Total synthesis of carbocyclic nucleoside (+)-neplanocin A

Article abstract of DOI:10.1016/j.tet.2014.12.093

Asymmetric total synthesis of (+)-neplanocin A was concisely achieved from readily available d-galactose via the regioselective and diastereoselective amination of carbocyclic polybenzyl ether using chlorosulfonyl isocyanate and intramolecular olefin meta

Full text of DOI:10.1016/j.tet.2014.12.093

Tetrahedron xxx (2015) 1e6
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of carbocyclic nucleoside (þ)-neplanocin A
*
Young Hoon Jung , Seung In Kim, Yeon Ju Hong, Sook Jin Park, Kyung Tae Kang,
So Yeon Kim, In Su Kim
School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric total synthesis of (þ)-neplanocin A was concisely achieved from readily available
D-galactose
Received 20 October 2014
Received in revised form 26 December 2014
Accepted 27 December 2014
Available online xxx
via the regioselective and diastereoselective amination of carbocyclic polybenzyl ether using chlor-
osulfonyl isocyanate and intramolecular olefin metathesis using second-generation Grubbs catalyst.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Amination
Chlorosulfonyl isocyanate
Metathesis
Neplanocin
Nucleoside
1. Introduction
Carbocyclic nucleosides, in which an oxygen atom in a furanose
ring of ribonucleosides is replaced by a methylene group, are among
the most interesting discoveries in the field of natural products.1
Due to the absence of a true glycosidic bond, carbocyclic nucleo-
sides are more chemically stable and not involved in the action of
the enzymes that cleave the N-glycosidic linkage in conventional
nucleosides.2 Thus carbocyclic nucleosides have been the focus of
much attention in the development of new therapeutic agents.3
(ꢀ)-Neplanocin
A
(1),4 an unsaturated analogue of
(ꢀ)-aristeromycin (2),5 is a naturally occurring carbocyclic nu-
cleoside isolated from the culture filtrate of the soil fungus
Ampullariella regularis in 1981 (Fig. 1). The absolute structures
of 1 and 2 were established by X-ray analysis.6 Other natural
neplanocin analogs, e.g., (ꢀ)-neplanocin B (3), (ꢀ)-neplanocin C
(4), (ꢀ)-neplanocin D (5), and (ꢀ)-neplanocin F (6), were also
identified.7 Among neplanocin family, (ꢀ)-neplanocin A has
received great attention due to its interesting biological prop-
erties such as potent antiviral and antitumor activities.4
Fig. 1. Structure of neplanocin family.
The protected tetrol 7 has been widely used as a convenient
precursor wherein a Mitsunobu inversion of a secondary hydroxyl
group with adenine followed by deprotection of hydroxyl groups
provided (ꢀ)-neplanocin A (Scheme 1). The formation of 7 and its
enantiomer is achieved from optically active ribonolactone de-
rivatives via the palladium-catalyzed rearrangement of the acetate
moiety,9 construction of a carbocyclic ring by intramolecular
HornereWadswortheEmmons or Wittig reactions,10 intra-
molecular aldol reaction,11 CeH insertion reaction of alkylidene-
carbenes,12 and ring-closing metathesis reaction using Grubbs
catalysts.13 Another approach for the preparation of 1 includes
(ꢀ)-Neplanocin
A efficiently inhibits cellular S-adenosylme-
thionine hydrolase in cells, which results in the accumulation
of S-adenosylhomocysteine, thus inhibiting cell and viral
methyltransferases involved in messenger RNA maturation and
the synthesis of other macromolecules.8
* Corresponding author. Tel.: þ82 31 290 7711; fax: þ82 31 290 7773; e-mail
address: yhjung@skku.edu (Y.H. Jung).
http://dx.doi.org/10.1016/j.tet.2014.12.093
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Jung, Y. H.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2014.12.093

2
Y.H. Jung et al. / Tetrahedron xxx (2015) 1e6
Scheme 1. Synthetic approach for the formation of neplanocin A.
