Synthesis of 2'-deoxy-4'-C-hydroxymethyl-4'-thioribonucleosides and their 2',3'-dideoxy and 2',3'didehydro-2',3'-dideoxy analogues

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HETEROCYCLES, Vol. 76, No. 2, 2008, pp. 1337 - 1360. © The Japan Institute of Heterocyclic Chemistry

Received, 7th April, 2008, Accepted, 13th May, 2008, Published online, 19th May, 2008. COM-08-S(N)100

SYNTHESIS

OF

2’-DEOXY-4’-C-HYDROXYMETHYL-4’-THIO-

RIBONUCLEOSIDES AND THEIR 2’,3’-DIDEOXY AND 2’,3’-

DIDEHYDRO-2’,3’-DIDEOXY ANALOGUES

Junzo Nokami,* Masayuki Mae, Satoshi Fukutake, Tomoyuki Ubuka,

and Mitsuhiro Yamada

Department of Applied Chemistry, Faculty of Engineering,

Okayama University of Science, 1-1 Ridai-cho, Okayama 700-0005, Japan

E-mail: nogami@dac.ous.ac.jp

Abstract - (±)- 2’-Deoxy-4’-C-hydroxymethyl-4’-thioribonucleosides ( 1)

and their

2’,3’-dideoxy- ( 2) and

2’,3’-didehydro-2’,3’-dideoxy- ( 3)

analogues have been prepared from

hydrothiophene derivatives 2,2-

bis(benzyloxymethyl)-3-benzyloxytetrahydrothiophene (

4), 2,2-bis-

(acetoxymethyl)tetrahydrothiophene ( 5) and 2,2-bis(acetoxym ethyl)-2,5-

dihydrothiophene ( 6), respectively. Preparation of the com pound 1 has

been carried out via N-glycosylation of the corresponding sulfoxide

9,

derived from 4 by m-CPBA oxidation, with trim ethylsilylated pyrimidines

and trim ethylsilyl triflate (Kita-O ’Niel-Matsuda’s m ethod; m odified

Pummerer rearrangement). On the other hand, the compounds 2 and 3 have

been obtained via N-glycosylation of the corresponding 4’-thiofuranoses 7

and 8 with trim ethylsilylated pyrim idines and SnCl , respectively, while

4

the compounds 7 and 8 have been prepared from compounds 5 and 6 by an

electrochemical 2-acetoxylation, respectively.

INTRODUCTION

Recently, a wide variety of sugar-m odified nucle osides have been prepared to search for

effective antiviral agents in which thioribonucleosides have received much attention mostly

This paper is dedicated to Professor Ryoji Noyori on the occasion of his 70^thbirthday.

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HETEROCYCLES, Vol. 76, No. 2, 2008

because of the reported anti-HIV activity of the 4’-thio-2’,3’-dideoxy analogues.¹Moreover, it

has been reported that (±)-4’-thio-3’-oxa-2’,3’-dideoxynucleosides, cis-5-fluorocytosine and

adenine derivatives (BCH-1081 and BCH-371) exhibited a good anti-HIV activity in MT-4 cell,

though all of the trans isomers were found to be inactive and non-toxic.²Here, we have

focused our attention on the synthesis of (±)-4’-C-hydroxymethyl-4’-thioribonucleoside

derivatives (1-3) which have both hydroxymethyl and nucleoside base substituents on

thiofuranose ring in cis geometry, because (i) the cis geometry is essential for biological

activities, (ii) many of 4’-substituted nucleosides have already been prepared and their

biological activities have been investigated,³(iii) we are much interested in a structure-activity

relationship of these compounds, although it has been reported that synthetic 4’-C-

hydroxymethylcarbocyclic nucleosides do not have any biological activity.⁴

Nu

O

NH₂

N

HO

S

R

NH

Nu =

HO

N

O

N

O

1

2

3

HO

a

b

R = Me

R = F

c

Y

BnO

AcO

S

BnO

AcO

5 Y = H

7 Y = OAc

6 Y = H

8 Y = OAc

BnO

4

O

S

O

BnO

AcO

S

Figure 1

10

BnO

9

RESULTS AND DISCUSSION

2,2-Bis(benzyloxymethyl)-3-benzyloxytetrahydrothiophene (4) was prepared as follows.

Dimethyl chloromalonate, derived from dimethyl malonate by chlorination with SO₂Cl₂, was

treated with 3-hydroxypropanethiol and sodium carbonate in THF at 40-50 °C for 20 h to give

the alcohol 11 in good yield. Treatment of 11 with PCC gave the corresponding aldol product

2,2-dimethoxycarbonyl-3-hydroxytetrahydrothiophene (12) directly in 86% yield. Protection of a

hydroxy group of 12 was conducted under an acidic condition with DHP to give the THP-ether

13 avoiding a retroaldol reaction of 12 under basic reaction conditions. Two methoxycarbonyl

groups in 13 were reduced by DIBAL-H to the diol 14. The desired compound 4 was obtained

in 72% overall yield via benzylation of hydroxy groups of 14 to the compound 15, followed by

its hydrolysis to the alcohol 16 and then its benzylation (Scheme 1).

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1339

Scheme 1. Preparation of 2,2-bis(benzyloxymethyl)-3-benzyloxytetrahydrothiophene 4

MeO₂C

a

c

MeO₂C

82%

Cl

MeO₂C

89%

S

OH

b

S

86%

MeO₂C

11

HO

dimethyl

malonate

dimethyl

2-chloromalonate

12

d

90%

MeO₂C

BnO

S

HO

f, g, h

e

S

15 R = THP (90%)

16 R = H (96%)

BnO

RO

71%

THPO

13

4

R = Bn (84%)

14

a. SO₂Cl₂/CH₂Cl₂, reflux for 3 days;

c. PCC (2 equiv)/4Å MS, CH₂Cl₂, rt;

b. HS(CH₂)₃OH/THF, 45 ºC for 20 h;

d. DHP, TsOH (cat.)/CH₂Cl₂, -30 ºC, 1 h;

e. DIBAL-H (4.2 equiv)/THF, 0 ºC, 1 h; f. NaH, BnCl (2.5 equiv)/DMF, -25 ºC (1 h)-rt (12 h);

g. TsOH (5 mol%)/MeOH, 0 ºC, 15 min; h. NaH, BnCl (2.4 equiv)/DMF, 0 ºC-rt (15 h).

2,2-Bis(acetoxymethyl)tetrahydrothiophene (5) was obtained easily via DIBAL-H reduction of

2,2-bis(ethoxycarbonyl)tetrahydrothiophene (17) followed by acetylation, where the compound

17 was prepared by Ikegami’s method⁵(Scheme 2).

Scheme 2. Preparation of 2,2-bis(acetoxymethyl)tetrahydrothiophene 5

EtO₂C

44%

EtO₂C

a

b

c

S

Br

99%

84%

EtO₂C Br

EtO₂C

diethyl

malonate

EtO₂C

17

diethyl 2-(3-bromopropyl)-

malonate

diethyl 2-bromo-2-

(3-bromopropyl)malonate

d

a. 1,3-dibromopropane (2 equiv), K₂CO₃/acetone, reflux;

b. Br₂/Et₂O, reflux;

c. Na₂S/EtOH, 0 ºC;

d. DIBAL-H (4.5 equiv)/Et₂O, 0 ºC;

e. Ac₂O, Et₃N, DMAP (cat)/CH₂Cl₂.

HO

e

S

5

68% from 17

18

2,2-Bis(acetoxymethyl)-2,5-dihydrothiophene (6) was very conveniently prepared from 12 as

shown in Scheme 3. Dehydration of 12 to 19 was performed by treating of 12 with 2

equivalents of trifluoromethanesulfonic anhydride and an excess amount of N,N-

dimethylaminopyridine (DMAP). The desired compound 6 was obtained via DIBAL-H

reduction of two methoxycarbonyl groups of 19 to the corresponding diol 20, followed by its

acetylation (Scheme 3).

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HETEROCYCLES, Vol. 76, No. 2, 2008

Scheme 3. Preparation of 2,2-bis(acetoxymethyl)-2,5-dihydrothiophene 6

HO

AcO

MeO₂C

a

b

c

S

12

74%

96%

88%

HO

AcO

19

20

6

a. Tf₂O (2.2 equiv), DMAP (5 equiv)/CH₂Cl₂, -30 ºC (1 h)-rt (15 h);

b. DIBAL-H (4.2 equiv)/THF, 0 ºC, 1 h;

c. Ac₂O (3 equiv), Et₃N (3 equiv), DMAP (cat.)/ClCH₂CH₂Cl, 0 ºC-rt (30 min).

4’-Thioribonucleosides (1-3) were successfully obtained from the corresponding

hydrothiophene derivatives (4-6) mainly by two methods, (A) and (B), as shown in Figure 2.

(A) A very convenient method for the N-thioglycosylation via the corresponding sulfoxide

(SO), in which the C-N bond formation may take place by a nucleophilic addition of nitrogen

atom (silylated nucleoside base) to an in situ generated stable cation (SC), formed by

Pummerer type rearrangement of SO via a transition state TS1.^1r,1u,6(B) A traditional method

which has been generally used for N- and O-glycosylation by glycosyl donor such as α-acetoxy

sulfide (AS) together with an activator (Lewis acid such as SnCl₄), in which glycosylation may

take place similarly as above with the stable cation (SC) formed from AS via a transition state

TS2.^1o,7

O

S

OE

S

R¹

R²

H

E

R²

SO

TS1

(A) Kita-O'Neil-Matsuda's method

(B) traditional method

(activated by Lewis acid)

(C) Pummerer rearrangement

(D) oxidation of S to SO

(A)

(C)

(D)

(E)

R¹

R²

R¹

R²

R¹

R²

Nu

S

T

SC

TN

(E) electrolysis (Nokami's)

(C)

(B)

LA

R¹

R²

R¹

OAc

LA

S

R²

TS2

AS

Figure 2. Synthesis of 4'-thioribonucleosides (TN) from tetrahydrothiophenes (T)

First, we investigated a conversion of the tetrahydrothiophene derivative 5 to the

corresponding 4’-thioribonucleoside 2 via pass (B) in Figure 2, in which 2-acetoxy-4,4-

bis(acetoxymethyl)tetrahydrothiophene (7; acetyl 4-C-acetoxymethyl-2,3-dideoxy-5-O-acetyl-

HETEROCYCLES, Vol. 76, No. 2, 2008

1341

4-thioribose) served as a glycosyl donor for N-glycosylation of silylated nucleoside bases 22.

The glycosyl donor 7 was derived from 5 via direct acetoxylation by electrolysis [pass (E) in

Figure 2]⁸or via acetoxylation by Pummerer rearrangement of the corresponding sulfoxide 9

[pass (D) and (C) in Figure 2]. We observed that electrochemical 2-acetoxylation of the sulfide

5 gave 2-acetoxytetrahydrothiophene derivative 7 in better yield than the process via Pummerer

rearrangement of the corresponding sulfoxide 10.⁹In the latter case, the conversion of the

sulfide 5 to the sulfoxide 10 by m-CPBA oxidation as well as that of 10 to 7 by Pummerer

rearrangement gave unsatisfactory yields. By-product 21, which may be formed via thermolysis

of 10, was isolated in 8% yield after column chromatography on silica gel. N-Glycosylation of

trimethylsilylated pyrimidines 22a-c was performed with 7 in the presence of anhydrous SnCl₄

in acetonitrile to give 23 in quantitative yields. 2’,3’-Dideoxy-4’-C-hydroxymethyl-4’-

thiothymidine (2a), 2’,3’-dideoxy-5-fluoro-4’-C-hydroxymethyl-4’-thiouridine (2b) and 2’,3’-

dideoxy-4’-C-hydroxymethyl-4’-thiocytidine (2c) were obtained via hydrolysis of 23a-c,

respectively, using aq. ammonia or aq. dimethylamine in 1,4-dioxane, although it took a long

reaction time (Scheme 4).

