Dimetalation of pyrazines. A one-pot synthesis of multisubstituted pyrazine C-nucleosides

Article abstract of DOI:10.1021/jo001555f

As a part of our efforts to pursue direct, convergent, and concise methodologies for the synthesis of pyrazine C-nucleosides, we have successfully established a sequential dilithiation-addition method, which allows one to introduce two different functional groups to a pyrazine ring in a onepot fashion. 2,6-Dichloropyrazine was dilithiated at -100 °C and then allowed to react with an electrophile, such as bromine, iodine, or disulfides, followed by a reaction with a protected ribonolactone to afford C-nucleosides. After reduction and deprotection, tetrasubstituted pyrazine C-nucleosides, including 2,6-dichloro-3-iodo-5-(β-D-ribofuranosyl)pyrazine and 2-bromo-3,5-dichloro-6-(β-D-ribofuranosyl)pyrazine, were obtained. A tandem reaction sequence occurred when disulfides were used, resulting in the formation of 5,6-bis-methylthio-2-chloro-3-(β-D-ribofuranosyl)pyrazine and 6-(β-D-ribofuranosyl)-2,3,5-tris-phenylthiopyrazine.

Full text of DOI:10.1021/jo001555f

J . Org. Chem. 2001, 66, 4783-4786
4783
Dim eta la tion of P yr a zin es. A On e-P ot Syn th esis of
Mu ltisu bstitu ted P yr a zin e C-Nu cleosid es
Weimin Liu,† Dean S. Wise,‡ and Leroy B. Townsend*
Department of Medicinal Chemistry, College of Pharmacy, and Department of Chemistry, College of
Literature, Science, and the Arts, The University of Michigan Ann Arbor, Michigan 48109
ltownsen@umich.edu
Received November 2, 2000
As a part of our efforts to pursue direct, convergent, and concise methodologies for the synthesis
of pyrazine C-nucleosides, we have successfully established a sequential dilithiation-addition
method, which allows one to introduce two different functional groups to a pyrazine ring in a one-
pot fashion. 2,6-Dichloropyrazine was dilithiated at -100 °C and then allowed to react with an
electrophile, such as bromine, iodine, or disulfides, followed by a reaction with a protected
ribonolactone to afford C-nucleosides. After reduction and deprotection, tetrasubstituted pyrazine
C-nucleosides, including 2,6-dichloro-3-iodo-5-(â-D-ribofuranosyl)pyrazine and 2-bromo-3,5-dichloro-
6-(â-D-ribofuranosyl)pyrazine, were obtained. A tandem reaction sequence occurred when disulfides
were used, resulting in the formation of 5,6-bis-methylthio-2-chloro-3-(â-D-ribofuranosyl)pyrazine
and 6-(â-D-ribofuranosyl)-2,3,5-tris-phenylthiopyrazine.
Sch em e 1
In tr od u ction
The reactions between lithiopyrazines and benzyl-
protected ribonolactones have yielded a number of pyra-
zine C-nucleosides.1 As an extension of this study, we
have developed a sequential dilithiation-addition method
to synthesize a number of multisubstituted pyrazine
C-nucleosides. Unlike aliphatic dimetalation which has
been used extensively in organic synthesis,2 dimetalation
of aromatic compounds, especially aromatic heterocycles,
has remained relatively understudied and underutilized,
except in isolated examples.3,4 Although the lithiation of
pyrazines has been studied by several groups,5,6 no
proven dilithiation of this heterocycle has been reported.
in our previous studies. The reaction was quenched with
excess deuterium oxide, and a dideuterated product was
detected by GC-MS. Since excess deuterium oxide would
react with LTMP, the dideuterated pyrazine must have
resulted from a simultaneous dilithiation of 2,6-dichloro-
pyrazine, i.e., the dilithiopyrazine 2. To the best of our
knowledge, this is the first example of a dilithiopyrazine
being formed by direct lithiation on the ring. This result
is contrary to other findings,6 where only monodeuterated
products were obtained.