a palladium-catalyzed desymmetrization of cyclopentenes with 6-
chloropurine,14 chemoenzymatic desymmetrization of bicyclic
DielseAlder adducts,15 intramolecular nitrone cycloaddition,16
zirconocene-mediated ring construction,17 and intramolecular
BayliseHillman reaction.18
literature (Scheme 2).20 Wittig reaction of 8 and subsequent Swern
oxidation of a secondary alcohol afforded the ketone 10 in high
yields. Second Wittig reaction of 10 was subjected under NaHMDS
as a base to give the diene 11, which was treated with second-
generation Grubbs catalyst in refluxing CH2Cl2 to provide the car-
bocyclic polybenzyl ether 12 in 90% yield. Next, after the screening
of various reaction conditions for the coupling between 12 and CSI,
we found that the reaction in methylene chloride at 0 ꢁC gave the
desired product 13 with an excellent level of diastereoselectivity
(anti/syn¼50:1) in 91% yield. The origin of stereochemistry can be
explained by competition between SNi mechanism and SN1
mechanism.19c In general, SNi mechanism leads to retention of
stereochemistry via a four-centered transition state by the forma-
tion of a tight ion pair. Another plausible SN1 mechanism may cause
the generation of a carbocation intermediate, which can provide
the racemization of products. However, in the case of anti-dibenzyl
ether 12, anti-amino alcohol 13 can be exclusively obtained due to
the facile approach of ꢀNCO2Bn species to the less sterically hin-
dered face in a carbocation intermediate.
As part of an ongoing research program aimed at developing
asymmetric total synthesis of biologically active compounds
through
a chlorosulfonyl isocyanate-mediated stereoselective
amination,19 we herein describe the asymmetric total synthesis of
(þ)-neplanocin A (ent-1) starting from commercially available
D-galactose via the highly regioselective and diastereoselective al-
lylic amination of cyclic polybenzyl ethers using chlorosulfonyl
isocyanate (CSI) and intramolecular olefin metathesis as the key
steps.
2. Results and discussion
Our initial investigation focused on the efficient construction of
carbocyclic polybenzyl ether 12, which can be subjected to our
amination methodology to give the protected amino alcohol 13.
Thus, the total synthesis of (þ)-neplanocin A began with the pro-
To obtain an essential precursor 14 for the formation of
(þ)-neplanocin A, we then screened a chemoselective removal of
the Cbz protection of 13 under various reaction conditions. After
tected lactol 8 derived from D-galactose according to the reported
Scheme 2.
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Y.H. Jung et al. / Tetrahedron xxx (2015) 1e6
3
several failed attempts such as BF3$OEt2/SMe2,21 BBr3,22 40% KOH/
4. Experimental
4.1. General
MeOH,23 and Pd(OAc)2/Et3SiH/Et3N,24 the chemoselective removal
of the Cbz protection of 13 was successfully achieved under basic
hydrolysis conditions (LiOH$H2O, 1,4-dioxane/water (3:1), 120 ꢁC,
48 h) to give the primary amine 14 in high yield (89%).
Commercially available reagents were used without additional
purification, unless otherwise stated. All reactions were per-
formed under an inert atmosphere of nitrogen or argon. Nuclear
magnetic resonance spectra (1H and 13C NMR) were recorded on
a Bruker Unity 300 MHz and Varian Unit 500 MHz spectrometer
for CDCl3 solutions, and chemical shifts are reported as parts per
million (ppm) relative to, respectively, residual CHCl3 dH
(7.26 ppm) and CDCl3 dC (77.0 ppm) as internal standards. Res-
onance patterns are reported with the notations s (singlet),
d (doublet), t (triplet), q (quartet), and m (multiplet). In addition,
the notation br is used to indicate a broad signal. Coupling con-
stants (J) are reported in hertz (Hz). IR spectra were recorded on
To construct the remaining adenine heterocycle, compound 14
was subjected to the three-step sequence as reported in the liter-
ature (Scheme 3).15a The condensation of 14 with 5-amino-4,6-
dichloropyrimidine in n-butyl alcohol at 120 ꢁC afforded our de-
sired product 15 in low yield (20%) (Table 1, entry 1). The yield of 15
was improved to 61% when DMF was employed (Table 1, entry 4),
however, the reaction required 48 h to go to completion. The best
result was realized when 14 was exposed to 5-amino-4,6-
dichloropyrimidine in isoamyl alcohol, which produced the py-
rimidine compound 15 in high yield (89%) within 24 h (Table 1,
entry 5). Intramolecular ring formation of 15 and subsequent
amination reaction using methanolic ammonia afforded the ade-
nine 17 in high yields. Finally, debenzylation of 17 under the stan-
dard reaction condition (BCl3 in anhydrous CH2Cl2) proceeded
cleanly to afford (þ)-neplanocin A (ent-1) with specific rotation and
spectral data (1H and 13C NMR) identical to those reported in the
literature.10c
a Bruker Infrared spectrophotometer and are reported as cmꢀ1
.
