Synthesis of 1,1,2-trisubstituted cyclopropane nucleosides in enantiomerically pure forms

Article abstract of DOI:10.1080/15257770.2019.1625380

Due to the unique rigid and small steric feature of cyclopropane, cyclopropane nucleosides (CPNs) in which the ribose (deoxyribose) of nucleosides are replaced by a hydroxy-substituted cyclopropane, are of great biological interest. Novel 1,1,2-trisubstit

Full text of DOI:10.1080/15257770.2019.1625380

Nucleosides, Nucleotides and Nucleic Acids
ISSN: 1525-7770 (Print) 1532-2335 (Online) Journal homepage: https://www.tandfonline.com/loi/lncn20
Synthesis of 1,1,2-trisubstituted cyclopropane
nucleosides in enantiomerically pure forms
Daichi Fushihara, Hayato Fukuda, Hiroshi Abe & Satoshi Shuto
To cite this article: Daichi Fushihara, Hayato Fukuda, Hiroshi Abe & Satoshi Shuto (2019):
Synthesis of 1,1,2-trisubstituted cyclopropane nucleosides in enantiomerically pure forms,
Nucleosides, Nucleotides and Nucleic Acids, DOI: 10.1080/15257770.2019.1625380
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Published online: 12 Jun 2019.
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NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
https://doi.org/10.1080/15257770.2019.1625380
Synthesis of 1,1,2-trisubstituted cyclopropane
nucleosides in enantiomerically pure forms
a,c
a
c
a,b
Daichi Fushihara , Hayato Fukuda , Hiroshi Abe , and Satoshi Shuto
a
Faculty of Pharmaceutical Sciences, Center for Research and Education on Drug Discovery,
b
Hokkaido University, Sapporo, Japan; Center for Research and Education on Drug Discovery,
Hokkaido University, Sapporo, Japan; Graduate School of Sciences, Nagoya University,
c
Nagoya, Japan
ABSTRACT
ARTICLE HISTORY
Due to the unique rigid and small steric feature of cyclopro-
pane, cyclopropane nucleosides (CPNs) in which the ribose
Received 18 April 2019
Accepted 21 May 2019
(
deoxyribose) of nucleosides are replaced by a hydroxy-substi-
tuted cyclopropane, are of great biological interest. Novel
,1,2-trisubstituted cyclopropane nucleosides were synthesized
KEYWORDS
Cyclopropane nucleoside;
carbocyclic nucleoside
1
in enantiomerically pure forms as potential antiviral agents. In
the synthesis, two cyclopropane tosylates, which were pre-
pared from chiral cyclopropane lactones previously reported
by us, were used effectively as common intermediates for the
CPNs. These CPNs are also potentially useful as nucleoside
units to incorporate into oligonucleotides in nucleic acids
chemotherapy studies.
Introduction
Carbocyclic nucleosides can be bioisosteres of natural nucleosides lacking the
biologically unstable N-ribosyl linkage, and therefore they have been studied
[
1
due to the biological and pharmacological interest. ] A number of antiviral
and antitumor carbocyclic nucleosides have been reported, typically exempli-
[
2]
[3]
fied by clinically useful entecavir and abacavir (Figure 1). In the course
of these studies on carbocyclic nucleosides, we have also studied design and
synthesis of anti-RNA virus carbocyclic nucleosides such as 1 derived from
[
4]
neplanocin A, an antibiotic cyclopentene nucleoside, as a prototype.
Because the smallest carbocycle cyclopropane has a characteristic steric-
ally unhindered and rigid structural feature, it is very effective for designing
conformationally restricted analogs using various conformationally flexible
[
5]
bioactive prototype compounds. Thus, we have been engaged in medi-
cinal chemistry studies using cyclopropane as a key unit for conformational
[
6]
restriction and identified various pharmacologically active compounds.
CONTACT Satoshi Shuto
shu@pharm.hokudai.ac.jp
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lncn.
ß 2019 Taylor & Francis Group, LLC

2
D. FUSHIHARA ET AL.
Due to the unique feature of cyclopropane, cyclopropane nucleosides
N
O
NH
N
N
N
NH
NH2
N
HO
HO
N
N
HO
NH2
entecavir
abacavir
NH2
N
NH2
N
N
N
N
N
HO
HO
N
N
HO
OH
HO
OH
1
neplanocin A
N
N
N
O
N
NH2
O
N
N
W%X
W%X
O
O
P
O
N
N
NH2
O
O
besifovir
AcO
famcyclovir
O
OAc
BH2
N
O
N
NH
NH2
HO
OH
HO
N
n
B = nucleobase
OH
A5021
I (n = 1)
II (n = 0)
Figure 1. Representative biologically active carbocyclic nucleosides.
[
7]
[7d]
(
CPNs) are of great interest.
Besifovir,
a cyclopropane nucleoside
phosphate derivative, was most recently approved as an anti-hepatitis B
viral drug, and some other cyclopropane nucleosides also have potent anti-
[
7]
viral activity. We recently reported synthesis of chiral 1,2,3-trisubstituted
CPNs I and II using Pd-catalyzed substitution via directing group-mediated
3
[8]
C(sp )–H activation of a chiral cyclopropane as a key step.
In this paper, we describe cyclopropane nucleosides CPNs III and IV in
[
9]
enantiomerically pure form as potential antiviral agents (Figure 2). These
have regioisomeric structures of A5021 with remarkable anti-herpes virus
effects.
[
7b]
CPNs III and IV are also of interest because they correspond to
conformationally restricted analogs of the potent anti-herpes virus drug
[
10]
famcyclovir.
Furthermore, these CPNs would be useful as nucleoside

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
3
Figure 2. Novel optically active cyclopropane nucleosides IIIa–d and IVa–d.
units to be incorporated into antisense, siRNA, and aptamer oligonucleoti-
des in nucleic acids chemotherapy studies.
Results and discussion
As described above, we have been engaged in medicinal chemistry studies
using cyclopropane as a key structure for conformational restriction of
compounds and identified a number of pharmacologically active com-
[
5,6]
pounds.
the synthesis of optically active cyclopropane compounds
In these studies, we also have developed various methods for
[
11,12]
which
effectively applied to this CPN synthesis. The retrosynthetic analysis is
summarized in Figure 3. All of four natural nucleobases in IIIa–d and
IVa–d would be introduced via S 2 substitution reaction using key com-
N
mon intermediates that were cyclopropane tosylates 2 for IIIa–d and 4 for
IVa–d, at a late stage in the synthesis. The tosylate 2 would be prepared
[
7b]
from a known chiral tri-substituted cyclopropane lactone 3.
Another
tosylate 4 would be prepared from a chiral methylene cyclopropane 5. We
recently reported a synthesis of 5 from another chiral tri-substituted lactone
[
10d]
6.
Both of lactones 3 and 6 in high optical purity were readily prepared
[
7b,11]
from (R)-epichlorohydrin.
Synthesis of the common intermediate tosylate 2 is shown in Scheme 1.
The known chiral lactone 3 prepared from (R)-epichlorohydrin
[
7b]
was
Figure 3. Retrosynthetic analysis for CPNs III and IV.

4
D. FUSHIHARA ET AL.
Scheme 1. Synthesis of key common intermediate 2.
7b]
[
treated with NaBH formed diol 7
lation provided 9.
of which protecting groups manipu-
4
[
11e,f]
[11f]
Reduction of 9 with LiBH gave alcohol 10.
4
Protecting groups of 10 was again manipulated to afford trihydroxymethyl-
cyclopropane 12, in which three of the two hydroxyls were protected with
a MOM group and a benzoyl group, respectively. Tosylation of the unpro-
tected hydroxyl of 12 gave the common intermediate tosylate 2.
The desired four CPNs IIIa–d were successfully synthesized from the
tosylate 2 as summarized in Scheme 2. We firstly treated 2 with unpro-
9
tected adenine and NaH in DMF to give a mixture of the desired N -prod-
7
[13]
uct 14 and the corresponding N -regioisoer 15
as shown in Scheme 3.
6
However, when N,N-di-Boc-adenine (N -Boc Ade) instead of adenine was
2
[
14]
9
used as a nucleophile
the N -product 13a was selectively obtained in
6
8
0% yield (Scheme 2). Treatment of 2 with O -BnGua and NaH in DMF
gave mainly the desired N -product 13b in 59% yield (Scheme 2) concomi-
tant with the N -isomer 16 (Figure 4).
9
7
[13]
4
Similar treatments of 2 with N -
3
BzCyt or N -BzThy in the presence of NaH in DMF successfully provided
the corresponding nucleoside products 13c and 13d, respectively. Removal
of all of the N- and/or O-protecting groups of 13a–d were carried out by
treating successively with HCl in dioxane or in dioxane/MeOH and with
NaOMe/MeOH to furnish the target CPNs IIIa, IIIb, IIIc, and IIId,
respectively.
Preparation of tosylate 4, the common intermediate for the synthesis of
CPNs IVa–d, is shown in Schemes 4 and 5. Oxidation of the optically
[
11d]
active methylenecyclopropane 5
with OsO stereoselectively occurred to
4
afford diol 17 in 92% yield. The stereochemistry of 17 was confirmed by
NOE experiments as shown in Figure 5.
After protecting the two hydroxyls of 17 with isopropylidene group,
removal of TBDPS group of the resulting acetonide 18 gave 19. Tosylation