Scheme 4. Preparation of 2',3'-dideoxy-4'-C-hydroxymethyl-4'-thioribonucleosides 2a-c

O

N

OTMS

NHAc

N

R

X

NH

O

N

O

N

OTMS

N

OTMS

AcO

HO

e

S

22c

22a R = Me

22b R = F

quant.

23a R = Me

23b R = F

2a R = Me

2b R = F

OAc

AcO

a

d

S

NHAc

NH₂

51%

quant.

N

5

7

43%

AcO

N

O

N

O

AcO

HO

f

b

S

c

quant.

69%

8%

AcO

O

S

23c

2c

AcO

21

a. electrolysis, AcONH₄/AcOH-MeCN; b. m-CPBA/CH₂Cl₂, rt, 2 h;

c. AcONBu₄/Ac₂O, 90 ºC, 2 days;

d. 22, SnCl₄/MeCN, 0 ºC, 30 min (22a), 15 min (22b), 20 min (22c);

e. aq. NH₃(30%)/1,4-dioxane, rt, 1 day (23a), 5 days (23b).

f. aq. Me₂NH/1,4-dioxane, 3 weeks.

AcO

10

Next, 2’,3’-didehydro-2’,3’-dideoxy-4’-C-hydroxymethyl-4’-thioribonucleosides 3a-c were

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HETEROCYCLES, Vol. 76, No. 2, 2008

similarly prepared from the compound 6 via several steps as shown in Scheme 5: electrolysis of

6 to the corresponding glycosyl donor 8, N-glycosylation of 22 with 8 to give 24, and its

hydrolysis.

Scheme 5. 2',3'-Didehydro-2',3'-dideoxy-4'-C-hydroxymethyl-4'-thioribonucleosides 3a-c

O

N

R

NH

O

N

O

AcO

HO

c

S

quant.

24a R = Me

24b R = F

3a R = Me

3b R = F

OAc

AcO

a

b

S

NHAc

NH₂

quant.

54%

8

6

N

O

N

O

AcO

HO

a. electrolysis, AcONH₄/AcOH-MeCN;

b. 22, SnCl₄/MeCN, 0 ºC, 15-20 min;

c. aq. Me₂NH (50%)/1,4-dioxane, rt, 1 day.

c

S

quant.

24c

3c

On the other hand, the conversion of 4 to 2’-deoxy-4’-C-hydroxymethyl-4’-thioribonucleosides

(1a,b) was carried out by Kita-O’Neil-Matsuda’s method⁶via pass (A) in Figure 2, in which

the corresponding sulfoxide 9 served as a glycosyl donor for N-glycosylation of thymine and 5-

fluorouracil to give 25 in satisfactory yield. Debenzylation of 25 by hydrogenation in the

presence of Pd(OH)₂(30 mol%) gave 1 in good yield (Scheme 6).

Scheme 6. Preparation of 2'-deoxy-4'-C-hydroxymethyl-4'-thioribonucleosides 1a,b

O

R

NH

O

S

N

O

N

O

BnO

HO

a

c

b

S

4

96%

BnO

HO

1a R = Me

1b R = F

25a R = Me

9

(60%, trans/cis = 1.2)

25b R = F

major/minor = 1.5

(67%, trans/cis = 2.4)

a. m-CPBA/(CH₂Cl)₂, -25 ºC, 15 min;

b. thymine or 5-fluorouracil (3.5 equiv), Et₃N (10 equiv), TMSOTf (10 equiv)/

CH₂Cl₂, rt, 5 min; and ZnI₂(0.3 equiv) at 0 ºC, rt, 19 h;

c. H₂/Pd(OH)₂-C (30 mol%)/EtOH, rt, 3 days.

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1343

Among the compounds 2a-c and 3a-c, where their anti-HIV activity was evaluated, 3b showed

a weak activity against HIV (MT-4) (50% inhibitory concentration: 2.73 µg/mL), although

other compounds did not show any activity at a concentration of 100 µg/mL.

EXPERIMENTAL

General

TLC was performed on aluminum-backed plates coated with silica gel 60 with F₂₅₄indicator. Column

chromatography was carried out on silica gel BW-300 (200-400 mesh, Fuji Silysia Chemical Ltd.).

Infrared spectra were recorded on a Nicolet Series II Magna-IR system 550 spectrometer. ¹H NMR (300,

13

400, 500 MHz) and C NMR (75, 100, 125 MHz) spectra were measured on a JEOL JNM-400 and

LAMBDA-300 and 500 spectrometers. High-resolution mass spectra were obtained with a JEOL JMS-

700 mass spectrometer. Elemental analyses were obtained on a Perkin-Elmer PE-2400 Series II CHN

analyzer.

Dimethyl 2-(3-hydroxypropylthio)malonate (11). To a solution of dimethyl 2-chloromalonate (4.43 g,

26.0 mmol) and 3-mercapto-1-propanol (1.76 mL, 20.0 mmol) in THF (50 mL) was added a finely

powdered Na₂CO₃(6.35 g, 60.0 mmol). After stirring at 40-50 °C for 20 h, the reaction mixture was

filtered off under reduced pressure and the filtrate was concentrated in vacuo. The crude residue was

column chromatographed on silica gel (Et₂O/hexane = 1:1) to afford 11 (3.76 g, 85%) as colorless oil; R_f

0.46 (Et₂O/hexane = 1:3); IR (neat) 3419, 1732 cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 1.78 (brs, 1H), 1.85

(tt, J = 6.1, 7.0 Hz, 2H), 2.87 (t, J = 7.0 Hz, 2H), 3.76 (t, J = 6.1 Hz, 2H), 3.81 (s, 6H), 4.22 (s, 1H); ¹³C

NMR (100 MHz, CDCl₃) δ 28.2, 31.3, 50.5, 53.3, 60.9, 167.4. HRMS m/z calcd for C₈H₁₄O₅S 222.0562,

found 222.0558.

2,2-Dimethoxycarbonyl-3-hydroxytetrahydrothiophene (12). To a suspension of pyridinium

chlorochromate (915 mg, 4.24 mmol) and molecular sieves (5Å) (powder, 610 mg) in dry

dichloromethane (CH₂Cl₂, 16 mL) was added a solution of 11 (470 mg, 2.12 mmol) in dry CH₂Cl₂(5

mL) at 0 °C under argon atmosphere. After stirring at room temperature (rt) for 6 h, the solvent was

removed in vacuo. The residue was column chromatographed on silica gel (EtOAc/hexane = 1:1) to

afford 404 mg (86%) of 12 as colorless oil. R_f= 0.37 (EtOAc/hexane= 1:1); IR (neat) 3541, 1731 cm^-1;

¹H NMR (300 MHz, CDCl₃) δ 2.33-2.41 (m, 2H), 2.95-3.03 (m, 2H), 3.13-3.22 (m, 1H), 3.78 (s, 3H),

3.82 (s, 3H), 4.80 (dd, J = 4.9, 10.1 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 28.9, 35.9, 53.3, 53.4, 69.1,

78.7, 169.2, 169.9. Anal. Calcd for C₈H₁₂O₅S: C, 43.63; H, 5.49. Found: C, 43.93; H, 5.35.

2,2-Dimethoxycarbonyl-3-(tetrahydropyranyloxy)tetrahydrothiophene (13). To a solution of 12

(893 mg, 4.06 mmol) and dihydropyran (DHP, 0.55 mL, 6.09 mmol) in CH₂Cl₂was added p-

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HETEROCYCLES, Vol. 76, No. 2, 2008

toluenesulfonic acid monohydrate (TSA·H₂O, ca. 40 mg) at 0 °C. After stirring for 15 min at 0 °C, the

reaction was quenched with saturated aq. NaHCO₃(10 mL). The organic layer was separated and the

aqueous layer was extracted with CHCl₃(3 x 10 mL). The combined organic extract was dried over

Na₂SO₄and concentrated in vacuo. The residue was column chromatographed on silica gel

(EtOAc/hexane = 1:5) to afford 1.10 g (90%) of a diastereoisomeric mixture (ca. 1:1) of 13 as white

solid. R_f= 0.39 and 0.33 (EtOAc/hexane = 1:3); mp (mixture) 50-51 °C; [less polar 13 (R_f= 0.39)] IR

(Nujol mull) 1768, 1729 cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 1.48-1.61 (m, 5H), 1.72-1.79 (m, 1H),

2.31-2.38 (m, 1H), 2.48-2.53 (m, 1H), 2.95 (ddd, J = 3.1, 7.1, 10.1 Hz, 1H), 3.26 (dt, J = 5.8, 10.1 Hz,

1H), 3.52-3.56 (m, 1H), 3.75 (s, 3H), 3.78 (s, 3H), 3.85 (ddd, J = 3.3, 7.9, 11.2 Hz, 1H), 4.73 (t, J = 4.0

Hz, 1H), 4.85 (t, J = 3.5 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 19.2, 25.1, 30.5, 37.2, 52.9, 52.9, 62.6,

70.2, 85.0, 100.7, 167.7, 169.8; and [polar 13 (R_f= 0.33)] IR (Nujol mull) 1768, 1731 cm^-1; ¹H NMR

(500 MHz, CDCl₃) δ 1.50-1.68 (m, 6H), 2.18-2.31 (m, 1H), 2.49 (dddd, J = 3.4, 3.4, 9.5, 23.2 Hz, 1H),

2.92 (ddd, J = 3.1, 11.9, 15.6 Hz, 1H), 3.16 (ddd, J = 9.3, 16.3, 19.0 Hz, 1H), 3.50-3.57 (m, 1H), 3.75 (s,

3H), 3.75-3.82 (m, 1H), 3.82 (s, 3H), 4.80 (brs, 1H), 5.00 (t, J = 4.3 Hz, 1H); ¹³C NMR (100 MHz,

CDCl₃) δ 18.2, 25.1, 30.0, 30.4, 33.1, 52.9, 53.0, 61.2, 70.4, 79.1, 93.5, 167.2, 169.7; Anal. Calcd for

C₁₃H₂₀O₆S (mixture): C, 51.30; H, 6.62. Found: C, 51.10; H: 6.65.

