An alternative method for the synthesis of 2′-halogeno-1′,2′-unsaturated uridine derivatives through syn-elimination of pivalic acid of 2′-halogeno- 2′-deoxy-1′-pivaloyloxyuracil nucleoside: preparation of its 2′-C-branched nucleosides

Article abstract of DOI:10.1080/15257770.2019.1641724

An alternative method for the preparation of 2′-bromo- (5b) and 2′-iodo- (5c) 1′,2′-unsaturated uracil nucleosides has been developed. The protocol was on the basis of the syn-elimination of pivalic acid from 2′-bromo-(7a,b) and 2′-iodo-(9a,b) 1′-pivaloyloxy-2′-deoxyuridine derivatives, which were derived from the halo-pivaloyloxylation of 3′,5′-bis-O-TBDMS-1′,2′-unsaturated uridine 1. Compounds 5b and 5c were shown to serve as versatile synthons for the respective 2′-C-branched 1′,2′-unsaturated uracil nucleosides, through palladium-catalyzed cross-coupling or halogen-lithium exchange reactions.

Full text of DOI:10.1080/15257770.2019.1641724

Nucleosides, Nucleotides and Nucleic Acids
ISSN: 1525-7770 (Print) 1532-2335 (Online) Journal homepage: https://www.tandfonline.com/loi/lncn20
An alternative method for the synthesis of 2′-
halogeno-1′,2′-unsaturated uridine derivatives
through syn-elimination of pivalic acid of 2′-
halogeno- 2′-deoxy-1′-pivaloyloxyuracil nucleoside:
preparation of its 2′-C-branched nucleosides
Kazuhiro Haraguchi, Eisen Gen, Hiroki Kumamoto, Yoshiharu Itoh &
Hiromichi Tanaka
To cite this article: Kazuhiro Haraguchi, Eisen Gen, Hiroki Kumamoto, Yoshiharu Itoh & Hiromichi
Tanaka (2019): An alternative method for the synthesis of 2′-halogeno-1′,2′-unsaturated uridine
derivatives through syn-elimination of pivalic acid of 2′-halogeno- 2′-deoxy-1′-pivaloyloxyuracil
nucleoside: preparation of its 2′-C-branched nucleosides, Nucleosides, Nucleotides and Nucleic
Acids, DOI: 10.1080/15257770.2019.1641724
To link to this article: https://doi.org/10.1080/15257770.2019.1641724
Published online: 20 Aug 2019.
Submit your article to this journal
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=lncn20

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
https://doi.org/10.1080/15257770.2019.1641724
An alternative method for the synthesis of 20-halogeno-
10,20-unsaturated uridine derivatives through
syn-elimination of pivalic acid of 20-halogeno-
20-deoxy-10-pivaloyloxyuracil nucleoside: preparation
of its 20-C-branched nucleosides
Kazuhiro Haraguchia, Eisen Genb, Hiroki Kumamotoa, Yoshiharu Itohb, and
Hiromichi Tanakab
aDepartment of Pharmaceutical Sciences, Nihon Pharmaceutical University, Saitama, Japan;
bSchool of Pharmacy, Showa University, Tokyo, Japan
ABSTRACT
ARTICLE HISTORY
Received 30 May 2019
Accepted 5 July 2019
An alternative method for the preparation of 20-bromo- (5b)
and 20-iodo- (5c) 10,20-unsaturated uracil nucleosides has
been developed. The protocol was on the basis of the syn-
elimination of pivalic acid from 20-bromo-(7a,b) and 20-iodo-
(9a,b) 10-pivaloyloxy-20-deoxyuridine derivatives, which were
derived from the halo-pivaloyloxylation of 30,50-bis-O-TBDMS-
10, 20-unsaturated uridine 1. Compounds 5b and 5c were
shown to serve as versatile synthons for the respective 20-C-
branched 10,20-unsaturated uracil nucleosides, through palla-
dium-catalyzed cross-coupling or halogen-lithium exchange
reactions.
KEYWORDS
Nucleoside; unsaturated
sugar; electrophilic addition;
syn-elimination; Pd-catalyst;
cross-coupling; halogen–
lithium exchange reaction
GRAPHICAL ABSTRACT
1. Introduction
Nucleoside analogs are recognized as an important class of biologically
active compounds, especially as antiviral and antitumor agents.[1–21]
Among sugar-modified nucleosides, nucleosides having an unsaturated
sugar moiety have been known for a long time. We have demonstrated
through a series of publications that this class of compounds are useful
substrates for constructing C–C bonds in the sugar portion.[22,23] Among
the possible four types of unsaturated-sugar nucleosides, the 10,20-
CONTACT Kazuhiro Haraguchi
harakazu@nichiyaku.ac.jp
Department of Pharmaceutical Sciences, Nihon
Pharmaceutical University, 10281 Komuro, Inamachi, Kita-adachi-gun, Saitama 362-0806, Japan.
ß 2019 Taylor & Francis Group, LLC

2
K. HARAGUCHI ET AL.
unsaturated derivatives (1) have attracted scant attention presumably due
to their reported instability, during deprotection to undergo further elimin-
ation which results in the formation of furan derovative (2a) (Figure 1).
In this context, we have reported a method for introducing substitu-
ents at the 20-position of 1, which furnished the first examples of
nucleoside analogs (Scheme 1).[24,25] Thus, when 6-tributylstannylated 3,
which could be prepared through LDA-lithiation of 1 followed by
quenching the 6-lithiated species with Bu3SnCl, was treated with LTMP,
anionic stannyl migration occurred to yield 20-stannylated product 4.