Optical rotations were measured with a Jasco P1020 polarimeter.
Thin layer chromatography was carried out using plates coated
with Kieselgel 60F254 (Merck). For flash column chromatography,
E. Merck Kieselgel 60 (230e400 mesh) was used. LC/mass spectra
(LC/MS) were recorded on a Waters 2767 LCMS system. High-
Scheme 3.
Table 1
resolution mass spectra (HRMS) were recorded on a JEOL JMS-
600 spectrometer.
Selected optimization for the coupling of 14 and 5-amino-4,6-dichloropyrimidine.a
Entry
Solvent
Temperature (ꢁC)
Time (h)
Yieldb (%)
1
2
3
4
5
n-BuOH
EtOH
1,4-Dioxane
DMF
Isoamyl alcohol
120
120
120
150
130
24
48
48
48
24
20
20
N.R.
61
89
4.2. (2R,3S,4R,5S)-1,3,4,5-Tetrakis(benzyloxy)hept-6-en-2-ol
(9)
To a stirred solution of MePPh3Br (17.6 g, 49.3 mmol) in THF
(54 mL) was carefully added n-BuLi (37.1 mL, 59.4 mmol in 1.6 M
solution) at 0 ꢁC under N2 atmosphere. The reaction mixture was
stirred for 2 h at room temperature to generate ylide. To a reaction
mixture was added a solution of 8 (6.78 g, 12.5 mmol) in THF
(7.5 mL) at ꢀ78 ꢁC. The resulting mixture was warmed to room
temperature and further stirred for 4 h. The reaction was quenched
with water (30 mL) and the aqueous layer was extracted with EtOAc
(100 mLꢂ2). The organic layer was washed with water and brine,
dried over MgSO4, and concentrated in vacuo. The residue was
purified by flash column chromatography (n-hexane/EtOAc¼5:1) to
a
Reaction conditions: (i) 13 (1 equiv), 5-amino-4,6-dichloropyrimidine (5 equiv),
Et3N (3 equiv), solvent (0.1 M).
b
Isolated yield by flash column chromatography.
3. Conclusion
We described a concise total synthesis of (þ)-neplanocin A
starting from readily available D-galactose via the highly regiose-
lective and diastereoselective amination of carbocyclic poly-
benzylic ether with retention of stereochemistry using
chlorosulfonyl isocyanate and intramolecular olefin metathesis. It is
believed that this synthetic strategy can be applied to the prepa-
ration of a broad range of biologically active compounds containing
a chiral amine moiety.
afford 5.07 g (9.41 mmol, 75%) of 9 as yellow syrup. Rf¼0.30 (n-
25
hexane/EtOAc¼5:1); [
a
]
D
ꢀ3.4 (c 0.5, CHCl3); IR (neat)
n 3030,
2867, 1497, 1454, 1210, 1095, 1067, 1028, 736, 698, 477, 419 cmꢀ1; 1H
NMR (500 MHz, CDCl3)
7.37e7.16 (m, 20H), 5.87 (ddd, J¼17.5, 10.0,
8.0 Hz, 1H), 5.36e5.30 (m, 2H), 4.76 (d, J¼12.0 Hz, 2H), 4.65 (d,
d
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4
Y.H. Jung et al. / Tetrahedron xxx (2015) 1e6
J¼12.0 Hz, 1H), 4.50e4.34 (m, 5H), 4.13e4.06 (m, 2H), 3.82e3.78
(m, 2H), 3.50 (dd, J¼9.5, 6.0 Hz, 2H), 3.02 (d, J¼5.5 Hz, 1H); 13C NMR
1453, 1357, 1271, 1094, 1027, 737, 699, 604, 419 cmꢀ1
(300 MHz, CDCl3)
;
1H NMR
d
7.39e7.16 (m, 20H), 5.99 (d, J¼1.5 Hz, 1H),
(125 MHz, CDCl3)
d
138.5, 138.4, 138.4, 138.3, 136.0, 128.6, 128.4,
4.80e4.75 (m, 1H), 4.73 (d, J¼11.8 Hz, 1H), 4.65 (d, J¼2.7 Hz, 1H),
4.62e4.60 (m, 4H), 4.53 (d, J¼1.8 Hz,1H), 4.49 (d, J¼3.9 Hz, 2H), 4.07
128.3, 128.1, 128.0, 127.9, 119.5, 82.3, 81.0, 76.8, 75.5, 73.4, 71.4, 70.5,
69.9; HRMS (CI) calcd for C35H39O5 [MþH]þ 539.2791, found
539.2792.
