3
(DHQD)2AQN
L4
(DHQD)2PHAL
L2
NQ
QN
H
H
N
HO
O
N
O
O
O
H
N
MeO
MeO
MeO
N
N
N
(QN)2AQN
L5
DHQD
QN
DHQ
t
yield ee
(%)b (%)c
entry
L
solvent
(oC)
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2
3
4
5
L1
L2
L3
L4
L5
L2
L2
rt
rt
rt
rt
rt
0
t-BuOH/H2O
t-BuOH/H2O
t-BuOH/H2O
t-BuOH/H2O
t-BuOH/H2O
t-BuOH/H2O
t-BuOH/H2O
t-BuOH/H2O
(2:1), 1 mL
t-BuOH/H2O
(2:1), 2 mL
i-PrOH/H2O
(2:1), 2 mL
Acetone/H2O
(2:1), 2 mL
t-BuOH/H2O
(2:1), 2 mL
95
97
96
96
83
95
94
29
55
-55
37
43
67
70
6
7d
0
8d,
L2
L2
L2
L2
0
0
0
0
0
95
93
60
48
92
72
76
43
51
66
9d
10d
11d
12d,e L2
aUnless otherwise noted, reaction conditions were as follows: 1a (0.05 mmol), K2OsO2(OH)4 (2
mol %), L (10 mol %), K3Fe(CN)6 (6 equiv.), K2CO3 (6 equiv.), MeSO2NH2 (2 equiv.) in
b
c
t-BuOH/H2O (1.0 mL, 1:1) at rt for 12 h. Isolated yield. Determined by HPLC analysis.
dK3Fe(CN)6 (3 equiv.) and K2CO3 (3 equiv.). eK2OsO2(OH)4 (1 mol %), L2 (5 mol %), 24 h.
Then, different protecting groups on N-allylcytosines were evaluated (Table 2). When
Boc-protected N-allylcytosine 1b was used, the enantioselectivity decreased (entry 2). In the case
of isobutyryl or Bn-protected N-allylcytosines 1c-d, the diols 2c and 2d were generated in 62% ee
and 72% ee, respectively (entries 3-4). Therefore, a Bz protecting group proved to be the most
suitable choice (entries 1-4). Next, a methyl group was introduced in the 2ʹ-position of the side
chain in N-allylcytosine. In doing so, the enantioselectivity of the diol product increased (2e, 90%
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ee, entry 5). When an ethyl group was introduced in the 2ʹ-position of the side chain, the diol 2f
5
6
was obtained in 93% ee (entry 6).
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Table 2. Evaluation of protecting or substituent groupsa
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yield
ee
entry
1
R1/Pg
R2
2
(%)b (%)c
1
2
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6
1a
1b
1c
1d
1e
1f
H/Bz
Boc/Boc
H/i-PrCO
H/Bn
H/Bz
H/Bz
H
H
H
H
2a
2b
2c
2d
93
91
89
96
95
97
76
38
62
72
90
93
Me 2e
Et 2f
aReaction conditions are same as Table 1, entry 9. bIsolated yield. cDetermined by HPLC analysis.
Subsequently, the scope of N1-allylcytosines in SAD reaction was explored (Scheme 2).
Various straight-chain, branched, or cyclic alkyl substituents were introduced in the 2ʹ-position of
the side chains, and the chiral diols 2e-2k were produced in excellent results. When TMS group
was linked to the 2ʹ-position of the side chain, the chiral acyclic nucleoside 2l was obtained in
95% ee. In the case of the phenyl substituted N1-allylcytosine 1m, the diol 2m was generated in
99% ee. Several Bz-protected N1-allylcytosines with different substituents (Me, F, Cl, or Br) in
the C5 position were evaluated, and the chiral acyclic nucleosides 2n-2q were afforded in 97-99%
ee. Upon changing the protecting group with a Boc or Ac group, the diols 2r-2s could also be
produced with excellent results. Therefore, various alkyl groups (linear chains, branched or cyclic)
provided similar results with phenyl provided the highest ee.
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Scheme 2. Substrate scope of N-allylcytosinesa
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aReaction conditions are same as Table 1, entry 9. Isolated yield are reported and the ee values
were determined by HPLC analysis.
Other N1-allylpyrimidines were also screened (Scheme 3). When the Bz-protected
N1-allylthymine 3a was employed, the chiral diol 4a was produced in 98% ee. The absolute
configuration of the acyclic nucleoside 4a was determined to be (S)-configuration by the
single-crystal X-ray diffraction analysis.13 N1-Allyluracils 3b-3e with different halogen
substituents (F, Cl, Br, or I) in the C5 position of uracil were examined, and the chiral diols 4b-4e
were produced in moderate yields and 96-99% ee. Therefore, this strategy also worked well with
N-allylthymine and N-allyluracil.
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Scheme 3. Substrate scope of other N-allylpyrimidinesa
5
6
7
8
O
N
O
R3
R3
Ph
BzN
O
BzN
O
K2OsO2(OH)4 (2 mol %)
L2 (10 mol %)
N
K3Fe(CN)6, K2CO3
MeSO2NH2, t-BuOH/H2O
Ph
OH
OH
9
3a-3e
4a-4e
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O
O
F
CH3
BzN
BzN
O
N
O
N
Ph
Ph
OH
OH
OH
OH
4b
4a
4a
66% yield, 98% ee
O
79% yield, 98% ee
O
O
Cl
Br
I
BzN
BzN
BzN
O
N
O
N
O
N
Ph
Ph
Ph
OH
OH
OH
OH
OH
OH
4c
4e
4d
58% yield, 97% ee
58% yield, 96% ee
57% yield, 99% ee
aReaction conditions are same as Table 1, entry 9. Isolated yield are reported and the ee values
were determined by HPLC analysis.
Scheme 4. Substrate scope of N-alkenylpurinesa
aReaction conditions are same as Table 1, entry 9. Isolated yield are reported and the ee values
were determined by chiral HPLC analysis. b L4 was used instead of L2.
The substrate scope of N9-alkenylpurines in the reaction was further evaluated (Scheme 4).
Several N9-allylpurines bearing a chloro (5a), alkoxy (5b), amino (5c), or alkyl sulfide (5d) group
in the C6 position were screened, delivering 6a-6d in good yields and 97-98% ee. Then, a
triethylsilyl group was introduced in the 3ʹ position of the extended side chain, and the chiral diol
6e was obtained in 95% ee. The absolute configuration of the acyclic nucleoside 6e was
determined to be (S)-configuration by the single-crystal X-ray diffraction analysis.13 Then, the
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N-allylpurine 5f with a phenyl group at the terminal position was examined, the SAD reaction
proceeded well, affording the acyclic nucleoside 6f in 76% yield, >20:1 dr, and 95% ee. When
N-allyladenine without additional substituent on the alkene was tested, only 35% ee was obtained
(See SI for details).
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Scheme 5. Synthesis of (S)-Cidofovir and (R)-Buciclovir
To further evaluate the applicability of this synthetic methodology, the SAD reaction of
TMS-substituted N1-allylcytosine 1l was performed on a 1 mmol scale (Scheme 5a). Under 2
mol % K2OsO2(OH)4 and 10 mol % L2, the SAD reaction of 1l proceeded smoothly, affording
0.32 g (88% yield) of the diol 2l with 95% ee. Addition of TBAF resulted in the removal of the
TMS group in diol 2l,14 affording the Bz-protected N1-(2,3-dihydroxypropyl)cytosine 2a in 73%
yield and 95% ee, which could be transformed into the drug (S)-Cidofovir (Scheme 5a). Compared
to Bronson group’s work to construct Bz-protected-N1-(2,3-dihydroxypropyl)cytosine 2a in two
steps with a 36% total yield, our developed route could afford a 64% total yield in two steps. The
absolute configuration of product 2a was determined to be (S)-configuration by comparison with
the reported optical rotation. With the chiral acyclic purine nucleoside 6e as the starting material in
hand, the triethylsilyl group could also be removed by treatment with TBAF,14 affording the chiral
diol 7e in 62% yield and 95% ee. After hydrolysis, (R)-Buciclovir could be obtained in 91% yield
(Scheme 5b).
In summary, we have developed an efficient method to synthesize chiral acyclic nucleosides
through SAD reaction of N-allylpyrimidines or N-alkenylpurines. Various of chiral acyclic
nucleosides, bearing two adjacent hydroxyl groups in the corresponding side chains, could be
afforded in 57-97% yields and 90-99% ee. Bz-protected-(S)-N1-(2,3-dihydroxypropyl)-cytosine,
the key intermediate for the synthesis of (S)-Cidofovir, could be obtained in two steps.
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Furthermore, an efficient route to produce (R)-Buciclovir has been developed. Compared to
conventional methods based on a chiral pool strategy, this method only employs catalytic amount
of chiral catalyst, which avoids the use of equivalent chiral source and will provide a new route to
synthesize chiral acyclic nucleosides.
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■ EXPERIMENTAL SECTION
General information. 1H, 13C{1H} NMR spectra were recorded on Bruker (1H 600 MHz, 13C{1H}
150 MHz) and Bruker (1H 400 MHz, 13C{1H} 100 MHz) . Chemical shifts are recorded in ppm
relative to tetramethylsilane and with the solvent resonance as the internal standard. Data are
reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, dd = doublet of doublets,
dt = doublet of triplets, t = triplet, q = quaternary, m = multiplet, br = broad). Coupling constants
(J) are reported in Hertz (Hz). Enantiomer excesses were determined by chiral HPLC analysis on
Chiralcel IA/ID/IE/AS-H/OD-H in comparison with the authentic racemates. Chiral HPLC
analysis recorded on Thermo scientific Dionex Ultimate 3000 and Agilent Technologies 1260
Infinity. Optical rotations were reported as follows: [α]DT (c: = g/100mL, in solvent). Optical
rotations recorded on Autopol Automatic Polarimeter. All products were further characterized by
high-resolution mass spectra (HRMS). The HRMS was obtained using a Q-TOF instrument
equipped with an ESI source. THF and Et2O were freshly distilled from a sodium benzophenone
ketyl. Other solvents used for work-up and purification purposes were purchased in technical
grade quality and distilled by rotary evaporator before use.
Synthesis of N-allylated pyrimidines and N-alkenyl purines.
To a suspension of N-protected-cytosine (8.40 mmol) in THF/DMF (100 mL, 1/1), NaH (202
mg, 8.40 mmol, 60% dispersion in oil) was added. The reaction mixture was heated by oil bath at
60 °C for 45 min, (H, Alkyl, Aryl, TMS)-substituted allyl acetate15 (4.20 mmol), DPPF (232 mg,
0.42 mmol) and Pd(PPh3)4 (485 mg, 0.42 mmol) were successively added. The reaction mixture
was heated to 60 °C for 10 h. The mixture was cooled to room temperature, diluted with EtOAc
(25 mL) and washed with an aqueous saturated solution of NH4Cl. The organic layer was dried
over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by flash column
chromatography on silica gel (petroleum ether/ethyl acetate 5:1 to 1:1) to give the products 1a-1s.
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In a dry 25 mL round bottom flask, N-protected-uracil or purine (8 mmol) and potassium
carbonate (8 mmol) were dissolved in DMF, after add (3-bromoprop-1-en-2-yl)benzene16 (4 mmol)
at the room temperature, for over night, the reaction was complete monitored by TLC. Then, the
reaction mixture was extracted with ethyl acetate and water for three times. The organic phases
were combined and then dried by Na2SO4. Concentrated under the reduced pressure, the residue
was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate 7:1) to
give the products 3a-3e, 5a-5d.