Reaction of 4 with I2, N-bromosuccinimide (NBS) or N-chlorosuccini-
mide (NIS) gave the respective 20-halogenated 5a-c. Compounds 4 and
5c could be utilized for introducing carbon-substituents to the 20-positon
by means of Stille coupling to furnish 6a–d. This study demonstrated
that the bulkiness of the 20-substituent led to conformational change
around the N1–C10 pivot bond avoiding sterically unfavorable coplanar-
ity which render 5a–c and 6a–d more stable. This assumption has been
supported by the UV absorption maximum of 5a–c and 6a–d in MeOH
appearing at 251–255 nm while a longer wavelength of 276 nm was
measured in 1. In fact, desilylation of 5a–c and 6a–d caused no further
elimination and furnished the hitherto unknown free nucleosides without
the formation of the furan derivatives. These compounds would be use-
ful precursors for novel nucleoside derivatives by manipulation of the
10,20-unsaturated bond.
The above chemistry stimulated us to develop another synthetic method,
which would be applicable to the respective adenine nucleoside. However,
the above strategy is not applicable to the adenine nucleoside. Therefore,
we have intended to develop an alternative method, which provides the
both of 20-halogeno-10,20-unsaturated pyrimidine and purine nucleosides In
this article, we will describe the novel synthetic method on the basis of
syn-elimination of pivalic acid of 20-halogeno-10-pivaloyloxyuracil nucleo-
sides, which would be applicable to the respective adenine nucleoside.[26]
Scheme 1. Previous protocol for the synthesis of 5a–c and 6a-d from 4 through anionic stannyl
migration of 3.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
3
Figure 1. Structures of 1 and 2.
Scheme 2. Synthetic plan for synthesis of 5b,c and II.
2. Results and discussion
2.1. Chemistry
Our synthetic plan is outlined in Scheme 2. The target molecule III was
intended to be synthesized from II through coupling reaction and halogen-
lithium exchange reaction.[27,28] 20-Halogenated II would be obtained from
I through syn-b-elimination of the pivalic acid derivative of I. This plan
was motivated by the fact that 5b was formed as a by-product in the reac-
tion of I and Al(CH2CHMe2)3.[29,30] The substrate I is accessible from elec-
trophilic halo-pivaloyloxylation to 1.[30]
Initially, synthesis of 20-bromo-10,20-unsaturated uridine derivative 5b
was examined (Scheme 3 and Table 1). The substrates 7a and 7b were pre-
pared in 91% yield in a ratio of 4.9:1, according to the published procedure
(Me3COOH/Et3N/NBS/Et2O).[29,30] To investigate whether or not the
desired syn-elimination proceed, a solution of 7a,b in toluene was heated

4
K. HARAGUCHI ET AL.
Scheme 3. Synthesis of 5b from 7a,b by syn-elimination of pivalic acid.
Table 1. Synthesis of 20-bromo-10,20-unsaturated uracil nucleoside 5b.
Isolated yields (%)
Entry
Solvent
Base
Temp (ꢀC)
Time (h)
5b
8
1
2
3
toluene
xylene
xylene
–
–
110
140
140
7
2
4
32
78
98
27
5
–
NaHCO3
under reflux conditions for 3 h, in which 5b was obtained in 32% isolated
yield (entry 1, Table 1). In this case, the furan derivative 8 was formed in
27% yield. The reaction temperature was elevated to 140 ꢀC by using xylene
as a solvent, the syn-elimination was completed in 1 h and 5b could be
obtained in 78% yield along with 5% of 8 (entry 2). One would readily
assume that the formation of 8 is promoted by concomitantly formed piv-
alic acid. To trap pivalic acid, the reaction was carried out in the presence
of sodium bicarbonate, 5b then being obtained in 98% yield without the
formation of 5b (entry 3).
We have previously demonstrated that 20-iodo-10,20-unsaturated 5c
was stable and a highly reactive substrate for palladium-catalyzed cross-
coupling reaction.[25] Therefore, the above-mentioned syn-elimination
protocol was examined for the synthesis of 5c (Scheme 4).
Unexpectedly, iodo-pivaloyloxylation of 1 (Me3COOH/Et3N/NIS/Et2O)
resulted in the formation of complex mixture. When the above reaction
was performed in benzene, the desired 9a,b were obtained in 45% yield
as a diasteromeric mixture along with the furan 2b (22%). It was found
that silver carbonate was effective for suppressing the formation of 2b,
resulting in the formation of 9a,b (67% yield). Next, when a diastereo-
meric mixture of 9a,b was heated in xylene in the presence of NaHCO3,
5c was obtained in 44% yield along with 2b (37% yield). On the other
hand, when the reaction was performed in the absence of NaHCO3, the
undesired formation of 2b was diminished to 7% yield and 5c[25] was
could be obtained in 79% yield.
With 5b and 5c in hand, introduction of carbon-substituents to the
20-position was examined (Scheme 5 and Table 2)[27,28] As shown in

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
5
Scheme 4. Synthesis of 20-iodo-10,20-unsaturated uridine derivative 5c by syn-elimination
of pivalic acid of 9a,b.
Scheme 5. Cross-coupling of 5b or 5c leading to 10 and 11.
Table 2. Palladium-catalyzed coupling reaction of 5b or 5c.
Isolated yields (%)
Entry
Substrate
Reagents (equiv) and conditions
10 or 11
10 (9)
10 (10)
10 (58)
11 (84)
5b
1
2
3
4
5b
5b
5c
5c
PhCꢁCH (4), (Ph3P)2PdCl2 (0.3), CuI (0.3), Et3N, THF, 80 ꢀC, 15 h
PhCꢁCSnBu3 (4), (Ph3P)4Pd (0.3), DMF, 60 ꢀC, 15 h
PhCꢁCSnBu3 (2), (Ph3P)4Pd (0.1), MF, 100 ꢀC, 10 min
HCꢁCSnBu3 (2), (Ph3P)4Pd (0.1), DMF, 100 ꢀC, 10 min
85
48
–
–
entry 1, Sonogashira coupling of 5b with ethynylbenzene was carried out
in the presence of (Ph3P)2PdCl2 and CuI in THF. This gave the target 20-C-
phenylethynyl derivative 10 in 9% yield with the recovery of 5b (85% yield).