2,2-Di(hydroxymethyl)-3-(tetrahydropyranyloxy)tetrahydrothiophene (14). To a hexane solution of

DIBAL-H (44.0 mL, 0.95 M, 41.8 mmol) was added dropwise a dry THF (49 mL) solution of 13 (a

diastereoisomeric mixture; 3 g, 9.87 mmol) at 0 °C under argon atmosphere. After stirring at 0 °C for 15

min, the reaction was quenched with EtOAc (4.2 mL) and then with H₂O (1.8 mL) at 0 °C. The mixture

was stirred for 30 min and the solvent was removed by filtration through a glass frit. The residue was

stirred in MeOH (30 mL) for 24 h and filtrated off under a reduced pressure. The combined filtrate was

concentrated in vacuo to give a crude product. The crude product was column chromatographed on silica

gel (from Et₂O/hexane = 1:3 to Et₂O) to afford 14 in 71% (2.40 g) yield as a mixture of

diastereoisomers. R_f= 0.36 (Et₂O); mp (mixture) 63-63.5 °C. A small portion of the crystal was again

carefully column chromatographed on silica gel (Et₂O/hexane = 1:3) to obtain the spectra of both

diastereoisomers separately; [less polar 14 (from faster eluent)] IR (Nujol mull) 3298 cm^-1; ¹H NMR

(500 MHz, CDCl₃) δ 1.52-1.60 (m, 4H), 1.71-1.82 (m, 2H), 2.25-2.31 (m, 1H), 2.38-2.44 (m, 1H), 2.56

(t, J = 6.1 Hz, 1H), 2.77 (ddd, J = 6.2, 9.8, 10.7 Hz, 1H), 2.85 (ddd, J = 4.5, 7.0, 11.2 Hz, 1H), 3.00-3.04

(m, 1H), 3.53-3.57 (m, 1H), 3.67 (dd, J = 8.9, 10.4 Hz, 1H), 3.73 (dd, J = 4.6, 11.6 Hz, 1H), 3.83 (dd, J

= 7.4, 11.6 Hz, 1H), 3.91 (ddd, J = 3.4, 7.4, 10.9 Hz, 1H), 4.10 (dd, J = 3.7, 11.9 Hz, 1H), 4.34 (dd, J =

13

5.1, 8.4 Hz, 1H), 4.74 (dd, J = 2.6, 5.0 Hz, 1H); C NMR (100 MHz, CDCl₃) δ 19.8, 25.1, 26.4, 30.7,

35.2, 62.9, 63.3, 66.0, 83.5, 100.9 and [polar 14 (from later eluent)] IR (Nujol mull) 3301 cm^-1; ¹H NMR

HETEROCYCLES, Vol. 76, No. 2, 2008

1345

(500 MHz, CDCl₃) δ 1.48-1.53 (m, 4H), 1.74-1.87 (m, 2H), 2.13-2.23 (m, 2H), 2.81 (ddd, J = 3.0, 6.9,

10.1 Hz, 1H), 3.03 (dt, J = 6.3, 10.2 Hz, 1H), 3.49-3.54 (m, 2H), 3.66-3.71 (m, 2H), 3.85 (dd, J = 3.4,

11.6 Hz, 1H), 4.00-4.02 (m, 1H), 4.22-4.26 (m, 2H), 4.48 (dd, J = 2.4, 7.6 Hz, 1H), 4.60 (t, J = 3.2 Hz,

13

1H); C NMR (100 MHz, CDCl₃) δ 21.6, 24.9, 28.6, 31.6, 35.3, 64.4, 66.0, 66.1, 69.2, 81.0, 100.7.

Anal. Calcd for C₁₃H₂₀O₆S (a diastereoisomeric mixture): C, 53.20; H, 8.12. Found: C, 53.32; H, 8.22.

2,2-Di(benzyloxymethyl)-3-(tetrahydropyranyloxy)tetrahydrothiophene (15). To a suspension of

NaH, prepared from 60 wt% of oil dispersion of NaH (400 mg, 10 mmol) by rinsing with dry hexane (2

x 10 mL), in DMF (25 mL) was added dropwise dry DMF (12 mL) solution of 13 (1.00 g, 4.04 mmol) at

-25 °C under argon atmosphere. After stirring for 30 min, benzyl chloride (1.2 mL, 10.4 mmol) was

added to a pale yellowish reaction mixture and the mixture was allowed to stir at -25 °C for 1 h and at rt

overnight, and then the reaction was quenched by careful addition of H₂O (50 mL) on an ice-water bath.

The organic layer was separated and the aqueous layer was extracted twice with a mixed solvent

(EtOAc/hexane = 1/1, 2 x 20 mL). The combined extract was dried over MgSO₄and concentrated in

vacuo. The residue was column chromatographed on silica gel (Et₂O/hexane = 1/1) to give 15 (1.48 g,

87% yield) as a mixture of diastereoisomers. R_f= 0.70 (Et₂O/hexane = 3/1); mp (mixture) 68-69 °C.

[less polar 15 (from faster eluent)] ¹H NMR (500 MHz, CDCl₃) δ 1.42-1.61 (m, 5H), 1.73-1.80 (m, 1H),

2.08-2.15 (m, 1H), 2.30-2.36 (m, 1H), 2.80 (ddd, J = 3.7, 6.9, 10.5 Hz, 1H), 3.03 (dt, J = 5.8, 9.9 Hz,

1H), 3.47 (ddd, J = 4.9, 4.9, 9.8 Hz, 1H), 3.52 (d, J = 9.5 Hz, 1H), 3.60 (d, J = 9.4 Hz, 1H), 3.69 (d, J =

8.6 Hz, 1H), 3.82-3.87 (m, 1H), 3.93 (d, J = 9.2 Hz, 1H), 4.23 (t, J = 1.33 Hz, 1H), 4.49-4.59 (m, 4H),

4.64 (t, J = 3.7 Hz, 1H), 7.25-7.33 (m, 10H); ¹³C NMR (100 MHz, CDCl₃) δ 19.5, 25.2, 28.3, 30.4, 36.6,

62.5, 63.1, 70.7, 73.0, 73.1, 83.5, 100.2, 127.1, 127.2, 127.2, 127.3, 127.9, 128.0, 128.0, 138.2, 138.3

1

and [polar 15 (from later eluent)] H NMR (500 MHz, CDCl₃) δ 1.43-1.56 (m, 4H), 1.66 (ddt, J = 3.3,

3.3, 11.5 Hz, 1H), 1.72-1.79 (m, 1H), 1.93-2.00 (m, 1H), 2.25 (ddd, J = 2.8, 2.8, 5.6, 13.4 Hz, 1H), 2.78

(ddd, J = 2.8, 7.3, 10.1 Hz, 1H), 2.95 (dt, J = 6.0, 10.5 Hz, 1H), 3.42-3.46 (m, 1H), 3.46 (d, J = 9.5 Hz,

1H), 3.67 (d, J = 9.5 Hz, 1H), 3.77-3.82 (m, 1H), 3.86 (d, J = 9.2 Hz, 1H), 4.12 (d, J = 9.2 Hz, 1H), 4.49

(t, J = 3.1 Hz, 1H), 4.51 (d, J = 12.2 Hz, 1H), 4.56 (d, J = 11.9 Hz, 1H), 4.57 (d, J = 12.5 Hz, 1H), 4.62

(d, J = 11.9 Hz, 1H), 4.71 (t, J = 3.2 Hz, 1H), 7.23-7.33 (m, 10H); ¹³C NMR (100 MHz, CDCl₃) δ 18.9,

25.2, 28.1, 30.6, 32.3, 61.6, 63.6, 71.0, 72.9, 73.2, 77.9, 94.5, 127.1, 127.2, 127.3, 128.0, 128.0, 138.4,

138.6. HRMS m/z calcd for C₂₅H₂₂O₄S (a diastereoisomeric mixture) 428.2021, found 428.2048.

2,2-Di(benzyloxymethyl)-3-hydroxytetrahydrothiophene (16). To a suspension of 15 (2.89 g, 6.74

mmol) in methanol (67 mL) was added TSA·H₂O (ca. 60 mg) at 0 °C. After stirring for 15 min, the

reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc (10 mL) and washed

with saturated aq. Na₂CO₃(10 mL) and brine (50 mL). The aqueous layer was extracted with EtOAc (3 x

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HETEROCYCLES, Vol. 76, No. 2, 2008

10 mL). The combined extract was dried over MgSO₄and concentrated in vacuo. The residue was

column chromatographed on silica gel (Et₂O/hexane = 1/1) to afford 16 (2.22 g, 95%) as colorless oil. R_f

= 0.36 (Et₂O/hexane = 1/1); IR (neat) 3453 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 2.09-2.27 (m, 2H), 2.80

(dt, J = 6.7, 10.5 Hz, 1H), 2.94 (dt, J = 6.9, 10.5 Hz, 1H), 3.05 (d, J = 4.6 Hz, 1H), 3.57 (d, J = 9.0 Hz,

1H), 3.75 (d, J = 9.0 Hz, 1H), 3.79 (d, J = 9.4 Hz, 1H), 3.92 (d, J = 9.2 Hz, 1H), 4.22 (dd, J = 5.1, 10.9

Hz, 1H), 4.50 (d, J = 12.3 Hz, 1H), 4.52 (d, J = 12.1 Hz, 1H), 4.57 (d, J = 12.1 Hz, 1H), 4.58 (d, J = 12.1

13

Hz, 1H), 7.25-7.38 (m, 10H); C NMR (100 MHz, CDCl₃) δ 27.2, 36.4, 60.9, 71.1, 73.3, 73.4, 74.1,

78.5, 127.4, 127.5, 127.5, 127.6, 128.2, 128.3, 137.7, 138.0. HRMS (FAB) m/z calcd for C₁₃H₁₇O₂S [M-

BnO]⁺237.0950, found 237.0917.

3-Benzyloxy-2,2-di(benzyloxymethyl)tetrahydrothiophene (4). To a suspension of NaH, prepared

from 60 wt% of oil dispersion of NaH (35 mg) by rinsing with dry hexane (2 x 5 mL), in DMF (5 mL)

was added dropwise a solution of 16 (128 mg, 0.37 mmol) in dry DMF (5 mL) at -25 °C under argon

atmosphere. After stirring for 15 min at 0 °C, benzyl chloride (0.1 mL, 0.87 mmol) was added to a pale

yellowish reaction mixture and then the mixture was allowed to stir at 0 °C for 1 h and at rt over night,

and then the reaction was quenched by careful addition of H₂O (30 mL) on an ice-water bath. The

organic layer was separated and the aqueous layer was extracted twice with a mixed solvent

(EtOAc/hexane = 1/1, 2 x 20 mL). The combined extract was dried over MgSO₄and concentrated in

vacuo. The residue was column chromatographed on silica gel (Et₂O/hexane = 1/1) to give 4 (135 mg,

84% yield) as colorless oil. R_f= 0.57 (Et₂O/hexane = 3/1); ¹H NMR (400 MHz, CDCl₃) δ 1.94-2.05 (m,

1H), 2.28 (dddd, J = 3.1, 3.1, 6.2, 13.4 Hz, 1H), 2.78 (ddd, J = 3.2, 7.1, 10.3 Hz, 1H), 3.01 (dt, J = 5.9,

10.3 Hz, 1H), 3.46 (d, J = 9.5 Hz, 1H), 3.65 (d, J = 9.5 Hz, 1H), 3.81 (d, J = 9.0 Hz, 1H), 4.04 (d, J = 9.2

Hz, 1H), 4.14 (t, J = 3.4 Hz, 1H), 4.46 (d, J = 11.9 Hz, 1H), 4.48 (d, J = 11.9 Hz, 2H), 4.52 (d, J = 11.7

Hz, 1H), 4.55 (d, J = 11.7 Hz, 1H), 4.61 (d, J = 12.1 Hz, 1H), 7.24-7.33 (m, 15H); ¹³C NMR (100 MHz,

CDCl₃) δ 28.3, 33.7, 63.6, 71.1, 71.7, 73.1, 73.3, 83.6, 127.3, 127.4, 127.4, 128.2, 128.3, 138.4, 138.7.

