Stereoselective synthesis of 3'-C-methylene- and 2'-methyl-3'-C-methylene-3'-deoxythymidine

Article abstract of DOI:10.1016/S0008-6215(99)00149-4

Stereoselective synthesis of 3'-C-methylene- and 2'-methyl-3'-C-methylene-3'-deoxythymidine is described, the key reaction being the formation of 3-C-methylene function by catalytic isomerization of a chiral epoxyalcohol, prepared from commercially availa

Full text of DOI:10.1016/S0008-6215(99)00149-4

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Carbohydrate Research 320 (1999) 161–166
Stereoselective synthesis of 3%-C-methylene- and
2%-methyl-3%-C-methylene-3%-deoxythymidine
Elena Riehokainen a,*, Igor E. Mikerin b, Nickolai N. Slobodyan b,
Marat B. Tulebaev b, Sergey E. Severin b
a Hytest Ltd., Eurocity, Tykistokatu 2B, Turku 20520, Finland
b Moscow Institute of Medical Ecology, Simferopolsky Boule6ard 8, Moscow 113149, Russia
Received 22 March 1999; accepted 9 June 1999
Abstract
Stereoselective synthesis of 3%-C-methylene- and 2%-methyl-3%-C-methylene-3%-deoxythymidine is described, the key
reaction being the formation of 3-C-methylene function by catalytic isomerization of a chiral epoxyalcohol, prepared
from commercially available 3-methyl-2-butenal and 3-methyl-2-pentenal. © 1999 Elsevier Science Ltd. All rights
reserved.
Keywords: Dideoxynucleoside; Asymmetric epoxidation; 3%-Substituted thymidine
C-3 and their use in nucleoside synthesis (see
Scheme 1).
1. Introduction
Monosaccharides with an exocyclic double
bond are essential components in the synthesis
of the branched glycoside moieties of 3%-sub-
stituted nucleosides with antiretroviral activity
[1,2]. It is known that 3%-C-methylene-2%,3%-
dideoxycytidine not only inhibits the reversed
HIV transcriptase, but also exhibits a pro-
nounced antitumor effect, which induced us to
synthesize new thymine analogs of this com-
pound. The synthetic availability of this class
of nucleosides depends to a great extent upon
the availability of the corresponding 2-de-
oxypentose derivatives. The objective of this
study was the development of a method for
the enantio- and stereoselective synthesis of
2. Results and discussion
The starting compounds in this synthesis
were the corresponding methyl derivatives of
2-butenal (1a,b). Silylation of 1a,b was accom-
plished by reaction with chlorotrimethylsilane
and triethylamine in the presence of sodium
iodide in an acetonitrile–pentane binary sys-
tem, according to the method described earlier
[3], which led to 1-trimethylsilyloxy-3-methyl-
1,3-butadiene (2a) and 1-trimethylsilyloxy-3,4-
dimethyl-1,3-butadiene (2b) in 72 and 70%
yields, respectively. Condensation of these
compounds with ethyl orthoformate in the
presence of ZnCl2 [4] gave 5,5-diethoxy-3-
methyl-2-pentenal (3a) and 5,5-diethoxy-3,4-
dimethyl-2-pentenal (3b). Compounds 3a,b
were obtained as mixtures of E and Z isomers
with ratios of 3:1 and 4:1, respectively, as
derivatives of 2-deoxy- -pentose branched at
D
* Corresponding author. Tel.: +358-2-512-0900; fax: +
358-2-512-0909.
E-mail address: hytest@hytestfinland.com (E. Riehokainen)
0008-6215/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(99)00149-4

162
E. Riehokainen et al. / Carbohydrate Research 320 (1999) 161–166
found by 13C NMR spectroscopy. Reduction
of E and Z isomers of pentenal (3a) by Red-
Al® (sodium bis(2-methoxyethoxy)aluminum
hydride) led to 5,5-diethoxy-3-methyl-2-pen-
ten-1-ol (4a) in 81% yield. Pentenal (3b) was
reduced according to a similar procedure,
which led to 5,5-diethoxy-3,4-dimethyl-2-pen-
ten-1-ol (4b) in 87% yield. The ratio of the
by column chromatography in 90% yield
(based on E alcohol (4a)). The enantiomeric
purity of 5a, determined by NMR spec-
troscopy of the Mosher ester derivative [7] was
95%.