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
5
Scheme 2. Synthesis of CPNs IIIa, IIIb, IIIc, and IIId.
7
Scheme 3. Formation of undesired N -regioisomers.
of the hydroxyl of 19 was examined under various conditions, however, the
desired tosylate 20 was not obtained at all. Introduction of thymine base
into 19 under Mitsunobu conditions, which was very effective for our
recent synthesis of CPN I and II, was also unsuccessful. Thus, we specu-
lated that, when an electron-withdrawing tosyl group was introduced, the
cyclopropane ring-opening readily occurred due to the electron-donating
effect of a lone pair of the oxygen directly attached to the cyclopropane
[
15]
ring as indicated in Scheme 4.
Therefore, we introduced an electron-

6
D. FUSHIHARA ET AL.
7
Figure 4. Structure of the N -regioisomer 16.
Scheme 4. Attempt to synthesize tosylate 20.
Figure 5. NOE data of the osmium oxidation product 17.
withdrawing benzoyl group at the hydroxyl to prevent the cyclopropane
ring-opening. Treatment of 17 with BzCl/pyridine gave dibenzoate 21, of
which treatment with TBAF/THF followed by with TsCl/pyridine provided
the desired tosylate 4 in a pure form after silica gel column chromatog-
raphy (Scheme 5).
The key intermediate tosylate 4 in hand, we investigated the synthesis of
CPNs IVa–d (Scheme 6). By the procedure same to the synthesis of CPNs
IIIa–d described above, CPNs IVa, IVb, and IVd were successfully
obtained. However, during deprotection procedure of guanine derivative
22b, it unfortunately decomposed, and thus we could not obtain IVb. Due
to the electron-withdrawing property of guanine base, ring opening of the
cyclopropane ring of IVb might occur like the case of tosylate 20.
As described, we successfully synthesized CPNs IIIa, IIIb, IIIc and IIId,
CPNs IIVa, IVb and IVd in enantiomerically pure forms.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
7
Scheme 5. Synthesis of tosylate 4.
Scheme 6. Synthesis of CPNs IVa, IVc, and IVd.
Experimental section
General information. All commercially available materials were used as
received unless otherwise noted. Column chromatography was performed
using silica gel WakogelVR 60 N (spherical, neutral, 63–210 lm) (Wako) and
Chromatorex NH DM1020 (Fuji Silysia). Compounds were characterized
1
by H NMR, 13C NMR, and mass spectra. Nuclear magnetic resonance
1
spectra were recorded on a JEOL 400 or 500 MHz instruments. H NMR
spectra are reported in d units and parts per million (ppm) and were meas-
ured relative to signals for tetramethylsilane (0.00 ppm) in the deuterated
solvent. 13C NMR spectra are reported in ppm relative to CDCl
３
1
(
77.00 ppm) unless otherwise stated, and were obtained with H decoupling.
Low- and high-resolution mass analysis was performed on a double-focus-
ing high-resolution magnetic sector mass-analyzer instrument.
(
1R,2R)-[1-Benzoyloxymethyl-2-(t-butyldiphenylsilyloxy)methyl-1-
(
1
methoxymeth-yloxy)methyl]cyclopropane (11). To a solution of
[
11f]
0
(755 mg, 1.82 mmol) in pyridine (9.1 mL) were added DMAP
(
11.3 mg, 92.5 lmol) and benzoyl chloride (525 mg, 4.55 mmol) at room
temperature. After stirring the mixture at room temperature for 3.5 h, the
reaction was quenched with cold water and evaporated in vacuo. The resi-
due was partitioned between AcOEt and saturated aqueous NaHCO . The
3
organic layer was washed with aqueous HCl (1 M) and brine, dried over
anhydrous Na SO and evaporated in vacuo. The residue was purified by
2
4

8
D. FUSHIHARA ET AL.
silica gel column chromatography (20% AcOEt in hexane) to give 11
850 mg, 1.64 mmol, 90%) as a colorless oil. [a]18D : ꢀ3.01 (c ¼ 3.75,
(
1
CHCl ); H NMR (CDCl , 400 MHz) d 8.07 (d, J ¼ 8.0 Hz, 2 H, aromatic),
3
3
7
.63–7.72 (m, 4 H, aromatic), 7.52–7.54 (m, 1 H, aromatic), 7.32–7.45 (m,
8
H, aromatic), 4.60 (s, 2 H, –OCH O–), 4.36 (d, J ¼ 11.4 Hz, 1 H,
2
BzOCH C–), 4.15 (d, J ¼ 11.4 Hz, 1 H, BzOCH C–), 3.73–3.87 (m, 2 H,
2
2
MOMOCH C–, –CHCH O–), 3.66–3.71 (m, 1 H, –CHCH O–), 3.58 (d,
2
2
2
J ¼ 11.0 Hz, 1 H, MOMOCH C–), 3.28 (s, 3 H, CH O–), 1.36 (m, 1 H,
2
3
–
CCH(CH )CH –), 1.03 (s, 9 H, –tBu), 0.84 (m, 1 H, –CCH CH–), 0.55 (m,
2 2 2
1
H, –CCH CH–); 13C NMR (CDCl , 100 MHz) d 162.3, 135.5, 133.6,
2 3
1
5
5
33.6, 132.8, 130.5, 130.1, 129.6, 128.3, 127.6, 127.6, 96.2, 69.1, 67.2, 63.4,
5.1, 26.7, 24.2, 24.1, 19.1, 13.7; HRMS (ESI) calcd for C H O NaSi:
3
1
38 5
þ
41.23807, found for 541.23836 [(M þ Na) ].
(
1R,2R)-[1-Benzoyloxymethyl-2-hydroxymethyl-1-(methoxymethyloxy)-
methyl]-cyclopropane (12). To a solution of 11 (79.8 mg, 154lmol) in THF
1.5 mL) were added AcOH (13 mL, 231 lmol) and a solution of tetrabutylam-
(
monium fluoride (1 M solution in THF, 0.23mL, 231lmol) at room tempera-
ture. After stirring the mixture at room temperature for 6 h, the solvent was
evaporated in vacuo. The residue was partitioned between AcOEt and saturated
aqueous NH Cl. The organic layer was washed with saturated aqueous
4
NaHCO and brine, dried over anhydrous Na SO , and evaporated in vacuo.
3
2
4
The residue was purified by silica gel column chromatography (33–50% AcOEt
in hexane) to give 12 (40.2 mg, 143lmol, 93%) as a colorless oil. [a]19D :
1
ꢀ
2.69 (c ¼ 4.00, CHCl ); H NMR (CDCl , 400MHz) d 8.06 (d, J ¼ 8.0 Hz,
3
3
2
H, aromatic), 7.57 (t, J ¼ 8.0 Hz, 1 H, aromatic), 7.45 (dd, J ¼ 8.0, 8.0 Hz, 2 H,
aromatic), 4.67 (s, 2 H, –OCH O–), 4.62 (d, J ¼ 12.0 Hz, 1 H, BzOCH C–), 4.12
2
2
(
–
d, J ¼ 12.0 Hz, 1 H, BzOCH C–), 3.96–4.02 (m, 2 H, MOMOCH C–,
2
2
CHCH O–), 3.30–3.42 (m, 5 H, MOMOCH C–, –CHCH O–, CH O–), 1.46
2 2 2 3
(
m, 1 H, –CCH(CH )CH –), 0.98 (dd, J ¼ 8.0, 6.0 Hz, 1 H, –CCH CH–), 0.55
2
2
2
(
1
dd, J ¼ 6.0, 4.0 Hz, 1 H, –CCH CH–); 13C NMR (CDCl , 100MHz) d 166.4,
2
3
32.9, 130.1, 129.5, 128.3, 96.5, 69.0, 68.3, 62.5, 55.5, 24.3, 24.0, 14.2; HRMS
þ
(ESI) calcd for C H O Na: 303.12029, found for 303.12040 [(Mþ Na) ].
15 20 5
(
1R,2R)-[1-Benzoyloxymethyl-1-(methoxymethyloxy)methyl-2-(tosylox-
y)methyl]-cyclopropane (2). To a solution of 12 (261 mg, 931 lmol) in
ꢁ
pyridine (4.7 mL) was added TsCl (799 mg, 4.19 mmol) at 0 C. After stir-
ꢁ
ring the mixture at 0 C for 5.5 h, the reaction mixture was partitioned
between AcOEt and aqueous HCl (1 M). The organic layer was washed
with saturated aqueous NaHCO and brine, dried over anhydrous Na SO ,
3
2
4
and evaporated in vacuo. The residue was purified by silica gel column
chromatography (20% AcOEt in hexane) to give 2 (392 mg, 902 lmol, 97%)
1
as a colorless oil. [a]19D : ꢀ3.67 (c ¼ 3.21, CHCl ); H NMR (CDCl ,
3
3
4
00 MHz) d 8.03 (d, J ¼ 8.0 Hz, 2 H, aromatic), 7.79 (d, J ¼ 8.4 Hz, 2 H,