HRMS m/z calcd for C₂₇H₃₀O₃S 434.1916, found 434.1892.

Diethyl 2-(3-bromopropyl)malonate. To a suspension of finely powdered K₂CO₃(22.1 g, 161 mmol)

in acetone (200 mL) were added 1,3-dibromopropane (21.7 mL, 214 mmol) and diethyl malonate (16.2

mL, 107 mmol), and the reaction mixture was refluxed with stirring for 4 days. After cooling down to rt,

an insoluble solid was removed by filtration and the filtrate was concentrated in vacuo. To the residue

was added water (50 mL) and extracted twice with EtOAc (2 x 50 mL). The combined extract was dried

over MgSO₄and distilled under reduced pressure to give colorless oil (145-147 °C/1.5-1.6 mmHg, 3.3g,

44%), which was column chromatographed on silica gel (Et₂O/hexane = 1/5) to give diethyl 2-(3-

bromopropyl)malonate (12.7 g, 42%). R_f= 0.58 (Et₂O/hexane = 1/1); IR (neat) 1732 cm^-1; ¹H NMR (400

HETEROCYCLES, Vol. 76, No. 2, 2008

1347

MHz, CDCl₃) δ 1.28 (t, J = 7.2 Hz, 6H), 1.91 (m, 2H), 2.05 (m, 2H), 3.35 (t, J = 7.2 Hz, 1H), 4.21 (q, J

= 7.2 Hz, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 14.1, 27.3, 30.3, 32.6, 51.1, 61.5, 169.1. Anal. Calcd for

C₁₀H₁₇O₄Br: C, 42.72; H, 6.09. Found: C, 42.98; H. 5.88.

Diethyl 2-bromo-2-(3-bromopropyl)malonate. To a solution of diethyl 2-(3-bromopropyl)malonate

(8.90 g, 31.6 mmol) in Et₂O (32 mL) was added bromine (1.63 mL, 31.6 mmol) at 0 °C, and the reaction

mixture was refluxed for 70 min. The mixture was added with saturated aq. NaHCO₃solution at 0 °C

and extracted twice with ether (2 x 30 mL). The combined extract was dried and concentrated in vacuo.

The residue was column chromatographed on silica gel to give diethyl 2-bromo-2-(3-

bromopropyl)malonate (11.3 g, 99%). R_f= 0.59 (Et₂O/hexane = 1/1); IR (neat) 1742 cm^-1; ¹H NMR (400

MHz, CDCl₃) δ 1.31 (t, J = 7.2 Hz, 6H), 2.02 (m, 2H), 2.44 (m, 2H), 3.44 (t, J = 6.4 Hz, 2H), 4.29 (q, J

13

= 7.2 Hz, 4H); C NMR (75 MHz, CDCl₃) δ 13.9, 28.7, 32.4, 36.9, 62.4, 63.2, 166.6. Anal. Calcd for

C₁₀H₁₆O₄Br₂: C, 33.36; H, 4.48. Found: C, 33.66; H, 4.41.

2,2-Di(methoxycarbonyl)tetrahydrothiophene (17). To a solution of diethyl 2-bromo-2-(3-

bromopropyl)malonate (5.67 g, 15.7 mmol) in EtOH (20 mL) was added a suspension of sodium sulfide

(Na₂S, 1.50 g, 17.3 mmol) in EtOH (40 mL) and the mixture was stirred for 1 h. It (a yellow

suspension) was filtrated and concentrated in vacuo to remove ethanol, and the residue was diluted with

EtOAc (50 mL) and washed with brine. The water layer was extracted twice with EtOAc (2 x 50 mL).

The combined extracts were dried over MgSO₄and concentrated in vacuo. The residue was column

chromatographed on silica gel to give 17 as colorless oil (3.05 g, 84%). R_f= 0.59 (Et₂O/hexane = 1/1);

1

IR (neat) 1736 cm^-1; H NMR (400 MHz, CDCl₃) δ 1.27 (t, J = 7.2 Hz, 6H), 2.19 (tt, J = 6.4, 6.4, 2H),

2.42 (t, J = 6.4 Hz, 2H), 3.01 (t, J = 6.4 Hz, 1H), 4.23 (q, J = 7.2 Hz, 4H); ¹³C NMR (75 MHz, CDCl₃) δ

14.0, 30.9, 34.1, 38.4, 62.2, 66.0, 170.3. Anal. Calcd for C₁₀H₁₆O₄S: C, 51.71; H, 6.94. Found: C, 51.55;

H. 6.84.

2,2-Di(hydroxymethyl)tetrahydrothiophene (18). To a solution of 17 (422 mg, 1.81 mmol) in EtOH

(4 mL) was added a suspension of sodium borohydride (NaBH₄, 206 mg, 5.43 mmol) in EtOH (2 ml) at

0 °C and the reaction mixture was stirred at rt for 1 day. The mixture was added with saturated aq.

ammonium chloride and then concentrated in vacuo. The residue was diluted with EtOAc (30 mL) and

washed with brine. The water layer was extracted twice with EtOAc (2 x 30 mL). The combined extract

was dried over MgSO₄and concentrated to give crude 18 (246 mg, 92%) as white crystal which was

pure enough to use for acetylation. The following characterization data of 18 was obtained after further

purification by column chromatography on silica gel (Et₂O). R_f= 0.53 (Et₂O); mp 68-72 °C; IR (Nujol

mull) 3296 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 1.27 (t, J = 7.2 Hz, 6H), 2.19 (tt, J = 6.4, 6.4, 2H), 2.42

(t, J = 6.4 Hz, 2H), 3.01 (t, J = 6.4 Hz, 1H), 4.23 (q, J = 7.2 Hz, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 30.6,

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HETEROCYCLES, Vol. 76, No. 2, 2008

33.0, 35.2, 65.3, 67.7. Anal. Calcd for C₆H₁₂O₂S: C, 48.62; H, 8.16. Found: C, 48.81; H. 7.89.

2,2-Di(acetoxymethyl)tetrahydrothiophene (5). To a solution of crude 18 (278 mg, 1.68 mmol) in

CH₂Cl₂(10 mL) were added Et₃N (1.41 mL, 10.1 mmol), acetic anhydride (0.97 mL, 5.04 mmol) and a

small amount of 4-N,N-dimethylaminopyridine (DMAP) at 0 °C and the mixture was stirred at rt for 100

min. It was then concentrated in vacuo, and the residue was diluted with EtOAc (30 mL) and

successively washed with saturated aq. tartaric acid (10mL), saturated aq. NaHCO₃and brine (10 mL).

The water layers were also extracted twice with EtOAc (2 x 30 mL). The combined extract was dried

over MgSO₄and concentrated in vacuo, and the residue was column chromatographed on silica gel

(Et₂O/hexane = 2/1) to afford 5 (366 mg, 93%). R_f= 0.46 (Et₂O/hexane = 2/1); IR (neat) 1743 cm^-1; ¹H

NMR (400 MHz, CDCl₃) δ 1.83 (t, J = 6.4 Hz, 2H), 2.00-2.22 (m, 2H), 2.08 (s, 6H), 2.91 (t, J = 6.4 Hz,

2H), 4.09 (d, J = 11.2 Hz, 2H), 4.27 (d, J = 11.2 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 20.8, 29.4, 32.6,

35.6, 67.0, 170.7. Anal. Calcd for C₁₀H₁₆O₄S: C, 51.71; H, 6.94. Found: C, 51.70; H. 6.92.

2,2-Di(methoxycarbonyl)-2,5-dihydrothiophene (19). To a solution of DMAP (3.16 g, 25.9 mmol) in

dry CH₂Cl₂(60 mL) was added dropwise a solution of 12 (1.14 g, 5.18 mmol) in dry CH₂Cl₂(10 mL) at

-25 °C under argon atmosphere. After stirring for 30 min, trifluoromethanesulfonic anhydride (Tf₂O, 1.9

mL 11.4 mmol) was added dropwise to the mixture for over 15 min at -25 °C and the stirring was

continued overnight at rt. To the reaction mixture was added water (30 mL), and then aqueous layer was

separated and extracted twice with Et₂O (2 x 30 mL). The combined extracts were dried over MgSO₄

and concentrated in vacuo. The residue was column chromatographed on silica gel (EtOAc/hexane =

1:3 and then Et₂O) to afford 778 mg (74%) of 19 as white solid. R_f= 0.73 (EtOAc/hexane = 1:1); mp

42.0-42.5 °C; IR (neat) 1726 cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 3.79 (s, 6H), 3.88 (t, J = 2.5 Hz, 2H),

5.98 (dt, J = 2.3, 6.3 Hz, 1H), 6.11 (dt, J = 2.6, 6.1 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 39.7, 53.5,

73.0, 128.4, 132.6, 169.3. HRMS m/z calcd for C₈H₁₀O₄S 202.0300, found 202.0307.

2,2-Di(hydroxymethyl)-2,5-dihydrothiophene (20). To a solution of diester 19 (125 mg, 0.62 mmol) in

dry THF (3 mL) was added dropwise a hexane solution of DIBAL-H (1.4 mL, 0.95 M, 1.33 mmol) at

0 °C under argon atmosphere. After stirring for 30 min, the reaction mixture was added dropwise with

EtOAc (0.1 mL), saturated aq. NaCl (10 mL) and tetrabutylammonium fluoride (0.92 mL, 1.0 M, 0.92

mmol). The mixture was filtrated off under reduced pressure and washed with CHCl₃(20 mL). The

filtrate was washed with saturated aq. NaCl (40 mL). The aqueous layer was extracted twice with CHCl₃.

The combined extracts were dried over MgSO₄and concentrated in vacuo. The residue was column

chromatographed on silica gel (EtOAc/hexane = 1:3 and then EtOAc) to afford 87 mg (96%) of 20 as

white crystal. R_f= 0.54 (EtOAc/hexane = 4:1); mp 73-74 °C; IR (neat) 3310 cm^-1; ¹H NMR (500 MHz,

CDCl₃) δ 2.14 (t, J = 6.6 Hz, 2H), 3.70-3.75 (m, 4H), 3.77 (t, J = 2.5 Hz, 2H), 5.67 (dt, J = 2.3, 6.2 Hz,

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1349

1H), 5.96 (dt, J = 2.6, 6.2 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 38.4, 66.9, 73.1, 130.1, 132.0.

HRMS m/z calcd for C₆H₁₀O₂S 146.0402, found 146.0409.

2,2-Di(acetoxymethyl)-2,5-dihydrothiophene (6). To a solution of crude 20 (320 mg, 2.19 mmol) in

CH₂Cl₂(22 mL) were added Et₃N (0.91 mL, 6.58 mmol), acetic anhydride (0.62 mL, 6.56 mmol) and a

small amount of DMAP at 0 °C and the mixture was stirred at rt for 30 min. It was then concentrated in

vacuo, and the residue was diluted with EtOAc (30 mL) and successively washed with saturated aq.

tartaric acid (10 mL), saturated aq. NaHCO₃(10 mL) and brine (10 mL). The water layers were also

extracted twice with EtOAc (2 x 30 mL). The combined extracts were dried over MgSO₄and

concentrated in vacuo, and the residue was column chromatographed on silica gel (Et₂O/hexane = 1/3) to

1

afford 4 (443 mg, 88%) as colorless oil. R_f= 0.62 (Et₂O/hexane = 2/1); IR (neat) 1744 cm^-1; H NMR

(400 MHz, CDCl₃) δ 2.08 (s, 6H), 3.73 (t, J = 2.2 Hz, 2H), 4.24 (d, J = 11.2 Hz, 1H), 4.28 (d, J = 11.2

13

Hz, 1H), 5.70 (dt, J = 2.4, 6.4 Hz, 1H), 5.98 (d, J = 2.4, 6.4 Hz, 1H); C NMR (100 MHz, CDCl₃) δ

20.8, 38.5, 65.5, 67.4, 130.5, 131.2, 170.6. Anal. Calcd for C₁₀H₁₄O₄S: C, 52.16; H, 6.13. Found: C,

52.18; H. 6.30.