Asymmetric epoxidation of alcohol 4b with
an asymmetric C2 atom affords a mixture of
erythro- and threodiastereomers of epoxide
5b. It is known that asymmetric epoxidation
of chiral primary allylic alcohols is accom-
plished with high stereo- (predominantly ery-
thro) and enantioselectivity, if the conditions
of kinetic resolving were applied [8,9]. If the
difference between epoxidation rates for the
two enantiomers was insignificant, a high
enantiomeric purity is observed at 50% con-
version of the starting alcohol, which in its
turn is achieved by decreasing the amount of
oxidative agent.
isomers
unchanged.
As our intention was to prepare nucleosides
with configurations in the sugar part, -
in
pentenols
4a,b
remained
D
D
(−)-diisopropyl tartrate was used for the sub-
sequent catalytic asymmetric epoxidation of
the pentenols 4a,b [5]. Epoxidation of the
double E bond in allylic alcohols is known to
be much faster, as compared with that of the
Z bond [6]; hence allylic alcohol 4a was epox-
idated without previous separation of E and Z
isomers. The ratio of E and Z isomers in
epoxide (5a) was 49:1, respectively, as deter-
mined by NMR spectroscopy. (2R,3R)-2,3-
Epoxy-3-methylpentanol (5a) was separated
In accordance with this, asymmetric epoxi-
dation of alcohol 4b with
D
-(−)-diisopropyl
tartrate and 0.6 molar equivalent of t-butyl
hydroperoxide led to erythro-(2R,3R)-2,3-
Scheme 1.

E. Riehokainen et al. / Carbohydrate Research 320 (1999) 161–166
163
Table 1
1H NMR data (l, ppm) for 3a,b–8a,b
Compound
C-1
C-2
C-3
C-4
C-5
C-3%
18.1
26.2
18.3
23.3
16.9
21.6
19.0
20.2
17.7
C-2%
a
E-3a
101.7
102.2
102.2
102.9
102.8
102.6
103.2
103.4
101.3
101.7
103.3
104.0
103.2
103.5
102.2
102.3
103.5
103.8
102.3
102.6
45.1
38.0
42.3
37.3
44.3
37.5
40.1
36.8
43.6
40.2
37.4
36.8
40.6
40.7
41.6
40.7
41.2
41.7
40.5
40.7
159.7
159.0
153.9
153.6
133.4
134.3
131.7
132.6
58.3
129.9
130.3
134.1
134.5
128.5
128.5
127.2
127.4
64.8
62.3
75.6
75.6
81.1
82.8
85.8
86.3
81.3
82.4
85.6
86.4
191.1
191.2
191.3
191.2
58.9
58.7
63.1
62.9
61.5
65.5
66.2
69.7
65.6
67.0
70.0
71.2
66.2
67.8
70.9
71.2
Z-3a a
E-3b a
Z-3b a
E-4a a
Z-4a a
E-4b a
Z-4b a
5a a
11.0
11.2
16.4
16.6
5b a
6a
6b
7a-a
7b-b
7b-a
7b-b
8a-a
8a-b
8b-a
8b-b
64.9
19.1
16.8
25.0
146.1
150.0
148.5
147.9
152.9
152.2
148.3
148.1
152.7
152.1
113.4
112.4
105.7
105.2
105.4
105.7
105.5
106.1
105.3
105.8
24.7
24.2
24.5
24.3
a Atom numbering corresponds to numbering of the sugar atoms in 6a,b–8a,b.
epoxy-3,4-dimethylpentanol (5b) in 85% yield,
if only one enantiomer of alcohol 4b was
taken into consideration. The enantiomeric
purity of 5b, determined by NMR spec-
troscopy of the Mosher ester derivative, was
93%.
on silica gel, 5%-O-protected nucleosides 9a,b
were obtained as anomeric mixtures. Treating
of anomeric mixtures 9a,b with sodium
methoxide–methanol and subsequent separa-
tion of anomers by column chromatography
on silica gel afforded the desired nucleosides
b-(10a,b) and a-(11a,b) with 54, 60, 22, and
Epoxides 5a,b were used as starting com-
pounds for the synthesis of 2,3-dideoxy-3-C-
1
19% yields, respectively. H NMR spectral
methylene-
D
-glycero-pentoses. Acyclic acetals
data for 9a,b–11a,b are presented in Table 2.