The inertness of 5b was observed in Stille coupling (10; 10%, 5b; 48%) (entry
2, Table 2). The above results prompted us to utilize 20-iodo derivative 5c
as a substrate in Stille coupling (entries 3–4, Table 2). The reaction of 5c with
PhCꢁCSnBu3 catalyzed by (Ph3P)4Pd was completed within 10 min to give
the target 10 in 58% yield (entry 3, Table 3). The respective 20-C-ethynyl
derivatives (11) was obtained in 84% yield (entry 4, Table 2).
Next, we carried out the halogen-lithium exchange reaction of the 20-
bromo derivative 5b (Scheme 6 and Table 3). Reaction of 5b with 3 equiv.
of BuLi in THF below –70 ꢀC followed by immediate addition of MeI gave
20-C-methyl-10,20-unsaturated uridine derivative 6c in 27% yield along with
1 (40% yield) (entry 1, Table 3). This observation suggests that the incipi-
ently formed vinyl lithium species is highly basic and thus is protonated
before reacting with the added electrophile. We finally found that an

6
K. HARAGUCHI ET AL.
Scheme 6. Halogen–lithium exchange reaction (in situ trapping) of 5b to lead to 6C, 12
and 13.
Table 3. Halogen–lithium exchange reaction (in-situ trapping) of 5b to lead to 6c, 12 and13.
Isolated yields (%)
Entry
Electrophile
BuLi (equiv)
6c, 12 or 13
1
ꢂ
1
MeI
MeI
PhCHO
ClCOOEt
3
2
9
9
6c (27)
6c (76)
12 (82)
13 (65)
40
11
6
2
3
4
ꢂ
18
Methyl iodide was added immediately after halogen–lithium exchange reaction.
“in-situ” trapping protocol, wherein a mixture of 5b and MeI (10 equiv.) is
reacted with BuLi (3 equiv), furnished a good yield of the desired product
6c (76% yield) (entry 2, Table 3).[27,28] This result suggests that the halo-
gen-lithium exchange reaction is an earlier event than the anticipated
deprotonation from N3H. To examine the applicability of this approach,
benzaldehyde was reacted (entry 3, Table 3). We found that 9 equiv. of
BuLi was necessary to assure complete disappearance of the starting mater-
ial and 12 was isolated in 82% yield. Diastereomeric ratio of 12 was deter-
1
mined to be ca 7:1 by inspecting the integrated H NMR spectrum. In this
reaction, 6% yield of 1 was inevitably formed (entry 3, Table 3). Finally, 20-
C-ethoxycarbonyl derivative 13 was synthesized in 65% yield (1; 18% yield)
by reacting with ClCO2Et (entry 4, Table 3) under the same reaction condi-
tions as for 12.
3. Conclusions
In this study, an alternative method for the synthesis of 20-bromo (5b)- and 20-
iodo-(5c) 10,20-unsaturated uracil nucleosides has been developed by way of
syn-elimination of pivalic acid from 20-halogeno-20-deoxy-10-pivaloyoxyuridine
derivative (7a,b and 9a,b). Stille coupling of 5c and halogen-lithium exchange
reaction of 5b has disclosed the novel 20-C-carbon-substituted (10–11 and
12–13) 10,20-unsaturated uridine derivatives. This method should be applicable
to adenine nucleosides and this chemistry is under investigation in
our laboratory.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
7
4. Methods
4.1. General methods
Melting points are uncorrected. 1H and 13C NMR spectra were recorded either
at 400 MHz or at 500 MHz. Chemical shifts are reported relative to Me4Si.
Mass spectra (MS) were taken in FAB mode with m-nitrobenzyl alcohol as a
matrix or ESI mode. Column chromatography was carried out on silica gel.
Thin-layer chromatography (TLC) was performed on silica gel. When neces-
sary, analytical samples were purified by high performance liquid chromatog-
raphy (HPLC). THF was distilled from benzophenone ketyl.
4.1.1. 1-[2-Bromo-3,5-bis-O-(tert-butyldimethylsilyl)-2-deoxy-1-pivaloyloxy-b-D-
arabinofuranosyl]uracil (7a) and 1-[2-Bromo-3,5-bis-O-(tert-butyldimethyl-
silyl)-2-deoxy-1-pivaloyloxy-a-D-ribofuranosyl]uracil (7b)
To a solution of pivalic acid (2.67 g, 26.20 mmol) in ether (40.0 mL) was
added triethylamine (3.66 mL, 26.20 mmol) and the mixture was stirred
for 0.5 h. To the resulting mixture was added 1 (2.38 g, 5.23 mmol) and
NBS (1.13 g, 6.33 mmol) and the mixture was stirred for 0.5 h. The reac-
tion mixture was partitioned between cold CHCl3/saturated NaHCO3
and silica gel column chromatography(hexane/ethyl acetate ¼ 9/1)of the
organic layer gave a mixture of 7a (2.64 g, 79%, solid) and 7b (0.39 g,
12%, foam).
Physical data for 7a: mp, 157–159 ꢀC; UV (MeOH) kmax 254 nm (e
1
10700) and kmin 227 nm (e 3500); H NMR (CDCl3) d 0.09, 0.12 and
0.17 (12H, each as s, Si–Me), 0.91 and 0.92 (18H, each as S, Si-tert-Bu),
1.20 (9H, s, C(CH3)3), 3.87–3.89 (2H, m, CH2-50), 4.12–4.13 (1H, m, H-
40), 4.73 (1H, d, J3 ,4 ¼ 3.3 Hz, H-30), 4.89 (1H, s, H-20), 5.68 (1H, dd,
0
0
J5,6 ¼ 8.4 and J5,NH ¼ 2.6 Hz, H-5), 7.82 (1H, d, J5,6 ¼ 8.4 Hz, H-6);;
FAB-MS (m/z) 657 and 659 (Mþ
C26H47BrN2O7Si2 (635.74): C, 49.12; H, 7.45; N, 4.41. Found: C, 49.13;
H, 7.72; N, 4.42.