(s, 2H), 4.00 (d, J¼6, 4.8 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 142.5,
138.9, 138.6, 138.5, 138.3, 130.5, 128.9, 128.8, 128.7, 128.6, 128.5,
128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.5, 127.2, 86.7, 84,6,
79.1, 72.9, 72.5, 72.1, 71.7, 67.5; HRMS (EI) calcd for C34H34O4 [M]þ
506.2457, found 506.2456.
4.3. (3R,4R,5S)-1,3,4,5-Tetrakis(benzyloxy)hept-6-en-2-one
(10)
To a stirred solution of oxalic chloride (0.32 mL, 3.7 mmol) in
CH2Cl2 (9 mL) were added dimethyl sulfoxide (0.53 mL, 7.4 mmol)
and 9 (1.33 g, 2.5 mmol) at ꢀ78 ꢁC. After stirring for 1 h at same
temperature, Et3N (1.74 mL, 12.1 mmol) was added. The reaction
mixture was further stirred for 4 h at ꢀ78 ꢁC. The resulting mixture
was carefully quenched with water (10 mL) and the aqueous layer
was extracted with CH2Cl2 (20 mLꢂ2). The organic layer was
washed with water and brine, dried over MgSO4, and concentrated
in vacuo. The residue was purified by flash column chromatography
4.6. Benzyl (1S,4S,5R)-4,5-bis(benzyloxy)-3-(benzylox-
ymethyl)cyclopent-2-enylcarbamate (13)
To a stirred solution of 12 (0.13 g, 0.26 mmol) in anhydrous
CH2Cl2 (2.6 mL) were added Na2CO3 (0.25 g, 2.3 mmol) and chlor-
osulfonyl isocyanate (0.18 mL, 2.0 mmol) at 0 ꢁC under N2 atmo-
sphere. The reaction mixture was stirred for 24 h at 0 ꢁC and
quenched with water (1.3 mL). The aqueous layer was extracted
with EtOAc (10 mLꢂ2). The organic layer was added to a solution of
aqueous 25% Na2SO3 (5 mL), and the reaction mixture was further
stirred for 24 h at room temperature. The organic layer was washed
with water and brine, dried over MgSO4, and concentrated in vacuo.
The residue was purified by flash column chromatography (n-
hexane/EtOAc¼5:1) to afford 0.13 g (0.236 mmol, 91%) of 13 as
white solid. Rf¼0.24 (n-hexane/EtOAc¼4:1); mp¼107e113 ꢁC;
(n-hexane/EtOAc¼4:1) to afford 1.17 g (2.2 mmol, 88%) of 10 as
25
yellow syrup. Rf¼0.57 (n-hexane/EtOAc¼4:1); [
a
]
D
þ2.9 (c 6.5,
CHCl3); IR (neat)
n
2869, 1728, 1497, 1454, 1273, 1103, 740, 699, 476,
7.35e7.15 (m, 20H), 5.85
419 cmꢀ1 1H NMR (300 MHz, CDCl3)
;
d
(ddd, J¼17.7, 10.5, 7.8 Hz, 1H), 5.40e5.24 (m, 2H), 4.72 (d, J¼11.4 Hz,
1H), 4.63e4.51 (m, 2H), 4.51e4.18 (m, 7H), 4.17 (d, J¼4.2 Hz, 1H),
4.10 (dd, J¼13.8, 6.0 Hz, 1H), 3.89 (dd, J¼5.9, 4.5 Hz, 1H); 13C NMR
[a
]
25 þ29.3 (c 4.0, CHCl3); IR (neat)
n 3309, 3031, 2857, 1690, 1544,
D
(125 MHz, CDCl3)
d
207.6, 138.4, 138.2, 137.7, 137.3, 135.4, 128.7,
1454, 1336, 1281, 1251, 1138, 1095, 734, 696, 476, 419 cmꢀ1; 1H NMR
128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.7,
119.9, 83.0, 82.3, 80.9, 75.0, 74.7, 73.3, 72.9, 70.9; HRMS (CI) calcd
for C35H37O5 [MþH]þ 537.2647, found 537.2646.