6a,b were formed as a result of epoxide–allylic
rearrangement of epoxyalcohols 5a,b. The op-
timal yield was achieved by refluxing 5a,b in
benzene in the presence of catalytic amounts
of titanium(IV) isopropoxide; the reaction was
completed in 1–2 h. Subsequent cyclization of
acetals 6a,b in ethanol in the presence of a
trace amount of HCl led to a- and b-ethylgly-
3. Experimental
General methods.—NMR spectra were
recorded in (CD3)2CO on either Bruker AM-
360 (90.56 MHz,) or Varian Gemini-300 (75
MHz) spectrometers. Optical rotations were
determined with a Jasco polarimeter in
MeOH. The progress of reaction was moni-
tored by TLC on Silufol254 (Cavalier,
Czechoslovakia) silica gel plates in 10:1
CHCl3–CH3OH with spot detection by UV or
by heating at 300–400 °C. Column chro-
matography was carried out on Silica Gel 60
(63–100 mm, E. Merck), and the systems are
indicated in the text. Melting points were de-
termined in open capillary tubes and are un-
corrected. For NMR data, see Tables 1 and 2.
1-Trimethylsilyloxy-3-methyl-1,3-butadiene
(2a).—To a suspension of anhyd NaI (180.0
cosides of 2,3-dideoxy-3-C-methylene-
D
-glyc-
ero-pentofuranoses (7a,b).
Reaction of 7a,b with p-toluoylchloride in
the presence of pyridine under mild conditions
afforded 5-O-toluoyloxy derivatives of the
ethylfuranosides 8a,b with 76 and 78% yields,
13
respectively. C NMR spectral data for 3a,b–
8a,b are presented in Table 1.
N-Glycosylation of p-toluoyloxyfuranosides
8a,b with bis(trimethylsilyloxy)thymine was
conducted in acetonitrile at 20 °C in the pres-
ence of trimethylsilyl triflate as a catalyst.
After separation by column chromatography

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E. Riehokainen et al. / Carbohydrate Research 320 (1999) 161–166
g, 1.2 mol) in dry MeCN (300 mL), triethy-l-
amine (112.0 g, 1.1 mol), 3-methyl-2-butenal
(1a) (84.0 g, 1.0 mol) and pentane (400 mL)
were added at room temperature (rt). The
mixture was cooled to 0 °C and ClMe3Si
(109.0 g, 1.0 mol) was added dropwise, fol-
lowed by heating at 40 °C. This temperature
was maintained for 4 h, the resulting solid was
filtered and washed with pentane (200 mL),
and the solvent was evaporated at atmo-
spheric pressure. Distillation of the residue
gave 2a (112.0 g, 72%): bp 56–60 °C/25
mmHg; n2D0 1.4496. Anal. Calcd for C8H16OSi:
C, 61.48; H, 10.32; Si, 17.97. Found: C, 61.52;
H, 10.38; Si, 17.88.
1 - Trimethylsilyloxy - 3,4-dimethyl - 1,3-buta-
diene (2b).—Prepared similarly to 2a, but
starting from 1b. Yield: 70%; bp 68–72 °C/25
mmHg; n2D0 1.4534. Anal. Calcd for C9H18OSi:
C, 63.47; H, 10.65; Si, 16.49. Found: C, 63.52;
H, 10.58; N, 16.52.
5,5-Diethoxy-3-methyl-2-pentenal (3a).—
To a mixture of ethyl orthoformate (118.0 g,
0.80 mol) and 15% soln of ZnCl2 in EtOAc
(700 mL) 2a was added (109.0 g, 0.70 mol)
dropwise with stirring at rt. After 1 h at rt,
satd aq NaHCO3 (600 mL) was added. The
resulting precipitate was filtered and washed
with ether (600 mL). The aq phase was sepa-
rated, the organic layer was washed with wa-
ter (200 mL), dried (K2CO3), and concd in
vacuo. Distillation of the residue gave 3a (78.3
g, 60%): bp 88–90 °C/0.1 mmHg; n2D0 1.4592.