2-Acetoxy-4,4-di(acetoxymethyl)tetrahydrothiophene (7; Acetyl 4-C-acetoxymethyl-5-O-acetyl-2,3-

dideoxy-4-thioribose). Electrolysis of the thiophene derivative 5 to the thioribose derivative 7

was carried out as follows. A solution of 5 (465 mg, 2.0 mmol) and ammonium acetate (102 mg,

1.32 mmol) in a mixed solvent of acetic acid (0.7 mL) and MeCN (1.5 mL) was electrolyzed at

a constant current of 50 mA/cm²at two platinum foil electrodes (1 cm²), placed parallel to each

other 4 mm apart, in an undivided cell without cooling. During the electrolysis, the applied

voltage was maintained at ca. 5.7 V. After passage of 2.5 F/mol of electricity, the solvent was

removed under reduced pressure, and the residue was purified by column chromatography on

silica gel to give the corresponding α-acetoxy sulfide 7 as colorless oil (295 mg, 51%). R_f=

0.33 (Et₂O/hexane = 2/1); IR (neat) 1742 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 1.89-2.18 (m, 2H), 2.06 (s,

3H), 2.08 (s, 6H), 2.20-2.36 (m, 2H), 4.09 (d, J = 11.2 Hz, 1H), 4.13 (d, J = 11.2 Hz, 1H), 4.18 (d, J =

11.2 Hz, 1H), 4.38 (d, J = 11.2 Hz, 1H), 6.12 (brd, J = 4.4 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 20.8,

21.2, 32.8, 35.3, 65.0, 68.3, 82.4, 170.3, 170.6. Anal. Calcd for C₁₂H₁₈O₆S: C, 49.64; H, 6.25. Found: C,

49.88; H. 6.10.

2,2-Di(acetoxymethyl)tetrahydrothiophene-S-oxide (10) and Pummerer rearrangement of 10 to 7.

To a solution of 5 (100 mg, 0.43 mmol) in CH₂Cl₂(10 mL) was added dropwise a suspension of m-

CPBA (121 mg 0.56 mmol) in CH₂Cl₂(2 mL) at 0 ºC and the reaction mixture was stirred at rt for 2 h.

The reaction was quenched with saturated aq. Na₂S₂O₃(1 mL) and the mixture was washed with

saturated aq. NaHCO₃(5 mL). The aqueous layer was extracted twice with CHCl₃(2 x 10 mL). The

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HETEROCYCLES, Vol. 76, No. 2, 2008

combined extracts were dried over MgSO₄and concentrated in vacuo. The residue was column

1

chromatographed on silica gel (Et₂O) to give 10 (73.3 mg, 69%) [R_f= 0.33 (EtOAc/hexane = 2/1); H

NMR (400 MHz, CDCl₃) δ 1.91 (dt, J = 6.8, 13.6 Hz, 1H), 2.04−2.12 (m, 1H), 2.10 (s, 6H), 2.22 (m,

1H), 2.56 (m 1H), 4.16 (d, J = 11.8 Hz, 1H), 4.24 (d, J = 11.8 Hz, 1H), 4.40 (s, 2H)]. A mixture of 10

(73.3 mg, 0.295 mmol), tetrabutylammonium acetate (98.0 mg, 0.325 mmol, 1.1 equiv.) and acetic

anhydride (2.5 mL) was stirred at 90 °C for 24 h under argon atmosphere. The mixture was concentrated

under reduced pressure and the residue was column chromatographed on silica gel to give 7 (37.1 mg,

43%) and by-product 21 (8%). 21; ¹H NMR (400 MHz, CDCl₃) δ 1.79-2.03 (m, 2H), 2.03-2.20 (m, 2H),

2.095 (s, 3H), 2.097 (s, 3H), 2.12 (s, 3H), 2.89 (t, J = 6.6 Hz, 2H), 4.20 (d, J = 11.4 Hz, 1H), 4.26 (d, J =

11.4 Hz, 1H), 7.01 (s, 1H).

4’-C-Acetoxymethyl-5’-O-acetyl-2’,3’-dideoxy-4’-thiothymidine (23a). To a solution of 7

(171 mg 0.59 mmol) and bis(trimethylsilyl)thymine 22a (0.40 mL, 1.47 mmol) in dry MeCN

(3.9 mL) was added SnCl₄(0.105 mL, 0.88 mmol) at rt under nitrogen atmosphere. After

stirring for 15 min, the reaction was quenched with saturated aq. NaHCO₃(20 mL) at 0 °C and

the mixture was extracted three times with CHCl₃(3 x 20 mL). The combined extracts were

dried over MgSO₄and concentrated in vacuo. The residue was column chromatographed on

silica gel (EtOAc/hexane = 1/1) to afford 23a (209 mg, 99%) as white crystal. R_f= 0.25

1

(EtOAc/hexane = 4/1); mp 177-178 °C; IR (Nujol mull) 3172, 3045, 1735, 1697, 1683, 1648 cm^-1; H

NMR (400 MHz, CDCl₃) δ 1.86-2.23 (m, 3Η), 1.98 (s, 3H), 2.11 (s, 3H), 2.14 (s, 3H), 2.52 (dt, J = 6.3,

13.0 Hz, 1H), 4.13 (d, J = 11.4, 1H), 4.29 (d, J = 11.4 Hz, 1H), 4.34 (d, J = 11.4 Hz, 1H), 4.40 (d, J =

13

11.4 Hz, 1H), 6.39 (t, J = 6.4 Hz, 1H), 7.60 (s, 1H), 9.50 (s; 1H); C NMR (100 MHz, CDCl₃) δ 12.7,

20.8, 20.9, 33.1, 35.6, 60.1, 63.1, 66.0, 66.7, 111.6, 135.9, 150.8, 163.6, 170.4, 170.6. Anal. Calcd for

C₁₅H₂₀N₂O₆S: C, 50.55; H, 5.66; N, 7.86. Found: C, 50.64; H, 5.81; N, 8.03.

4’-C-Acetoxymethyl-5’-O-acetyl-2’,3’-dideoxy-5-fluoro-4’-thiouridine (23b). To a solution

of 7 (38 mg 0.131 mmol) and bis(trimethylsilyl)-5-fluorouracil 22b (0.09 mL, 0.33 mmol) in

dry MeCN (1.0 mL) was added SnCl₄(0.023 mL, 0.197 mmol) at rt under nitrogen atmosphere.

After stirring for 15 min, the reaction was quenched with saturated aq. NaHCO₃(20 mL) at

0 °C and the mixture was extracted three times with CHCl₃(3 x 20 mL). The combined extracts

were dried over MgSO₄and concentrated in vacuo. The residue was column chromatographed

on silica gel (EtOAc) to afford 23b (46 mg, 98%) as white solid. R_f= 0.31 (EtOAc/hexane = 2/1);

mp 168-169 °C; IR (Nujol mull) 3160, 3101, 1738, 1716, 1693, 1660 cm^-1; ¹H NMR (400 MHz, CDCl₃)

δ 2.02 (µ, 2Η), 2.11 (s, 3H), 2.17 (s, 3H), 2.14-2.28 (m, 1H), 2.56 (dt, J = 7.2, 14.0 Hz, 1H), 4.12 (d, J =

11.4, 1H), 4.26 (d, J = 12.0 Hz, 1H), 4.35 (d, J = 11.4 Hz, 1H), 4.40 (d, J = 12.0 Hz, 1H), 6.30 (t, J = 4.8

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1351

Hz, 1H), 8.18 (d, J = 12.0 Hz, 1H), 9.82 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 20.8, 20.8, 32.3, 36.2,

60.8, 64.7, 66.1, 66.6, 125.1 (d, ²J_CF= 34.8 Hz), 140.2 (d, ¹J_CF= 235.9 Hz), 149.3, 156.8 (d, ²J_CF= 27.4

Hz), 170.4, 170.5. Anal. Calcd for C₁₄H₁₇FN₂O₆S: C, 46.66; H, 4.75; N, 7.77. Found: C, 46.68; H, 4.50;

N, 7.70.

4’-C-Acetoxymethyl-4-N,5’-O-diacetyl-2’,3’-didehydro-2’,3’-dideoxy-4’-thiouridine (23c).

To a solution of 7 (277 mg 0.954 mmol) and 4-N-acetyl-2-O-(trimethylsilyl)cytosine 22c (0.537

mL, 2.39 mmol) in dry MeCN (6.4 mL) was added SnCl₄(0.17 mL, 1.43 mmol) at rt under

nitrogen atmosphere. After stirring for 20 min, the reaction was quenched with saturated aq.

NaHCO₃(20 mL) at 0 °C and the mixture was extracted three times with CHCl₃(3 x 20 mL).

The combined extracts were dried over MgSO₄and concentrated in vacuo. The residue was

column chromatographed on silica gel (MeOH/EtOAc = 1/10) to afford 23c (344 mg, 94%) as

white solid. R_f= 0.25 (MeOH/EtOAc = 1/10); mp 187.5-188.5 °C; IR (Nujol mull) 3232, 3125, 3070,

1

1734, 1712, 1656, 1643, 1620, 1608, 1565 cm^-1; H NMR (400 MHz, CDCl₃) δ 2.10 (s, 3H), 2.11 (s,

3H), 2.31 (s, 3H), 4.27 (d, J = 11.4, 1H), 4.31 (d, J = 11.4 Hz, 2H), 4.37 (d, J = 11.4 Hz, 1H), 5.97 (dd, J

= 2.6, 6.2 Hz, 1H), 6.15 (dd, J = 1.8, 6.2 Hz, 1H), 7.14 (brs, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.96 (d, J =

7.4 Hz, 1H), 10.1 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 20.775, 20.845, 24.9, 32.2, 36.4, 60.7, 66.06,

66.148, 66.4, 96.9, 145.5, 155.5, 162.7, 170.4, 170.4, 171.2. Anal. Calcd for C₁₆H₂₁N₃O₆S: C, 50.12; H,

5.52; N, 10.96. Found: C, 50.11; H, 5.44; N, 10.76.