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In a dry 50 mL round bottom flask, 6-(benzyloxy)-9H-purin-2-amine (2.41 g, 10 mmol) and
potassium
carbonate
(1.38
g,
10
mmol)
were
dissolved
in
DMF,
(4-bromobut-1-en-2-yl)triethylsilane17 (1.25 g, 5 mmol) was added at the room temperature. The
reaction was complete monitored by TLC. Then, the reaction mixture was extracted with ethyl
acetate and water for three times. The organic phases were combined and then dried by Na2SO4.
Concentrated under the reduced pressure, the residue was purified by flash column
chromatography on silica gel (petroleum ether/ethyl acetate 8:1) to give the product 5e (1.33 g, 3.3
mmol, 65 % yield).
In a dry 25 mL round bottom flask, adenine (1.1 g, 8 mmol) and potassium carbonate (1.3 g,
9.6 mmol) were dissolved in DMF, (H, phenyl, ethoxycarbonyl, or TMS)-substituted allyl
bromide (7.2 mmol) was added at the room temperature. The reaction was complete monitored by
TLC. Then, the reaction mixture was extracted with ethyl acetate and water for three times. The
organic phases were combined and then dried by Na2SO4. Concentrated under the reduced
pressure, the residue was purified by flash column chromatography on silica gel (petroleum
ether/ethyl acetate 3:1 to 1:2) to give the products 5f-5i.
General procedure for the asymmetric dihydroxylation
To a mixture of tert-butyl alcohol and water (2:1, 2 mL) were added sequentially potassium
ferricyanide (49.4 mg, 0.15 mmol), potassium carbonate (20.7 mg, 0.15 mmol), (DHQD)2PHAL
L2 (3.9 mg, 0.005 mmol), MeSO2NH2, (9.5 mg, 0.1 mmol) and K2OsO2(OH)4 (0.36 mg, 0.001
mmol) at room temperature with stirring. The mixture stirred at room temperature for 30 minutes,
then added to the alkene, and the heterogeneous slurry was stirred at 0 oC for 12 hours monitored
by TLC. The reaction was quenched at 0 °C by addition of Na2S2O3 and the mixture stirred at
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room temperature for 2 hours. The reaction mixture was then dried over anhydrous Na2SO4,
filtered and concentrated in vacuo to afford a crude product. Purification by flash column
chromatography (VDCM/VMeOH = 20:1-60:1 as eluent) to afford afford the corresponding chiral
dihydroxylation products 2a-2s, 4a-4e, 6a-6d and 6f-6i.
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To a mixture of tert-butyl alcohol and water (2:1, 2 mL) were added sequentially potassium
ferricyanide (49.4 mg, 0.15 mmol), potassium carbonate (20.7 mg, 0.15 mmol), (DHQD)2AQN L4
(4.3 mg, 0.005 mmol), MeSO2NH2, (9.5 mg, 0.1 mmol) and K2OsO2(OH)4 (0.36 mg, 0.001 mmol)
at room temperature with stirring. The mixture stirred at room temperature for 30 minutes, then
o
added to the alkene, and the heterogeneous slurry was stirred at 0 C for 12 hours monitored by
TLC. The reaction was quenched at 0 °C by addition of Na2S2O3 and the mixture stirred at room
temperature for 2 hours. The reaction mixture was then dried over anhydrous Na2SO4, filtered and
concentrated in vacuo to afford a crude product. Purification by flash column chromatography
(VDCM/VMeOH = 60:1 as eluent) to afford 6e.
Synthesis of (S)-Cidofovir and (R)-Buciclovir
To a mixture of tert-butyl alcohol and water (2:1, 25 mL) were added sequentially potassium
ferricyanide (0.98 g, 3 mmol), potassium carbonate (0.41 g, 3 mmol), (DHQD)2PHAL L2 (78 mg,
0.1 mmol), MeSO2NH2, (0.19 g, 2 mmol) and K2OsO2(OH)4 (7.2 mg, 0.02 mmol) at room
temperature with stirring. The mixture stirred at room temperature for 30 minutes, then added to
o
the alkene 1l, and the heterogeneous slurry was stirred at 0 C for 18 hours monitored by TLC.
The reaction was quenched at 0 °C by addition of Na2S2O3 and the mixture stirred at room
temperature for 2 hours. The reaction mixture was then dried over anhydrous Na2SO4, filtered and
concentrated in vacuo to afford a crude product. Purification by flash column chromatography
(VDCM/VMeOH = 50:1 as eluent) to afford 2l (0.32 g, 88% yield, 95% ee ). A solution of 2l (36.1 mg,
0.1 mmol) in anhydrous DMF (2 mL) at 0 oC was added with TBAF (0.5 mL of an 1 M solution in
THF, 0.5 mmol). The mixture was stirred at room temperature for 18 h. The mixture was quenched
with saturated water and then extracted three times with AcOEt. The combined organic phases
were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The
crude product was purified by flash column chromatography (VDCM/VMeOH =25:1 as eluent) to
afford 2a (26 mg, 73% yield, 95% ee).
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A solution of 6e (44.3 mg, 0.1 mmol) in anhydrous DMF (2 mL) at 0 C, was added with
TBAF (0.35 mL of an 1 M solution in THF, 0.35 mmol). The mixture was stirred at room
temperature for 12 h. The mixture was quenched with saturated water and then extracted three
times with AcOEt. The combined organic phases were washed with brine, dried over Na2SO4,
filtered and concentrated under reduced pressure. The crude product was purified by flash column
chromatography (VDCM/VMeOH = 30:1 as eluent) to afford 7e (27 mg, 62% yield, 95% ee). A
solution of 7e (33 mg, 0.1 mmol) in THF and methanol (1:1, 2 mL) at rt was added with 0.4 mL
HCl (4 M). The mixture was stirred at room temperature for 18 h, and then NaOH (2 M) was
added to adjust pH value with 7.1-7.3. The reaction mixture was extracted with ethyl acetate and
water for three times. The combined organic phases were washed with brine, dried over Na2SO4,
filtered and concentrated under reduced pressure. The crude product was purified by flash column
chromatography (VDCM/VMeOH = 4:1 as eluent) to afford (R)-Buciclovir (30 mg, 91% yield).
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Characterization of Compounds
N-(1-Allyl-2-oxo-1,2-dihydropyrimidin-4-yl)benzamide (1a)18 White solid, 0.57 g, 53% yield
m.p. 174.4-174.8 oC 1H NMR (400 MHz, CD3OD) δ 8.02 (d, J = 7.2 Hz, 1H), 8.00-7.93 (m, 2H),
7.64 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 6.8 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H), 6.06-5.97 (m, 1H),
5.31-5.23 (m, 2H), 4.55 (d, J = 6.0 Hz, 2H). HRMS (ESI-TOF) calcd for C14H13N3O2Na [M +
Na]+ 278.0900, found 278.0902.
Di-tert-butyl-(1-allyl-2-oxo-1,2-dihydropyrimidin-4-yl)-4-azanedicarboxylate (1b) White solid,
o
1
0.83 g, 56% yield m.p. 102.1-103.2 C H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.2 Hz, 1H),
7.00 (d, J = 7.2 Hz, 1H), 5.97-5.87 (m, 1H), 5.30-5.22 (m, 2H), 4.47 (d, J = 6.0 Hz, 2H), 1.54 (s,
18H). 13C NMR (100 MHz, CDCl3) δ 162.5, 155.0, 149.7, 147.3, 131.8, 119.7, 96.6, 85.0, 52.2,
27.8. HRMS (ESI-TOF) calcd for C17H25N3O5Na [M + Na]+ 374.1686, found 374.1687.
N-(1-Allyl-2-oxo-1,2-dihydropyrimidin-4-yl)isobutyramide (1c) White solid, 0.55 g, 59% yield
m.p. 160.2-160.9 oC 1H NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.41 (d,
J = 7.2 Hz, 1H), 5.98-5.88 (m, 1H), 5.31-5.22 (m, 2H), 4.50 (d, J = 6.0 Hz, 2H), 2.69 (dt, J = 14.0,
6.8 Hz, 1H), 1.19 (d, J = 6.8 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 177.5, 162.7, 155.9, 148.2,
131.7, 119.7, 96.9, 52.2, 36.6, 19.2. HRMS (ESI-TOF) calcd for C11H15N3O2Na [M + Na]+
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244.1056, found 244.1052.
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1-Allyl-4-(benzylamino)pyrimidin-2(1H)-one (1d) White solid, 0.62 g, 61% yield m.p.
172.1-173.2 oC 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 15.2 Hz, 5H), 6.15-5.97 (m, 1H), 5.83
(s, 2H), 5.36 (t, J = 14.0 Hz, 2H), 4.82-4.65 (m, 2H), 4.52 (d, J = 5.2 Hz, 2H). 13C NMR (150
MHz, CDCl3) δ 163.8, 157.0, 143.8, 138.2, 133.0, 128.8, 128.2, 127.6, 118.5, 100.1, 95.2, 51.4,
44.9. HRMS (ESI-TOF) calcd for C14H16N3O [M + H]+ 242.1288, found 242.1289.
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N-(1-(2-Methylallyl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzamide (1e) White solid, 0.56 g,
o
1
51% yield m.p. 138.4-139.6 C H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 7.89 (d, J = 6.6 Hz,
2H), 7.59 (t, J = 7.2 Hz, 2H), 7.49 (t, J = 7.6 Hz, 3H), 5.02 (s, 1H), 4.83 (s, 1H), 4.47 (s, 2H), 1.75
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.3, 155.7, 148.3, 139.7, 133.3, 133.2, 129.1, 127.7,
114.6, 97.0, 54.7, 20.1. HRMS (ESI-TOF) calcd for C15H15N3O2Na [M + Na]+ 292.1056, found
292.1054.
N-(1-(2-Methylenebutyl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzamide (1f) White solid, 0.70 g,
o
1
59% yieldm.p. 145.5-146.7 C H NMR (600 MHz, CDCl3) δ 8.75 (s, 1H), 7.90 (d, J = 5.4 Hz,
2H), 7.67-7.57 (m, 2H), 7.51 (t, J = 7.2 Hz, 3H), 5.05 (s, 1H), 4.87 (s, 1H), 4.52 (s, 2H), 2.06 (q, J
= 7.2 Hz, 2H), 1.09 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 162.2, 148.3, 145.4, 133.3,
129.1, 127.7, 112.6, 97.0, 77.4, 53.8, 26.5, 11.9. HRMS (ESI-TOF) calcd for C16H17N3O2Na [M +
Na]+ 306.1213, found 306.1211.
N-(1-(2-Methylenepentyl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzamide (1g) White solid, 0.67
g, 54% yield m.p. 131.5-132.6 oC 1H NMR (600 MHz, CDCl3) δ 8.77 (s, 1H), 7.90 (d, J = 6.6 Hz,
1H), 7.66 (dd, J = 11.4, 7.8 Hz, 1H), 7.62-7.59 (m, 2H), 7.55-7.50 (m, 2H), 7.47-7.45 (m, 1H),
5.04 (s, 1H), 4.87 (s, 1H), 4.50 (s, 2H), 2.01 (t, J = 7.2 Hz, 2H), 1.53-1.50 (m, 2H), 0.92 (t, J = 7.2
Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 162.2, 143.8, 133.3, 132.3, 132.2, 132.1, 129.2, 128.7,
128.6 127.7, 113.9, 97.0, 53.6, 35.7, 20.7, 13.8. HRMS (ESI-TOF) calcd for C17H20N3O2 [M +
H]+ 298.1550, found 298.1549.