Anal. Calcd for C10H18O3: C, 64.49; H, 9.74.
Found: C, 64.55; H, 9.70.
5,5-Diethoxy-3-methyl-2-penten-1-ol (4a).—
Red-Al® (200 mL of a 30% soln in toluene,
Aldrich) was added dropwise with stirring at
0 °C to a soln of 3a (50.0 g, 0.27 mol) in ether
(50 mL), and the mixture was stirred for 1 h at
0–5 °C. Satd aq NH4Cl (150 ml) was then
added dropwise at 0–5 °C, and the mixture
was stirred for 1 h at 0–5 °C. The precipitated
solid was filtered and washed with ether (200
mL). The organic phase was separated, dried
(K2CO3), and concd in vacuo. Distillation of
the residue gave 4a (41.2 g, 81%); bp 95–
96 °C/0.1 mmHg; n2D0 1.4548. Anal. Calcd for
C10H20O3: C, 63.79; H, 10.71. Found: C,
63.84; H, 10.63.
5,5 - Diethoxy - 3,4 - dimethyl - 2 - penten - 1 - ol
(4b).—Prepared similarly to 4a, but starting
from 3b. Yield: 87%; bp 106–107 °C/0.1
mmHg; n2D0 1.4538. Anal. Calcd for C11H22O3:
C, 65.31; H, 10.96. Found: C, 65.40; H, 11.01.
(2R,3R)-5,5-Diethoxy-2,3-epoxy-3-methyl-
pentan-1-ol (5a).—A mixture of powdered ac-
,
tivated 4 A molecular sieves (5 g) and CH2Cl2
(300 mL) was cooled to −20 °C. -(−)-Di-
D
isopropyl tartrate (3.51 g, 15.0 mmol), Ti(IV)
isopropoxide (2.84 g, 10.0 mmol), and t-butyl
hydroperoxide (45.5 mL, 4.4 M in CH2Cl2)
were added sequentially at −20 °C, and the
resulting mixture was stirred for 30 min. A
soln of 4a (18.8 g, 100.0 mmol) in CH2Cl2 (20
mL) was then added dropwise, and stirring
was maintained for 8 h at −20 °C; water (200
mL) was then added and the mixture was
stirred for 1 h. The resulting suspension was
filtered through a Celite pad, dried (MgSO4),
and evaporated. Column chromatography
(hexane–ether, gradient elution) of the residue
on silica gel gave 5a (13.7 g, 67%): Rf 0.36; nD20
1.4465; [h]D +19.0° (c 3.5, CH3OH). Anal.
5,5-Diethoxy-3,4-dimethyl-2-pentenal (3b).
—Prepared similarly to 3a, but starting from
2b. Yield: 40%; bp 98–100 °C/0.1 mmHg; nD20
1.4601. Anal. Calcd for C11H20O3: C, 65.97;
H, 10.07. Found: C, 65.92; H, 10.12.