þ
Na). Anal. Calcd for
Physical data for 7b: UV (MeOH) kmax 255 nm (e 10800) and kmin
1
227 nm (e 2900); H NMR (CDCl3) d 0.07, 0.08, 0.14 and 0.16 (12H, each
as s, Si–Me), 0.91 and 0.93 (18H, each as s, Si-tert-Bu), 1.17 (9H, s,
C(CH3)3), 3.69 (1H, dd, J4 ,5 a ¼ 1.8 and J5 a,5 b ¼ 12.1 Hz, CH2a-50), 3.96
0
0
0
0
0
0
0
0
(1H, dd, J4 ,5 a ¼ 4.8 and J5 a,5 b ¼ 12.1 Hz,CH2b-5’), 4.26–4.28 (1H, m, H-
0
0
0
0
0
0
4’), 4.41 (1H, dd, J2 ,3 ¼ 8.8 and J3 ,4 ¼ 4.4 Hz, H-3’), 4.89 (1H, d, J2 ,3
¼
8.8 Hz, H-2’), 5.70 (1H, dd, J5,6 ¼ 8.4 and J5,NH ¼ 2.2 Hz, H-5), 7.91 (1H,
d, J5,6 ¼ 8.4 Hz, H-6); FAB-MS (m/z) 657 and 659 (Mþ þ Na). Anal.
Calcd for C26H47BrN2O7Si2 (635.74): C, 49.12; H, 7.45; N, 4.41. Found: C,
49.53; H, 7.62; N, 4.28.

8
K. HARAGUCHI ET AL.
4.1.2. Syn-elimination of pivalic acid in toluene under reflux conditions;
formation of 1-[3,5-Bis-O-(tert-butyldimethylsilyl)-2-bromo-2-deoxy-
erythro-pento-1-enofuranosyl]uracil (5b) and 1-[5-O-(tert-
Butyldimethylsilyl)-2-bromofuryl]uracil (8) (entry 1, Table 1)
A solution of a mixture of 7a and 7b (99.8 mg, 0.16 mmol) in toluene
(3.0 mL) was stirred under reflux conditions for 4.0 h. The reaction mixture
was chromatographed on silica gel(hexane/ethyl acetate ¼ 4/1)to give 5b
(27.3 mg, 32%, syrup) and 8 (17.3 mg, 27%, foam).
Physical data for 5b; UV (MeOH) kmax 254 nm (e 9600) and kmin
1
236 nm (e 8100); H NMR (CDCl3) d 0.09, 0.15 and 0.18 (12H, each as s,
0
0
Si–Me), 0.90 and 0.92 (18H, each as S, Si-tert-Bu), 3.74 (1H, dd, J4 ,5 a ¼ 5.9
0
0
0
0
and J5 a,5 b ¼ 11.0 Hz, CH2a-5’), 3.83 (1H, dd, J4 ,5 a ¼ 5.0 and
0
0
J5 a,5 b ¼ 11.0 Hz, CH2b-5’), 4.44–4.47 (1H, m, H-4’), 4.95 (1H, d,
0
0
J3 ,4 ¼ 3.3 Hz, H-3’), 5.79 (1H, d, J5,6 ¼ 8.1 Hz, H-5), 7.19 (1H, d,
J5,6 ¼ 8.1 Hz, H-6), 8.85 (1H, br, NH); FAB-MS (m/z) 555 and 557 (Mþ þ
Na) and 533 and 535 (Mþ þ H). Anal. Calcd for C21H37BrN2O5Si2
(533.63): C, 47.27; H, 5.25; N, 6.99. Found: C, 47.30; H, 5.18; N, 7.08.
1
Physical data for 8; H NMR (CDCl3) d 0.09, 0.11 (6H, s, Si–Me), 0.91
(9H, s, Si-tert-Bu), 4.61 (2H, s, CH2-5’), 5.79 (1H, d, J5,NH ¼ 1.8 and
J5,6 ¼ 8.1 Hz, H-5), 6.41 (1H, s, H-3’), 7.17 (1H, d, J5,6 ¼ 8.1 Hz, H-6), 9.53
(1H, br, NH); 13C NMR (CDCl3) d: –5.0, 18.7, 26.1, 58.5, 97.8, 104.0,
111.9139.9, 144.0, 149.3, 154.3, 163.5. ESI-MS(m/z): 423 and 425
(Mþ þ Na); ESI-HRMS (m/z): calcd for C15H21O4N2BrNaSi2: 423.03462,
found: 423.03409 (Mþ þ Na).
4.1.3. Syn-elimination of pivalic acid in xylene under reflux conditions in the
presence of NaHCO3; formation of 5b (entry 3, Table 1)
To a solution of a mixture of 7a and 7b (53.6 mg, 0.084 mmol) in xylene
(3.0 mL) was added sodium hydrogen carbonate (7.1 mg, 0.084 mmol) and
the mixture was stirred under reflux conditions for 4.0 h. The reaction
mixture was partitioned between CHCl3/saturated NaHCO3 and silica gel
column chromatography(hexane/ethyl acetate ¼ 7/1)of the organic layer
gave a mixture of 5b (43.9 mg, 98%) as a syrup.
4.1.4. 1-[3,5-Bis-O-(tert-butyldimethylsilyl)-2-deoxy-2-iodo-erythro-pento-
1-enofuranosyl]uracil (5c)
To a solution of a mixture of pivalic acid (362.6 mg, 3.55 mmol) and
silver carbonate (117.5 mg, 0,43 mmol) in benzene (20.0 mL) was added
triethylamine (0.49 mL, 3.55 mmol) and the mixture was stirred for 0.5 h.