Resu lts a n d Discu ssion
In our studies, as shown in Scheme 1, 2,6-dichloropy-
razine (1) was treated with 3 equiv of LTMP at -100 °C
for 1 h to give an orange-colored solution, which was
visually distinct from the monolithiopyrazine obtained1
After establishing the conditions for pyrazine dilithia-
tion, we investigated reactions between the corresponding
dilithiopyrazines and a number of electrophiles. The
results are illustrated in Scheme 2. The addition of 2,3,5-
tri-O-benzyl-D-ribono-1,4-lactone (4) to the dilithiated
pyrazine 2 led to the formation of a tetrasubstituted
pyrazine (5a ), which, upon reduction with triethylsilane
in the presence of boron trifluoride diethyl etherate, gave
3,5-bis-(2,3,5-tri-O-benzyl-â-D-ribofuranosyl)-2,6-dichloro-
pyrazine (6a ). The C-2 symmetry of this compound was
† Present address: Boehringer Ingelheim Pharmaceuticals, Inc., P.O.
Box 368, Ridgefield, CT 06877.
‡ Berry and Associates, Inc., 2434 Bishop Circle E, Dexter, MI 48130.
(1) (a) Liu, W.; Walker, J . A., II.; Chen, J . J .; Wise, D. S.; Townsend,
L. B. Tetrahedron Lett. 1996, 37, 5325-5328. (b) Walker, J . A., II.;
Liu, W.; Wise, D. S.; Drach, J . C.; Townsend, L. B. J . Med. Chem. 1998,
41, 1236-1241. (c) Liu, W. Ph.D. Thesis, University of Michigan, Ann
Arbor, Michigan 1997.
1
established by an inspection of the H NMR spectrum,
(2) For reviews, see: (a) Thompson, C. M. Dianion Chemistry in
Organic Synthesis; CRC Press: Boca Raton, 1994. (b) Kaiser, E. M.;
Petty, J . D.; Knutson, P. L. A. Synthesis 1976, 509-555. (c) Stowell,
J . C. Carbanions in Organic Synthesis; J . Wiley & Sons: New York,
1979.
which displayed only one set of peaks representing the
carbohydrate portion.
Next, we investigated the possibility of introducing
sequentially two different electrophiles. Thus, dilithio-
pyrazine 2 was subjected to the sequential treatment of
a variety of electrophiles. In the first reaction sequence,
1 equiv of iodine was added to 2, followed by 1 equiv of
lactone 4 2 h later to provide the hemiketal 5b. Reduction
of this hemiketal was accomplished with triethylsilane
in the presence of boron trifluoride diethyl etherate to
give the protected iodopyrazine C-nucleoside, 2,6-dichloro-
(3) (a) Wilson, W. D.; Tanious, F. A.; Watson, R. A.; Baron, H. J .;
Strekowska, A.; Harden, D. B.; Srekowski, L. Biochemistry 1989, 28,
1984-1992. (b) Feringa, B. L.; Hulst, R.; Rikers, R.; Brandsma, L.
Synthesis 1988, 316-318.
(4) Ple´, N.; Turck, A.; Heynderickx, A.; Que´guiner, G. Tetrahedron
1998, 54, 4899-4912.
(5) Turck, A.; Trohay, D.; Mojovic, L.; Ple´, N.; Que´guiner, G. J .
Organomet. Chem. 1991, 412, 301-310.
(6) Ple´, N.; Turck, A.; Couture, K.; Que´guiner, G. J . Org. Chem.
1995, 60, 3781-3786.
10.1021/jo001555f CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/16/2001

4784 J . Org. Chem., Vol. 66, No. 14, 2001
Liu et al.
1
Sch em e 2
The H NMR spectrum of this compound indicated that
the product contained multiple phenylthio group substi-
tutions. Unfortunately, the aromatic peaks for the O-
benzyl groups on the sugar moiety also appear in the
same region, making it difficult to identify the number
of phenylthio groups on the molecule. This problem was
resolved by removing the benzyl groups on the sugar
moiety. The treatment of 6d with boron trichloride
furnished the free nucleoside 7d as a light yellow
crystalline product. That a complete removal of the
protecting groups had been accomplished was apparent
from the absence of benzylic signals in the 1H NMR
spectrum of the compound. However, the 1H NMR
spectrum of this compound indicated that there were still
three phenyl groups in the aromatic region. This result
suggested that, instead of the expected single phenylthio
group, three phenylthio groups had been introduced onto
the pyrazine ring. The 13C NMR spectrum and elemental
analysis of 6d also supported this structure. Evidently,
compound 5d was a result of a nucleophilic substitution
by phenylthiolithium, the byproduct of the first nucleo-
philic reaction between the pyrazine dianion and phenyl
disulfide. Thus, compound 6d and 7d were identified as
2,3,5-tris-phenylthio-6-(2,3,5-tri-O-benzyl-â-D-ribofurano-
syl)pyrazine and 2,3,5-tris-phenylthio-6-(â-D-ribofurano-
syl)pyrazine, respectively. Because phenyl disulfide is a
very reactive electrophile, it is possible that the pyrazine
dianion may react with two molecules of the disulfide,
especially toward the end of the addition when the
majority of the dianion has been consumed. The dispro-
portionate consumption of pyrazine dianion could gener-
ate excess phenylthiolithium, which, in return, would
serve as a nucleophile. This hypothesis could also explain
the low yield of the nucleoside and the formation of the
less polar byproducts.