N-(1-(2-Methylenehexyl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzamide (1h) White solid, 0.47 g,
1
36% yield m.p. 119.6-120.1 oC H NMR (600 MHz, CDCl3) δ 8.76 (s, 1H), 7.90 (d, J = 5.4 Hz,
1H), 7.67 (dd, J = 11.4, 7.8 Hz, 1H), 7.62-7.59 (m, 2H), 7.54-7.50 (m, 2H), 7.46 (t, J = 6.0 Hz,
1H), 5.05 (s, 1H), 4.86 (s, 1H), 4.51 (s, 2H), 2.03 (t, J = 7.2 Hz, 2H), 1.48-1.45 (m, 2H), 1.35-1.30
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(m, 2H), 0.90 (t, J = 7.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 162.2, 144.1, 133.3, 132.3,
132.2, 129.2, 128.7, 128.6, 127.7 113.7, 53.6, 33.4, 29.7, 22.5, 14.0. HRMS (ESI-TOF) calcd for
C18H22N3O2 [M + H]+ 312.1707, found 312.1711.
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N-(1-(3-Methyl-2-methylenebutyl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzamide (1i) White
solid, 0.75 g, 63% yield m.p. 138.2-139.3 oC 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 7.90 (d,
J = 5.6 Hz, 2H), 7.59-7.51 (m, 5H), 5.07 (s, 1H), 4.78 (s, 1H), 4.56 (s, 2H), 2.28-2.45 (m, 1H),
1.11 (d, J = 6.4 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 162.2, 150.1, 148.4, 133.3, 132.2, 132.0,
129.1, 128.7, 128.5, 127.7, 111.4, 52.5, 31.8, 21.7. HRMS (ESI-TOF) calcd for C17H20N3O2 [M +
H]+ 298.1550, found 298.1555.
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N-(1-(3,3-Dimethyl-2-methylenebutyl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzamide
(1j)
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White solid, 0.81 g, 62% yield m.p. 202.1-203.1 oC H NMR (600 MHz, CDCl3) δ 8.75 (s, 1H),
7.90 (d, J = 6.0 Hz, 2H), 7.62-7.60 (m, 2H), 7.51 (t, J = 7.2 Hz, 3H), 5.11 (s, 1H), 4.60 (s, 2H),
4.57 (s, 1H), 1.16 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 162.3, 152.1, 133.3, 132.3, 132.2, 129.2,
128.7, 128.6, 127.7, 110.2, 77.4, 50.6, 35.7, 29.3. HRMS (ESI-TOF) calcd for C18H22N3O2 [M +
H]+ 312.1707, found 312.1701.
N-(1-(2-Cyclohexylallyl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzamide (1k) White solid, 0.87 g,
1
61% yield m.p. 207.2-208.2 oC H NMR (600 MHz, CDCl3) δ 8.77 (s, 1H), 7.90 (d, J = 6.0 Hz,
1H), 7.67 (dd, J = 12.0, 7.8 Hz, 1H), 7.62-7.50 (m, 4H), 7.47-7.45 (m, 1H), 5.06 (s, 1H), 4.79 (s,
1H), 4.54 (s, 2H), 1.88-1.77 (m, 6H), 1.68 (d, J = 12.0 Hz, 1H), 1.28 (d, J = 12.0 Hz, 1H),
1.24-1.14 (m, 3H). 13C NMR (150 MHz, CDCl3) δ 162.2, 149.3, 133.3, 132.3, 132.2, 132.1, 129.2,
128.7, 128.6, 127.7, 112.2, 52.7, 42.0, 32.3, 26.6, 26.3. HRMS (ESI-TOF) calcd for C20H24N3O2
[M + H]+ 338.1863, found 338.1868.
N-(2-Oxo-1-(2-(trimethylsilyl)allyl)-1,2-dihydropyrimidin-4-yl)benzamide (1l) White solid,
0.62 g, 45% yield m.p. 162.2-163.4oC 1H NMR (600 MHz, CDCl3) δ 8.93 (s, 1H), 7.92 (d, J = 6.6
Hz, 2H), 7.70-7.55 (m, 2H), 7.50 (t, J = 7.2 Hz, 2H), 7.46 (d, J = 6.0 Hz, 1H), 5.57 (s, 1H), 5.52 (s,
1H), 4.65 (s, 2H), 0.13 (s, 9H). 13C NMR (150 MHz, CDCl3) δ 162.2, 146.5, 133.3, 132.9, 132.3,
132.2, 132.1, 132.0, 129.1, 128.7, 128.6, 127.8, 127.2, 53.7, -1.7. HRMS (ESI-TOF) calcd for
C17H22N3O2Si [M + H]+ 328.1476, found 328.1478.
N-(2-Oxo-1-(2-phenylallyl)-1,2-dihydropyrimidin-4-yl)benzamide (1m) White solid, 0.5 g,
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36% yield m.p. 178.1-179.2 oC H NMR (600 MHz, CDCl3) δ 8.66 (s, 1H), 7.86 (d, J = 7.2 Hz,
2H), 7.60 (t, J = 7.2 Hz, 2H), 7.49 (t, J = 7.8 Hz, 2H), 7.44 (d, J = 7.2 Hz, 3H), 7.34 (t, J = 7.2 Hz,
2H), 7.30 (t, J = 7.2 Hz, 1H), 5.68 (s, 1H), 5.28 (s, 1H), 5.01 (s, 2H). 13C NMR (100 MHz,
CD3OD) δ 164.7, 152.7, 143.3, 134.7, 134.1, 129.8, 129.3, 129.2, 128.6, 127.0, 98.0, 78.0, 68.4,
57.2. HRMS (ESI-TOF) calcd for C20H18N3O2 [M + H]+ 332.1394, found 332.1398.
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N-(5-Methyl-2-oxo-1-(2-phenylallyl)-1,2-dihydropyrimidin-4-yl)benzamide (1n) White solid,
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0.77 g, 53% yield m.p. 194.5-195.4 C H NMR (400 MHz, CD3OD) δ 7.76-7.70 (m, 3H),
7.54-7.50 (m, 3H), 7.47-7.44 (m, 2H), 7.38-7.35 (m, 3H), 5.57 (s, 1H), 5.31 (s, 1H), 4.87 (s, 2H),
1.87 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 179.7, 160.2, 148.7, 142.5, 140.2, 137.3, 137.0,
132.6, 130.0, 129.0, 128.9, 128.2, 126.2, 116.9, 112.1, 50.8, 13.6. HRMS (ESI-TOF) calcd for
C21H20N3O2 [M + H]+ 346.1550, found 346.1559.
N-(5-Fluoro-2-oxo-1-(2-phenylallyl)-1,2-dihydropyrimidin-4-yl)benzamide (1o) Yellow solid,
0.82 g, 56% yield m.p. 207.2-208.2 oC 1H NMR (600 MHz, CDCl3) δ 12.93 (s, 1H), 8.26 (d, J =
7.2 Hz, 2H), 7.54 (t, J = 7.2 Hz, 1H), 7.45-7.42 (m, 4H), 7.40-7.31 (m, 4H), 5.70 (s, 1H), 5.36 (s,
1H), 4.86 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 153.0 (d, JC-F = 18.1 Hz), 147.7, 142.0,
139.9 (d, JC-F = 237.1 Hz), 136.5, 136.1, 133.1, 130.1, 129.1, 129.0, 128.4, 128.2 (d, JC-F = 30.2
Hz), 126.2, 118.2, 51.4. HRMS (ESI-TOF) calcd for C20H16NaFN3O2 [M + Na]+ 372.1119, found
372.1127.
N-(5-Chloro-2-oxo-1-(2-phenylallyl)-1,2-dihydropyrimidin-4-yl)benzamide (1p) Yellow solid,
0.80 g, 52% yield m.p. 163.3-164.5 oC 1H NMR (400 MHz, CDCl3) δ 13.12 (s, 1H), 8.31 (d, J =
7.6 Hz, 2H), 7.54 (t, J = 7.2 Hz, 1H), 7.49-7.42 (m, 5H), 7.39-7.34 (m, 3H), 5.69 (s, 1H), 5.35 (s,
1H), 4.88 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 156.2, 147.9, 142.0, 140.7, 136.5, 133.8, 133.1,
130.3, 130.2, 129.1, 128.6, 128.4, 126.2, 118.1, 109.2, 51.3. HRMS (ESI-TOF) calcd for
C20H16NaClN3O2 [M + Na]+ 388.0823, found 388.0823.
N-(5-Bromo-2-oxo-1-(2-phenylallyl)-1,2-dihydropyrimidin-4-yl)benzamide (1q) Yellow solid,
0.84 g, 49% yield m.p. 170.5-171.2 oC 1H NMR (400 MHz, CDCl3) δ 13.25 (s, 1H), 8.32 (d, J =
7.6 Hz, 2H), 7.59 (s, 1H), 7.56-7.52 (m, 1H), 7.49-7.30 (m, 7H), 5.69 (s, 1H), 5.34 (s, 1H), 4.87 (s,
2H). 13C NMR (100 MHz, CDCl3) δ 156.4, 148.0, 143.4, 142.1, 136.6, 133.1, 130.3, 129.1, 128.6,
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128.4, 126.3, 118.0, 97.3, 51.4. HRMS (ESI-TOF) calcd for C20H17BrN3O2 [M + H]+ 410.0499,
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found 410.0492.
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N-(2-Oxo-1-(2-phenylallyl)-1,2-dihydropyrimidin-4-yl)ditert-butoxycarbonylamide
(1r)
White solid, 1.02 g, 57% yield m.p. 161.1-162.2oC 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 7.2
Hz, 1H), 7.42 (dd, J = 8.0, 1.6 Hz, 2H), 7.36-7.27 (m, 3H), 6.93 (d, J = 7.6 Hz, 1H), 5.64 (s, 1H),
5.25 (s, 1H), 4.95 (s, 2H), 1.53 (s, 18H). 13C NMR (150 MHz, CDCl3) δ 162.3, 155.2, 149.7,
146.6, 142.5, 137.1, 129.0, 128.7, 126.3, 117.4, 96.6, 85.0, 52.1, 27.8. HRMS (ESI-TOF) calcd
for C23H30N3O5 [M + H]+ 428.2180, found 428.2171.
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3-Benzo-N-(2-oxo-1-(2-phenylallyl)-1,2-dihydropyrimidin-4-yl)acetamide (1s) Brown solid,
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0.44 g, 39% yield m.p. 190.2-191.3 oC H NMR (600 MHz, CDCl3) δ 9.73 (s, 1H), 7.55 (d, J =
7.8 Hz, 1H), 7.42-7.41 (m, J = 8.1, 2H), 7.34-7.29 (m, 4H), 5.64 (s, 1H), 5.24 (s, 1H), 4.98 (s, 2H),
2.23 (s, 3H). 13C NMR (150 MHz, CD3OD) δ 173.0, 164.3, 158.7, 150.4, 144.7, 139.2, 129.7,
129.5, 127.4, 116.0, 98.2, 53.5, 24.5. HRMS (ESI-TOF) calcd for C15H16N3O2 [M + H]+ 270.1237,
found 270.1231.
3-Benzoyl-5-methyl-1-(2-phenylallyl)pyrimidine-2,4(1H,3H)-dione (3a) White solid, 0.50 g,
52% yield m.p. 134.0-135.2 oC 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 7.6 Hz, 2H), 7.63 (t, J
= 7.2 Hz, 1H), 7.47-7.42 (m, 4H), 7.37 (s, 3H), 7.06 (s, 1H), 5.63 (s, 1H), 5.34 (s, 1H), 4.83 (s,
2H), 1.89 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 168.9, 163.0, 150.1, 143.1, 138.5, 137.1, 135.1,
131.7, 130.6, 129.2, 129.0, 128.9, 126.5, 117.3, 111.4, 50.4, 12.6. HRMS (ESI-TOF) calcd for
C21H18N2NaO3 [M + Na]+ 369.1210, found 369.1207.