To the resulting mixture was added a solution of 1 (321.9 mg, 0.71 mmol)
in benzene (5.0 mL) and a solution of NIS (287.5 mg, 1.28 mmol) in THF

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
9
(1.0 mL) at 0 ꢀC under Ar atmosphere and the mixture was stirred for
5 min. The reaction mixture was partitioned between cold benzene/0.5 M
Na2S2O3-saturated NaHCO3 and neutral silica gel column chromato-
graphy(hexane/ethyl acetate ¼ 10/1)of the organic layer gave a mixture
of 9a and 9b (325.3 mg, 67%) as a solid. The solution of the mixture
of 9a,b (136.2 mg, 0.2 mmol) in xylene (10.0 mL) was heated under reflux
conditions for 50 min. Silica gel column chromatography (hexane/ethyl
acetate ¼ 9:1) gave 5c (129.0 mg, 79%, syrup) and 2 (5.0 mg, 7%, syrup).
Physical data of 5c; UV (MeOH) ksholder 242 nm (e 13400) 227 nm
1
(e 15800); H NMR (CDCl3) d 0.08, 0.15 and 0.20 (12H, each as s, Si–Me),
0
0
0.90 and 0.92 (18H, each as S, Si-tert-Bu), 3.74 (1H, dd, J4 ,5 a ¼ 5.9
and J5 a,5 b ¼ 11.4 Hz, CH2a-50), 4.50 (1H, dd, J4 ,5 a ¼ 4.8 and J5 a,5 b
¼
0
0
0
0
0
0
11.4 Hz,CH2b-50), 4.49–4.52 (1H, m, H-4’), 4.90 (1H, d, J3 ,4 ¼ 2.9 Hz, H-3’),
5.80 (1H, dd, J5,6 ¼ 8.1 and J5,NH ¼ 1.8 Hz, H-5), 7.18 (1H, d, J5,6 ¼ 8.1 Hz,
H-6);; FAB-MS (m/z) 603 (Mþ þ Na) and 581 (M þ H). Anal. Calcd for
C21H37IN2O5Si2 (580.61): C, 43.44; H, 6.42; N, 4.82. Found: C, 43.44; H,
6.48; N, 4.78.
0
0
4.1.5. 1-[3,5-Bis-O-(tert-butyldimethylsilyl)-2-deoxy-2-C-phenylethynyl-erythro-
pento-1-enofuranosyl]uracil (10)
To a solution of 5c (93.1 mg, 0.16 mmol) in DMF (1.0 mL) was added
Bu3SnCꢁCPh (0.11 mL, 0.32 mmol) and Pd(PPh3)4 (18.5 mg, 0.03 mol) at rt
under Ar atmosphere. The mixture was stirred at 100 ꢀC for 10 min. The
reaction mixture was partitioned between ethyl acetate/H2O and silica gel
column chromatography (hexane/ethyl acetate ¼ 4/1) of the organic layer
1
gave 10 (51.5 mg, 58%) as a syrup; H NMR (CDCl3) d 0.09, 0.10, 0.19 and
0.21 (12H, each as s, Si–Me), 0.91 and 0.94 (18H, each as s, Si-tert-Bu),
0
0
0
0
3.74 (1H, dd, J4 ,5 a ¼ 6.2 and J5 a,5 b ¼ 10.8 Hz, CH2a-5’), 3.85 (1H, dd,
0
0
0
0
J4 ,5 a ¼ 5.2 and J5 a,5 b ¼ 10.8 Hz, CH2b-5’), 4.51–4.53 (1H, m, H-4’), 5.08
0
0
(1H, d, J3 ,4 ¼ 2.9 Hz, H-3’), 5.81 (1H, dd, J5,6 ¼ 7.9 and J5,NH ¼ 2.2 Hz,
H-5), 7.27–7.38 (5H, m, Ph), 7.41 (1H, d, J5,6 ¼ 7.9 Hz, H-6), 8.64 (1H, br,
NH); 13C NMR (CDCl3) d: –5.42, –5.37, –4.6, –4.0, 18.1, 18.4, 25.8, 25.9,
61.9, 79.9, 89.8, 95.4, 96.9, 102.8, 122.8, 126.3, 128.4, 131.1, 131.5, 142.8,
147.5, 152.4, 162.6. ESI-MS(m/z): 577 (MþþNa); ESI-HRMS (m/z): calcd
for C29H42O5N2NaSi2: 577.25245, found: 577.25201 (MþþNa).
4.1.6. 1-[3,5-Bis-O-(tert-butyldimethylsilyl)-2-deoxy-2-C-ethynyl-erythro-pento-
1-enofuranosyl]uracil (11)
To a solution of 5c (94.9 mg, 0.16 mmol) in DMF (1.0 mL) was added
Bu3SnCꢁCH (93 lL, 0.32 mmol) and Pd(PPh3)4 (18.5 mg, 0.02 mol) at rt
under Ar atmosphere. The mixture was stirred at 100 ꢀC for 10 min. The

10
K. HARAGUCHI ET AL.
reaction mixture was partitioned between ethyl acetate/H2O and silica gel
column chromatography (hexane/ethyl acetate ¼ 7/1) of the organic layer
gave 11 (64.7 mg, 84%) as a foam; UV (MeOH) kmax 248 nm (e 15500),
1
kmin 222 nm (e 8700); H NMR (CDCl3) d 0.08, 0.14 and 0.16 (12H, each
as s, Si–Me), 0.89 and 0.91 (18H, each as s, Si-tert-Bu), 3.23 (1H,
0
0
0
0
s, CꢁCH), 3.70 (1H, dd, J4 ,5 a ¼ 6.2 and J5 a,5 b ¼ 11.2 Hz, CH2a-5’), 3.81
0
0
0
0
(1H, dd, J4 ,5 a ¼ 4.8 and J5 a,5 b ¼ 11.0 Hz,CH2b-5’), 4.47–4.59 (1H, m, H-4’),
0
0
5.00 (1H, d, J3 ,4 ¼ 2.9 Hz, H-3’), 5.79 (1H, dd, J5,6 ¼ 8.1 and J5,NH ¼ 1.2 Hz,
H-5), 7.32 (1H, d, J5,6 ¼ 8.1 Hz, H-6), 8.73 (1H, br, NH); FAB-MS (m/z)
501 (Mþ þ Na) and 479 (M þ H). Anal. Calcd for C23H38N2O3Si2ꢃ1/2 H2O:
C, 57.17; H, 8.03; N, 5.80. Found: C, 57.28; H, 8.06; N, 5.66.