3-iodo-5-(2,3,5-tri-O-benzyl-â-D-ribofuranosyl)pyrazine (6b).
In a second reaction, the addition order was reversed,
i.e., lactone 4 was introduced first followed by iodine, and
the same product6b was obtained. Compound 6b was then
debenzylated with boron trichloride in dichloromethane
to furnish 2,6-dichloro-3-iodo-5-(â-D-ribofuranosyl)pyra-
zine (7b).
Attempts to access 5b with N-iodosuccinimide (NIS)
were unsuccessful. Although NIS has been used as an
electrophile in similar reactions, it is not reactive enough
to iodinate the lithiopyrazines. We later found that this
is a general phenomenon among most of the halogenated
succinimides. No halogenation was achieved with N-
bromosuccinimide (NBS) or N-chlorosuccinimide (NCS)
when either was allowed to react with dilithiopyrazine
2. The bromopyrazine C-nucleoside was eventually ob-
tained by reacting dilithiopyrazine 2 with 1 equiv of
bromine followed by the introduction of lactone 4 2 h
later. The tetrasubstituted pyrazine hemiketal (5c) was
isolated and then reduced to give 2-bromo-3,5-dichloro-
6-(2,3,5-tri-O-benzyl-â-D-ribofuranosyl)pyrazine (6c). De-
benzylation of this compound afforded 2-bromo-3,5-
dichloro-6-(â-D-ribofuranosyl)pyrazine (7c).
The secondary nucleophilic substitution which had
occurred in the above reaction presented us a new
prospect for this type of synthesis. To understand the
above reaction sequence better, we chose methyl disulfide
and repeated the above sequence. In this instance the
methyl peak of the methylthio group is very distinct in
1
the H NMR spectra, which would make it easy for us to
follow the reaction. Therefore, dilithiopyrazine 2 was first
treated with 1 equiv of methyl disulfide at -100 °C, and
2 h later with 1 equiv of lactone 4 to afford 5e. Unlike
the reaction of phenyl disulfide, only two peaks repre-
senting methyl groups were detected in the 1H NMR
spectrum of the hemiketal, indicating the presence of only
two methylthio groups in this compound. Reduction of
the hemiketal 5e by triethylsilane and boron trifluoride
diethyl etherate gave 2-chloro-5,6-bis-methylthio-3-(2,3,5-
tri-O-benzyl-â-D-ribofuranosyl)pyrazine (6e). The free
nucleoside, 2-chloro-5,6-bis-methylthio-3-(â-D-ribofura-
nosyl)pyrazine (7e) was obtained by debenzylation of 6e
1
with boron trichloride. The H NMR of 7e confirmed that
In our search for other electrophiles, we found a
literature report7 where 6-lithiouridines were reacted
with phenyl disulfide. We followed this procedure by
treating 2 first with 1 equiv of phenyl disulfide then with
1 equiv of lactone 4. This afforded a complex reaction
mixture from which a sugar adduct (5d ) was isolated in
37% yield. Treatment of this material with triethylsilane
in the presence of boron trifluoride diethyl etherate in
dichloromethane afforded a protected C-nucleoside (6d ).
only two methylthio groups were introduced in this
reaction sequence. The regiochemistry of these two
groups was determined by a NOE experiment on 6e.
When either methyl peak was irradiated, an enhance-
ment was observed on the other methyl peak. This result
established the ortho relationship between the two meth-
yl peaks.