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
9
aromatic), 7.57 (t, J ¼ 8.0 Hz, 1 H, aromatic), 7.45 (dd, J ¼ 8.0, 8.0 Hz, 2 H,
aromatic), 7.32 (d, J ¼ 8.4 Hz, 2 H, aromatic), 4.58 (m, 2 H, –OCH O–),
2
4
.26 (d, J ¼ 11.6 Hz, 1 H, BzOCH C–), 4.13–4.21 (m, 3 H, –CHCH O–,
2
2
BzOCH C–), 3.69 (d, J ¼ 11.2 Hz, 1 H, MOMOCH C–), 3.48 (d, J ¼ 11.2 Hz,
2
2
1
1
H, MOMOCH C–), 3.31 (s, 3 H, CH O–), 2.43 (s, 3 H, CH Ph–), 1.36 (m,
2 3 3
H, –CCH(CH )CH –), 0.99 (dd, J ¼ 8.8, 5.8 Hz, 1 H, –CCH CH–), 0.55
2
2
2
(
dd, J ¼ 5.8, 5.6 Hz, 1 H, –CCH CH–); 13C NMR (CDCl , 100 MHz) d
2
3
1
6
4
66.3, 144.7, 133.3, 133.0, 130.0, 129.8, 129.5, 128.4, 127.8, 96.3, 70.6, 68.1,
6.9, 55.3, 25.2, 21.6, 20.0, 14.3; HRMS (ESI) calcd for C H O NaS:
2
2
26 7
þ
57.12914, found for 457.12915 [(M þ Na) ].
(
1R,2R)-{1-Benzoyloxymethyl-2-(adenin-9-yl)methyl-1-(methoxymethy-
loxy)-methyl}cyclopropane (14) and (1 R,2R)-{1-benzoyloxymethyl-2-
adenin-7-yl)methyl-1-(methoxymethyloxy)-methyl}cyclopropane (15). To
(
a solution of adenine (9.72 mg, 71.9 lmol) in DMF (0.25 mL) was added
NaH (60% dispersion in mineral oil, 2.88 mg, 71.9 lmol) at room tempera-
ture. After stirring the mixture at room temperature for 30 min, to the mix-
ture was added a solution of 2 (28.4 mg, 65.4 lmol) in DMF (0.10 mL) at
ꢁ
room temperature. After stirring the mixture at 50 C for 4 h, the resulting
mixture was partitioned between 50% AcOEt in hexane and saturated aque-
ous NaHCO . The organic layer was washed with brine, dried over anhyd-
3
rous Na SO , and evaporated in vacuo. The residue was purified by silica
2
4
gel column chromatography (5–9% MeOH in CHCl ) to give 14 (9.33 mg,
3
2
3.5 lmol, 36%) as a colorless waxy solid and 15 (3.12 mg, 7.83 lmol, 12%)
1
as a colorless waxy solid. 14: H NMR (400 MHz, CDCl ) d 8.36 (s, 1 H,
3
adenine-H2), 8.07 (s, 1 H, adenine-H8), 7.96 (d, J ¼ 8.0 Hz, 2 H, aromatic),
7
5
–
.56 (t, J ¼ 7.7 Hz, 1 H, aromatic), 7.44 (dd, J ¼ 8.0, 7.7 Hz, 2 H, aromatic),
.82 (s, 2 H, NH –), 4.64 (s, 2 H, –OCH O–), 4.38–4.44 (m, 2 H,
2
2
CHCH N–, BzOCH C–), 4.26 (dd, J ¼ 14.8, 8.0 Hz, 1 H, –CHCH N–),
2
2
2
4
.19 (d, J ¼ 11.6 Hz, 1 H, BzOCH C–), 4.02 (d, J ¼ 11.0 Hz, 1 H,
2
MOMOCH C–), 3.60 (d, J ¼ 11.0 Hz, 1 H, MOMOCH C–), 3.33 (s, 3 H,
2
2
CH O–), 1.61 (m, 1 H, –CCH(CH )CH –), 1.07 (dd, J ¼ 9.0, 5.9 Hz, 1 H,
3
2
2
–
CCH CH–), 0.79 (dd, J ¼ 5.9, 5.6 Hz, 1 H, –CCH CH–); UV (water) k
2
2
max
1
261 nm. 15: H NMR (400 MHz, CDCl ) d 8.51 (s, 1 H, adenine-H2), 8.14
3
(
1
s, 1 H, adenine-H8), 7.99 (d, J ¼ 8.4 Hz, 2 H, aromatic), 7.69 (t, J ¼ 8.0 Hz,
H, aromatic), 7.47 (dd, J ¼ 8.4, 8.0 Hz, 2 H, aromatic), 5.40 (s, 2 H,
NH –), 4.67 (s, 2 H, –OCH O–), 4.58 (dd, J ¼ 15.2, 6.5 Hz, 1 H,
2
2
–
6
CHCH N–), 4.43 (d, J ¼ 11.8 Hz, 1 H, BzOCH C–), 4.34 (dd, J ¼ 15.2,
2
2
.5 Hz, 1 H, –CHCH N–), 4.21 (d, J ¼ 11.8 Hz, 1 H, BzOCH C–), 4.10 (d,
2
2
J ¼ 11.0 Hz,
1 H,
MOMOCH C–),
3.54
(d,
J ¼ 11.0 Hz,
1 H,
2
MOMOCH C–), 3.36 (s, 3 H, CH O–), 1.57 (m, 1 H, –CCH(CH )CH –),
2
3
2
2
1
–
.16 (dd, J ¼ 9.0, 5.8 Hz, 1 H, –CCH CH–), 0.82 (dd, J ¼ 6.0, 5.6 Hz, 1 H,
2
CCH CH–); UV (water) k
265 nm.
max
2

1
0
D. FUSHIHARA ET AL.
6
(
1R,2R)-{1-Benzoyloxymethyl-2-[N6,N -bis(t-butoxycarbonyl)adenin-9-
yl)methyl-1-(methoxymethyloxy)methyl]cyclopropane (13a). To a solution
[16]
of N,N-di-Boc-adenine (180 mg, 506 lmol) in DMF (2.3 mL) was added NaH
60% dispersion in mineral oil, 20.2 mg, 506 lmol) at room temperature. After
(
stirring the mixture at room temperature for 30 min, to the mixture was added
a solution of 2 (200 mg, 460 lmol) in DMF (2.3 mL) at room temperature.
ꢁ
After stirring the mixture at 40 C for 24 h, the resulting mixture was partitioned
between 50% AcOEt in hexane and saturated aqueous NaHCO . The organic
3
layer was washed with brine, dried over anhydrous Na SO , and evaporated in
2
4
vacuo. The residue was purified by silica gel column chromatography (33%
AcOEt in hexane) to give 13a (221 mg, 369 lmol, 80%) as a white solid.
1
[
a]17D : 2.98 (c¼ 0.62, CHCl ); H NMR (CDCl , 500MHz) d 8.86 (s, 1 H,
3
3
adenine-H2), 8.44 (s, 1 H, adenine-H8), 8.01 (d, J¼ 7.5Hz, 2H, aromatic), 7.57
d, J¼ 7.4 Hz, 1 H, aromatic), 7.45 (dd, J¼ 7.5, 7.4 Hz, 2 H, aromatic), 4.61 (m,
H, –OCH O–), 4.53 (dd, J¼ 14.7, 7.0 Hz, 1 H, –CHCH N–), 4.45 (d,
(
2
2
2
J¼ 11.5Hz, 1H, BzOCH C–), 4.37 (dd, J¼ 14.7, 8.0 Hz, 1 H, –CHCH N–), 4.18
2
2
(
3
–
–
d, J¼ 11.5 Hz, 1 H, BzOCH C–), 4.09 (d, J¼ 11.0Hz, 1H, MOMOCH C–),
2
2
.58 (d, J¼ 11.0Hz, 1H, MOMOCH C–), 3.31 (s, 3 H, CH O–), 1.65 (m, 1 H,
2
3
CCH(CH )CH –), 1.45 (s, 18 H, –tBu), 1.10 (dd, J¼ 8.8, 5.7 Hz, 1 H,
2
2
CCH CH–), 0.55 (dd, J¼ 5.7, 5.5 Hz, 1 H, –CCH CH–); 13C NMR (CDCl ,
2
2
3
1
25 MHz) d 166.0, 153.1, 151.5, 150.1, 149.8, 144.7, 132.8, 129.6, 129.2, 128.3,
1
28.1, 96.1, 83.2, 68.0, 66.9, 55.0, 42.9, 27.4, 25.1, 20.8, 14.0; HRMS (ESI) calcd
þ
for C H O N Na: 620.26908, found for 620.26986 [(M þ Na) ].
3
0 39 8 5
6
(
1R,2R)-[1-Benzoyloxymethyl-2-(O -benzylguanin-9-yl)methyl-1-
(
methoxymethyl-oxy)methyl]cyclopropane (13b), (1R,2R)-[1-ben-
6
zoyloxymethyl-2-(O -benzylguanin-7-yl)methyl-1-(methoxymethyloxy)
methyl]cyclopropane (16). To a solution of O -benzylguanine
6
(
36.7 mg, 152 lmol) in DMF (0.55 mL) was added NaH (60% disper-
sion in mineral oil, 6.08 mg, 152 lmol) at room temperature. After
stirring the mixture at room temperature for 30 min, to the mixture
was added a solution of 2 (60 mg, 138 lmol) in DMF (0.14 mL) at
room temperature. After stirring the mixture at room temperature
for 5 h, the reaction mixture was partitioned between 50% AcOEt in
hexane and saturated aqueous NaHCO . The organic layer was
3
washed with brine, dried over anhydrous Na SO , and evaporated in
2
4
vacuo. The residue was purified by silica gel column chromatography
5% MeOH in CHCl ) to give 13b (38.9 mg, 77.3 lmol, 56%) as a
(
3
white solid and 16 (26.4 mg, 52.4 lmol, 38%) as a white solid. 13b:
1
[
(
(
(
a]17D : 7.43 (c ¼ 1.09, CHCl ); H NMR (CDCl , 400 MHz) d 7.96
3
3
d, J ¼ 7.0 Hz, 2 H, aromatic), 7.84 (s, 1 H, guanine-H8), 7.31–7.56
m, 8 H, aromatic), 5.57 (s, 2 H, –OCH Ph), 4.84 (s, 2 H, –NH ), 4.65
m, 2 H, –OCH O–), 4.35 (d, J ¼ 11.6 Hz, 1 H, BzOCH C–), 4.11–4.27
2
2
2
2