3-Benzoyl-5-fluoro-1-(2-phenylallyl)pyrimidine-2,4(1H,3H)-dione (3b) White solid, 0.82 g,
56% yield m.p. 129.9-130.3 oC 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.6 Hz, 2H), 7.67 (t, J
= 7.2 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 7.42-7.38 (m, 5H), 7.31 (d, J = 5.6 Hz, 1H), 5.68 (s, 1H),
5.41 (s, 1H), 4.84 (s, 2H). 13C{1H} NMR (150 MHz, CDCl3) δ 167.1, 156.1 (d, JC-F = 27.0 Hz),
148.6, 142.5, 140.3 (d, JC-F = 238.5 Hz), 136.5, 135.5, 131.0, 130.7, 129.4, 129.1, 129.0, 126.7 (d,
JC-F = 35.0 Hz), 126.5, 118.5, 51.0. HRMS (ESI-TOF) calcd for C20H15FN2NaO3 [M + Na]+
373.0959, found 373.0959.
N-(5-Chloro-2-oxo-1-(2-phenylallyl)-1,2-dihydropyrimidin-4-yl)benzamide (3c) Yellow solid,
0.97 g, 63% yield m.p. 151.5-151.9oC 1H NMR (600 MHz, CDCl3) δ 7.76-7.74 (m, 2H), 7.66 (t, J
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= 7.2 Hz, 1H), 7.48-7.45 (m, 3H), 7.42-7.40 (m, 2H), 7.39-7.36 (m, 3H), 5.68 (s, 1H), 5.41 (s, 1H),
4.87 (s, 2H). 13C NMR (150 MHz, CDCl3) δ 167.3, 158.1, 149.1, 142.5, 139.4, 136.5, 135.5,
131.0, 130.7, 129.4, 129.1, 129.0, 126.5, 118.4, 109.3, 51.0. HRMS (ESI-TOF) calcd for
C20H15ClN2NaO3 [M + Na]+ 389.0663, found 389.0659.
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N-(5-Bromo-2-oxo-1-(2-phenylallyl)-1,2-dihydropyrimidin-4-yl)benzamide (3d) White solid,
0.95 g, 55% yield m.p. 161.9-163.1 oC 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 6.8 Hz, 2H),
7.66 (s, 1H), 7.57 (s, 1H), 7.46-7.34 (m, 7H), 5.68 (s, 1H), 5.40 (s, 1H), 4.87 (s, 2H). 13C NMR
(150 MHz, CDCl3) δ 167.4, 158.1, 149.4, 142.5, 142.0, 136.6, 135.4, 131.0, 130.7, 129.4, 129.2,
129.1, 126.5, 118.3, 97.0, 51.1. HRMS (ESI-TOF) calcd for C20H15BrN2NaO3 [M + Na]+
433.0158, found 433.0150.
N-(5-Iodo-2-oxo-1-(2-phenylallyl)-1,2-dihydropyrimidin-4-yl)benzamide (3e) White solid,
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0.94 g, 49% yield m.p. 153.9-154.5 oC H NMR (600 MHz, CDCl3) δ 7.74 (d, J = 7.8 Hz, 2H),
7.70-7.62 (m, 2H), 7.46 (t, J = 7.2 Hz, 2H), 7.39 (d, J = 13.8 Hz, 5H), 5.66 (s, 1H), 5.38 (s, 1H),
4.86 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 167.6, 159.0, 149.7, 147.2, 142.6, 136.7, 135.3,
131.0, 130.6, 129.3, 129.1, 129.0, 126.5, 118.1, 100.1, 68.2, 51.0. HRMS (ESI-TOF) calcd for
C20H15IN2NaO3 [M + Na]+ 481.0020, found 481.0014
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6-Chloro-9-(2-phenylallyl)-9H-purine (5a) White solid, 0.61 g, 54% yield m.p. 87.1-88.2 oC H
NMR (600 MHz, CD3OD) δ 8.74 (s, 1H), 8.47 (s, 1H), 7.48 (d, J = 7.2 Hz, 2H), 7.32-7.24 (m,
3H), 5.58 (s, 1H), 5.44 (s, 2H), 5.17 (s, 1H). 13C NMR (100 MHz, CD3OD) δ 153.3, 153.1, 151.3,
148.3, 144.3, 138.9, 132.0, 129.7, 129.6, 127.3, 116.7, 48.6. HRMS (ESI-TOF) calcd for
C14H12ClN4 [M + H]+ 271.0745, found 271.0755.
6-Methoxy-9-(2-phenylallyl)-9H-purine (5b) White solid, 0.70 g, 63% yield m.p. 110.8-111.5 oC
1H NMR (600 MHz, CDCl3) δ 8.57 (s, 1H), 7.86 (s, 1H), 7.42 (d, J = 7.2 Hz, 2H), 7.31-7.27 (m,
3H), 5.59 (s, 1H), 5.27 (s, 2H), 5.13 (s, 1H), 4.17 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 161.2,
152.3, 152.2, 142.6, 142.2, 137.4, 128.9, 128.7, 126.1, 121.4, 116.3, 54.3, 47.3. HRMS (ESI-TOF)
calcd for C15H15N4O [M + H]+ 267.1240, found 267.1237.
9-(2-Phenylallyl)-6-(piperidin-1-yl)-9H-purine (5c) White solid, 0.60 g, 45% yield m.p.
105.5-106.4 oC 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.67 (s, 1H), 7.45 (dd, J = 8.4, 2.0 Hz,
2H), 7.35-7.27 (m, 3H), 5.59 (s, 1H), 5.20 (s, 2H), 5.10 (s, 1H), 4.22 (s, 4H), 1.73-1.67 (m, 6H).
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13C NMR (150 MHz, CDCl3) δ 154.1, 152.8, 151.0, 142.8, 138.0, 137.7, 128.8, 128.6, 126.2,
119.7, 115.9, 46.8, 26.3, 25.0. HRMS (ESI-TOF) calcd for C19H22N5 [M + H]+ 320.1870, found
320.1863.
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9-(2-Phenylallyl)-6-(propylthio)-9H-purine (5d) Yellow oil, 0.76 g, 56% yield H NMR (600
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MHz, CDCl3) δ 8.68 (s, 1H), 7.84 (s, 1H), 7.37 (d, J = 7.2 Hz, 2H), 7.25-7.21 (m, 3H), 5.55 (s,
1H), 5.20 (s, 2H), 5.09 (s, 1H), 3.31 (t, J = 7.2 Hz, 2H), 1.76 (dd, J = 14.4, 7.2 Hz, 2H), 1.02 (t, J
= 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 161.8, 152.2, 148.5, 142.5, 137.3, 131.2, 128.9,
128.8, 126.1, 116.4, 100.1, 47.1, 30.9, 23.0, 13.6. HRMS (ESI-TOF) calcd for C17H19N4S [M +
H]+ 311.1325, found 311.1318.
6-(Benzyloxy)-9-(3-(triethylsilyl)but-3-en-1-yl)-9H-purin-2-amine (5e) White solid, 0.61 g,
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36% yield m.p. 123.3-123.9 oC H NMR (400 MHz, CDCl3) δ 7.56 (s, 1H), 7.50 (d, J = 6.8 Hz,
2H), 7.37-7.28 (m, 3H), 5.62 (s, 1H), 5.57 (s, 2H), 5.42 (s, 1H), 4.88 (s, 2H), 4.12 (t, J = 7.6 Hz,
2H), 2.61 (t, J = 7.2 Hz, 2H), 0.93 (t, J = 8.0 Hz, 9H), 0.63 (q, J = 8.0 Hz, 6H). 13C NMR (150
MHz, CDCl3) δ 161.2, 159.2, 154.1, 144.8, 139.6, 136.6, 128.5, 128.4, 128.3, 128.1, 115.8, 68.2,
43.1, 35.7, 7.4, 2.9. HRMS (ESI-TOF) calcd for C22H32N5OSi [M + H]+ 410.2371, found
410.2372
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9-Cinnamyl-9H-purin-6-amine (5f) White solid, 1.17 g, 65% yield m.p. 235.4-236.7 C H
NMR (400 MHz, d6-DMSO) δ 8.18 (s, 1H), 8.15 (s, 1H), 7.42 (d, J = 7.2 Hz, 2H), 7.32 (t, J = 3.6
Hz, 2H), 7.25 (d, J = 7.2 Hz, 1H), 7.22 (s, 2H), 6.53-6.51 (m, 2H), 4.94 (d, J = 4.0 Hz, 2H). 13C
NMR (100 MHz, d6-DMSO) δ 156.0, 152.5, 149.4, 140.6, 135.9, 132.4, 128.7, 127.9, 126.5,
124.7, 118.7, 44.6. HRMS (ESI-TOF) calcd for C14H14N5 [M + H]+ 252.1244, found 252.1241.
Ethyl (E)-4-(6-amino-9H-purin-9-yl)but-2-enoate (5g) White solid, 0.84 g, 47% yield m.p.
133.3-133.9 oC 1H NMR (400 MHz, d6-DMSO) δ 8.43 (s, 1H), 8.20 (s, 1H), 7.35 (s, 2H), 7.22 (d,
J = 14.4 Hz, 1H), 6.70-6.63 (m, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.32 (dd, J = 7.2, 1.2 Hz, 2H), 1.21
(t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, d6-DMSO) δ 170.9, 156.1, 153.1, 148.6, 138.8, 123.7,
119.1, 112.6, 60.4, 34.8, 14.1. HRMS (ESI-TOF) calcd for C11H14N5O2 [M + H]+ 248.1142, found
248.1142.
9-Allyl-9H-purin-6-amine (5h) White solid, 1.29 g, 74% yield m.p. 73.9-75.3 oC 1H NMR (600
MHz, CDCl3) δ 8.37 (s, 1H), 7.80 (s, 1H), 6.07-6.00 (m, 3H), 5.31 (d, J = 10.2 Hz, 1H), 5.20 (d, J
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= 16.8 Hz, 1H), 4.81 (d, J = 5.4 Hz, 2H). HRMS (ESI-TOF) calcd for C8H10N5 [M + H]+
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(E)-9-(3-(Trimethylsilyl)allyl)-9H-purin-6-amine (5i) White solid, 1.24 g, 70% yield m.p.
198.2.3-199.9 oC 1H NMR (600 MHz, CDCl3) δ 8.36 (s, 1H), 7.79 (s, 1H), 6.15 (dt, J = 18.6, 4.8
Hz, 1H), 5.98 (s, 2H), 5.75 (d, J = 18.6 Hz, 1H), 4.84 (d, J = 3.6 Hz, 2H), 0.04 (s, 9H). 13C NMR
(150 MHz, CDCl3) δ 155.7, 153.3, 150.1, 140.6, 138.8, 134.6, 119.6, 47.8, -1.4. HRMS (ESI-TOF)
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calcd for C11H18N5Si [M + H]+ 248.1326, found 248.1327.