(300 MHz, CDCl3) d 7.37e7.24 (m, 20H), 5.81 (s, 1H), 5.17e5.12 (m,
2H), 4.87 (br s, 1H), 4.73 (s, 2H), 4.65 (d, J¼11.4 Hz, 2H), 4.55 (d,
J¼5.0 Hz,1H), 4.53e4.48 (m, 3H), 4.08 (s, 2H), 3.77 (d, J¼4.5 Hz,1H);
13C NMR (125 MHz, CDCl3)
d 143.4, 138.7, 138.2, 129.7, 128.8, 128.7,
4.4. ((3S,4R,5S)-2-Methylenehept-6-ene-1,3,4,5-tetrayl)tetra-
kis(oxy)tetrakis(methylene)tetrabenzene (11)
128.6, 128.5, 128.4, 128.2, 128.0, 127.9, 127.8, 83.0, 73.2, 71.9, 67.2,
67.0, 60.5; HRMS (EI) calcd for C35H35NO5 [M]þ 549.2515, found
549.2516.
To a stirred solution of MePPh3Br (2.39 g, 6.7 mmol) in THF
(11 mL) was slowly added NaHMDS (6.7 mL, 6.7 mmol) at 0 ꢁC
under N2 atmosphere. The reaction mixture was stirred for 2 h at
room temperature, and a solution of 10 (1.44 g, 2.7 mmol) in THF
(2.4 mL) was added at 0 ꢁC. The reaction mixture was stirred for
1 h at 0 ꢁC. The resulting mixture was quenched with water (20 mL)
and the aqueous layer was extracted with EtOAc (30 mLꢂ2). The
organic layer was washed with water and brine, dried over MgSO4,
and concentrated in vacuo. The residue was purified by flash col-
umn chromatography (n-hexane/EtOAc¼5:1) to afford 1.22 g
(2.3 mmol, 85%) of 11 as yellow syrup. Rf¼0.64 (n-hexane/
4.7. (1S,4S,5R)-4,5-Bis(benzyloxy)-3-(benzyloxymethyl)cyclo-
pent-2-enamine (14)
To a stirred solution of 13 (0.16 g, 0.28 mmol) in 1,4-dioxane
(5.4 mL) was added LiOH$H2O (0.14 g, 3.4 mmol) in water
(1.8 mL) at room temperature. The reaction mixture was stirred at
120 ꢁC for 48 h, and then cooled to room temperature. The resulting
mixture was evaporated to dryness, and the residue was parti-
tioned between water (20 mL) and CH2Cl2 (10 mL). The aqueous
layer was extracted with CH2Cl2 (10 mLꢂ2). The organic layer was
washed with water, dried over MgSO4, and concentrated in vacuo.
The residue was purified by flash column chromatography (CH2Cl2/
EtOAc¼6:1); [
a]
25 þ22.4 (c 1.7, CHCl3); IR (neat)
n 3031, 2863, 1496,
D
1454, 1391, 1208, 1092, 1071, 1028, 923, 736, 698, 476, 419 cmꢀ1; 1H
NMR (300 MHz, CDCl3)
d
7.35e7.12 (m, 20H), 5.94e5.73 (m, 1H),
MeOH¼20:1) to afford 0.103 g (0.248 mmol, 89%) of 14 as yellow
25
5.58e5.09 (m, 5H), 4.84e4.79 (m, 1H), 4.66 (s, 1H), 4.62 (d,
J¼11.0 Hz, 2H), 4.54 (d, J¼11.0 Hz, 2H), 4.50 (d, J¼2.5 Hz,1H), 4.40 (d,
J¼2.5 Hz, 1H), 4.29 (d, J¼11.9 Hz, 1H), 4.18e4.04 (m, 4H), 3.57 (dd,
syrup. Rf¼0.37 (CH2Cl2/MeOH¼15:1); [
a
]
þ91.6 (c 2.4, CHCl3); IR
D
(neat)
n
3030, 2856, 1724, 1662, 1496, 1453, 1360, 1209, 1095, 1027,
7.40e7.21
737, 698, 604, 477, 419 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
J¼7.9, 3.5 Hz 1H); 13C NMR (125 MHz, CDCl3)
d
138.7, 138.6, 138.5,
(m, 15H), 5.80 (d, J¼1.5 Hz, 1H), 4.78 (d, J¼11.7 Hz, 1H), 4.64e4.49
136.5, 128.6, 128.5, 128.4, 128.3, 128.2, 127.9, 127.7, 127.6, 127.5,
118.4, 115.7, 83.8, 80.4, 79.8, 75.1, 72.8, 70.8, 70.7, 70.5; HRMS (CI)
calcd for C36H39O4 [MþH]þ 535.2851, found 535.2848.