Con clu sion
In conclusion, we have prepared and studied the
chemistry of a dilithopyrazine. This dilithiopyrazine has
(7) Tanaka, H.; Hayakawa, H.; Miyasaka, T. Tetrahedron 1982, 38,
2635-2642.

Dimetalation of Pyrazines
J . Org. Chem., Vol. 66, No. 14, 2001 4785
vacuo. The residue was purified by silica gel flash chromatog-
been successfully used in sequential addition reactions,
allowing two different functional groups to be introduced
onto the pyrazine ring. This reaction sequence provides
an efficient method to access multisubstituted pyrazine
C-nucleosides. When the first nucleophilic substitution
between the dianion and an electrophile releases a
nucleophilic byproduct, a secondary nucleophilic substi-
tution reaction might occur at the pyrazine, thus allowing
up to four new functional groups to be added to the
pyrazine ring.
raphy (4 × 10 cm) and eluted with ethyl acetate/hexane (1:19,
1
Rf ) 0.3) to give 6a as a clear oil (2.09 g 69% yield). H NMR
(CDCl3) δ 7.31-7.15 (m, 30H), 4.97 (d, J ) 6.2 Hz, 2H), 4.72-
4.44 (m, 16H), 4.09 (m, 2H), 3.66 (m, 4H). 13C NMR (CDCl3) δ
150.1, 145.8, 138.2, 137.8, 137.6, 137.3, 128.6, 128.5, 128.5,
128.3, 128.1, 128.0, 128.0, 127.7, 83.0, 80.8, 78.6, 77.8, 73.6,
72.8, 72.5, 70.4. Anal. Calcd for C60H54Cl2N2O8: C, 70.50; H,
5.71; N, 2.94. Found: C, 70.85; H, 6.04; N, 2.84.
2,6-Dich lor o-3-iod o-5-(2,3,5-tr i-O-ben zyl-â-D-r ibofu r a -
n osyl)p yr a zin e (6b). Meth od A: To a solution of n-butyl-
lithium (1.6 M solution in hexane, 10 mL, 16.0 mmol) in 50
mL of dry THF at 0 °C under argon was added 2,2,6,6-
tetramethylpiperidine (2.70 mL, 16.0 mmol). The mixture was
stirred at 0 °C for 30 min at which time the pale yellow solution
was cooled to -100 °C. A solution of 2,6-dichloropyrazine (0.90
g, 6.0 mmol) in 30 mL of dry THF was then added dropwise,
and the mixture was stirred at -100 °C for 1 h to give an
orange-colored solution. Iodine (1.52 g, 6.0 mmol) in 30 mL of
dry THF was added dropwise while the temperature was
maintained at -100 °C for 2 h. 2,3,5-Tri-O-benzyl-D-ribono-
1,4-lactone (2.51 g, 6.0 mmol) was dissolved in 30 mL of dry
THF and then transferred dropwise into the lithiopyrazine
solution at -100 °C. The mixture was stirred at -100 °C under
argon for 3 h and then warmed to room temperature and
stirred for 10 h. The reaction was quenched by the addition of
a saturated ammonium chloride solution (30 mL). The reaction
mixture was extracted with diethyl ether (3 × 50 mL), and
the combined extracts were dried over magnesium sulfate.
After filtration, the solvent was removed in vacuo, and the
resultant orange oil was purified by silica gel flash chroma-
tography (4 × 10 cm) and eluted with ethyl acetate/hexane
(1:5, Rf ) 0.45) to give 5b as a clear oil (3.05 g, 73% yield).