(S)-4-(Benzoyl-l2-azanyl)-1-(2,3-dihydroxypropyl)pyrimidin-2(1H)-one (2a) White solid, 10.9
mg, 69% yield, 95% ee. [α]20D = -65.00 (c = 0.30, CH3OH). (Reported: [α]20D = -81.95 (c = 1.09,
CH3OH), > 99% ee)5 m.p. 189.1-191.9 oC. TLC: Rf = 0.36 (dichloromethane:methanol = 25:1)
[UV]. The ee value was determined by chiral HPLC OD-H, n-hexane/2-propanol = 70/30, flow
rate 0.8 mL/min, λ = 250 nm, retention time: 14.072 min (minor), 19.470 min (major). 1H NMR
(400 MHz, CD3OD) δ 8.03 (d, J = 7.2 Hz, 1H), 7.98 (d, J = 7.2 Hz, 2H), 7.65 (t, J = 7.2 Hz, 1H),
7.57-7.53 (m, 3H), 4.28 (dd, J = 13.6, 3.6 Hz, 1H), 4.00 (dd, J = 8.4, 3.2 Hz, 1H), 3.74 (dd, J =
13.6, 8.4 Hz, 1H), 3.58 (d, J = 5.2 Hz, 2H). 13C NMR (150 MHz, d6-DMSO) δ 167.7, 163.4,
156.0, 152.1, 133.7, 133.1, 128.9, 128.8, 95.7, 69.1, 64.2, 53.6. HRMS (ESI-TOF) calcd for
C14H15N3NaO4 [M + Na]+ 312.0955, found 312.0956.
(S)-N-(1-(2,3-Dihydroxy)-2-oxo-1,2-dihydropyrimidin-4-yl) di-tert-butoxycarbonylamide (2b)
White solid, 17.5 mg, 91% yield, 38% ee. [α]25 = -7.94 (c = 1.0, CH3OH), m.p. 128.1-128.9 oC.
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TLC: Rf = 0.42 (dichloromethane:methanol = 30:1) [UV]. The ee value was determined by chiral
HPLC AS-H, n-hexane/2-propanol = 90/10, flow rate 0.8 mL/min, λ = 250 nm, retention time:
21.081 min (minor), 30.753 min (major). 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.2 Hz, 1H),
7.04 (d, J = 7.2 Hz, 1H), 4.19 (s, 1H), 4.11-4.06 (m, 1H), 3.98 (s, 1H), 3.84-3.77 (m, 1H), 3.73 (s,
1H), 3.54 (s, 2H), 1.53 (s, 18H). 13C NMR (100 MHz, CDCl3) δ 162.6, 156.6, 150.1, 149.6, 96.6,
85.2, 69.8, 63.6, 53.3, 27.8. HRMS (ESI-TOF) calcd for C17H27N3NaO7 [M + Na]+ 408.1741,
found 408.1741.
(S)-N-(1-(2,3-Dihydroxypropyl)-2-oxo-1,2-dihydropyrimidin-4-yl)isobutyramide (2c) White
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solid, 11.3 mg, 89% yield, 62% ee. [α]25D = -15.3 (c = 0.5, CH3OH), m.p. 181.2-182.3 oC. TLC: Rf
= 0.32 (dichloromethane:methanol = 25:1) [UV]. The ee value was determined by chiral HPLC
OD-H, n-hexane/2-propanol = 90/10, flow rate 0.8 mL/min, λ = 250 nm, retention time: 21.843
min (minor), 26.312 min (major). 1H NMR (400 MHz, CD3OD) δ 7.95 (d, J = 7.6 Hz, 1H), 7.42
(d, J = 7.2 Hz, 1H), 4.24 (dd, J = 13.2, 3.2 Hz, 1H), 4.00-3.94 (m, 1H), 3.71 (dd, J = 13.6, 8.4 Hz,
1H), 3.56 (d, J = 5.2 Hz, 2H), 2.72-2.65 (m, 1H), 1.18 (d, J = 6.8 Hz, 6H). 13C NMR (100 MHz,
CD3OD) δ 179.7, 164.6, 159.1, 152.4, 97.6, 70.4, 64.9, 54.7, 37.2, 19.4. HRMS (ESI-TOF) calcd
for C11H17N3NaO4 [M + Na]+ 278.1111, found 278.1112.
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(S)-4-(Benzylamino)-1-(2,3-dihydroxypropyl)pyrimidin-2(1H)-one (2d) White solid, 13.2 mg,
96% yield, 72% ee. [α]25 = -23.5 (c = 1.25, CH3OH), m.p. 192.3-193.1 oC. TLC: Rf = 0.39
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(dichloromethane:methanol = 25:1) [UV]. The ee value was determined by chiral HPLC IE,
n-hexane/2-propanol = 60/40, flow rate 0.8 mL/min, λ = 250 nm, retention time: 17.112 min
(major), 23.875 min (minor). 1H NMR (400 MHz, CD3OD) δ 7.45 (d, J = 7.2 Hz, 1H), 7.34-7.28
(m, 4H), 7.26-7.25 (m, 1H), 5.84 (d, J = 7.2 Hz, 1H), 4.58 (dd, J = 18.0, 14.8 Hz, 2H), 4.05 (dd, J
= 13.6, 3.6 Hz, 1H), 3.94-3.90 (m, 1H), 3.61 (dd, J = 13.6, 7.6 Hz, 1H), 3.52 (d, J = 5.2 Hz, 2H).
13C NMR (150 MHz, CD3OD) δ 165.8, 160.0, 147.5, 139.8, 129.5, 128.8, 128.3, 96.2, 71.1, 64.7,
53.7, 45.2. HRMS (ESI-TOF) calcd for C14H17N3NaO3 [M + Na]+ 298.1162, found 298.1163.
(S)-N-(1-(2,3-Dihydroxy-2-methylpropyl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzamide (2e)
White solid, 14.5 mg, 95% yield, 90% ee. [α]25 = -31.6 (c = 1.7, CH3OH), m.p. 177.2-178.3 oC.
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TLC: Rf = 0.41 (dichloromethane:methanol = 30:1) [UV]. The ee value was determined by chiral
HPLC OD-H, n-hexane/2-propanol = 80/20, flow rate 0.8 mL/min, λ = 250 nm, retention time:
28.248 min (minor), 32.724 min (major). 1H NMR (600 MHz, CD3OD) δ 8.05 (d, J = 7.2 Hz, 1H),
7.98 (d, J = 7.8 Hz, 2H), 7.67-7.63 (m, 1H), 7.59-7.53 (m, 3H), 4.06 (dd, J = 13.8, J = 9.6 Hz,
2H), 3.35 (dd, J = 11.4, 6.0 Hz, 2H), 1.20 (s, 3H). 13C NMR (100 MHz, CD3OD) δ 169.1, 164.8,
159.9, 152.9, 134.7, 134.1, 129.8, 129.1, 98.2, 73.9, 68.2, 56.6, 22.8. HRMS (ESI-TOF) calcd for
C15H17N3NaO4 [M + Na]+ 326.1111, found 326.1116.
(S)-N-(1-(2-Hydroxy-2-(hydroxymethyl)butyl)-2-oxo-1,2-dihydropyrimidin-4-yl) benzamide
(2f) White solid, 15.3 mg, 97% yield, 93% ee. [α]25D = -40.2 (c = 0.6, CH3OH), m.p. 205.2-206.7
oC. TLC: Rf = 0.43 (dichloromethane:methanol = 30:1) [UV]. The ee value was determined by
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chiral HPLC OD-H, n-hexane/2-propanol = 80/20, flow rate 0.8 mL/min, λ = 250 nm, retention
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Hz, 2H), 4.20 (d, J = 13.8 Hz, 1H), 3.91 (d, J = 13.8 Hz, 1H), 3.37 (d, J = 11.4 Hz, 1H), 3.27 (d, J
= 11.4 Hz, 1H), 1.69-1.54 (m, 2H), 0.99 (t, J = 7.8 Hz, 3H). 13C NMR (100 MHz, CD3OD) δ
164.9, 153.1, 134.7, 134.1, 130.9, 129.8, 129.2, 98.3, 75.7, 64.5, 55.9, 29.0, 7.3. HRMS (ESI-TOF)
calcd for C16H19N3NaO4 [M + Na]+ 340.1268, found 340.1270.
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(S)-N-(1-(2-Hydroxy-2-(hydroxymethyl)pentyl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzamide
(2g) White solid, 14.0 mg, 90% yield, 96% ee. [α]25D = -43.1 (c = 0.8, CH3OH), m.p. 151.9-152.6
oC. TLC: Rf = 0.39 (dichloromethane:methanol = 35:1) [UV].The ee value was determined by
chiral HPLC IA, n-hexane/2-propanol = 70/30, flow rate 0.8 mL/min, λ = 250 nm, retention time:
36.190 min (minor), 43.572 min (major). 1H NMR (400 MHz, CD3OD) δ 8.04 (d, J = 7.2 Hz, 1H),
7.98 (d, J = 7.6 Hz, 2H), 7.67-7.53 (m, 4H), 4.19 (d, J = 13.9 Hz, 1H), 3.91 (d, J = 13.6 Hz, 1H),
3.36 (d, J = 11.6 Hz, 1H), 3.26 (d, J = 11.6 Hz, 1H), 1.61-1.39 (m, 4H), 0.96 (t, J = 6.4 Hz, 3H).
13C NMR (100 MHz, CD3OD) δ 164.9, 153.1, 134.7, 134.1, 129.8, 129.2, 101.4, 98.3, 75.6, 65.1,
56.1, 39.0, 17.0, 15.0. HRMS (ESI-TOF) calcd for C17H21N3NaO4 [M + Na]+ 354.1424, found
354.1428.
(S)-N-(1-(2-Hydroxy-2-(hydroxymethyl)hexyl)-2-oxo-1,2-dihydropyrimidin-4-yl) benzamide
(2h) White solid, 15.4 mg, 89% yield, 94% ee. [α]25 = 31.6 (c =2.2, CH3OH), m.p. 157.9-158.3
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oC. TLC: Rf = 0.41 (dichloromethane:methanol = 35:1) [UV]. The ee value was determined by
chiral HPLC IE, n-hexane/2-propanol = 70/30, flow rate 0.8 mL/min, λ = 250 nm, retention time:
23.802 min (minor), 35.495 min (major). 1H NMR (400 MHz, CD3OD) δ 8.04 (d, J = 7.2 Hz, 1H),
8.01-7.97 (m, 2H), 7.67-7.53 (m, 4H), 4.19 (d, J = 13.6 Hz, 1H), 3.91 (d, J = 14.0 Hz, 1H), 3.36 (d,
J = 11.6 Hz, 1H), 3.26 (d, J = 11.6 Hz, 1H), 1.67-1.48 (m, 2H), 1.47-1.31 (m, 4H), 0.95 (t, J = 7.2
Hz, 3H). 13C NMR (100 MHz, CD3OD) δ 164.9, 153.1, 134.7, 134.1, 129.8, 129.2, 98.3, 75.6,
65.1, 56.1, 36.4, 25.9, 24.4, 14.4. HRMS (ESI-TOF) calcd for C18H23N3NaO4 [M + Na]+ 368.1581,
found 368.1591.
(S)-N-(1-(2-Hydroxy-2-(hydroxymethyl)-3-methylbutyl)-2-oxo-1,2-dihydropyrimidin-4-yl)be
nzamide (2i) White solid, 13.7 mg, 82% yield, 92% ee. [α]25 = -40.9 (c = 0.2, CH3OH), m.p.