2’,3’-Dideoxy-4’-C-hydroxymethyl-4’-thiothymidine (2a). To a solution of 23a (150 mg,

0.420 mmol) in 1,4-dioxane (2.1 mL) was added aq. NH₃(29%, 4.2 mL) and the mixture was

stirred at rt for 22 h and then concentrated in vacuo. The residue was heated at 50 °C to remove

acetamide and then recrystallized from CHCl₃to afford 2a as white solid (110 mg, 97%). R_f=

1

0.46 (MeOH/CHCl₃= 1/5); mp 179.0-180.0 °C; IR (Nujol mull) 3260, 3190, 1706, 1665 cm^-1; H

NMR (400 MHz, DMSO-d₆) δ 1.75-1.84 (m, 1H), 1.80 (s, 3H), 1.94 (m, 1H), 2.16 (dt, J = 6.0, 13.5 Hz,

1H), 2.29 (dt, J = 7.1, 13.5 Hz, 1H), 3.39 (dd, J = 5.4, 10.8 Hz, 1H), 3.49 (dd, J = 5.4, 10.8 Hz, 1H), 3.61

(dd, J = 5.4, 11.2 Hz, 1H), 3.72 (dd, J = 5.4, 11.2 Hz, 1H), 4.99 (t, J = 5.4 Hz, 1H), 5.20 (t, J = 5.4 Hz,

13

1H), 6.06 (t, J = 6.0 Hz, 1H), 8.02 (s, 1H), 11.3 (s, 1H); C NMR (100 MHz, DMSO-d₆) δ 12.2, 30.9,

34.9, 62.1, 64.0, 64.9, 66.3, 109.1, 137.1, 150.5, 163.5.

2’,3’-Dideoxy-5-fluoro-4’-C-hydroxymethyl-4’-thiouridine (2b). To a solution of 23b (120

mg, 0.333 mmol) in 1,4-dioxane (1 mL) was added aq. NH₃(29%, 2.2 mL) and the mixture was

stirred at rt for 120 h and then concentrated in vacuo at 50 °C. The residue was column

chromatographed on silica gel (MeOH/CHCl₃= 1/8) to afford 2b in 98% (90 mg) as white solid.

R_f= 0.53 (MeOH/CHCl₃= 1/5); mp 179.5-180.5 °C; IR (Nujol mull) 3367, 3127, 1714, 1697, 1647

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HETEROCYCLES, Vol. 76, No. 2, 2008

cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 1.80 (dt, J = 6.7, 13.8 Hz, 1H), 1.93 (dt, J = 6.7, 13.8 Hz, 1H), 2.18

(m, 1H), 2.33 (ddt, J = 3.2, 6.7, 13.6 Hz, 1H), 3.27-3.43 (m, 1H), 3.47 (dd, J = 4.8, 10.8 Hz, 1H), 3.63

(dd, J = 4.8, 11.0 Hz, 1H), 3.70 (d, J = 4.8, 11.0 Hz, 1H), 5.04 (t, J = 4.8 Hz, 1H), 5.35 (t, J = 4.8 Hz,

1H), 6.00 (brs, 1H), 8.65 (d, J = 7.6 Hz, 1H), 11.8 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 30.4, 35.4, 63.5,

63.9, 65.1, 66.7, 126.2 (d, ²J_CF= 35.0 Hz), 139.2 (d, ¹J_CF= 227.7 Hz), 149.2, 156.9 (d, ²J_CF= 26.2 Hz).

2’,3’-Dideoxy-4’-C-hydroxymethyl-4’-thiocytidine (2c). To a solution of 23c (101 mg 0.263

mmol) in 1,4-dioxane (1.3 mL) was added 50% aq. Me₂NH (1.3 mL) and the mixture was

stirred at rt for 3 weeks and then concentrated in vacuo at 50 °C to remove 1,4-dioxane and

N,N-dimethylacetamide. The residue was recrystallized from MeOH to afford 2c quantitatively

(67 mg) as white solid. R_f= 0.34 (MeOH/CHCl₃= 1/2); mp 211.0-212.0 °C; IR (Nujol mull) 3331,

1

3138, 1680, 1634, 1522 cm^-1; H NMR (400 MHz, CDCl₃) δ 1.82 (m, 2H), 2.,04 (dt, J = 6.0, 13.0 Hz,

1H), 2.31 (dt, J = 6.0, 13.0 Hz, 1H), 3.25-3.45 (m, 1H), 3.50 (dd, J = 5.2, 10.8 Hz, 1H), 3.58 (dd, J = 5.2,

10.8 Hz, 1H), 3.70 (dd, J = 5.2, 10.8 Hz, 1H), 4.97 (t, J = 5.2 Hz, 1H), 5.10 (t, J = 5.2 Hz, 1H), 1H), 5.77

13

(s, 1H), 6.12 (brs, 1H), 7.12 (brs, 2H), 8.10 (d, J = 7.2 Hz, 1H); C NMR (100 MHz, CDCl₃) δ 30.8,

35.2, 62.9, 64.2, 64.6, 65.9, 142.1, 142.1, 155.2, 165.2.

2-Acetoxy-4,4-di(acetoxymethyl)-2,5-dihydrothiophene (8; Acetyl 4-C-acetoxymethyl-5-O-acetyl-

2,3-didehydro-2,3-dideoxy-4-thioribose). A solution of 6 (229 mg, 1.0 mmol) and ammonium

acetate (102 mg, 1.32 mmol) in a mixed solvent of acetic acid (0.7 mL) and MeCN (1.5 mL)

was electrolyzed at a constant current of 50 mA/cm²at two platinum foil electrodes (1 cm²),

placed parallel to each other 4 mm apart, in an undivided cell without cooling. During the

electrolysis, the applied voltage was maintained at ca. 5.7 V. After passage of 2.5 F/mol of

electricity, the solvent was removed under reduced pressure, and the residue was purified by

column chromatography on silica gel to give the corresponding α-acetoxy sulfide 7 as colorless

1

oil (137 mg, 54%). R_f= 0.39 (Et₂O/hexane = 2/1); IR (neat) 1743 cm^-1; H NMR (400 MHz, CDCl₃)

δ 2.06 (s, 6H), 2.09 (s, 3H), 2.20-2.36 (m, 2H), 4.26 (s, 2H), 4.29 (d, J = 4.8 Hz, 2H), 6.03 (dd, J = 2.8,

13

6.4 Hz, 1H), 6.10 (d, J = 6.4 Hz, 1H), 6.69 (d, J = 2.8 Hz, 1H); C NMR (100 MHz, CDCl₃) δ 20.7,

20.8, 21.0, 65.1, 66.4, 67.2, 84.8, 130.3, 136.4, 170.4, 170.4. Anal. Calcd for C₁₂H₁₆O₆S: C, 49.99; H,

5.59. Found: C, 50.02; H. 5.56. HRMS m/z calcd for C₁₂H₁₆O₆S: 288.0668, found 288.0575.

4’-C-Acetoxymethyl-5’-O-acetyl-2’,3’-didehydro-2’,3’-dideoxy-4’-thiothymidine (24a). To

a solution of 8 (154 mg 0.53 mmol) and bis(trimethylsilyl)thymine 22a (0.35 mL, 1.33 mmol)

in dry MeCN (3.5 mL) was added SnCl₄(0.10 mL, 0.80 mmol) at rt under nitrogen atmosphere.

After stirring for 15 min, the reaction was quenched with saturated aq. NaHCO₃(20 mL) at

0 °C and the mixture was extracted three times with CHCl₃(3 x 20 mL). The combined extracts

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1353

were dried over MgSO₄and concentrated in vacuo. The residue was column chromatographed

on silica gel (EtOAc/hexane = 1/1 and then MeOH/EtOAc = 1/4) to afford 24a (137 mg, 73%)

as white crystal. R_f= 0.32 (EtOAc/hexane = 4/1); mp 160-161 °C; IR (Nujol mull) 3169, 3047, 1746,

1693, 1644 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 1.95 (s, 3H), 2.11 (s, 3H), 2.14 (s, 3H), 4.24 (d, J = 11.6,

1H), 4.31 (d, J = 11.6 Hz, 1H), 4.36 (d, J = 11.6 Hz, 1H), 4.39 (d, J = 11.6 Hz, 1H), 5.88 (dd, J = 2.4,

6.2 Hz, 1H), 6.12 (dd, J = 1.6, 6.2 Hz, 1H), 7.10 (dd, J = 2.1, 2.1 Hz, 1H), 7.23 (s, 1H), 9.52 (s; 1H); ¹³C

NMR (100 MHz, CDCl₃) δ 12.7, 20.8, 20.9, 66.1, 66.7, 67.2, 67.5, 112.3, 130.8, 135.6, 136.5, 150.7,

170.3, 170.4. Anal. Calcd for C₁₅H₁₈N₂O₆S: C, 50.84; H, 5.12; N, 7.91. Found: C, 50.89; H, 5.12; N,

8.05.

4’-C-Acetoxymethyl-5’-O-acetyl-2’,3’-didehydro-2’,3’-dideoxy-5-fluoro-4’-thiouridine

(24b). To a solution of 8 (62 mg 0.21 mmol) and bis(trimethylsilyl)-5-fluorouracil 22b (0.14

mL, 0.53 mmol) in dry MeCN (1.4 mL) was added SnCl₄(0.04 mL, 0.32 mmol) at rt under

nitrogen atmosphere. After stirring for 15 min, the reaction was quenched with saturated aq.

NaHCO₃(20 mL) at 0 °C and the mixture was extracted three times with CHCl₃(3 x 20 mL).

The combined extracts were dried over MgSO₄and concentrated in vacuo. The residue was

column chromatographed on silica gel (EtOAc and then MeOH/EtOAc = 1/10) to afford 24b

(74 mg, 99%) as white solid. R_f= 0.28 (EtOAc/hexane = 2/1); mp 163-165 °C; IR (Nujol mull) 3172,

1

1741, 1721 cm^-1; H NMR (400 MHz, CDCl₃) δ 2.11 (s, 3H), 2.15 (s, 3H), 4.23 (d, J = 11.4 Hz, 1H),

4.31 (d, J = 11.2 Hz, 1H), 4.39 (d, J = 11.4 Hz, 1H), 4.46 (d, J = 11.2 Hz, 1H), 5.88 (dd, J = 2.4, 6.2 Hz,

1H), 6.12 (dd, J = 2.0, 6.2 Hz, 1H), 7.11 (brd, J = 2.4 Hz, 1H), 7.76 (d, J = 5.6 Hz, 1H), 9.61 (s; 1H); ¹³C

NMR (100 MHz, CDCl₃) δ 20.7, 20.7, 66.6, 66.8, 68.07, 68.11, 124.5 (d, ²J_CF= 34.7 Hz), 130.3, 137.3,

1

2

140.8 (d, J_CF= 237.7 Hz), 149.2, 156.6 (d, J_CF= 28.4 Hz), 170.2, 179.3. Anal. Calcd for

C₁₄H₁₅FN₂O₆S: C, 46.93; H, 4.22; N, 7.82. Found: C, 46.70; H, 4.32; N, 7.63.

4’-C-Acetoxymethyl-4-N,5’-O-diacetyl-2’,3’-didehydro-2’,3’-dideoxy-4’-thiouridine (24c).

To a solution of 8 (107 mg 0.37 mmol) and 4-N-acetyl-2-O-(trimethylsilyl)cytosine 22c (0.21

mL, 0.93 mmol) in dry MeCN (2.5 mL) was added SnCl₄(0.07 mL, 0.56 mmol) at rt under

nitrogen atmosphere. After stirring for 20 min, the reaction was quenched with saturated aq.

NaHCO₃(20 mL) at 0 °C and the mixture was extracted three times with CHCl₃(3 x 20 mL).