Table 2
1H NMR (l, ppm) data for 9a,b–11a,b
Compound
H%-1
H%-2
H%-2%
H%-4
H%-5
H%-5%
2%-CH3
ꢀCH2
H-6
5-CH3
NH
9a-a
5.11
5.15
5.08
5.10
5.24
5.18
5.25
5.20
2.44
2.47
2.41
2.43
2.47
2.40
2.49
2.43
2.70
2.71
4.45
4.30
4.39
4.31
4.44
4.32
4.39
4.38
3.49
3.61
3.40
3.42
3.51
3.60
3.41
3.43
3.60
3.62
3.33
3.40
3.64
3.32
3.66
3.38
4.95
4.97
4.94
4.98
5.01
4.98
4.96
4.98
7.55
7.64
7.54
7.61
7.57
7.56
7.65
7.67
1.86
1.87
1.85
1.86
1.85
1.88
1.86
1.85
8.52
8.55
8.54
8.55
8.57
8.55
8.54
8.56
9a-b
9b-a
9b-b
10a-b
10b-b
11a-a
11b-a
1.25
1.27
2.68
2.72
1.26
1.25

E. Riehokainen et al. / Carbohydrate Research 320 (1999) 161–166
165
A cold (0 °C) soln of 7a (1.58 g, 10 mmol) in
dry pyridine (10 mL) was treated with p-tolu-
oylchloride (2.07 g, 13.0 mmol). The mixture
was stirred at constant temperature for 3 h,
then it was concd in vacuo. The soln of the
residue in CHCl3 (100 mL) was washed in
succession with satd aq NaHCO3 (20 mL) and
water (20 mL). The organic phase was dried
(Na2SO4) and concd in vacuo. The residue
was purified by column chromatography with
CHCl3, which afforded 8a (2.11 g, 76%) as an
anomeric mixture; Rf 0.75. Anal. Calcd for
C16H20O4: C, 69.54; H, 7.30. Found: C, 69.48;
H, 7.32.
Calcd for C10H20O4: C, 58.80; H, 9.87. Found:
C, 58.72; H, 9.91.
Erythro-(2R,3R)-5,5-diethoxy-2,3-epoxy-
3,4-dimethylpentan-1-ol (5b).—Prepared simi-
larly to 5a, but starting from 4b and with 0.6
mol equiv of t-butyl hydroperoxide. Yield:
85%; Rf 0.38; n2D0 1.4445; [h]D +9.8° (c 4.2,
CH3OH). Anal. Calcd for C11H22O4: C, 60.52;
H, 10.16. Found: C, 60.57; H, 10.19.
2,3-Dideoxy-3-C-methylene- -glycero-pen-
D
tose diethyl acetal (6a).—To a soln of 5a (2.04
g, 10.0 mmol) in dry benzene (100 mL) Ti(IV)
isopropoxide (1.42 g, 5.0 mmol) was added.
The mixture was stirred at 80 °C for 2 h, then
satd aq NaHCO3 (20 mL) was added. The
precipitate was separated and washed with
ether (3×20 mL). The organic layer was dried
(K2CO3) and the solvent was evaporated. The
residue was subjected to column chromatogra-
phy with CHCl3–CH3OH (20:1, v/v), to give
6a (1.78 g, 87%) (oil); Rf 0.36; [h]D +12.2° (c
2.2, CH3OH). Anal. Calcd for C10H20O4: C,
58.80; H, 9.84. Found: C, 58.77; H, 9.86.
Ethyl-2,3-dideoxy-3-C-methylene-2-methyl-
5 - O - toluoyl - h,i -
D
- glycero - pentofuranoside
(8b).—Prepared similarly to 8a but starting
from 7b. Yield: 78%; Rf 0.83. Anal. Calcd for
C17H22O4: C, 70.32; H, 7.64. Found: C, 70.41;
H, 7.59.
1-(2,3-Dideoxy-3-C-methylene-5-O-toluoyl-
h,i- -glycero-pentofuranosyl)thymine (9a).—
D
A soln of 8a (1.39 g, 5.0 mmol) and
bis(trimethylsilyloxy)thymine (1.44 g, 10
mmol) in dry MeCN (60 mL) was treated with
trimethylsilyl triflate (2.1 mL, 10 mmol). The
mixture was stirred at ambient temperature
for 16 h, then cooled to 0 °C; the reaction was
quenched with satd aq NaHCO3 (20 mL) and
CHCl3 (100 mL) was added. The precipitate
was filtered, the filtrate was dried (Na2SO4),
and was then concd in vacuo. The residue was
purified by column chromatography with
100:1 CHCl3–CH3OH, which afforded oily 9a
(1.14 g, 64%) as an anomeric mixture; Rf 0.47.
Anal. Calcd for C19H20O5N2: C, 64.04; H,
5.66; N, 7.86. Found: C, 64.11; H, 5.62; N,
7.84.