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
11
(
m, 3 H, BzOCH C–, –CHCH N–), 3.99 (d, J ¼ 11.2 Hz, 1 H,
2
2
MOMOCH C–), 3.61 (d, J ¼ 11.2 Hz, 1 H, MOMOCH C–), 3.34 (s,
2
2
3
5
1
1
6
H, CH O–), 1.57 (m, 1 H, –CCH(CH )CH –), 1.05 (dd, J ¼ 9.2,
3
2
2
.8 Hz, 1 H, –CCH CH–), 0.75 (dd, J ¼ 6.0, 5.8 Hz, 1 H, –CCH CH–);
2
2
3C NMR (CDCl , 125 MHz) d 166.3, 164.0, 159.1, 157.0, 144.6,
3
36.0, 133.1, 129.8, 129.4, 128.6, 128.4, 128.4, 128.3, 107.1, 96.4,
8.3, 68.1, 67.1, 55.4, 46.7, 25.2, 22.0, 14.1; HRMS (ESI) calcd for
þ
C H O N : 504.22415, found for 504.22405 [(M þ H) ]; UV
2
7
30
5
5
1
(
water) k
281 nm. 16: H NMR (CDCl , 400 MHz) d 7.93–7.96 (m,
max 3
3
7
–
–
H, guanine-H8, aromatic), 7.57 (t, J ¼ 7.6 Hz, 1 H, aromatic),
.33–7.47 (m, 7 H, aromatic), 5.52 (s, 2 H, –OCH Ph), 4.93 (s, 2 H,
2
NH ), 4.56 (m, 2 H, –OCH O–), 4.24–4.39 (m, 3 H, BzOCH C–,
2
2
2
CHCH N–), 4.08 (d, J ¼ 12.0 Hz, 1 H, BzOCH C–), 3.87 (d,
2
2
J ¼ 10.8 Hz, 1 H, MOMOCH C–), 3.37 (d, J ¼ 10.8 Hz, 1 H,
2
MOMOCH C–),
3.29
(s,
3 H,
CH O–),
1.54
(m,
1 H,
2
3
–
CCH(CH )CH –), 0.91 (dd, J ¼ 9.2, 5.6 Hz, 1 H, –CCH CH–), 0.66
2
2
2
(
dd, J ¼ 5.6, 5.6 Hz, 1 H, –CCH CH–); UV (water) k
295 nm.
2
max
4
(
1R,2R)-[2-(N -Benzoylcytosin-1-yl)methyl-1-benzoyloxymehtyl-1-
4
(
methoxymeth-yloxy)methyl]cyclopropane (13c). To a solution of N -
benzoylcytosine (109 mg, 506 lmol) in DMF (2.3 mL) was added NaH (60%
dispersion in mineral oil, 20.2mg, 506lmol) at room temperature. After stir-
ring the mixture at room temperature for 30 min, to the mixture was added a
solution of 2 (200 mg, 460 lmol) in DMF (2.3 mL) at room temperature. After
ꢁ
stirring the mixture at 40 C for 24 h, the reaction mixture was partitioned
between 50% AcOEt in hexane and saturated aqueous NaHCO . The organic
3
layer was washed with brine, dried over anhydrous Na SO , and evaporated in
2
4
vacuo. The residue was purified by silica gel column chromatography (1%
MeOH in CHCl ) to give 13c (99.7 mg, 208 lmol, 45%) as a white solid.
3
1
[
–
a]24D : 12.35 (c ¼ 4.73, CHCl ); H NMR (CDCl , 500 MHz) d 8.97 (br, 1 H,
3
3
NH), 8.01–8.04 (m, 3 H, aromatic, cytosine-H6), 7.92 (d, J ¼ 7.5 Hz, 2 H, aro-
matic), 7.53–7.62 (m, 2 H, aromatic), 7.43–7.52 (m, 5 H, aromatic, cytosine-
H5), 4.63 (m, 2 H, –OCH O–), 4.36 (d, J ¼ 11.3 Hz, 1 H, BzOCH C–),
2
2
4
.22–4.27 (m, 2 H, BzOCH C–, –CHCH N–), 3.91–3.98 (m, 2 H,
2 2
MOMOCH C–, –CHCH N–), 3.56 (d, J ¼ 11.0 Hz, 1 H, MOMOCH C–), 3.32
2
2
2
(
1
s, 3 H, CH O–), 1.54 (m, 1 H, –CCH(CH )CH –), 1.06 (dd, J ¼ 8.5, 5.3 Hz,
3
2
2
H, –CCH CH–), 0.77 (dd, J ¼ 6.0, 5.3 Hz, 1 H, –CCH CH–); 13C NMR
2
2
(CDCl , 125 MHz) d 166.6, 166.2, 161.9, 155.6, 148.3, 133.0, 133.0, 132.9, 129.8,
3
1
29.3, 128.8, 128.3, 127.4, 96.4, 68.5, 67.2, 55.3, 48.7, 25.1, 20.4, 14.0; HRMS
þ
(ESI) calcd for C H O N : 478.19726, found for 478.19737 [(Mþ H) ].
26 28 6 3
{
(1R,2R)-[2-(3-Benzoylthymin-1-yl]methyl-1-benzoyloxymethyl-1-
(
methoxymeth-yloxy)methyl]cyclopropane (13d). To a solution of
3
[17]
N -benzoylthymine
(159 mg, 690 lmol) in DMF (2.3 mL) was added