The combined extracts were dried over MgSO₄and concentrated in vacuo. The residue was

column chromatographed on silica gel (MeOH/EtOAc = 1/10) to afford 24c (132 mg, 94%) as

white solid. R_f= 0.36 (MeOH/EtOAc = 1/10); mp 177.5-178.5 °C; IR (Nujol mull) 3259, 3077, 1747,

1

1727, 1661, 1632, 1554 cm^-1; H NMR (400 MHz, CDCl₃) δ 2.10 (s, 3H), 2.11 (s, 3H), 2.31 (s, 3H),

4.27 (d, J = 11.4, 1H), 4.31 (d, J = 11.4 Hz, 2H), 4.37 (d, J = 11.4 Hz, 1H), 5.97 (dd, J = 2.6, 6.2 Hz,

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HETEROCYCLES, Vol. 76, No. 2, 2008

1H), 6.15 (dd, J = 1.8, 6.2 Hz, 1H), 7.14 (brs, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.96 (d, J = 7.4 Hz, 1H),

10.1 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 20.8, 20.9, 25.0, 66.2, 66.8, 67.6, 68.8, 98.0, 130.5, 137.0,

145.0, 155.5, 162.9, 170.3, 170.3, 171.2. Anal. Calcd for C₁₆H₁₉N₃O₆S: C, 50.39; H, 5.02; N, 11.02.

Found: C, 50.51; H, 5.06; N, 10.84.

2’,3’-Didehydro-2’,3’-dideoxy-4’-C-hydroxymethyl-4’-thiothymidine (3a). To a solution of

24a (107 mg, 0.30 mmol) in 1,4-dioxane (3 mL) was added 50% aq. Me₂NH (6.0 mL) and the

mixture was stirred at rt for 29 h and then concentrated in vacuo at 50 °C. The residue was

column chromatographed on silica gel (MeOH/CHCl₃= 1/7) to afford 3a quantitatively as a

white solid (82 mg). R_f= 0.44 (MeOH/CHCl₃= 1/5); mp 200.0-201.0 °C; IR (Nujol mull) 3471, 3427,

3140, 3067, 1697, 1682 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 1.75, (d, J = 1.0 Hz, 3H), 3.53 (dd, J = 6.4,

10.4, 1H), 3.57 (dd, J = 5.2, 10.4 Hz, 1H), 3.66 (dd, J = 5.2, 11.2 Hz, 1H), 3.77 (dd, J = 5.2, 11.2 Hz,

1H), 5.14 (t, J = 5.2 Hz, 1H), 5.27 (t, J = 5.2 Hz, 1H), 5.84 (dd, J = 2.4, 6.4 Hz, 1H), 6.12 (dd, J = 2.0,

6.4 Hz, 1H), 6.79 (brs, 1H), 7.73 (d, J = 1.0 Hz, 1H), 11.4 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 12.2,

64.6, 66.2, 66.3, 73.1, 109.6, 128.4, 136.9, 139.0, 150.5, 163.6. HRMS (FAB) m/z calcd for

C₁₁H₁₅N₂O₄S [MH]⁺271.0753, found 271.0773.

2’,3’-Didehydro-2’,3’-dideoxy-5-fluoro-4’-C-hydroxymethyl-4’-thiouridine (3b). To

a

solution of 24b (59 mg, 0.16 mmol) in 1,4-dioxane (3 mL) was added 50% aq. Me₂NH (3.0

mL) and the mixture was stirred at rt for 29 h and then concentrated in vacuo at 50 °C. The

residue was column chromatographed on silica gel (MeOH/CHCl₃= 1/7) to afford 3b in 98%

(43 mg) as a white solid. R_f= 0.39 (MeOH/CHCl₃= 1/5); mp 171.0-172.0 °C; IR (Nujol mull) 3174,

1

3050, 1723, 1658 cm^-1; H NMR (400 MHz, CDCl₃) δ 3.51 (d, J = 10.6 Hz, 1H), 3.58 (d, J = 10.6 Hz,

1H), 3.63 (d, J = 11.2 Hz, 1H), 3.82 (d, J = 11.2 Hz, 1H), 5.20 (s, 1H), 5.40 (s, 1H), 5.84 (dd, J = 2.4,

6.4 Hz, 1H), 6.12 (dd, J = 1.2, 6.4 Hz, 1H), 6.78 (brd, J = 2.0 Hz, 1H), 8.31 (d, J = 6.8 Hz, 1H), 11.9 (s,

2

1H); ¹³C NMR (100 MHz, CDCl₃) δ 64.5, 66.7, 66.9, 73.4, 125.7 (d, J_CF= 35.0 Hz), 128.2, 139.5,

139.7 (d, ¹J_CF= 229.1 Hz), 149.1, 156.9 (d, ²J_CF= 26.3 Hz). HRMS (FAB) m/z calcd for C₁₀H₁₂FN₂O₄S

[MH]⁺m/z 275.0502, found 275.0501.

2’,3’-Didehydro-2’,3’-dideoxy-4’-C-hydroxymethyl-4’-thiocytidine (3c). To a solution of

24c (101 mg 0.27 mmol) in 1,4-dioxane (2.6 mL) was added 50% aq. Me₂NH (5.2 mL) and the

mixture was stirred at rt for 28 h and then concentrated in vacuo at 50 °C to remove 1,4-

dioxane and N,N-dimethylacetamide. The residue was recrystallized from MeOH to afford 3c in

94% (65 mg) as a white crystal. R_f= 0.11 (MeOH/CHCl₃= 1/5); mp 204.0-205.0 °C; IR (Nujol

mull) 3353, 3146, 1665, 1591, 1518 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 3.54 (dd, J = 6.4, 10.6 Hz, 1H),

3.58 (dd, J = 5.2, 10.6 Hz, 1H), 3.64 (dd, J = 5.2, 11.2 Hz, 1H), 3.69 (dd, J = 5.2, 11.2 Hz, 1H), 5.09 (t, J

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1355

= 5.2 Hz, 1H), 5.11 (t, J = 5.2 Hz, 1H), 1H), 5.75 (dd, J = 7.6 Hz, 1H), 5.81 (dd, J = 2.4, 6.4 Hz, 1H),

6.11 (dd, J = 1.6, 6.4 Hz, 1H), 6.83 (brs, 1H), 7.20 (brd, J = 12.8 Hz, 2H), 7.69 (d, J = 7.2 Hz, 1H), ¹³C

NMR (100 MHz, CDCl₃) δ 64.8, 65.9, 66.9, 72.3, 94.7, 128.8, 138.5, 141.8, 155.2, 165.4. HRMS (FAB)

m/z calcd for C₁₀H₁₄N₃O₃S [MH]⁺256.0756, found 256.0799.

3-Benzyloxy-2,2-di(benzyloxymethyl)tetrahydrothiophene-S-oxide (9). To a solution of 4 (1.20 g,

2.77 mmol) in CH₂Cl₂(29.0 mL) was added dropwise a suspension of m-CPBA (889 mg, 80 wt%, 4.13

mmol) in CH₂Cl₂(6 mL) at -25 °C and the mixture was stirred for 25 min. The reaction was quenched

with saturated aq. Na₂S₂O₃(5 mL) and the reaction mixture was washed with saturated aq. Na₂CO₃(10

mL). The aqueous layer was extracted twice with CHCl₃(2 x 10 mL). The combined extracts were dried

over MgSO₄and concentrated in vacuo. The crude residue was column chromatographed on silica gel

(EtOAc/hexane = 1/1 and then EtOAc) to afford 1.20 g (96%) of a diastereoisomeric mixture (1/1.5) of 9.

R_f= 0.56 (EtOAc); less polar isomer: IR (neat) 1099 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 2.33 (dt, J =

5.5, 18.9 Hz, 1H), 2.46 (ddt, J = 6.7, 10.2, 13.5 Hz, 1H), 2.87 (dt, J = 6.5, 12.5 Hz, 1H), 2.97 (ddd, J =

6.4, 10.5, 13.o Hz, 1H), 3.71 (d, J = 9.8 Hz, 1H), 3.81 (d, J = 10.7 Hz, 1H), 3.86 (d, J = 9.8 Hz, 1H),

4.04 (d, J = 10.7 Hz, 1H), 4.21 (dd, J = 5.7, 6.9 Hz, 1H), 4.41 (d, J = 11.9 Hz, 1H), 4.45 (d, J = 11.9 Hz,

1H), 4.46 (d, J = 11.6 Hz, 1H), 4.47 (d, J = 11.6 Hz, 1H), 4.57 (d, J = 11.9 Hz, 1H), 4.66 (d, J = 11.9 Hz,

1H), 7.20-7.33 (m, 15H); ¹³C NMR (100 MHz, CDCl₃) δ 31.3, 49.3, 65.1, 70.6, 72.3, 73.0, 73.6, 73.7,

82.2, 127.4, 127.5, 127.7, 127.8, 128.2, 128.3, 128.4, 137.5, 137.9, 138.3; polar isomer: IR (neat) 1104

cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 2.30-2.38 (m, 1H), 2.59-2.70 (m, 2H), 3.26-3.36 (m, 1H), 3.56 (d,

J = 10.1 Hz, 1H), 3.90 (d, J = 10.1 Hz, 1H), 3.91 (d, J = 10.4 Hz, 1H), 4.03 (d, J = 10.1 Hz, 1H), 4.27 (t,

J = 5.7 Hz, 1H), 4.42 (d, J = 11.9 Hz, 1H), 4.48 (d, J = 11.9 Hz, 1H), 4.51 (d, J = 11.6 Hz, 1H), 4.52 (d,

J = 11.6 Hz, 1H), 4.54 (d, J = 11.9 Hz, 1H), 4.61 (d, J = 11.9 Hz, 1H), 7.21-7.34 (m, 15H); ¹³C NMR

(100 MHz, CDCl₃) δ 30.4, 50.4, 67.0, 67.2, 72.5, 72.9, 73.6, 73.8, 82.4, 127.5, 127.6, 127.6, 127.8,

128.3, 128.4, 137.8, 137.9, 138.0. HRMS m/z calcd for C₂₇H₃₀O₄S (diastereoisomeric mixture) 450.1865,

found 450.1892.