This oil was dissolved in 60 mL of dry dichloromethane. To
this solution at -78 °C, under argon, were added boron
trifluoride diethyl etherate (3.60 mL, 30.0 mmol) and triethyl-
silane (4.60 mL, 20.0 mmol). The mixture was allowed to stand
at 0 °C for 24 h, quenched with a saturated sodium bicarbonate
solution, and extracted with diethyl ether (3 × 40 mL). The
combined extracts were dried over sodium sulfate, filtered, and
evaporated in vacuo. The residue was purified by silica gel
flash chromatography (4 × 8 cm) and eluted with ethyl acetate/
hexane (1:9, Rf ) 0.3) to give 6b as a clear oil (2.40 g, 79%
Exp er im en ta l Section
Gen er a l Meth od s. Unless otherwise noted, materials were
obtained from commercial suppliers and were used as pro-
vided. Acetonitrile (calcium hydride), dichloromethane (phos-
phorus pentoxide), dimethylformamide (calcium oxide), nitro-
methane (phosphorus pentoxide), and tetrahydrofuran (sodium/
benzophenone) were distilled from the indicated drying agent
and stored over activated 4 Å molecular sieves under a positive
pressure of argon prior to use (if not used immediately). The
phrase “evaporated in vacuo” describes the use of a rotary
evaporator with a bath temperature not exceeding 40 °C using
a water aspirator. Thin-layer chromatography (TLC) was
carried out on Analtech 60F-254 silica gel plates, and detection
of components on TLC was made by UV light absorption at
254 nm, 365 nm, staining with iodine vapor, or heating to a
char following treatment with 10% sulfuric acid in methanol.
Solvent systems are expressed as a ratio of the more polar
component with respect to total volumes (v/v%). Mallinckrodt
SilicAR 230-400 mesh (40-63 µm) was used for chromatog-
raphy. Melting points are uncorrected. The 1H (300, 360, or
500 MHz) and 13C (67.5, 90, or 125 MHz) NMR spectra were
recorded, and the chemical shift values are expressed in δ
values (parts per million) relative to tetramethylsilane as an
internal standard for 1H NMR, and relative to the standard
chemical shift of the solvent for 13C NMR. Mass spectroscopy
and elemental analyses were performed by the University of
Michigan Chemistry Department or by MHW Laboratories,
Phoenix, AZ.
3,5-Bis(2,3,5-t r i-O-b e n zyl-â-D-r ib ofu r a n osyl)-2,6-d i-
ch lor op yr a zin e (6a ). To a solution of n-butyllithium (1.6 M
solution in hexane, 7.5 mL, 12.0 mmol) in 40 mL of dry THF
at 0 °C under argon was added 2,2,6,6-tetramethylpiperidine
(2.0 mL, 12.0 mmol). The reaction mixture was stirred at 0 °C
for 30 min at which time the pale yellow solution was cooled
to -78 °C. A solution of 2,6-dichloropyrazine8 (0.75 g, 5.0
mmol) in 30 mL of dry THF was then added dropwise, and
the reaction mixture was stirred at -78 °C for 1 h to give an
orange-colored solution. 2,3,5-Tri-O-benzyl-D-ribono-1,4-lactone
(4.18 g, 10.0 mmol) was dissolved in 40 mL of dry THF and
then transferred dropwise into the lithiopyrazine solution at
-78 °C. The mixture was stirred at -78 °C for 3 h, and the
reaction was then warmed to room temperature and stirred
for an additional 10 h. The reaction mixture was quenched by
the addition of a saturated ammonium chloride solution and
then extracted with diethyl ether (3 × 30 mL). The combined
extracts were dried over magnesium sulfate, and after filtra-
tion, the solvent was removed in vacuo. The resultant orange
oil was purified by silica gel flash chromatography (5 × 18
cm) and eluted with ethyl acetate/hexane (1:4, Rf ) 0.4) to give
5a as a clear oil (3.16 g, 64% yield). This oil was then dissolved
in 60 mL of dry dichloromethane. Boron triflouride diethyl
etherate (1.20 mL, 9.0 mmol) and triethylsilane (1.44 mL, 9.0
mmol) were added to this solution at -78 °C, under argon.
The mixture was allowed to stand at 5 °C for 5 days, quenched
with a saturated sodium bicarbonate solution, and extracted
with diethyl ether (3 × 30 mL). The combined organic extracts
were dried over sodium sulfate, filtered, and evaporated in
1
yield). H NMR (CDCl3) δ 7.29 (m, 15H), 5.34(d, 1H, J ) 6.0
Hz), 4.69-4.38 (m, 6H), 4.37 (ABq, J ) 4.5 Hz, 1H), 4.32 (dd,
J ) 5.8 Hz, 1H), 4.11 (dd, J ) 4.8 Hz, 1H), 3.56 (d, J ) 4.6 Hz,
2H). 13C NMR (CDCl3) δ 152.0, 150.8, 146.8, 138.3, 137.7,
128.7, 128.6, 128.6, 128.4, 128.1, 127.9, 127.8, 115.4, 83.1, 80.9,
78.8, 77.9, 73.7, 72.9, 72.6, 70.5. Anal. Calcd for C30H27Cl2-
IN2O4: C, 53.20; H, 4.02; N, 4.14. Found: C, 53.46; H, 4.15;
N, 4.11.