4.1.7. 1-[3,5-Bis-O-(tert-butyldimethylsilyl)-2-deoxy-2-C-methyl-erythro-pento-1-
enofuranosyl]uracil (6c)
To a solution of 5b (111.2 mg, 0.21 mmol) and MeI (0.13 mL, 2.10 mmol)
in THF (10.0 mL) was added BuLi (1.34 M hexane solution) (0.47 mL,
0.63 mmol) and at –78 ꢀC under Ar atmosphere. After being stirred for
15 min, the mixture was quenched with AcOH (36.0 lL) and partitioned
between chloroform/saturated NaHCO3. Silica gel column chromatogra-
phy(hexane/ethyl acetate ¼ 3/1)of the organic layer gave 6c (74.9 mg, 76%,
syrup) and 1 (10.5 mg, 11%, solid).
Physical data for 6c; UV (MeOH) kmax 257 nm (e 8400), kmin 235 nm (e
1
6100); H NMR (CDCl3) d 0.07 and 0.11 (12H, each as s, Si–Me), 0.89 and
0
0
0
0
0.90 (18H, each as s, Si-tert-Bu), 3.68 (1H, dd, J4 ,5 a ¼ 5.9 and J5 a,5 b ¼ 11.0 Hz,
0
0
0
0
CH2a-5’), 3.77 (1H, dd, J4 ,5 a ¼ 5.3 and J5 a,5 b ¼ 11.0 Hz, CH2b-5’), 4.29–4.31
0
0
(1H, m, H-4’), 4.81 (1H, d, J3 ,4 ¼ 3.3 Hz, H-3’), 5.75 (1H, d, J5,6 ¼ 8.1 Hz, H-
5), 7.22 (1H, d, J5,6 ¼ 8.1 Hz, H-6), 8.93 (1H, br, NH); FAB-MS (m/z) 491
(Mþ þ Na) and 469 (Mþ þ H). Anal. Calcd for C22H40N2O5Si2: C, 56.37; H,
5.98; N, 8.60. Found: C, 56.28; H, 5.98; N, 8.84.
4.1.8. 1-[3,5-Bis-O-(tert-butyldimethylsilyl)-2-deoxy-2-C-(1-phenylhydroxymethyl)-
erythro-pento-1-enofuranosyl]uracil (12)
To a solution of 5b (334.1 mg, 0.60 mmol) and PhCHO (0.61 mL, 6.0 mmol)
in THF (30.0 mL) was added BuLi (1.34 M hexane solution) (3.60 mL,
5.40 mmol) dropwise at –78 ꢀC under Ar atmosphere. After being stirred
for 15 min, the reaction mixture was quenched with AcOH (0.31 mL) and
partitioned between chloroform/saturated NaHCO3. Silica gel column chro-
matography(hexane/ethyl acetate ¼ 2/1)of the organic layer gave a mixture
of diastereomer of 12 (0.0 mg, 82%, major:minor ¼ 7:1) and 1 (16.4 mg, 6%,
solid). The major 12 and minor 12 were separated by HPLC (hexane/ethyl

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
11
acetate ¼ 2/1) to give major 12 (248.5 mg, 71%, syrup) and minor 12
(38.5 mg, 11%, syrup).
Physical data for major 12; UV (MeOH) kmax 257 nm (e 9000), kmin
1
238 nm (e 6200); H NMR (CDCl3) d 0.04, 0.05, 0.06 and 0.10 (12H, each
as s, Si–Me), 0.88 and 0.92 (18H, each as s, Si-tert-Bu), 3.42 (1H, d,
0
0
0
0
JCH,OH ¼ 8.8 Hz, CH(OH)Ph), 3.64 (1H, dd, J4 ,5 a ¼ 6.2 and J5 a,5 b ¼ 11.0 Hz,
0
0
0
0
CH2a-5’), 3.78 (1H, dd, J4 ,5 a ¼ 5.5 and J5 a,5 b ¼ 11.0 Hz, CH2b-5’), 4.36–4.40
0
0
(1H, m, H-4’), 5.05 (1H, d, J3 ,4 ¼ 2.9 Hz, H-3’), 5.37 (1H, d,
JCH,OH ¼ 8.8 Hz, CH(OH)Ph), 5.56 (1H, dd, J5,NH ¼ 1.8 and J5,6 ¼ 7.9 Hz, H-
5), 7.06 (1H, d, J5,6 ¼ 7.9 Hz, H-6), 7.17–7.36 (5H, m, Ph), 8.41 (1H, br,
NH); FAB-MS (m/z) 583 (Mþ þ Na) and 561 (Mþ þ H). Anal. Calcd for
C28H44N2O6Si2: C, 59.97; H, 5.00; N, 7.91. Found: C,60.30; H, 4.75; N, 8.03.