(m, 7H), 4.06 (s, 2H), 4.10 (s, 2H), 3.54 (dd, J¼11.1, 5.4 Hz, 1H); 13C
NMR (125 MHz, CDCl3)
d 140.0, 139.0, 138.6, 138.4, 135.4, 128.7,
128.6, 128.3, 128.1, 128.0, 127.9, 127.8, 88.3, 79.3, 73.0, 72.7, 71.5,
67.6, 61.0; HRMS (CI) calcd for C27H30NO3 [MþH]þ 416.2226, found
416.2227.
4.5. ((1S,2R,3S)-4-(Benzyloxymethyl)cyclopent-4-ene-1,2,3-
triyl)tris(oxy)tris(methylene)tribenzene (12)
4.8. N4-((1S,4S,5R)-4,5-Bis(benzyloxy)-3-(benzyloxymethyl)
To a stirred solution of 11 (1.11 g, 2.08 mmol) in CH2Cl2 (21 mL)
was added second-generation Grubbs catalyst (0.35 g, 0.41 mmol).
The reaction mixture was refluxed for 8 h. The solution was evap-
orated to dryness and the residue was purified by flash column
chromatography (n-hexane/EtOAc¼8:1) to afford 1.01 g (1.99 mmol,
cyclopent-2-enyl)-6-chloropyrimidine-4,5-diamine (15)
To a stirred solution of 14 (0.57 g, 1.37 mmol) in isoamyl alcohol
(13.7 mL) were added 5-amino-4,6-dichloropyrimidine (1.12 g,
6.8 mmol) and triethylamine (0.58 mL, 4.17 mmol) at room tem-
perature under N2 atmosphere. The reaction mixture was stirred at
130 ꢁC for 24 h. The resulting mixture was cooled to room
95%) of 12 as brown syrup. Rf¼0.25 (n-hexane/EtOAc¼8:1);
25
[
a]
þ61.6 (c 1.0, CHCl3); IR (neat)
n 3031, 2864, 1723, 1602, 1496,
D
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Y.H. Jung et al. / Tetrahedron xxx (2015) 1e6
5
temperature and evaporated to dryness. The residue was purified
by flash column chromatography (n-hexane/EtOAc¼3:1) to afford
0.66 g (1.22 mmol, 89%) of 15 as yellow syrup. Rf¼0.50 (n-hexane/
ion-exchange resin DOWEX 50WX8-100 using aqueous 0.5 M
NH4OH to afford 0.044 g (0.167 mmol, 72%) of ent-1 as white solid.
25
Rf¼0.53 (CH2Cl2/MeOH/EtOH/NH4OH 5:2:1:1); [
MeOH); IR (neat)
419 cmꢀ1; 1H NMR (300 MHz, DMSO/D2O)
a
]
þ8.2 (c 0.9,
D
EtOAc¼1:1); [
a
]
25 þ32.9 (c 0.4, CHCl3); IR (neat)
n
3357, 3030, 2858,
n
3383, 2948, 2834, 1652, 1453, 1032, 657,
8.14 (s, 1H), 8.11 (s, 1H),
D
1576, 1496, 1455, 1420, 1360, 1210, 1097, 749, 698, 746, 419 cmꢀ1; 1H
d
NMR (500 MHz, CDCl3)
d
8.12 (s, 1H), 7.36e7.27 (m, 15H), 5.91 (d,
5.71 (d, J¼3.6 Hz, 1H), 5.36 (br s, 1H), 4.43 (d, J¼5.7 Hz, 1H), 4.26 (t,
J¼1.5 Hz, 1H), 5.32 (dd, J¼3.5, 1.5 Hz 1H), 4.86 (d, J¼12.0 Hz, 1H),
4.72 (d, J¼12.5 Hz, 1H), 4.66 (d, J¼12.0 Hz, 1H), 4.47 (d, J¼11.5 Hz,
1H), 4.59e4.51 (m, 4H), 4.13 (s, 2H), 3.88 (dd, J¼4.5, 4.4 Hz,1H), 3.21
J¼5.7 Hz, 1H), 4.12 (s, 2H); 13C NMR (125 MHz, DMSO/D2O)
d 155.8,
152.3, 150.2, 149.9, 140.8, 124.3, 119.4, 77.2, 72.6, 65.0, 59.0; HRMS
(EI) calcd for C11H13N5O3 [M]þ 263.1018, found 263.1019.