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162.3-163.2 C. TLC: Rf = 0.39 (dichloromethane:methanol = 35:1) [UV]. The ee value was
determined by chiral HPLC OD-H, n-hexane/2-propanol = 70/30, flow rate 0.8 mL/min, λ = 250
nm, retention time: 16.276 min (minor), 19.138 min (major). 1H NMR (400 MHz, CD3OD) δ 8.05
(d, J = 7.6 Hz, 1H), 7.98-7.97 (m, 2H), 7.66-7.52 (m, 4H), 4.33 (d, J = 14.0 Hz, 1H), 3.89 (d, J =
14.0 Hz, 1H), 3.44 (d, J = 11.6 Hz, 1H), 3.24 (d, J = 11.6 Hz, 1H), 2.03-1.96 (m, 1H), 1.04 (t, J =
7.2 Hz, 6H). 13C NMR (100 MHz, CD3OD) δ 169.1, 164.8, 160.5, 153.3, 134.7, 134.1, 129.8,
129.2, 98.3, 97.0, 77.1, 63.5, 54.7, 33.6, 17.2, 17.0. HRMS (ESI-TOF) calcd for C17H21N3NaO4
[M + Na]+ 354.1424, found 354.1430.
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(S)-N-(1-(2-Hydroxy-2-(hydroxymethyl)-3,3-dimethylbutyl)-2-oxo-1,2-dihydropyrimidin-4-yl
)benzamide (2j) White solid, 16.1 mg, 93% yield, 94% ee. [α]25D = 47.33 (c = 1.7, CH3OH), m.p.
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74.9-75.6 C. TLC: Rf = 0.38 (dichloromethane:methanol = 40:1) [UV]. The ee value was
determined by chiral HPLC OD-H, n-hexane/2-propanol = 70/30, flow rate 0.8 mL/min, λ = 250
nm, retention time: 23.010 min (minor), 28.112 min (major). 1H NMR (600 MHz, CD3OD) δ 8.08
(d, J = 7.2 Hz, 1H), 7.99 (d, J = 7.8 Hz, 2H), 7.65 (t, J = 7.2 Hz, 1H), 7.60 (d, J = 6.6 Hz, 1H),
7.55 (t, J = 7.2 Hz, 2H), 4.58 (d, J = 14.4 Hz, 1H), 3.96 (d, J = 13.8 Hz, 1H), 3.66 (d, J = 12.0 Hz,
1H), 3.28 (d, J = 12.6 Hz, 1H), 1.10 (s, 9H). 13C NMR (100 MHz, CD3OD) δ 164.8, 153.7, 134.7,
134.1, 129.9, 129.2, 98.3, 77.9, 63.7, 53.5, 38.2, 26.1. HRMS (ESI-TOF) calcd for C18H23N3NaO4
[M + Na]+ 368.1581, found 368.1582.
(S)-N-(1-(2-Cyclohexyl-2,3-dihydroxypropyl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzamide
(2k) White solid, 16.3 mg, 88% yield, 93% ee. [α]25 = -30.76 (c = 1.5, CH3OH), m.p.
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214.9-215.7 C. TLC: Rf = 0.36 (dichloromethane:methanol = 35:1) [UV]. The ee value was
determined by chiral HPLC IA, n-hexane/2-propanol = 80/20, flow rate 0.8 mL/min, λ = 250 nm,
retention time: 13.956 min (minor), 16.616 min (major). 1H NMR (600 MHz, d6-DMSO) δ 11.20
(s, 1H), 8.03 (d, J = 6.6 Hz, 1H), 8.01 (d, J = 7.8 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H), 7.51 (t, J = 7.2
Hz, 2H), 7.34 (d, J = 5.4 Hz, 1H), 4.68-4.62 (m, 2H), 4.12 (d, J = 13.8 Hz, 1H), 3.81 (d, J = 13.8
Hz, 1H), 3.23 (dd, J = 11.4, 7.8 Hz, 1H), 3.09 (dd, J = 11.4, 4.2 Hz, 1H), 1.81 (dd, J = 23.4, 10.8
Hz, 2H), 1.73 (s, 2H), 1.61 (d, J = 10.8 Hz, 1H), 1.50 (t, J = 10.2 Hz, 1H), 1.22-1.05 (m, 5H). 13
C
NMR (100 MHz, d6-DMSO) δ 167.2, 163.0, 157.2, 152.1, 133.1, 132.7, 128.5, 95.8, 75.3, 62.1,
52.7, 42.4, 26.5, 26.4, 26.2, 26.1. HRMS (ESI-TOF) calcd for C20H25N3NaO4 [M + Na]+ 394.1737,
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found 394.1739.
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(R)-N-(1-(2,3-Dihydroxy-2-(trimethylsilyl)propyl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzami
de (2l) White solid, 16.4 mg, 91% yield, 95% ee. [α]25 = 53.15 (c =1.0, CH3OH), m.p.
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151.2-152.8 C. TLC: Rf = 0.34 (dichloromethane:methanol = 50:1) [UV]. The ee value was
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determined by chiral HPLC OD-H, n-hexane/2-propanol = 80/20, flow rate 0.8 mL/min, λ = 250
nm, retention time: 24.481 min (minor), 39.200 min (major). 1H NMR (600 MHz, CD3OD) δ 8.06
(d, J = 7.2 Hz, 1H), 7.98 (d, J = 7.8 Hz, 2H), 7.64 (t, J = 7.2 Hz, 1H), 7.59 (d, J = 7.2 Hz, 1H),
7.55 (t, J = 7.2 Hz, 2H), 4.47 (d, J = 14.4 Hz, 1H), 4.01 (d, J = 14.4 Hz, 1H), 3.54 (d, J = 11.4 Hz,
1H), 3.40 (d, J = 11.4 Hz, 1H), 0.16 (s, 9H). 13C NMR (150 MHz, CD3OD) δ 164.8, 153.2, 134.7,
134.1, 129.8, 129.2, 98.1, 70.6, 65.2, 55.0, -3.4. HRMS (ESI-TOF) calcd for C17H23N3NaSiO4 [M
+ Na]+ 384.1350, found 384.1359.
(S)-N-(1-(2,3-Dihydroxy-2-phenylpropyl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzamide (2m)
White solid, 16.9 mg, 93% yield, 99% ee. [α]25 = -38.3 (c = 1.4, CH3OH), m.p. 147.5-148.2 oC.
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TLC: Rf = 0.38 (dichloromethane:methanol = 50:1) [UV]. The ee value was determined by chiral
HPLC OD-H, n-hexane/2-propanol = 70/30, flow rate 0.8 mL/min, λ = 250 nm, retention time:
18.287 min (major), 24.454 min (minor). 1H NMR (400 MHz, CD3OD) δ 7.96 (d, J = 7.2 Hz, 1H),
7.88 (d, J = 7.6 Hz, 2H), 7.63 (t, J = 7.2 Hz, 1H) 7.54 (dd, J = 15.2, 7.6 Hz, 4H), 7.46 (d, J = 7.2
Hz, 1H), 7.35 (t, J = 7.2 Hz, 2H), 7.27 (t, J = 7.2 Hz, 1H), 4.62 (d, J = 14.0 Hz, 1H), 4.17 (d, J =
14.0 Hz, 1H), 3.78 (d, J = 11.6 Hz, 1H), 3.69 (d, J = 11.6 Hz, 1H). 13C NMR (100 MHz, CD3OD)
δ 164.7, 152.7, 143.3, 134.7, 134.1, 129.8, 129.3, 129.2, 128.6, 127.0, 98.0, 78.0, 68.4, 57.2.
HRMS (ESI-TOF) calcd for C20H19N3NaO4 [M + Na]+ 388.1268, found 388.1267.
(S)-N-(1-(2,3-Dihydroxy-2-phenylpropyl)-5-methyl-2-oxo-1,2-dihydropyrimidin-4-yl)benzam
ide (2n) White solid, 15.9 mg, 84% yield, 98% ee. [α]25 = -93.0 (c = 0.4, CH3OH), m.p.
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171.0-171.8 C. TLC: Rf = 0.36 (dichloromethane:methanol = 50:1) [UV]. The ee value was
determined by chiral HPLC IA, n-hexane/2-propanol = 80/20, flow rate 0.8 mL/min, λ = 250 nm,
retention time: 23.040 min (minor), 27.874 min (major). 1H NMR (400 MHz, CD3OD) δ 8.22 (s,
2H), 7.54 (d, J = 7.2 Hz, 3H), 7.45 (t, J = 7.2 Hz, 3H), 7.38-7.33 (m, 2H), 7.30-7.26 (m, 1H), 4.37
(d, J = 7.2 Hz, 1H), 4.08 (d, J = 14.0 Hz, 1H), 3.83 (d, J = 11.6 Hz, 1H), 3.73 (d, J = 11.6 Hz, 1H),
2.00 (s, 3H).13C NMR (100 MHz, CD3OD) δ 170.2, 165.0, 144.6, 136.2, 132.8, 131.4, 130.9,
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130.3, 129.2, 129.0, 128.6, 127.1, 126.5, 109.9, 78.1, 68.7, 12.2. HRMS (ESI-TOF) calcd for
C21H21N3NaO4 [M + Na]+ 402.1424, found 402.1429.
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(S)-N-(1-(2,3-Dihydroxy-2-phenylpropyl)-5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)benzami
de (2o) White solid, 16.7 mg, 87% yield, 99% ee. [α]25 = -79.3 (c = 0.6, CH3OH), m.p.
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162.7-163.5 C. TLC: Rf = 0.37 (dichloromethane:methanol = 50:1) [UV]. The ee value was
determined by chiral HPLC OD-H, n-hexane/2-propanol = 70/30, flow rate 0.8 mL/min, λ = 250
nm, retention time: 15.469 min (minor), 19.806 min (major). 1H NMR (600 MHz, CD3OD) δ 7.99
(d, J = 24.0 Hz, 3H), 7.61 (t, J = 7.2 Hz, 1H), 7.56 (d, J = 7.2 Hz, 2H), 7.50 (t, J = 7.8 Hz, 2H),
7.35 (t, J = 7.8 Hz, 2H), 7.27 (t, J = 7.2 Hz, 1H), 4.48 (d, J = 6.0 Hz, 1H), 4.15 (d, J = 14.4 Hz,
1H), 3.80 (d, J = 11.4 Hz, 1H), 3.71 (d, J = 11.4 Hz, 1H). 13C{1H} NMR (150 MHz, CD3OD) δ
143.0, 140.5, 138.9, 134.2, 130.5, 130.0, 129.6, 129.5, 129.3，129.2, 128.6, 126.9, 126.3, 77.9,
68.4, 56.9. HRMS (ESI-TOF) calcd for C20H18FN3NaO4 [M + Na]+ 406.1174, found 406.1183.
(S)-N-(5-Chloro-1-(2,3-dihydroxy-2-phenylpropyl)-2-oxo-1,2-dihydropyrimidin-4-yl)
benzamide (2p) White solid, 16.2 mg, 81% yield, 97% ee. [α]25D = -73.1 (c = 1.2, CH3OH), m.p.
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71.4-72.5 C. TLC: Rf = 0.38 (dichloromethane:methanol = 50:1) [UV]. The ee value was
determined by chiral HPLC AS-H, n-hexane/2-propanol = 50/50, flow rate 0.8 mL/min, λ = 250
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nm, retention time: 18.957 min (minor), 28.531 min (major). H NMR (400 MHz, CD3OD) δ
8.36-7.78 (m, 3H), 7.62-7.51 (m, 3H), 7.47 (d, J = 6.4 Hz, 2H), 7.35 (t, J = 7.2 Hz, 2H), 7.27 (t, J
= 7.2 Hz, 1H), 4.39 (s, 1H), 4.13 (d, J = 13.6 Hz, 1H), 3.84 (d, J = 11.2 Hz, 1H), 3.72 (d, J = 11.6
Hz, 1H). 13C NMR (100 MHz, CD3OD) δ 167.4, 150.3, 142.4, 140.1, 135.5, 131.0, 130.7, 129.4,
129.1, 128.6, 125.5, 108.4, 67.4, 55.0, 29.5. HRMS (ESI-TOF) calcd for C20H18ClN3NaO4 [M +
Na]+ 422.0878, found 422.0888.