1
Physical data for minor 12; H NMR (CDCl3) d 0.04, 0.06, 0.07 and 0.09
(12H, each as s, Si–Me), 0.89 and 0.91 (18H, each as s, Si-tert-Bu), 3.15 (1H,
0
0
0
0
br, CH(OH)Ph), 3.68 (1H, dd, J4 ,5 a ¼ 6.2 and J5 a,5 b ¼ 10.6 Hz, CH2a-5’), 3.80
0
0
0
0
(1H, dd, J4 ,5 a ¼ 4.8 and J5 a,5 b ¼ 10.6 Hz, CH2b-5’), 4.92–4.96 (1H, m, H-4’),
0
0
4.97 (1H, d, J3 ,4 ¼ 2.6 Hz, H-3’), 5.43 (1H, br, CH(OH)Ph), 5.49 (1H, d,
J5,6 ¼ 8.1 Hz, H-5), 6.96 (1H, d, J5,6 ¼ 8.1 Hz, H-6), 7.17–7.47 (5H, m, Ph), 8.78
(1H, br, NH); 13C NMR (CDCl3) d: –5.44, –5.42, –4.7, –4.1, 17.9, 18.5, 25.8,
25.9, 62.2, 69.2, 78.2, 87.0, 102.1, 112.6, 126.3, 127.9, 128.5, 140.7, 142.9, 144.8,
148.8, 162.4. ESI-MS (m/z) 583 (Mþ þ Na); ESI-HRMS (m/z): calcd for
C28H44O6N2NaSi2: 583.26301, found: 583.26301 (MþþNa).
4.1.9. 1-[3,5-Bis-O-(tert-butyldimethylsilyl)-2-deoxy-2-C-ethoxycarbonyl-erythro-
pento-1-enofuranosyl]uracil (13)
To a solution of 5b (59.1 mg, 0.11 mmol) and ethyl chloroformate (0.11 mL,
1.10 mmol) in THF (10.0 mL) was added BuLi (1.34 M hexane solution)
(0.75 mL, 1.10 mmol) and at –78 ꢀC under Ar atmosphere. After being
stirred for 15 min, the mixture was quenched with AcOH (63.0 lL) and
partitioned between chloroform/saturated NaHCO3. Silica gel column chro-
matography (hexane/ethyl acetate ¼ 2/1) of the organic layer gave 13
(37.7 mg, 65%, foam) and 1 (9.0 mg, 18%, solid).
1
Physical data of 13; H NMR (CDCl3) d 0.08, 0.13 and 0.16 (12H, each
as s, Si–Me), 0.89 and 0.90 (18H, each as s, Si-tert-Bu), 1.25 (3H, t,
0
0
JCH2,CH3 ¼ 7.0 Hz, COOCH2CH3), 3.68 (1H, dd, J4 ,5 a ¼ 6.6 and
0
0
0
0
0
0
J5 a,5 b ¼ 11.0 Hz, CH2a-5’), 3.83 (1H, dd, J4 ,5 a ¼ 5.1 and J5 a,5 b ¼ 11.0 Hz,
CH2b-5’), 4.13 and 4.21 (2H, each as m, COOCH2CH3), 4.47–4.51 (1H, m,
0
0
H-4’), 5.17 (1H, d, J3 ,4 ¼ 1.8 Hz, H-3’), 5.79 (1H, d, J5,NH ¼ 1.8 and
J5,6 ¼ 8.1 Hz, H-5), 7.23 (1H, d, J5,6 ¼ 8.1 Hz, H-6), 8.59 (1H, br, NH); 13C
NMR (CDCl3) d: –5.49, –5.46, –4.7, 14.3, 18.0, 18.3, 25.7, 25.8, 60.5, 61.7,
74.4, 90.2, 102.4, 104.7, 131.0, 142.7, 147.7, 156.4, 162.6, 162.7; ESI-MS (m/

12
K. HARAGUCHI ET AL.
z) 549 (Mþ þ Na); ESI-HRMS (m/z): calcd for C24H42O7N2NaSi2:
549.24228, found: 549.24115 (MþþNa).
Funding
Financial supports from Japan Society for the Promotion of Science (KAKENHI No.
24590144 to K. H.) are gratefully acknowledged.
References
[1] Huryn, D. M.; Okabe, M. AIDS-Driven Nucleoside Chemistry. Chem. Rev. 1992, 92,
1745–1768. DOI: 10.1021/cr00016a004.
[2] Chu, C. K.; Baker, D. C.; Eds. Nucleosides and Nucleotides as Antitumor and
Antiviral Agents. New York: Plenum Press, 1993.
[3] Franchetti, P.; Grifantini, M. Nucleoside and Non-Nucleoside IMP Dehydrogenase
Inhibitors as Antitumor and Antiviral Agents. Curr. Med. Chem. 1999, 6, 599–614.
DOI: 10.1002/chin.199940260.
[4] Ichikawa, E.; Kato, K. Sugar-Modified Nucleosides in Past 10 Year, A Review. CMC.
2001, 8, 385–423. DOI: 10.2174/0929867013373471.
[5] Simons C., Ed. Nucleoside Mimetics: Their Chemistry and Biological Properties.
Amsterdam: Gordon and Breach Science Publishers, 2001.
[6] Ichikawa, E.; Kato, K. Synthesis of Oxcetanocin a and Related Unusual Nucleosides
with Bis(Hydroxymethyl)-Branched Sugars. Synthesis 2002, 2002, 1–28. DOI: 10.
1055/s-2002-19289.
[7] Chu, C. K., Ed. Recent Advances in Nucleosides: Chemistry and Chemotherapy.
Amsterdam: Elsevier B. V., 2002.
[8] Chu, C. K., Ed. Antiviral Nucleosides: Chemical Synthesis and Chemotherapy.
Amsterdam: Elsevier B. V., 2003.
[9] Vaghefi, M. Ed. Nucleoside Triphosphates and Their Analogs: Chemistry,
Biotechnology, and Biological Applications. Boca Raton, London, New York,
Singapore: Tayler & Francis, 2005.
[10] Lawton, P. Purine Analogues as Antiparasitic Agents. Expert. Opin. Ther. Patents.
2005, 15, 987–994. DOI: 10.1517/13543776.15.8.987.
[11] Richardson, S.; K.; Howell, A. R.; Taboada, R. Synthesis and Properties of Psico-
Nucleosides. Org. Prep. Proc. Int. 2006, 38, 101–176. DOI: 10.1080/
00304940609355987.