(s, 2H); 13C NMR (125 MHz, CDCl3)
d 154.8, 150.0, 144.1, 143.9, 138.6,
138.4, 138.2, 129.5, 128.7, 128.6, 128.5, 128.4, 128.1, 128.0, 127.9,
127.8, 121.9, 82.6, 79.3, 73.4, 72.0, 71.7, 67.3, 60.3; HRMS (CI) calcd
for C31H32ClN4O3 [MþH]þ 543.2163, found 543.2163.
Acknowledgements
This work was supported by the National Research Foundation
of Korea (NRF-2012-002506) funded by the Ministry of Education,
Science and Technology.
4.9. 9-((1S,4S,5R)-4,5-Bis(benzyloxy)-3-(benzyloxymethyl)cy-
clopent-2-enyl)-6-chloro-9H-purine (16)
Supplementary data
To a stirred solution of 15 (0.542 g, 0.998 mmol) in isoamyl al-
cohol (25 mL) was added triethyl orthoformate (1.1 mL, 6.61 mmol)
at room temperature under N2 atmosphere. The reaction mixture
was stirred at 120 ꢁC for 12 h. The resulting mixture was evaporated
to dryness and the residue was purified by flash column chroma-
1H NMR and 13C NMR copies of all compounds. Supplementary
data associated with this article can be found in the online version,
at http://dx.doi.org/10.1016/j.tet.2014.12.093.
tography (n-hexane/EtOAc¼3:1) to afford 0.496 g (0.897 mmol,
References and notes
25
90%) of 16 as yellow syrup. Rf¼0.43 (n-hexane/EtOAc¼1:1); [
a]
D
1. (a) Agrofoglio, L. A.; Challand, S. R. Acyclic, Carbocyclic and L-nucleosides; Kluwer
þ72.0 (c 1.4, CHCl3); IR (neat)
1402, 1338, 1200, 1125, 1028, 938, 948, 747, 699, 638, 476, 458,
419 cmꢀ1 1H NMR (500 MHz, CDCl3)
8.65 (s, 1H), 7.92 (s, 1H),
n 3030, 2864, 1592, 1559, 1495, 1454,
Academic: Dordrecht, The Netherlands, 1998; (b) Crimmins, M. T. Tetrahedron
1998, 54, 9229; (c) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S.
R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611; (d) Borthwick, A. D.; Big-
gadike, K. Tetrahedron 1992, 48, 571.
;
d
7.35e7.30 (m, 10H), 7.13e7.05 (m, 3H), 7.01e6.97 (m, 2H), 5.95 (d,
J¼1.5 Hz, 1H), 5.74 (dd, J¼4.5, 1.5 Hz, 1H), 4.79 (d, J¼11.5 Hz, 1H),
4.68 (d, J¼5.5 Hz, 1H), 4.56 (d, J¼12.0 Hz, 1H), 4.61 (d, J¼¼11.6 Hz,
1H), 4.58e4.54 (m, 2H), 4.38 (d, J¼12.5 Hz, 1H), 4.30 (dd, J¼11.5,
2. Montgomery, J. A. Med. Res. Rev. 1982, 2, 271.
3. (a) Marquez, V. E.; Lim, M.-I. Med. Res. Rev. 1986, 6, 1; (b) Saunders, J.; Cameron,
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Kirk, B. In Topics in Medicinal Chemistry; Leeming, P. R., Ed.; Royal Society of
Chemistry: London, UK, 1998; (d) Song, G. Y.; Paul, V.; Choo, H.; Morrey, J.;
Sidwell, R. W.; Schinazi, R. F.; Chu, C. K. J. Med. Chem. 2001, 44, 3985.