1
2
D. FUSHIHARA ET AL.
NaH (60% dispersion in mineral oil, 27.6 mg, 690 lmol) at room tem-
perature. After stirring the mixture at room temperature for 30 min, to
the mixture was added a solution of 2 (200 mg, 460 lmol) in DMF
(
2.3 mL) at room temperature. After stirring the mixture at room tem-
perature for 24 h, the reaction mixture was partitioned between 50%
AcOEt in hexane and saturated aqueous NaHCO . The organic layer
3
was washed with brine, dried over anhydrous Na SO , and evaporated
2
4
in vacuo. The residue was purified by silica gel column chromatography
50% AcOEt in hexane) to give 13d (158 mg, 321 lmol, 70%) as a white
(
1
solid. [a]18D : 14.38 (c ¼ 0.66, CHCl ); H NMR (CDCl , 500 MHz) d
3
3
8
7
7
4
.03 (d, J ¼ 7.5 Hz, 2 H, aromatic), 7.91 (d, J ¼ 8.5 Hz, 2 H, aromatic),
.62 (t, J ¼ 6.5 Hz, 1 H, aromatic), 7.55 (t, J ¼ 7.5 Hz, 1 H, aromatic),
.38–7.50 (m, 5 H, aromatic, thymine-H6), 4.61 (s, 2 H, –OCH O–),
2
.38 (d, J ¼ 10.5 Hz, 1 H, BzOCH C–), 4.18 (d, J ¼ 10.5 Hz, 1 H,
2
BzOCH C–), 4.01 (dd, J ¼ 14.4, 7.0 Hz, 1 H, –CHCH N–), 3.95 (d,
2
2
J ¼ 10.8 Hz, 1 H, MOMOCH C–), 3.76 (dd, J ¼ 14.4, 7.8 Hz, 1 H,
2
–
CHCH N–), 3.49 (d, J ¼ 10.8 Hz, 1 H, MOMOCH C–), 3.33 (s, 3 H,
2
2
5
CH O–), 1.86 (s, 3 H, C CH ), 1.44 (m, 1 H, –CCH(CH )CH –), 1.00
3
3
2
2
(
dd, J ¼ 8.5, 5.3 Hz, 1 H, –CCH CH–), 0.69 (dd, J ¼ 5.5, 5.3 Hz, 1 H,
2
–
1
6
CCH CH–); 13C NMR (CDCl , 125 MHz) d 169.0, 166.2, 163.0, 149.8,
2 3
40.1, 134.9, 133.0, 131.3, 130.1, 130.0, 129.3, 129.0, 128.3, 110.3, 96.3,
8.4, 67.1, 55.2, 46.8, 25.0, 20.8, 13.8, 12.1; HRMS (ESI) calcd for
þ
C H O N Na: 515.17887, found for 515.17910 [(M þ Na) ].
2
7
28
7
2
0
(
R)-[2-(Adenin-9 -yl)methyl-1,1-bis(hydroxymethyl)]cyclopropane (IIIa).
A solution of 13a (210 mg, 350 lmol) in HCl (4.0 M in dioxane, 3.5 mL) was
stirred at room temperature for 6 h, and then the solvent was evaporated in
vacuo. To the solution of the residue in MeOH (3.5mL) was added a solu-
tion of NaOMe (5 M in MeOH, 94 lL, 470 lmol) at room temperature. After
stirring the mixture at room temperature for 2 h, the reaction was quenched
with aqueous HCl (1 M) and evaporated in vacuo. The residue was purified
by NH silica gel column chromatography (17% MeOH in CHCl ) to give
3
ꢁ
IIIa (56.2 mg, 225 lmol, 64%) as a white solid. mp. 163.1–165.2 C; [a]24D :
1
ꢀ
7.40 (c ¼ 0.25, CH OH); H NMR (CD OD, 500 MHz) d 8.29 (s, 1 H,
3
3
adenine-H2), 8.20 (s, 1 H, adenine-H8), 4.34 (d, J ¼ 7.5 Hz, 2 H,
CHCH N–), 4.02 (d, J ¼ 11.8 Hz, 1 H, OHCH C–), 3.62–3.67 (m, 2 H,
–
2
2
OHCH C–), 3.39 (d, J ¼ 11.3 Hz, 1 H, OHCH C–), 1.39 (m, 1 H,
2
2
–
CCH(CH )CH –), 0.79 (dd, J ¼ 8.5, 5.3 Hz, 1 H, –CCH CH–), 0.61 (dd,
2
2
2
J ¼ 5.3, 5.0 Hz, 1 H, –CCH CH–); 13C NMR (CD OD, 125MHz) d 157.3,
2
3
1
53.53, 150.5, 142.8, 120.0, 66.9, 62.4, 44.5, 30.7, 22.2, 13.7; HRMS (ESI)
þ
calcd for C H O N : 250.12985, found for 250.13010 [(M þ H) ].
11 16 2 5
(
R)-[2-(Guanin-9-yl)methyl-1,1-bis(hydroxymethyl)]cyclopropane (IIIb).
To a solution of 13b (79.0 mg, 157 lmol) in MeOH (0.78 mL) was added a

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
13
solution of HCl (4.0M in dioxane, 0.78 mL) at room temperature. After stir-
ring the mixture at room temperature for 5 h, the solvent was evaporated in
vacuo. To the solution of the residue in MeOH (0.72 mL) was added a solu-
tion of NaOMe (5 M in MeOH, 42 lL, 210 lmol) at room temperature. After
stirring the mixture at room temperature for 2 h, the reaction mixture was
quenched with aqueous HCl (1 M) and evaporated in vacuo. The residue
was purified by NH silica gel column chromatography (17% MeOH in
CHCl ) to give IIIb (38.9 mg, 146lmol, 93%) as a white solid. mp.
3
ꢁ
1
2
5
–
13.2–215.1 C; [a]23D : ꢀ9.42 (c ¼ 0.19, CH OH); H NMR (CD OD,
3
3
00 MHz) d 7.88 (s, 1 H, guanine-H8), 4.19 (dd, J ¼ 14.7, 7.5 Hz, 1 H,
CHCH N–), 4.11 (dd, J ¼ 14.7, 7.8 Hz, 1 H, –CHCH N–), 3.99 (d,
2
2
J ¼ 11.8 Hz, 1 H, OHCH C–), 3.60–3.64 (m, 2 H, OHCH C–), 3.38 (d,
2
2
J ¼ 11.3 Hz, 1 H, OHCH C–), 1.35 (m, 1 H, –CCH(CH )CH –), 0.76 (dd,
2
2
2
J ¼ 8.8, 5.4 Hz, 1 H, –CCH CH–), 0.59 (dd, J ¼ 5.4, 5.0 Hz, 1 H, –CCH CH–);
2
2
1
4
3C NMR (CD OD, 125 MHz) d 159.5, 155.3, 152.9, 139.7, 117.4, 67.0, 62.5,
3
þ
4.1, 30.6, 22.3, 13.8; LRMS (ESI) m/z 266 [(M þ H) ]; HRMS (ESI) calcd
þ
for C H O N : 266.12477, found for 266.12512 [(Mþ H) ].
11 16 3 5
(
R)-[2-(Cytosin-1-yl)methyl-1,1-bis(hydroxymethyl)]cyclopropane (IIIc).
To a solution of 13c (86.9mg, 181 lmol) in MeOH (0.91 mL) was added a
solution of HCl (4.0M in dioxane, 0.91 mL) at room temperature. After stir-
ring the mixture at room temperature for 5 h, the solvent was evaporated in
vacuo. To the solution of the residue in MeOH (1.8mL) was added a solu-
tion of NaOMe (5 M in MeOH, 97 lL, 485 lmol) at room temperature. After
stirring the mixture at room temperature for 2 h, the reaction mixture was
quenched with aqueous HCl (1 M) and evaporated in vacuo. The residue
was purified by NH silica gel column chromatography (17% MeOH in
CHCl ) to give IIIc (38.3 mg, 170 lmol, 93%) as a white solid. mp.
3
ꢁ
1
2
5
03.4–205.8 C; [a]21D : ꢀ20.28 (c ¼ 0.24, CH OH); H NMR (CD OD,
3
3
00 MHz) d 7.73 (d, J ¼ 7.3 Hz, 1 H, cytosine-H6), 5.86 (d, J ¼ 7.3 Hz, 1 H,
cytosine-H5), 3.99 (dd, J ¼ 14.3, 7.3 Hz, 1 H, –CHCH N–), 3.94 (d,
2
J ¼ 11.3 Hz, 1 H, OHCH C–), 3.80 (dd, J ¼ 14.3, 7.3 Hz, 1 H, –CHCH N–),
2
2
3
3
(
–
.62 (d, J ¼ 11.8 Hz, 1 H, OHCH C–), 3.56 (d, J ¼ 11.8 Hz, 1 H, OHCH C–),
2
2
.36 (d, J ¼ 11.3 Hz, 1 H, OHCH C–), 1.23 (m, 1 H, –CCH(CH )CH –), 0.72
2
2
2
dd, J ¼ 8.8, 5.2 Hz, 1 H, –CCH CH–), 0.51 (dd, J ¼ 5.5, 5.2 Hz, 1 H,
2
CCH CH–); 13C NMR (CD OD, 125 MHz) d 167.9, 159.3, 147.3, 95.8,
2 3
6
7.1, 62.6, 30.4, 21.8, 13.3; HRMS (ESI) calcd for C H O N : 226.11862,
10 16 3 3
þ
found for 226.11885 [(M þ H) ].
(R)-[2-(Thymin-1-yl)methyl-1,1-bis(hydroxymethyl)]cyclopropane (IIId).
A solution of 13d (146 mg, 296 lmol) in HCl (4.0 M in dioxane, 3.0 mL) was
stirred at room temperature for 6 h, and then the solvent was evaporated in
vacuo. To the solution of the residue in MeOH (3.0 mL) was added a solution
of NaOMe (5 M in MeOH, 0.16mL, 800 lmol) at room temperature. After