Meth od B: The dilithiopyrazine was prepared as in method
A. 2,3,5-Tri-O-benzyl-D-ribono-1,4-lactone was dissolved in 30
mL of dry THF and then transferred dropwise into the
dilithiopyrazine solution at -100 °C. The reaction mixture was
stirred at -100 °C for 1.5 h, and then the iodine solution was
added. The reaction was worked up as described in method A
to give the intermediate 5b in 74% yield.
3,5-Dich lor o-2-iod o-6-(â-D-r ibofu r a n osyl)p yr a zin e (7b).
Compound 6b (2.40 g, 3.54 mmol) was dissolved in 30 mL of
dry dichloromethane. At -78 °C, under argon, boron trichloride
(1.0 M, 20 mL, 20 mmol) was added. The reaction mixture was
kept at 0 °C for 10 h and then quenched with 5 mL of water
and 0.5 g of sodium bicarbonate. The solvent was removed in
vacuo, and the residue was purified by silica gel flash chro-
matography (4 × 7 cm) and eluted with methanol/dichloro-
methane (1:19, Rf ) 0.2) to give 7b as a white crystalline
product (1.20 g, 83% yield). mp 154-155 °C. 1H NMR (acetone-
d6) δ 5.24 (d, J ) 3.8 Hz, 1H), 4.44 (dd, J ) 3.1 Hz, 1H), 4.29
(dd, J ) 3.90 Hz, 1H), 4.06-4.11 (m, 1H), 3.75-3.85 (m, 1H),
3.62-3.65 (m, 1H). 13C NMR (acetone-d6) δ 152.8, 151.6, 145.8,
115.8, 85.6, 81.3, 76.0, 71.4, 62.0. Anal. Calcd for C9H9Cl2-
IN2O4: C, 26.56; H, 2.23; N, 6.88. Found: C, 26.34; H, 2.26;
N, 6.80.
(8) Purchased from Pyrazine Specialties, Inc. or prepared from
chloropyrazine as described: Cheeseman, G. W. H.; To¨rzs, E. S. G.
Pyrazines. J . Chem. Soc. (C) 1965, 6681-6688.

4786 J . Org. Chem., Vol. 66, No. 14, 2001
Liu et al.
2-Br om o-3,5-dich lor o-6-(2,3,5-tr i-O-ben zyl-â-D-r ibofu r a-
n osyl)p yr a zin e (6c). This was prepared following a similar
procedure described in method A. 1H NMR (CDCl3) δ 7.15-
7.37 (m, 15H), 5.37 (d, J ) 6.2 Hz, 1H), 4.69-4.32 (m, 9H),
4.12 (dd, J ) 4.6 Hz, 1H), 3.57 (d, J ) 4.6 Hz, 2H). 13C NMR
(CDCl3) δ 150.1, 145.8, 138.2, 137.8, 137.6, 137.3, 128.6, 128.5,
128.5, 128.3, 128.1, 128.0, 128.0, 127.7, 83.0, 80.8, 78.6, 77.7,
73.6, 72.8, 72.5, 70.4. Anal. Calcd for C30H27BrCl2N2O4: C,
57.16; H, 4.12; N, 4.44. Found: C, 57.42; H, 4.54; N, 4.47.
2-Br om o-3,5-dich lor o-6-(â-D-r ibofu r an osyl)pyr azin e (7c).
This was prepared following a similar procedure described in
(DMSO-d6) δ 151.7, 149.7, 148.4, 147.5, 134.2, 134.1, 133.5,
129.6, 129.5, 129.4, 129.3, 129.1, 128.5, 127.5, 85.1, 80.4, 73.9,
71.8, 62.3. HRMS calcd for C27H24N2O4S3: 536.0898. Found
536.0897.