(S)-N-(5-Bromo-1-(2,3-dihydroxy-2-phenylpropyl)-2-oxo-1,2-dihydropyrimidin-4-yl)benzami
de (2q) White solid, 15.9 mg, 72% yield, 98% ee. [α]25D = -87.7 (c = 0.8, CH3OH), m.p. 73.9-74.6
oC. TLC: Rf = 0.36 (dichloromethane:methanol = 50:1) [UV]. The ee value was determined by
chiral HPLC AS-H, n-hexane/2-propanol = 60/40, flow rate 0.8 mL/min, λ = 250 nm, retention
time: 23.567 min (minor), 35.255 min (major). 1H NMR (600 MHz, CD3OD) δ 8.28 (s, 1H), 7.97
(s, 1H), 7.54 (d, J = 7.8 Hz, 4H), 7.46 (s, 2H), 7.36 (t, J = 7.2 Hz, 2H), 7.28 (t, J = 7.2 Hz, 1H),
4.36 (d, J = 12.0 Hz, 1H), 4.13 (d, J = 12.6 Hz, 1H), 3.85 (d, J = 7.2 Hz, 1H), 3.73 (d, J = 11.4 Hz,
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1H). 13C NMR (150 MHz, CDCl3) δ 156.6, 146.8, 140.4, 133.2, 130.1, 129.0, 128.8, 128.5, 128.4
127.5, 125.5, 100.0, 76.7, 67.1, 55.9. HRMS (ESI-TOF) calcd for C20H18N3BrNaO4 [M + Na]+
466.0373, found 466.0378.
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(S)-N6-(1-(2,3-Dihydroxy-2-phenylpropyl)-2-oxo-1,2-dihydropyrimidin-4-yl)
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ditert-butoxycarbonylamide (2r) White solid, 21.7 mg, 94 % yield, 99% ee. [α]25 =81.1 (c =
D
1.1, CH2Cl2), m.p. 73.1-74.2 oC. TLC: Rf = 0.41 (dichloromethane:methanol = 50:1) [UV]. The ee
value was determined by chiral HPLC IA, n-hexane/2-propanol = 80/20, flow rate 0.8 mL/min, λ
= 250 nm, retention time: 12.075 min (major), 14.332 min (minor). 1H NMR (600 MHz, CDCl3) δ
7.42 (d, J = 7.8 Hz, 2H), 7.35 (t, J = 7.2 Hz, 2H), 7.29 (t, J = 7.2 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H),
6.91 (d, J = 7.2 Hz, 1H), 4.58 (s, 1H), 4.36 (d, J = 15.6 Hz, 1H), 4.04 (d, J = 14.4 Hz, 1H), 3.87 (d,
J = 7.8 Hz, 1H), 3.72 (s, 1H), 3.64 (d, J = 12.0 Hz, 1H), 1.54 (s, 18H). 13C NMR (150 MHz,
CDCl3) δ 162.7, 157.5, 149.5, 149.5, 141.0, 128.8, 128.1, 125.5, 96.6, 85.4, 76.6, 66.8, 57.9, 27.8.
HRMS (ESI-TOF) calcd for C23H31N3NaO7 [M + Na]+ 484.2054, found 484.2053.
(S)-N-(1-(2,3-Dihydroxy-2-phenylpropyl)-2-oxo-1,2-dihydropyrimidin-4-yl)acetamide
(2s)
White solid, 13.1 mg, 87% yield, 99% ee. [α]25 =70.8 (c = 1.2, CH3OH), m.p. 113.1-114.5 oC.
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TLC: Rf = 0.33 (dichloromethane:methanol = 50:1) [UV]. The ee value was determined by chiral
HPLC OD-H, n-hexane/2-propanol = 70/30, flow rate 0.8 mL/min, λ = 250 nm, retention time:
21.519 min (major), 31.785 min (minor). 1H NMR (600 MHz, CD3OD) δ 7.78 (d, J = 7.8 Hz, 1H),
7.54 (d, J = 7.2 Hz, 2H), 7.33 (t, J = 7.2 Hz, 2H), 7.26 (t, J = 7.2 Hz, 2H), 4.59 (d, J = 13.8 Hz,
1H), 4.13 (d, J = 13.8 Hz, 1H), 3.75 (d, J = 11.4 Hz, 1H), 3.67 (d, J = 11.4 Hz, 1H), 2.15 (s, 3H).
13C NMR (100 MHz, CD3OD) δ 173.0, 164.2, 160.1, 152.5, 143.3, 129.3, 128.6, 127.0, 97.6, 78.0,
68.4, 57.3, 24.5. HRMS (ESI-TOF) calcd for C15H17N3NaO4 [M + Na]+ 326.1111, found 326.1119.
(S)-3-Benzoyl-1-(2,3-dihydroxy-2-phenylpropyl)pyrimidine-2,4(1H,3H)-dione (4a) White
solid, 14.9 mg, 79% yield, 98% ee. [α]25D = 59.5 (c = 0.6, CH3OH), m.p. 138.4-139.2 oC. TLC: Rf
= 0.44 (dichloromethane:methanol = 50:1) [UV]. The ee value was determined by chiral HPLC
OD-H, n-hexane/2-propanol = 70/30, flow rate 0.8 mL/min, λ = 250 nm, retention time: 15.430
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min (major), 20.891 min (minor). H NMR (600 MHz, CD3OD) δ 7.70 (t, J = 7.2Hz, 3H), 7.52
(dd, J = 13.2, 7.2 Hz, 5H), 7.35 (t, J = 7.2 Hz, 2H), 7.29 (t, J = 7.2 Hz, 1H), 4.20 (s, 2H), 3.86 (d, J
= 11.4 Hz, 1H), 3.71 (d, J = 11.4 Hz, 1H), 1.84 (s, 3H). 13C NMR (100 MHz, CD3OD) δ 170.2,
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165.0, 151.9, 144.6, 142.8, 136.2, 132.8, 131.4, 130.3, 129.2, 128.6, 127.1, 109.8, 78.1, 68.7, 54.8,
12.2. HRMS (ESI-TOF) calcd for C21H20N2NaO5 [M + Na]+ 403.1264, found 403.1258.
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(S)-3-Benzoyl-1-(2,3-dihydroxy-2-phenylpropyl)-5-fluoropyrimidine-2,4(1H,3H)-dione (4b)
White solid, 12.8 mg, 66% yield, 98% ee. [α]25D = 48.7 (c = 0.5, CH3OH), m.p. 60.9-61.5 oC. TLC:
Rf = 0.42 (dichloromethane:methanol = 50:1) [UV]. The ee value was determined by chiral HPLC
OD-H, n-hexane/2-propanol = 70/30, flow rate 0.8 mL/min, λ = 250 nm, retention time: 15.812
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min (minor), 20.708 min (major). H NMR (400 MHz, CD3OD) δ 7.96 (d, J = 6.4 Hz, 1H),
7.77-7.60 (m, 3H), 7.55-7.50 (m, 4H), 7.38-7.28 (m, 3H), 4.24 (d, J = 10.4 Hz, 1H), 4.16 (d, J =
12.8 Hz, 1H), 3.88 (d, J = 11.6 Hz, 1H), 3.70 (d, J = 11.2 Hz, 1H). 13C{1H} NMR (150 MHz,
CDCl3) δ 167.1, 156.3 (d, JC-F = 27 Hz), 149.7, 140.1, 139.6 (d, JC-F = 237 Hz), 135.6, 132.3,
130.9, 130.7, 130.1 (d, JC-F = 33 Hz), 129.4, 129.0, 128.8, 128.5, 127.5, 125.5, 77.0, 67.5, 43.5.
HRMS (ESI-TOF) calcd for C20H17FN2NaO5 [M + Na]+ 407.1014, found 407.1016.
(S)-3-Benzoyl-5-chloro-1-(2,3-dihydroxy-2-phenylpropyl)pyrimidine-2,4(1H,3H)-dione (4c)
White solid, 11.5 mg, 58% yield, 97% ee. [α]25 = 32.2 (c =0.8, CH3OH), m.p. 121.3-122.8 oC.
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TLC: Rf = 0.46 (dichloromethane:methanol = 50:1) [UV]. The ee value was determined by chiral
HPLC OD-H, n-hexane/2-propanol = 70/30, flow rate 0.8 mL/min, λ = 250 nm, retention time:
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15.127 min (major), 19.893 min (minor). H NMR (600 MHz, CD3OD) δ 8.00 (s, 3H), 7.62 (s,
1H), 7.56 (d, J = 7.8 Hz, 2H), 7.51 (d, J = 7.2 Hz, 2H), 7.36 (t, J = 7.2 Hz, 2H), 7.28 (t, J = 7.2 Hz,
1H), 4.47 (s, 1H), 4.16 (d, J = 13.2 Hz, 1H), 3.81 (d, J = 11.4 Hz, 1H), 3.71 (d, J = 11.4 Hz, 1H).
13C NMR (100 MHz, CDCl3) δ 167.4, 158.3, 150.3, 142.4, 140.1, 135.5, 131.0, 130.7, 129.4,
129.1, 128.6, 125.5, 108.4, 77.4, 67.4, 55.1. HRMS (ESI-TOF) calcd for C20H17ClN2NaO5 [M +
Na]+ 423.0718, found 423.0712.
(S)-3-Benzoyl-5-bromo-1-(2,3-dihydroxy-2-phenylpropyl)pyrimidine-2,4(1H,3H)-dione (4d)
White solid, 16.2 mg, 57% yield, 99% ee. [α]25 = 54.6 (c = 2.1, CH3OH), m.p. 102.1-103.3 oC.
D
TLC: Rf = 0.44 (dichloromethane:methanol = 50:1) [UV]. The ee value was determined by chiral
HPLC OD-H, n-hexane/2-propanol = 70/30, flow rate 0.8 mL/min, λ = 250 nm, retention time:
14.675 min (major), 20.778 min (minor). 1H NMR (600 MHz, CD3OD) δ 8.03 (s, 1H), 7.74-7.70
(m, 3H), 7.54-7.50 (m, 4H), 7.38-7.28 (m, 3H), 4.23 (s, 2H), 3.89 (d, J = 11.2 Hz, 1H), 3.71 (d, J =
11.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 167.4, 158.3, 150.3, 142.4, 140.1, 135.5, 131.0,
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130.7, 129.4, 129.1, 128.6, 125.5, 108.4, 77.4, 67.4. HRMS (ESI-TOF) calcd for
C20H17BrN2NaO5 [M + Na]+467.0213, found 467.0220.
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(S)-3-Benzoyl-1-(2,3-dihydroxy-2-phenylpropyl)-5-iodopyrimidine-2,4(1H,3H)-dione
(4e)
White solid, 11.5 mg, 58% yield, 96% ee. [α]25 = 58.1 (c = 0.6, CH3OH), m.p. 150.6-152.1 oC.
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TLC: Rf = 0.45 (dichloromethane:methanol = 50:1) [UV]. The ee value was determined by chiral
HPLC IA, n-hexane/2-propanol = 70/30, flow rate 0.8 mL/min, λ = 250 nm, retention time: 17.465
min (minor), 22.058 min (major). 1H NMR (600 MHz, CD3OD) δ 7.96 (d, J = 6.0 Hz, 1H), 7.72 (t,
J = 7.2 Hz, 3H), 7.53 (d, J = 7.2 Hz, 4H), 7.36 (t, J = 7.2 Hz, 2H), 7.31 (t, J = 7.2 Hz, 1H), 4.26 (s,
1H), 4.17 (s, 1H), 3.88 (d, J = 11.4 Hz, 1H), 3.70 (d, J = 11.4 Hz, 1H). 13C NMR (150 MHz,
CDCl3) δ 167.6, 159.2, 150.9, 150.1, 140.1, 135.5, 130.9, 130.6, 129.4, 129.0, 128.5, 125.5, 76.8,
67.3, 67.0. HRMS (ESI-TOF) calcd for C20H17IN2NaO5 [M + Na]+ 515.0074, found 515.0079.