1
4
D. FUSHIHARA ET AL.
stirring the mixture at room temperature for 2 h, the reaction mixture was
quenched with aqueous HCl (1 M) and evaporated in vacuo. The residue was
purified by silica gel column chromatography (5–9% MeOH in CHCl ) to give
3
IIId (55.3 mg, 230 lmol, 78%) as a white amorphous solid. [a]20D : ꢀ17.12
1
(
c ¼ 2.57, CH OH); H NMR (CD OD, 500 MHz) d 7.59 (d, J ¼ 0.8 Hz, 1 H,
3
3
thymine-H6), 4.61 (s, 2 H, –OCH O–), 3.763.82 (m, 2 H, OHCH C–,
2
2
–
1
1
–
CHCH N–), 3.79 (dd, J ¼ 14.5, 7.5 Hz, 1 H, –CHCH N–), 3.60 (d, J ¼ 11.3 Hz,
2
2
H, OHCH C–), 3.56 (d, J ¼ 11.8 Hz, 1 H, OHCH C–), 3.39 (d, J ¼ 11.3 Hz,
2
2
H, OHCH C–), 1.87 (d, J ¼ 0.8 Hz, 3 H, tymine-5–CH ), 1.23 (m, 1 H,
2
3
CCH(CH )CH –), 0.73 (dd, J ¼ 8.5, 5.0 Hz, 1 H, –CCH CH–), 0.53 (dd,
2
2
2
J ¼ 5.5, 5.0 Hz, 1 H, –CCH CH–); 13C NMR (CD OD, 125MHz) d 166.9,
2
3
153.1, 143.1, 111.0, 67.1, 62.6, 48.4, 30.3, 21.5, 13.5, 12.2; HRMS (ESI) calcd for
þ
C H O N Na: 263.10023, found for 263.10022 [(Mþ Na) ].
11 16 4 2
(
1R,2S)-[2-(t-Butyldiphenylsilyloxy)methyl-1-hydroxy-1-hydroxymethyl]-
cyclo-propane (17). To a solution of NMO (24.0 mg, 204 lmol) in acetone
0.23 mL) were added water (0.46 mL) and a solution of OsO (5mg/mL in
(
4
tBuOH, 23 lL, 0.465 lmol) at room temperature. After stirring the mixture
at room temperature for 30 min, to the mixture was added a solution of
[
10 ]
5
d (30.0 mg, 93.0lmol) in acetone (0.23 mL) at room temperature. After
stirring the mixture at room temperature for 50 h, the reaction was
quenched with saturated aqueous Na S O and evaporated in vacuo. The
2
2 3
residue was partitioned between CHCl and water, and the organic layer
3
was dried over anhydrous Na SO and evaporated in vacuo. The residue
2
4
was purified by silica gel column chromatography (33% AcOEt in hexane)
to give 17 (30.5 mg, 85.5lmol, 92%) as a colorless oil. [a]19D : 2.51
1
(
c ¼ 2.40, CHCl ); H NMR (CDCl , 500 MHz) d 7.65–7.72 (m, 4 H, aro-
3
3
matic), 7.39–7.49 (m, 6 H, aromatic), 4.03–4.09 (m, 2 H, OHCH C–,
2
–
1
–
CHCH O–), 3.59 (m, 1 H, OHCH C–), 3.35 (m, 1 H, –CH OH), 3.19 (s,
2 2 2
H, –COH), 3.14 (dd, J ¼ 10.5, 11.0 Hz, 1 H, –CHCH O–), 1.45 (m, 1 H,
2
CCH(CH )CH –), 1.02–1.08 (m, 10 H, –tBu, –CCH CH–), 0.45 (dd,
2
2
2
J ¼ 6.0, 6.0 Hz, 1 H, –CCH CH–); 13C NMR (CDCl , 100 MHz) d 135.5,
2
3
135.4, 132.7, 132.7, 130.0, 130.0, 127.9, 66.5, 65.7, 60.5, 26.8, 26.2, 19.0, 16.4;
HRMS (ESI) calcd for C H O NaSi: 379.16999, found for
2
1
28 3
þ
3
79.17004 [(M þ Na) ].
(
1R,2S)-[1-Benzoyloxy-1-benzoyloxymethyl-2-(t-butyldiphenylsilyloxy)
methyl]-cyclopropane (21). To a solution of 17 (30.0 mg, 84.1 lmol) in
pyridine (0.43 mL) was added BzCl (87 lL, 0.756 mmol) at room tem-
perature. After stirring the mixture at room temperature for 3 h, the
reaction mixture was partitioned between AcOEt and ice water. The
organic layer was washed with saturated aqueous NaHCO , aqueous
3
HCl (1 M) and brine, dried over anhydrous Na SO , and evaporated in
2
4
vacuo. The residue was purified by silica gel column chromatography

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
15
(
5% AcOEt in hexane) to give 21 (43.2 mg, 76.6 lmol, 91%) as a color-
1
less oil. [a]21D : ꢀ24.17 (c ¼ 1.67, CHCl ); H NMR (CDCl , 500 MHz)
3
3
d 7.98–8.05 (m, 4 H, aromatic), 7.68 (m, 4 H, aromatic), 7.54 (m, 2 H,
aromatic), 7.36–7.44 (m, 8 H, aromatic), 7.33 (dd, J ¼ 7.5, 7.5 Hz, 2 H,
aromatic), 5.03 (d, J ¼ 13.3 Hz, 1 H, –OCH C–), 4.67 (d, J ¼ 13.3 Hz, 1 H,
2
–
–
(
(
OCH C–),
3.94
(m,
2 H,
–CHCH O–),
1.70
(m,
1 H,
2
2
CCH(CH )CH –), 1.30 (dd, J ¼ 10.5, 6.8 Hz, 1 H, –CCH CH–), 1.16
2
2
2
dd, J ¼ 7.5, 6.8 Hz, 1 H, –CCH CH–), 1.05 (s, 9 H, –tBu); 13C NMR
2
CDCl , 100 MHz) d 166.3, 166.2, 135.6, 135.6, 133.4, 133.2, 133.0,
3
1
6
32,9, 130.2, 130.1, 129.7, 129.7, 129.7, 129.6, 128.3, 128.3, 127.7, 127.7,
5.6, 61.8, 60,7, 26.8, 25.9, 19.2, 15.5; HRMS (ESI) calcd for
þ
C H O NaSi: 587.22242, found for 587.22247 [(M þ Na) ].
35
36
5
{
(1R,2S)-(1-Benzoyloxy-1-benzoyloxymehtyl-2-tosyloxymethyl)cyclo-
propane (4). To a solution of 21 (43.2 mg, 76.6 lmol) in THF (0.77 mL)
was added a solution of tetrabutylammonium fluoride (1 M solution in
THF, 0.12 mL, 0.12 mmol) at room temperature. After stirring the mix-
ture at room temperature for 3 h, the solvent was evaporated in vacuo.
The residue was partitioned between CHCl and saturated aqueous
3
NH Cl, and the organic layer was dried over anhydrous Na SO and
4
2
4
evaporated in vacuo. To the solution of the residue in pyridine
ꢁ
(
0.70 mL) was added TsCl (66.8 mg, 350 lmol) at 0 C. After stirring the
ꢁ
mixture at 0 C for 8 h, the reaction mixture was partitioned between
AcOEt and aqueous HCl (1 M). The organic layer was washed with satu-
rated aqueous NaHCO and brine, dried over anhydrous Na SO , and
3
2
4
evaporated in vacuo. The residue was purified by silica gel column chro-
matography (20% AcOEt in hexane) to give 4 (23.7 mg, 49.3 lmol, 64%)
1
as a colorless oil. [a]22D : ꢀ30.55 (c ¼ 1.06, CHCl ); H NMR (CDCl ,
3
3
5
00 MHz) d 8.02 (m, 2 H, aromatic), 7.97 (m, 2 H, aromatic), 7.78 (d,
J ¼ 8.0 Hz, 2 H, aromatic), 7.52–7.57 (m, 2 H, aromatic), 7.37–7.44 (m,
4
1
–
1
1
1
6
5
H, aromatic), 7.27 (d, J ¼ 8.0 Hz, 2 H, aromatic), 4.98 (d, J ¼ 13.3 Hz,
H, –OCH C–), 4.43 (d, J ¼ 13.3 Hz, 1 H, –OCH C–), 4.25 (m, 2 H,
2
2
CHCH O–), 2.39 (s, 3 H, CH Ph–), 1.84 (m, 1 H, –CCH(CH )CH –),
2
3
2
2
.42 (dd, J ¼ 10.3, 7.4 Hz, 1 H, –CCH CH–), 1.14 (dd, J ¼ 7.5, 7.4 Hz,
2
H, –CCH CH–); 13C NMR (CDCl , 100 MHz) d 165.9, 165.8, 144.8,
2
3
33.2, 133.0, 132.7, 129.8, 129.6, 129.5, 129.5, 128.3, 128.2, 127.7, 69.1,
4.4, 60.5, 22.5, 21.4, 16.5; HRMS (ESI) calcd for C H O NaS:
2
6
24
7
þ
03.11349, found for 503.11331 [(M þ Na) ].
0
0
6
6
(
1R,2S)-{1-Benzoyloxy-1-benzoyloxymethyl-2-[N ,N -bis(t-butoxycar-
bonyl)-adenin-9-yl]methyl}cyclopropane (22a). To a solution of N,N-di-
Boc-adenine (111 mg, 312 lmol) in DMF (1.0 mL) was added NaH (60%
dispersion in mineral oil, 12.5 mg, 312 lmol) at room temperature. After
stirring the mixture at room temperature for 30 min, to the mixture was