2,3 - Dideoxy - 3 - C - methylene - 2 - methyl - -
D
glycero-pentose diethyl acetal (6b).—Prepared
similarly to 6a, but starting from 5b. Yield:
85% (oil); Rf 0.28; [h]D +6.2° (c 4.2,
CH3OH). Anal. Calcd for C11H22O4: C, 60.52;
H, 10.16. Found: C, 60.58; H, 10.11.
Ethyl-2,3-dideoxy-3-C-methylene-h,i- -
D
glycero-pentofuranoside (7a).—To a soln of 6a
(1.75 g, 8.6 mmol) in dry EtOH (230 mL) a
10% soln of HCl in EtOH (0.22 mL) was
added at rt. The mixture was stirred for 30
min, then NaHCO3 (0.8 g) was added, and the
mixture was stirred for an additional 1 h. The
precipitate was filtered, and the filtrate was
concd in vacuo. The residue was purified by
column chromatography with CHCl3, which
afforded 7a (1.14 g, 84%) (oil) as an anomeric
mixture; Rf 0.55 (b anomer) and 0.60 (a
anomer). Anal. Calcd for C8H14O3: C, 60.74;
H, 8.92. Found: C, 60.70; H, 8.95.
1-(2,3-Dideoxy-3-C-methylene-2-methyl-
5 - O - toluoyl - h,i - - glycero - pentofuranosyl)-
D
thymine (9b).—Prepared similarly to 9a, but
starting from 8b; Rf 0.53. Yield: 59% (oil).
Anal. Calcd for C20H22O5N2: C, 64.88; H,
5.99; N, 7.56. Found: C, 64.79; H, 6.01; N,
7.51.
Ethyl-2,3-dideoxy-3-C-methylene-2-methyl-
h,i-D
-glycero-pentofuranoside
(7b).—Pre-
pared similarly to 7a, but starting from 6b; Rf
0.62 (b anomer) and 0.70 (a anomer). Yield:
87%. Anal. Calcd for C9H16O3: C, 62.76; H,
9.37. Found: C, 62.81; H, 9.33.
1-(2,3-Dideoxy-3-C-methylene-h-
pentofuranosyl)thymine (11a) and 1-(2,3-
dideoxy-3-C-methylene-i- -glycero-pentofuran
D
-glycero-
D
osyl)thymine (10a).—A soln of 9a (1.79 g, 5.0
mmol) in dry CH3OH (40 mL) was treated
with 0.2 M methanolic CH3ONa (20 mL). The
Ethyl - 2,3 - dideoxy - 3 - C - methylene - 5 - O-
toluoyl-h,i- -glycero-pentofuranoside (8a).—
D

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E. Riehokainen et al. / Carbohydrate Research 320 (1999) 161–166
mixture was maintained at ambient tempera-
ture for 4 h and neutralized with Dowex®
50W×1 (H+-form, 10 mL). The mixture was
then filtered and the filtrate was concd in
vacuo. The residue was purified by column
chromatography with 40:1 CHCl3–CH3OH,
which afforded 11a (0.65 g, 54%): mp 124–
125 °C (C2H5OH); Rf 0.25; [h]D +9.1° (c 0.77,
CH3OH) and oily 10a (0.26 g, 22%): Rf 0.38.
Anal. Calcd for C11H14O4N2 (11a): C, 55.46;
H, 5.92; N, 11.76. Found: C, 55.41; H, 5.95;
N, 11.72.
C, 57.13; H, 6.39; N, 11.10. Found: C, 57.16;
H, 6.35; N, 11.13.
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1-(2,3-Dideoxy-3-C-methylene-2-methyl-h-
D
-glycero-pentofuranosyl)thymine (11b) and 1-
(2,3-dideoxy-3-C-methylene-2-methyl-i- -glyc
D
ero-pentofuranosyl)thymine (10b).—Prepared
similarly to 11a and 10a, but starting from 9b.
a Anomer 11b: yield 20%; oil; Rf 0.22. b
Anomer 10b: yield 59%; mp 130–131 °C
(C2H5OH); Rf 0.29; [h]D +11.4° (c 0.85,
CH3OH). Anal. Calcd for C12H16O4N2 (10b):
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[8] M. Isobe, Tetrahedron Lett., 23 (1982) 221–223.
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.