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1981, 34, 359.
5.5 Hz, 1H), 4.20e4.18 (m, 2H); 13C NMR (125 MHz, CDCl3)
d 151.9,
151.7, 151.2, 145.9,144.2,138.3,137.9,137.0, 132.3,128.7, 128.6,128.5,
128.4, 128.3, 128.2, 128.1, 128.0, 126.7, 82.7, 76.9, 73.2, 72.8, 72.7,
67.1, 64.4; HRMS (CI) calcd for C32H30ClN4O3 [MþH]þ 553.2006,
found 553.1996.
5. Kusuka, T.; Yamamoto, H.; Shibata, M.; Muroi, M.; Kishi, T.; Mizuno, K. J. Anti-
biot. 1968, 21, 255.
6. Hayashi, M.; Yaginuma, S.; Yoshioka, H.; Nakatsu, K. J. Antibiot. 1981, 34, 675.
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1711; (b) Herdewijin, P. Modified Nucleosides: In Biochemistry, Biotechnology and
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4.10. 9-((1S,4S,5R)-4,5-Bis(benzyloxy)-3-(benzyloxymethyl)cy-
clopent-2-enyl)-9H-purin-6-amine (17)
A solution of 16 (0.16 g, 0.29 mmol) dissolved in ammonia so-
lution (3 mL, 2 M in MeOH) was stirred at 80 ꢁC for 24 h in a sealed
tube. The solution was evaporated to dryness and the residue was
purified by flash column chromatography (CH2Cl2/MeOH¼15:1) to
afford 0.124 g (0.232 mmol, 80%) of 17 as yellow syrup. Rf¼0.23
25
(CH2Cl2/MeOH¼15:1); [
a]
þ61.1 (c 0.9, CHCl3); IR (neat)
n 3166,
D
2865, 1644, 1598, 1474, 1416, 1365, 1329, 1252, 1207, 1127, 746, 699,
477, 419 cmꢀ1; 1H NMR (500 MHz, CDCl3)
d
8.33 (s, 1H), 7.63 (s, 1H),
7.37e7.28 (m, 10H), 7.21e7.12 (m, 3H), 7.10e7.07 (m, 2H), 5.97 (d,
J¼1.5 Hz, 1H), 5.72 (dd, J¼4.0, 1.5 Hz, 1H), 5.55 (s, 2H), 4.76 (d,
J¼11.0 Hz,1H), 4.58 (d, J¼11.0 Hz, 1H), 4.69 (d, J¼5.0 Hz,1H), 4.65 (d,
J¼12.0 Hz, 1H), 4.52 (d, J¼12.0 Hz, 1H), 4.60e4.54 (m, 2H), 4.30 (dd,
J¼11.0, 5.0 Hz, 1H), 4.21e4.18 (m, 2H); 13C NMR (125 MHz, CDCl3)
d
155.4, 153.1, 150.2, 145.3, 139.5, 138.4, 138.0, 137.4, 128.7, 128.6,
128.4, 128.2, 128.1, 128.0, 127.9, 127.4, 120.3, 82.9, 78.7, 73.1, 72.4,
67.1, 63.8; HRMS (CI) calcd for C32H32N5O3 [MþH]þ 534.2505, found
534.2501.
4.11. (D)-Neplanocin A (ent-1)
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To a stirred solution of 17 (0.13 g, 0.23 mmol) in CH2Cl2 (1.2 mL)
was added BCl3 (4.93 mL, 4.93 mmol, 1 M in CH2Cl2) at ꢀ78 ꢁC. The
reaction mixture was stirred for 24 h at ꢀ78 ꢁC and then quenched
with MeOH (4.6 mL). The resulting mixture was warmed to room
temperature and evaporated to dryness. The residue was dissolved
in MeOH (10 mL) and then evaporated. The residue was purified by
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Chem. 2014, 79, 8059.
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2011, 83, 2489; (c) Lee, S. H.; Kim, I. S.; Li, Q. R.; Dong, G. R.; Jeong, L. S.; Jung, Y.
H. J. Org. Chem. 2011, 76, 10011; (d) Dong, G. R.; Hong, S.; Kim, S. I.; Kim, I. S.;
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