1
6
D. FUSHIHARA ET AL.
added a solution of 4 (100 mg, 208 lmol) in DMF (1.0 mL) at room tem-
ꢁ
perature. After stirring the mixture at 60 C for 24 h, the reaction mixture
was partitioned between 50% AcOEt in hexane and saturated aqueous
NaHCO . The organic layer was washed with brine, dried over anhydrous
3
Na SO , and evaporated in vacuo. The residue was purified by silica gel
2
4
column chromatography (33% AcOEt in hexane) to give 22a (36.0 mg,
1
5
5.9 lmol, 27%) as a white solid. [a]22D : ꢀ1.18 (c ¼ 1.79, CHCl ); H
3
NMR (CDCl , 500 MHz) d 8.86 (s, 1 H, adenine-H2), 8.34 (s, 1 H, aden-
3
ine-H8), 8.05 (d, J ¼ 7.0 Hz, 2 H, aromatic), 7.98 (d, J ¼ 7.0 Hz, 2 H, aro-
matic), 7.58 (m, 2 H, aromatic), 7.40–7.47 (m, 4 H, aromatic), 5.14 (d,
J ¼ 13.5 Hz, 1 H, –OCH C–), 4.78 (d, J ¼ 13.5 Hz, 1 H, –OCH C–), 4.65
2
2
(
–
–
dd, J ¼ 14.9, 6.8 Hz, 1 H, –CHCH N–), 4.43 (dd, J ¼ 14.9, 8.5 Hz, 1 H,
2
CHCH N–), 2.07 (m, 1 H, –CCH(CH )CH –), 1.46 (m, 19 H, –tBu,
2 2 2
CCH CH–), 1.32 (dd, J ¼ 7.5, 7.0 Hz, 1 H, –CCH CH–); 13C NMR
2
2
(
CDCl , 125 MHz) d 166.2, 166.1, 150.5, 150.3, 133.4, 133.3, 129.7, 129.7,
3
1
29.5, 128.7, 128.5, 128.4, 83.7, 64.6, 60.9, 43.5, 27.8, 24.4, 16.8; HRMS
(
[
ESI) calcd for C H O N Na: 666.25343, found for 666.25320
3
4
37
8
5
þ
(M þ Na) ].
6
(
1R,2S)-[1-Benzoyloxy-1-benzoyloxymethyl-2-(O -benzylguanin-9-yl)
6
methyl]-cyclopropane (22b). To a solution of O -benzylguanine
75.3 mg, 312 lmol) in DMF (1.0 mL) was added NaH (60% dispersion
(
in mineral oil, 12.5 mg, 312 lmol) at room temperature. After stirring
the mixture at room temperature for 30 min, to the resulting mixture
was added a solution of 4 (100 mg, 208 lmol) in DMF (1.0 mL) at room
ꢁ
temperature. After stirring the mixture at 50 C for 24 h, the reaction
mixture was partitioned between 50% AcOEt in hexane and saturated
aqueous NaHCO . The organic layer was washed with brine, dried over
3
anhydrous Na SO , and evaporated in vacuo. The residue was purified
2
4
by silica gel column chromatography (67% AcOEt in hexane) to give
2b (41.0 mg, 74.6 lmol, 36%) as a white solid. [a]21D : ꢀ13.07
2
1
(
c ¼ 2.05, CHCl ); H NMR (CDCl , 500 MHz) d 7.98 (d, J ¼ 7.5 Hz, 2 H,
3
3
aromatic), 7.93 (d, J ¼ 7.0 Hz, 2 H, aromatic), 7.82 (s, 1 H, guanine-H8),
.47–7.59 (m, 4 H, aromatic), 7.27–7.43 (m, 7 H, aromatic), 5.50 (d,
7
J ¼ 12.5 Hz, 1 H, –OCH Ph), 5.44 (d, J ¼ 12.5 Hz, 1 H, –OCH Ph), 5.17
2
2
(
1
d, J ¼ 13.0 Hz, 1 H, –OCH C–), 4.94 (s, 2 H, –NH ), 4.66 (d, J ¼ 13.0 Hz,
2
2
H, –OCH C–), 4.39 (dd, J ¼ 15.0, 7.5 Hz, 1 H, –CHCH N–), 4.16 (dd,
2
2
J ¼ 15.0, 8.0 Hz, 1 H, –CHCH N–), 2.04 (m, 1 H, –CCH(CH )CH –), 1.44
2
2
2
(
dd, J ¼ 10.3, 7.2 Hz, 1 H, –CCH CH–), 1.25 (dd, J ¼ 7.2, 7.0 Hz, 1 H,
2
–
1
1
CCH CH–); 13C NMR (CDCl , 125 MHz) d 166.1, 166.0, 160.9, 159.2,
2 3
54.0, 138.8, 136.4, 133.3, 133.1, 129.6, 129.6, 129.6, 129.4, 128.4, 128.3,
28.1, 127.9, 67.9, 64.8, 60.7, 42.5, 24.2, 16.9; HRMS (ESI) calcd for
þ
C H O N : 550.20850, found for 550.20911 [(M þ H) ].
3
1
28
5
5

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
17
4
(
1R,2S)-[2-(N -Benzoylcytosyn-1-yl)methyl-1-benzoyloxy-1-benzoyloxy-
4
methyl)-cyclopropane (22c). To a solution of N -benzoylcytosine (67.1 mg,
12 lmol) in DMF (1.0 mL) was added NaH (60% dispersion in mineral
3
oil, 12.5 mg, 312 lmol) at room temperature. After stirring the mixture at
room temperature for 30 min, to the resulting mixture was added a solution
of 4 (100 mg, 208 lmol) in DMF (1.0 mL) at room temperature. After stir-
ꢁ
ring the mixture at 50 C for 24 h, the reaction mixture was partitioned
between 50% AcOEt in hexane and saturated aqueous NaHCO . The
3
organic layer was washed with brine, dried over anhydrous Na SO , and
2
4
evaporated in vacuo. The residue was purified by silica gel column chroma-
tography (33–67% AcOEt in hexane) to give 22c (59.2 mg, 113 lmol, 54%)
1
as a white solid. [a]19D : 0.09 (c ¼ 2.96, CHCl ); H NMR (CDCl ,
3
3
5
00 MHz) d 8.88 (br, 1 H, –NH), 7.98–8.01 (m, 5 H, aromatic,cytosine-H6),
.90 (d, J ¼ 7.5 Hz, 2 H, aromatic), 7.59 (t, J ¼ 7.5 Hz, 1 H, aromatic), 7.55
7
(
t, J ¼ 7.5 Hz, 1 H, aromatic), 7.48–7.51 (m, 4 H, aromatic), 7.40–7.43 (m,
4
H, aromatic, cytosine-H5), 5.13 (d, J ¼ 13.0 Hz, 1 H, –OCH C–), 4.67 (d,
2
J ¼ 13.0 Hz, 1 H, –OCH C–), 4.17 (m, 2 H, –CHCH N–), 2.09 (m, 1 H,
2
2
–
CCH(CH )CH –), 1.46 (dd, J ¼ 10.0, 7.3 Hz, 1 H, –CCH CH–), 1.28 (dd,
2
2
2
J ¼ 7.3, 7.0 Hz, 1 H, –CCH CH–); 13C NMR (CDCl , 125 MHz) d 166.1,
2
3
1
1
66.1, 162.2, 148.7, 133.3, 133.1, 133.0, 129.6, 129.6, 129.6, 129.4, 128.9,
28.9, 128.3, 128.1, 127.5, 125.2, 96.8, 64.9, 60.8, 49.6, 23.2, 16.7; HRMS
(
5
ESI)
calcd
for
C H O N Na:
546.16356,
found
for
3
0
25 6 3
þ
46.16390 [(M þ Na) ].
(
1R,2S)-[1-Benzoyloxy-1-benzoyloxymethyl-2-(3-benzoylthymin-1-yl)
3
methyl]-cyclopropane (22d). To a solution of N -benzoylthymine
17.0 mg, 74.0 lmol) in DMF (0.25 mL) was added NaH (60% dispersion
(
in mineral oil, 2.96 mg, 74.0 lmol) at room temperature. After stirring
the mixture at room temperature for 30 min, to the resulting mixture
was added a solution of 4 (23.7 mg, 49.3 lmol) in DMF (0.25 mL) at
ꢁ
room temperature. After stirring the mixture at 50 C for 24 h, the reac-
tion mixture was partitioned between 50% AcOEt in hexane and satu-
rated aqueous NaHCO . The organic layer was washed with brine, dried
3
over anhydrous Na SO , and evaporated in vacuo. The residue was puri-
2
4
fied by silica gel column chromatography (33–43% AcOEt in hexane) to
give 22d (20.5 mg, 38.1 lmol, 77%) as a white amorphous solid. [a]22D :
1
4
.60 (c ¼ 1.94, CHCl ); H NMR (CDCl , 500 MHz) d 8.00–8.03 (m, 6 H,
3
3
aromatic), 7.54–7.65 (m, 3 H, aromatic), 7.40–7.50 (m, 6 H, aromatic),
.29 (s, 1 H, thymine-H6), 4.97 (d, J ¼ 13.0 Hz, 1 H, –OCH C–), 4.69 (d,
7
2
J ¼ 13.0 Hz, 1 H, –OCH C–), 4.11 (m, 1 H, –CHCH N–), 3.83 (m, 1 H,
2
2
–
5
7
CHCH N–), 1.94 (m, 1 H, –CCH(CH )CH –), 1.86 (s, 3 H, thymine-
2 2 2
–CH ), 1.45 (dd, J ¼ 10.5, 7.3 Hz, 1 H, –CCH CH–), 1.15 (dd, J ¼ 7.5,
3
2
.3 Hz, 1 H, –CCH CH–); 13C NMR (CDCl , 125 MHz) d 169.1, 166.2,
2
3