[12] Peters, G. J., Ed. Deoxynucleoside Analogs in Cancer Therapy. New Jersey: Humana
Press, 2006.
[13] Herdewijn, P., Ed. Modified Nucleosides in Biochemistry, Biotechnology and
Medicine. Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
[14] Romeo, G.; Chiacchio, U.; Corsaro, A.; Merino, P. Chemical Synthesis of
Heterocyclic-Sugar Nucleoside Analogues. Chem. Rev. 2010, 110, 3337–3370. DOI:
10.1021/cr800464r.
[15] DeClercq, E., Ed. Antiviral Drug Design. Weinheim: Wiley-VCH Verlag GmbH &
Co. KGaA, 2011.
[16] Calenbergh, S. V.; Pochet, S.; Munier-Lehman, H. Frug Design and Identification of
Potent Leads against Mycobacterium tuberculosis Thymidine Monophosphate
Kinase. CTMC. 2012, 12, 694–705. DOI: 10.2174/156802612799984580.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
13
[17]
Merino, P., Ed. Chemical Synthesis of Nucleoside Analogues. Hoboken, New Jersey:
John Wiley & Sons, 2013.
[18] De Clercq, E. Highlights in Antiviral Drug Research: antivirals at the Horizon. Med.
Res. Rev. 2013, 33, 1215–1248. DOI: 10.1002/med.21256.
[19] Jordheim, L. P.; Durantel, D.; Zoulim, F.; Dumontet, C. Advances in the
Development of Nucleoside and Nucleotide Analogues for Cancer and Viral
Diseases. Nat. Rev. Drug Discov. 2013, 12, 447–464. DOI: 10.1038/nrd4010.
[20] De Clercq, E.; Li, G. Approved Antiviral Drugs Over the Past 50 Years. Clin.
Microbiol. Rev. 2016, 29, 695–747. DOI: 10.1128/CMR.00102-15.
[21] Shelton, J.; Lu, X.; Hollenbaugh, J. A.; Cho, J. H.; Amblard, F.; Schinazi, R. F.
Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer
Nucleosides, Nucleotides, and Base Analogs. Chem. Rev. 2016, 116, 14379–14455.
DOI: 10.1021/acs.chemrev.6b00209.
[22] Haraguchi, K.; Itoh, Y.; Tanaka, H. Carbon-Carbon Bond Formation at the Sugar
Portion of Nucleosides: synthetic Potential of Unsaturated-Sugar Nucleosides. J. Syn.
Org. Chem Jpn. 2003, 61, 974. DOI: 10.5059/yukigoseikyokaishi.61.974.
[23] Haraguchi, K.; Takeda, S.; Kubota, Y.; Kumamoto, H.; Tanaka, H.; Hamasaki, T.; E.;
Baba, M.; Paintsil, E.; Cheng, Y.-C.; Urata, Y. Next Generation Anti-HIV Agent 4’-
Ethynylstavudine: From The Bench To The Clinic. In Frontiers in Clinical Drug
Research: HIV, Atta-ur-Rahman, J., ed.; Bentham Science Publishing: Sharjah,
U.A.E., 2015; Vol. 1, pp. 123–184.
[24] Kumamoto, H.; Shindoh, S.; Tanaka, H.; Gen, E.; Haraguchi, K.; Kittaka, A.;
Miyasaka, T. Stannyl Migration from the Base to the Sugar Portion of 1’,2’-
Unsaturated Uridine: The First Example of Substitution at the 2’-Position.
Tetrahedron Lett. 1998, 39, 3761–3764. DOI: 10.1016/S0040-4039(98)00579-6.
[25] Kumamoto, H.; Shindoh, S.; Tanaka, H.; Itoh, Y.; Haraguchi, K.; Gen, E.; Kittaka,
A.; Miyasaka, T.; Kondo, M.; Nakamura, K. T. An Intramolecular Anionic
Migration of a Stannyl Group from the 6-Position of 1-(2-deoxy-D-Erythro-Pent-1-
Enofuranosyl)Uracil to the 2’-Position: Synthesis of 2’-Substituted 1’,2’-Unsaturated
Uridines. Tetrahedron 2000, 56, 5363–5371. DOI: 10.1016/S0040-4020(00)00441-5.
[26] A part of the results of this study has been appeared inTetrahedron, 2000, 56,
5363–5371.
[27] Haraguchi, K.; Itoh, Y.; Tanaka, H.; Miyasaka, T. Preparation and Reactions of 2’-
and 3’-Vinyl Bromides of Uracilnucleosides: Versatile Synthons for anti-HIV
Agents. Tetrahedron Lett. 1991, 32, 3391–3394. DOI: 10.1016/S0040-4039(00)92715-
1.
[28] Haraguchi, K.; Itoh, Y.; Tanaka, H.; Akita, T.; Miyasaka, T. Uracil and Adenine
Nucleosides Having a 2’- or 3’-Bromovinyl Structure: highly Versatile Synthons for
the Synthesis of 2’-C- and 3’-C-Branched 2’,3’-Unsaturated Derivatives. Tetrahedron
1993, 49, 1371–1390. DOI: 10.1016/S0040-4020(01)90190-5.
[29] Haraguchi, K.; Itoh, Y.; Tanaka, H.; Yamaguchi, K.; Miyasaka, T. Anomeric
Manipulation of Nucleosides: Stereospecific Entry to 1’-C-Branched Uracil
Nucleosides. Tetrahedron Lett. 1993, 34, 6913–6916. DOI: 10.1016/S0040-
4039(00)91829-X.
[30] Itoh, Y.; Haraguchi, K.; Tanaka, H.; Gen, E.; Miyasaka, T. Divergent and Stereo-
Controlled Approach to the Synthesis of Uracil Nucleosides Branched at the
Anomeric Position. J. Org. Chem. 1995, 60, 656–662. DOI: 10.1021/jo00108a031.