3’-O-Benzyl-4’-C-benzyloxymethyl-2’-deoxy-4’-thiothymidine (25a). To a suspension of thymine

(236 mg, 1.87 mmol) in CH₂Cl₂(5.5 mL) were added dropwise triethylamine (0.73 mL, 5.30 mmol) and

TMSOTf (0.96 mL, 5.30 mmol) at 0 °C under argon atmosphere. After stirring at rt for 5 min, 9 (241 mg,

0.53 mmol) in CH₂Cl₂(10 mL) solution and ZnI₂(51 mg, 0.16 mmol) were added to the reaction

mixture at 0 °C. The mixture was stirred at rt for 4 h and then poured into saturated aq. NaHCO₃(20

mL) at 0 °C. The organic layer was separated and the aqueous layer was extracted twice with EtOAc (2 x

20 mL). The combined extracts were dried over MgSO₄and concentrated in vacuo. The residue was

column chromatographed on silica gel (EtOAc/hexane = 1/2) to afford 25a (179 mg) in 60% yield as a

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mixture of cis and trans isomers (trans/cis = 1.2/1). The isomers were separated by column

chromatography on silica gel (EtOAc/hexane = 1/5→1/3) followed by recrystallization (MeOH/CHCl₃)

to give trans-25a and cis-25a. trans-24a: R_f= 0.44 (EtOAc/hexane = 3/1); mp 138-142 ºC, IR (neat)

3163, 1708, 1677, 1460 cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 1.60 (d, J = 0.9 Hz, 3H), 2.31 (ddd, J = 4.3,

8.0, 13.3 Hz, 1H), 2.58 (ddd, J = 4.4, 6.5, 13.5 Hz, 1H), 3.72 (t, J = 9.2 Hz, 2H), 3.88 (t, J = 8.7 Hz, 2H),

4.24 (t, J = 4.1 Hz, 1H), 4.44 (d, J = 11.9 Hz, 1H), 4.51 (d, J = 11.9 Hz, 1H), 4.55 (d, J = 11.9 Hz, 1H),

4.58 (d, J = 11.9 Hz, 1H), 4.59 (d, J = 11.9 Hz, 1H), 4.61 (d, J = 11.6 Hz, 1H), 6.41 (t, J = 7.2 Hz, 1H),

7.26-7.36 (m, 15H), 7.84 (d, J = 1.2 Hz, 1H), 8.30 (brs, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 12.2, 40.3,

60.2, 65.1, 71.9, 72.2, 73.5, 73.6, 73.8, 82.1, 111.1, 127.5, 127.6, 127.8, 128.0, 128.3, 128.4, 128.6,

137.1, 137.6, 137.6, 138.0, 150.5, 163.4; HRMS m/z calcd for C₃₂H₃₅N₂O₅S [MH]⁺559.2267, found

559.2285. cis-24a: R_f= 0.43 (EtOAc/hexane = 3/1); mp 115-116 ºC, IR (neat) 3231, 1708, 1458 cm^-1; ¹H

NMR (500 MHz, CDCl₃) δ 1.50 (d, J = 0.9 Hz, 3H), 2.42 (ddd, J = 3.2, 3.2, 14.5 Hz, 1H), 2.57 (ddd, J =

4.2, 7.7, 14.6 Hz, 1H), 3.43 (d, J = 9.5 Hz, 1H), 3.69 (d, J = 9.5 Hz, 1H), 3.99 (d, J = 9.2 Hz, 1H), 4.08

(d, J = 9.4 Hz, 1H), 4.18 (d, J = 3.8 Hz, 1H), 4.42 (s, 2H), 4.49 (d, J = 9.5 Hz, 1H), 4.55 (d, J = 12.3 Hz,

1H), 4.62 (s, 2H), 6.26 (dd, J = 3.1, 7.7 Hz, 1H), 7.26-7.35 (m, 15H), 7.95 (d, J = 1.3 Hz, 1H), 7.96 (brs,

1H); ¹³C NMR (100 MHz, CDCl₃) δ 12.1, 40.4, 60.6, 66.7, 70.4, 72.0, 72.8, 73.4, 73.5, 82.8, 110.0,

127.6, 127.6, 127.6, 127.7, 127.8, 128.0, 128.4, 128.4, 128.5, 137.1, 137.8, 137.9, 138.7, 150.8, 163.5;

HRMS m/z calcd for C₃₂H₃₅N₂O₅S [MH]⁺559.2267, found 559.2248.

3’-O-Benzyl-4’-C-benzyloxymethyl-2’-deoxy-5-fluoro-4’-thiouridine (25b). To a suspension of 5-

fluorouracil (215 mg, 1.71 mmol) in CH₂Cl₂(5 mL) were added dropwise triethylamine (0.65 mL, 4.70

mmol) and TMSOTf (0.85 mL, 4.70 mmol) at 0 °C under argon atmosphere. After stirring at rt for 5 min,

9 (213 mg, 0.47 mmol) in CH₂Cl₂(10 mL) solution and ZnI₂(45 mg, 0.14 mmol) were added to the

reaction mixture at 0 °C. The mixture was stirred at rt for 19 h and then poured into saturated aq.

NaHCO₃(20 mL) at 0 °C. The organic layer was separated and the aqueous layer was extracted twice

with EtOAc (2 x 20 mL). The combined extracts were dried over MgSO₄and concentrated in vacuo. The

residue was column chromatographed on silica gel (EtOAc/hexane = 1/2) to afford 25b (179 mg) in 67%

yield as a mixture of cis and trans isomers (trans/cis = 2.4/1). The isomers were separated by column

chromatography on silica gel (EtOAc/hexane = 1/5→1/3) followed by recrystallization (MeOH/CHCl₃)

to give trans-25b and cis-25b. trans-25b: R_f= 0.60 (EtOAc/hexane = 3/1); mp 46-47 ºC, IR (neat) 3169,

1718, 1463 cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 2.27 (ddd, J = 4.3, 7.5, 13.1 Hz, 1H), 2.57 (ddd, J = 4.4,

6.3, 13.4 Hz, 1H), 3.67 (d, J = 9.2 Hz, 1H), 3.74 (d, J = 10.1 Hz, 1H), 3.83 (t, J = 10.1 Hz, 1H), 3.83 (d,

J = 9.2 Hz, 1H), 4.19 (t, J = 4.4 Hz, 1H), 4.41 (d, J = 11.9 Hz, 1H), 4.51 (d, J = 11.9 Hz, 1H), 4.53 (d, J

= 11.9 Hz, 1H), 4.55 (d, J = 11.9 Hz, 1H), 4.60 (d, J = 11.6 Hz, 1H), 6.31 (t, J = 6.9 Hz, 1H), 7.23-7.37

HETEROCYCLES, Vol. 76, No. 2, 2008

1357

(m, 15H), 8.30 (brd, J = 4.3 Hz, 1H), 8.36 (d, J = 6.4 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 40.5, 61.1,

65.1, 68.0, 71.8, 72.2, 73.5, 73.5, 73.7, 81.9, 125.6, 125.9, 127.4, 127.6, 127.8, 128.0, 128.1, 128.3,

128.3, 128.5, 137.0, 137.4, 137.8, 139.0, 149.4, 156.8, 157.0; HRMS m/z calcd for C₃₁H₃₁FN₂O₅SNa

[MNa]⁺585.1835, found 585.1866. cis-25b: R_f= 0.60 (EtOAc/hexane = 3/1); mp 118-120 ºC, IR (neat)

3231, 1720, 1712, 1458 cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 2.38 (ddd, J = 2.9, 2.9, 14.6 Hz, 1H), 2.56

(ddd, J = 4.4, 7.9, 14.7 Hz, 1H), 3.40 (d, J = 9.8 Hz, 1H), 3.66 (d, J = 9.85 Hz, 1H), 3.95 (d, J = 9.2 Hz,

1H), 4.04 (d, J = 9.2 Hz, 1H), 4.16 (d, J = 3.7 Hz, 1H), 4.42 (d, J = 11.3 Hz, 1H), 4.45 (d, J = 11.6 Hz,

1H), 4.48 (d, J = 11.2 Hz, 1H), 4.53 (d, J = 11.2 Hz, 1H), 4.58 (d, J = 12.4 Hz, 1H), 4.61 (d, J = 12.2 Hz,

1H), 6.18 (t, J = 7.3 Hz, 1H), 7.17-7.35 (m, 15H), 8.35 (d, J = 4.2 Hz, 1H), 8.52 (brd, J = 4.6 Hz, 1H);

¹³C NMR (100 MHz, CDCl₃) δ 40.6, 61.8, 67.0, 70.2, 72.3, 72.6, 73.4, 73.6, 82.5, 127.1, 127.5, 127.7,

127.7, 127.8, 128.1, 128.4, 128.4, 128.6, 136.8, 137.7, 137.9, 141.0, 149.6, 156.6, 157.0; HRMS m/z

calcd for C₃₁H₃₁FN₂O₅S [MH]⁺562.1938, found 562.1945.

trans-2’-Deoxy-4’-C-hydroxymethyl-4’-thiothymidine (trans-1a). To a solution of trans-25a (199 mg,

0.34 mmol) in EtOH (7 mL) was added Pd(OH)₂on carbon (299 mg), and the mixture was stirred at rt

for 3 days under hydrogen (balloon). The mixture was filtered off and concentrated in vacuo. The residue

was column chromatographed on silica gel (MeOH/CHCl₃= 1/5) to give white solid, which could be

recrystallized from MeOH/CHCl₃for further purification (85 mg, 83%). trans-1a; R_f= 0.55

(MeOH/CHCl₃= 1/5); HRMS (FAB) m/z calcd for C₁₁H₁₇N₂O₅S [MH]⁺289.0858, found 289.0818.

cis-2’-Deoxy-4’-C-hydroxymethyl-4’-thiothymidine (cis-1a). To a solution of cis-25a (160 mg, 0.29

mmol) in EtOH (6 mL) was added Pd(OH)₂on carbon (240 mg), and the mixture was stirred at rt for 3

days under hydrogen (balloon). The mixture was filtered off and concentrated in vacuo. The residue was

column chromatographed on silica gel (MeOH/CHCl₃= 1/5) to give white solid, which could be

recrystallized from MeOH/CHCl₃for further purification (75 mg, 91%). cis-1a; R_f= 0.55 (MeOH/CHCl₃

= 1/5); HRMS (FAB) m/z calcd for C₁₁H₁₇N₂O₅S [MH]⁺289.0858, found 289.0854.

trans-2’-Deoxy-5-fluoro-4’-C-hydroxymethyl-4’-thiothymidine (trans-1b). To a solution of trans-

25b (101 mg, 0.18 mmol) in EtOH (4 mL) was added Pd(OH)₂on carbon (152 mg), and the mixture was

stirred at rt for 3 days under hydrogen (balloon). The mixture was filtered off and concentrated in vacuo.

The residue was column chromatographed on silica gel (MeOH/CHCl₃= 1/5) to give white solid, which

could be recrystallized from MeOH/CHCl₃for further purification (46 mg, 88%). trans-1b; R_f= 0.32

(MeOH/CHCl₃= 1/5); HRMS (FAB) m/z calcd for C₁₀H₁₄FN₂O₅S [MH]⁺293.0607, found 293.0628.

cis-2’-Deoxy-5-fluoro-4’-C-hydroxymethyl-4’-thiothymidine (cis-1b). To a solution of cis-25b (56

mg, 0.10 mmol) in EtOH (2 mL) was added Pd(OH)₂on carbon (84 mg), and the mixture was stirred at

rt for 3 days under hydrogen (balloon). The mixture was filtered off and concentrated in vacuo. The

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HETEROCYCLES, Vol. 76, No. 2, 2008

residue was column chromatographed on silica gel (MeOH/CHCl₃= 1/5) to give white solid, which

could be recrystallized from MeOH/CHCl₃for further purification (26 mg, 89%). cis-1b; R_f= 0.32

(MeOH/CHCl₃= 1/5); HRMS (FAB) m/z calcd for C₁₀H₁₄FN₂O₅S [MH]⁺293.0607, found 293.0565.

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9. In our preliminary experiments, we have obtained some following results. Electrochemical 2-

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However, Pummerer reaction of sulfides bearing a benzyloxy functionality, such as 4, gave the

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corresponding 2-substituted sulfides, such as 25a,b (via m-CPBA oxidation of 4 to 9), in better yield

rather than that of the corresponding acetoxy derivative, although 30 mol% of Pd(OH)₂-C

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ols 1a,b in good yield.

Article Doi

Synthesis of 2'-deoxy-4'-C-hydroxymethyl-4'-thioribonucleosides and their 2',3'-dideoxy and 2',3'didehydro-2',3'-dideoxy analogues

DOI: 10.3987/COM-08-S(N)100

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