3-(6-Chloro-9H-purin-9-yl)-2-phenylpropane-1,2-diol (6a) White solid, 11.2 mg, 74% yield,
98% ee. [α]25 = -66.8 (c = 1.2, CH2Cl2), m.p. 90.1-91.7 oC. TLC: Rf = 0.38
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(dichloromethane:methanol = 60:1) [UV]. The ee value was determined by chiral HPLC OD-H,
n-hexane/2-propanol = 70/30, flow rate 0.8 mL/min, λ = 250 nm, retention time: 10.770 min
(major), 18.116 min (minor). 1H NMR (600 MHz, CD3OD) δ 8.58 (s, 1H), 8.31 (s, 1H), 7.43 (d, J
= 7.2 Hz, 2H), 7.21 (t, J = 7.2 Hz, 2H), 7.16 (t, J = 7.2 Hz, 1H), 4.82-4.70 (m, 2H), 3.90 (d, J =
11.4 Hz, 1H), 3.75 (d, J = 11.4 Hz, 1H). 13C NMR (100 MHz, CD3OD) δ 153.9, 152.6, 150.8,
149.1, 142.5, 131.4, 129.1, 128.6, 126.8, 77.5, 68.6, 52.1. HRMS (ESI-TOF) calcd for
C14H13ClN4O2 [M + H]+ 305.0800, found 305.0792.
3-(6-Methoxy-9H-purin-9-yl)-2-phenylpropane-1,2-diol (6b) White solid, 11.4 mg, 89% yield,
97% ee. [α]25 = -63.7 (c = 0.3, CH2Cl2), m.p. 102.1-103.4 oC. TLC: Rf = 0.42
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(dichloromethane:methanol = 60:1) [UV]. The ee value was determined by chiral HPLC ID,
n-hexane/2-propanol = 80/20, flow rate 0.8 mL/min, λ = 250 nm, retention time: 24.380 min
(minor), 26.692 min (major). 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.49 (s, 1H), 7.34-7.26
(m, 5H), 4.59 (d, J = 14.4 Hz, 1H), 4.52 (d, J = 14.4 Hz, 1H), 4.41 (s, 1H), 4.36 (s, 1H), 4.18 (s,
3H), 3.79 (d, J = 12.0 Hz, 1H), 3.65 (d, J = 12.0 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 161.4,
152.2, 152.0, 143.8, 140.6, 128.8, 128.2, 125.3, 121.2, 76.4, 66.8, 54.6, 51.5. HRMS (ESI-TOF)
calcd for C15H16N4NaO3 [M + Na]+ 323.1115, found 323.1117.
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2-Phenyl-3-(6-(piperidin-1-yl)-9H-purin-9-yl)propane-1,2-diol (6c) White solid, 15.8 mg, 85%
o
yield, 98% ee. [α]25 = -82.7 (c = 1.2, CH2Cl2), m.p. 113.1-114.2 C. TLC: Rf = 0.41
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(dichloromethane:methanol = 60:1) [UV]. The ee value was determined by chiral HPLC IA,
n-hexane/2-propanol = 95/5, flow rate 0.8 mL/min, λ = 250 nm, retention time: 60.961 min
(minor), 66.002 min (major). 1H NMR (600 MHz, CDCl3) δ 8.28 (s, 1H), 7.31-7.27 (m, 5H), 7.21
(s, 1H), 4.52 (d, J = 14.4 Hz, 1H), 4.37 (d, J = 15.0 Hz, 1H), 4.23 (s, 4H), 3.79 (d, J = 12.0 Hz,
1H), 3.56 (d, J = 12.0 Hz, 1H), 1.73-1.69 (m, 6H).13C NMR (100 MHz, CDCl3) δ 153.9, 152.0,
150.8, 141.1, 139.4, 128.6, 128.0, 125.3, 119.3, 76.2, 66.5, 51.3, 46.5, 26.2, 24.8. HRMS
(ESI-TOF) calcd for C19H23N5NaO2 [M + Na]+ 376.1744, found 376.1737.
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2-Phenyl-3-(6-(propylthio)-9H-purin-9-yl)propane-1,2-diol (6d) Colorless oil, 15.9 mg, 93%
yield, 98% ee. [α]25D = -75.9 (c = 1.5, CH2Cl2); TLC: Rf = 0.44 (dichloromethane:methanol = 50:1)
[UV]. The ee value was determined by chiral HPLC IA, n-hexane/2-propanol = 70/30, flow rate
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0.8 mL/min, λ = 250 nm, retention time: 7.883 min (minor), 8.643 min (major). H NMR (400
MHz, CDCl3) δ 8.66 (s, 1H), 7.52 (s, 1H), 7.38-7.26 (m, 5H), 4.54 (dd, J = 22.8, 14.4 Hz, 2H),
4.28 (s, 1H), 4.22 (s, 1H), 3.78 (d, J = 12.0 Hz, 1H), 3.65 (d, J = 12.0 Hz, 1H), 3.36 (t, J = 7.2 Hz,
2H), 1.81 (dd, J = 14.4, 7.2 Hz, 2H), 1.08 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ
162.7, 151.5, 148.5, 144.1, 140.6, 131.1, 128.9, 128.3, 125.3, 76.3, 66.7, 51.3, 30.9, 23.0, 13.6.
HRMS (ESI-TOF) calcd for C17H20N4NaO2S [M + Na]+ 367.1199, found 367.1205.
(S)-4-(2-Amino-6-(benzyloxy)-9H-purin-9-yl)-2-(triethylsilyl)butane-1,2-diol (6e) Colorless oil,
21.3 mg, 96% yield, 95% ee [α]25 = 43.17 (c = 0.99, CH3OH); TLC: Rf = 0.38
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(dichloromethane:methanol = 50:1) [UV]. The ee value was determined by chiral HPLC IE,
n-hexane/2-propanol = 70/30, flow rate 0.8 mL/min, λ = 250 nm, retention time: 17.813 min
(major), 29.852 min (minor). 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.41 (d, J = 6.8 Hz, 2H),
7.26-7.20 (m, 3H), 5.47 (s, 2H), 5.38 (s, 2H), 4.18 (s, 2H), 3.78 (d, J = 11.2 Hz, 1H), 3.65 (d, J =
11.2 Hz, 1H), 2.05 (s, 2H), 0.91 (t, J = 7.2 Hz, 9H), 0.58 (d, J = 7.6 Hz, 6H). 13C NMR (150 MHz,
CDCl3) δ 161.2, 159.3, 153.4, 139.6, 136.4, 128.5, 128.3, 128.1, 115.6, 69.7, 68.3, 67.0, 39.8, 36.6,
7.9, 2.0. HRMS (ESI-TOF) calcd for C22H34N5O3Si+ [M + H]+ 444.2425, found 444.2427.
3-(6-Amino-9H-purin-9-yl)-1-phenylpropane-1,2-diol (6f) White solid, 10.8 mg, 76%
yield, >20:1 dr, 95% ee [α]25 = 29.56 (c = 0.60, CH3OH), m.p. 114.3-115.2 oC. TLC: Rf = 0.25
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(dichloromethane:methanol = 30:1) [UV]. The ee value was determined by chiral HPLC ID,
n-hexane/2-propanol = 60/40, flow rate 0.8 mL/min, λ = 250 nm, retention time: 21.720 min
(major), 33.050 min (minor). 1H NMR (600 MHz, d6-DMSO) δ 8.11 (s, 1H), 8.00 (s, 1H), 7.40 (d,
J = 7.2 Hz, 2H), 7.33 (t, J = 7.8 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H), 7.15 (s, 2H), 5.55 (d, J = 4.8 Hz,
1H), 5.14 (d, J = 6.0 Hz, 1H), 4.58 (d, J = 4.8 Hz, 1H), 4.20 (dd, J = 13.8, 3.0 Hz, 1H), 4.00-3.98
(m, 1H), 3.90 (dd, J = 13.8, 9.6 Hz, 1H). 13C NMR (150 MHz, d6-DMSO) δ 155.9, 152.2, 149.6,
142.4, 141.6, 127.8, 127.0, 126.9, 118.6, 73.9, 72.5, 46.1. HRMS (ESI-TOF) calcd for
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C14H16N5O2 [M + H]+ 286.1299, found 286.1293.
3-(6-amino-9H-purin-9-yl)propane-1,2-diol (6h) White solid, 8.6 mg, 82% yield, 35% ee [α]25
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= -7.82 (c = 0.29, CH3OH). m.p. 212.6-213.3 oC. TLC: Rf = 0.25 (dichloromethane:methanol =
20:1) [UV]. The ee value was determined by chiral HPLC AD-H, n-hexane/2-propanol = 80/20,
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flow rate 0.8 mL/min, λ = 250 nm, retention time: 16.798 min (minor), 20.835 min (major). H
NMR (400 MHz, d6-DMSO) δ 8.13 (s, 1H), 8.02 (s, 1H), 7.17 (s, 2H), 5.09 (d, J = 5.6 Hz, 1H),
4.83 (t, J = 5.6 Hz, 1H), 4.29 (dd, J = 14.0, 3.6 Hz, 1H), 3.99 (dd, J = 14.0, 8.0 Hz, 1H), 3.86-3.79
(m, 1H), 3.41-3.36 (m, 1H), 3.31-3.27 (m, 1H). 13C NMR (150 MHz, d6-DMSO) δ 155.9, 152.2,
+
149.7, 141.7, 118.6, 69.7, 63.5, 46.4. HRMS (ESI-TOF) calcd for C8H12N5O2 [M + H]+ 210.0986,
found 210.0988.
3-(6-Amino-9H-purin-9-yl)-1-(trimethylsilyl)propane-1,2-diol (6i) White solid, 8.9 mg, 63%
yield, 98:2 dr, 65% ee [α]25 = 12.00 (c = 0.30, CH3OH), m.p. 102.5-103.6 oC. TLC: Rf = 0.45
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(dichloromethane:methanol = 40:1) [UV]. The ee value was determined by chiral HPLC AD-H,
n-hexane/2-propanol = 90/10, flow rate 0.8 mL/min, λ = 250 nm, retention time: 26.622 min
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(major), 39.662 min (minor), 62.843 min (minor), 73.258 min (minor). H NMR (400 MHz,
CD3OD) δ 8.21 (s, 1H), 8.09 (s, 1H), 4.41-4.29 (m, 2H), 4.04 (ddd, J = 8.0, 5.6, 2.4 Hz, 1H), 3.27
(d, J = 2.4 Hz, 1H), 0.09 (s, 9H). 13C NMR (150 MHz, CD3OD) δ 157.3, 153.6, 150.8, 143.6,
120.0, 72.5, 67.7, 48.6, -2.8. HRMS (ESI-TOF) calcd for C11H20N5O2Si+ [M + H]+ 282.1381,
found 282.1379.
(R)-4-(2-Amino-6-(benzyloxy)-9H-purin-9-yl)butane-1,2-diol (7e) White solid, 20.3 mg, 62%
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yield, 95% ee [α]25 = 59.25 (c = 1.13, CH3OH), m.p. 143.1-144.2 C. TLC: Rf = 0.35
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(dichloromethane:methanol = 30:1) [UV]. The ee value was determined by chiral HPLC IE,
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