1
8
D. FUSHIHARA ET AL.
1
1
63.1, 150.0, 134.9, 133.4, 133.3, 131.6, 130.6, 129.7, 129.6, 129.6, 129.5,
29.1, 128.4, 110.9, 77.2, 64.8, 60.7, 23.9, 16.1, 12.3; HRMS (ESI) calcd
þ
for C H O N Na: 561.16322, found for 561.16365 [(M þ Na) ].
3
1
26
7
2
(
1R,2S)-[2-(Adenine-9-yl)methyl-1-hydroxy-1-hydroxymethyl)cyclopro-
pane (IVa). A solution of 22a (36.0 mg, 55.9 lmol) in HCl (4.0 M in dioxane,
.56 mL) was stirred at room temperature for 24 h, and the solvent was
0
evaporated in vacuo. To a solution of the residue in MeOH (0.56 mL) was
added a solution of NaOMe (5 M in MeOH, 30 lL, 150 lmol) at room tem-
perature. After stirring the mixture at room temperature for 2 h, the reaction
was quenched with aqueous HCl (1 M) and evaporated in vacuo. The residue
was purified by NH silica gel column chromatography (5% MeOH in
CHCl ) to give IVa (8.24 mg, 35.0 lmol, 62%) as a white solid. mp
3
ꢁ
1
1
5
57–161 C; [a]19D : ꢀ10.00 (c ¼ 0.48, CH OH); H NMR (CD OD,
3
3
00 MHz) d 8.27 (s, 1 H, adenine-H2), 8.20 (s, 1 H, adenine-H8), 4.28 (dd,
J ¼ 15.3, 7.0 Hz, 1 H, –CHCH N–), 4.24 (dd, J ¼ 15.3, 8.3 Hz, 1 H,
2
–
–
–
CHCH N–), 4.00 (d, J ¼ 12.5 Hz, 1 H, –OCH C–), 3.70 (d, J ¼ 12.5 Hz, 1 H,
2
2
OCH C–), 1.64 (m, 1 H, –CCH(CH )CH –), 0.96 (dd, J ¼ 10.0, 6.0 Hz, 1 H,
2
2
2
CCH CH–), 0.69 (dd, J ¼ 6.5, 6.0 Hz, 1 H, –CCH CH–); 13C NMR
2
2
(
CD OD, 125 MHz) d 157.3, 153.6, 150.5, 142.8, 119.9, 65.3, 60.2, 44.7, 25.8,
3
1
2
6.6; HRMS (ESI) calcd for C H O N : 236.11420, found for
1
0
14
2
5
þ
36.11415 [(M þ H) ].
(
1R,2S)-[2-(Cytosyn-1-yl)methyl-1-hydroxy-1-hydroxymethyl]cyclopro-
pane (IVc). To a solution of 22c (59.2 mg, 113 lmol) in MeOH (1.0 mL)
was added a solution of NaOMe (5 M in MeOH, 91 lL, 455 lmol) at room
temperature. After stirring the mixture at room temperature for 2 h, the
reaction was quenched with aqueous HCl (1 M) and evaporated in vacuo.
The residue was purified by NH silica gel column chromatography (9–17%
MeOH in CHCl ) to give IVc (17.1 mg, 81.0 lmol, 72%) as a white solid.
3
ꢁ
1
mp 180–181 C; [a]19D : ꢀ27.72 (c ¼ 0.75, CH OH); H NMR (CD OD,
3
3
5
00 MHz) d 7.71 (d, J ¼ 7.3 Hz, 1 H, cytosine-H6), 5.86 (d, J ¼ 7.3 Hz, 1 H,
cytosine-H5), 3.91 (d, J ¼ 12.5 Hz, 1 H, –OCH C–), 3.87 (dd, J ¼ 14.3,
2
8
(
.0 Hz, 1 H, –CHCH N–), 3.75 (dd, 1 H, J ¼ 14.3, 7.0 Hz, –CHCH N–), 3.62
2
2
d, J ¼ 12.5 Hz, 1 H, –OCH C–), 1.49 (m, 1 H, –CCH(CH )CH –), 0.89 (dd,
2
2
2
J ¼ 10.3, 5.9 Hz, 1 H, –CCH CH–), 0.58 (dd, J ¼ 7.0, 5.9 Hz, 1 H,
2
–
CCH CH–); 13C NMR (CD OD, 125 MHz) d 167.9, 159.3, 147.4, 95.8,
2 3
6
2
5.6, 60.2, 50.2, 49.2, 25.3, 16.3; HRMS (ESI) calcd for C H O N :
9
14 3 3
þ
12.10297, found for 212.10327 [(M þ H) ].
(
1R,2S)-[2-(Thymin-1-yl)methyl-1-hydroxy-1-hydroxymethyl]cyclopro-
pane (IVd). To a solution of 22d (20.1 mg, 34.8 lmol) in MeOH (0.34 mL)
was added a solution of NaOMe (5 M in MeOH, 28 lL, 140 lmol) at room
temperature. After stirring the mixture at room temperature for 2 h, the
reaction mixture was quenched with aqueous HCl (1 M) and evaporated in

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
19
vacuo. The residue was purified by NH silica gel column chromatography
7–10% MeOH in CHCl ) to give IVd (7.25 mg, 32.1 lmol, 92%) as a white
(
3
1
amorphous solid. [a]20D : ꢀ21.84 (c ¼ 0.56, CH OH); H NMR (CD OD,
3
3
5
–
00 MHz) d 7.57 (s, 1 H, thymine-H6), 3.93 (d, J ¼ 12.0 Hz, 1 H,
OCH C–), 3.81 (dd, J ¼ 14.4, 7.5 Hz, 1 H, –CHCH N–), 3.73 (dd, 1 H,
2
2
J ¼ 14.4, 7.3 Hz, –CHCH N–), 3.60 (d, J ¼ 12.0 Hz, 1 H, –OCH C–), 1.88 (s,
2
2
3
5
H, thymine-5–CH ), 1.48 (m, 1 H, –CCH(CH )CH –), 0.91 (dd, J ¼ 10.0,
3
2
2
.8 Hz, 1 H, –CCH CH–), 0.60 (dd, J ¼ 6.5, 5.8 Hz, 1 H, –CCH CH–); 13C
2
2
NMR (CD OD, 125 MHz) d 166.9, 153.2, 143.2, 111.1, 65.6, 60.1, 48.7,
3
2
5.1, 16.5, 12.2; HRMS (ESI) calcd for C H O N Na: 249.08458, found
10 14 4 2
þ
for 249.08463 [(M þ Na) ].
Acknowledgments
This work was supported by Grants-in-Aid for Scientific Research (15H02495 and
9H01014) from the Japan Society for the Promotion of Science. We are grateful to Sanyo
1
Fine Co., Ltd. for the gift of the chiral epichlorohydrins.
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9
7
[
13] The structures of N - and N -isomers, 14 vs 15 and 13b vs 16, were confirmed as
9
7
follows. (1) In UV spectrum, kmax (nm) of the N -isomer < that of the N -isomer;

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
21
1
9
(
2) in H NMR spectrum (d), H-2 and H-8 signals of the N -isomer < those of the
7
N -isomer: see, (a) Geen, G. R.; Grinter, T. J.; Kincey, P. M.; Jarvest, R. L.
Tetrahedron. 1990, 46, 6903–6914. (b) Kjellberg, J.; Johansson, N. G. Tetrahedron.
1
986, 42, 6541–6552.
6
[
[
14] Yin, X-q.; Li, W-k.; Schneller, S. W. Employing N -Boc -Adenine Effectively
2
9
Improve the N -Regioselectivity in the Mitsunobu Reaction. Tetrahedron Lett. 2006,
4
7, 9187–9189.
15] In 1H NMR Spectra of the Reaction Mixtures, Signals Characteristic for
Cyclopropane Structure were not Observed Suggesting the Cyclopropane Ring-
Opening.
[16] Dey, S.; Garner, P. Synthesis of Tert-Butoxycarbonyl (Boc)-Protected Purines. J. Org.
Chem. 2000, 65, 7697–7699.
[17] Frieden, M.; Giraud, M.; Reese, C. B.; Song, Q. Synthesis of 1-[Cis-3-
(
Hydroxymethyl)Cyclobutyl]-Uracil, -Thymine and -Cytosine. J. Chem. Soc, Perkin
Trans. 1. 1998, 1, 2827–2832. DOI: 10.1039/a803878c.