2-Ch lor o-3,5-b is-m et h ylt h io-6-(2,3,5-t r i-O-b en zyl-â-D-
r ibofu r a n osyl)p yr a zin e (6e). To a solution of n-butyllithium
(1.6 M solution in hexane 13.0 mL, 20.8 mmol) in 100 mL of
dry THF at 0 °C under argon was added 2,2,6,6-tetramethyl-
piperidine (3.40 mL, 20.0 mmol). The mixture was stirred at
0 °C for 30 min at which time the pale yellow solution was
cooled to -100 °C. A solution of 2,6-dichloropyrazine (1.50 g,
10.0 mmol) in 30 mL of dry THF was then added dropwise,
and the mixture was stirred at -100 °C for 1 h to give an
orange-colored solution. Methyl disulfide (0.90 mL, 10.0 mmol)
was added, and the reaction mixture was kept at -100 °C for
2 h. 2,3,5-Tri-O-benzyl-D-ribono-1,4-lactone (4.18 g, 10.0 mmol)
was dissolved in 50 mL of dry THF and then transferred
dropwise into the lithiopyrazine solution at -100 °C. The
mixture was stirred at -100 °C under argon for 3 h and then
warmed to room temperature and stirred for 10 h. The reaction
was quenched by the addition of a saturated ammonium
chloride solution. The reaction mixture was extracted with
diethyl ether (3 × 50 mL), and the combined extracts were
dried over magnesium sulfate. After filtration, the solvent was
removed in vacuo and the resultant yellow oil was purified by
silica gel flash chromatography (5 × 12 cm) and eluted with
ethyl acetate/hexane (1:5, Rf ) 0.5) to give 5e as a clear oil
(4.25 g, 68% yield). This oil was then dissolved in 60 mL of
dry dichloromethane. To this solution at -78 °C, under argon,
were added boron trifluoride diethyl etherate (5.0 mL, 50.2
mmol) and triethylsilane (10.0 mL, 40.0 mmol). The mixture
was allowed to stand at 5 °C for 72 h, quenched with a
saturated sodium bicarbonate solution, and extracted with
diethyl ether (3 × 50 mL). The combined extracts were dried
over magnesium sulfate, filtered, and evaporated in vacuo. The
residue was purified by silica gel flash chromatography (4 ×
10 cm) and eluted with ethyl acetate/hexane (1:19, Rf ) 0.5)
to give 6e as a crystalline solid (2.68 g, 65% yield). mp 78-79
°C. 1H NMR (CDCl3) δ 7.34-7.21 (m, 15H), 5.51(d, 1H, J )
4.8 Hz), 4.70-4.51 (m, 6H), 4.44-4.41 (m, 1H), 4.33-4.31 (m,
1H), 4.24-4.21 (m, 1H), 3.60-3.65 (m, 2H), 2.60 (s, 3H), 2.12
(s, 3H). 13C NMR (CDCl3) δ 154.5, 452.9, 143.7, 142.9, 138.5,
138.2, 138.0, 128.9, 128.7, 128.4, 128.3, 128.3, 128.1, 128.0,
81.9, 80.3, 79.9, 77.9, 77.9, 73.9, 73.5, 72.4, 70.6, 13.9, 13.6.
Anal. Calcd for C32H33N2O4S2: C, 63.09; H, 5.46; N, 4.60.
Found: C, 62.89; H, 5.36; N, 4.71.
1
7b. H NMR (DMSO-d6) δ 5.26 (d, J ) 4.8 Hz, 1H), 5.05 (dd,
J ) 5.9 Hz, 2H), 4.59 (dd, J ) 5.0 Hz, 1H), 4.21 (ddd, J ) 4.8
Hz, 1H), 3.94 (ddd, J ) 5.5 Hz, 1H), 3.88 (ddd, J ) 5.3 Hz,
1H), 3.40-3.58 (m, 2H). 13C NMR (DMSO-d6) δ 151.3, 146.1,
144.4, 136.9, 85.1, 80.2, 74.5, 71.1, 61.9. Anal. Calcd for C9H9-
BrCl2N2O4: C, 30.03; H, 2.52; N, 7.78. Found: C, 30.19; H,2.29;
N,7.58.
2,3,5-Tr is-p h en ylth io-6-(2,3,5-tr i-O-ben zyl-â-D-r ibofu r a -
n osyl)p yr a zin e (6d ). To a solution of n-butyllithium (1.6 M
solution in hexane, 4.5 mL, 7.2 mmol) in 40 mL of dry THF at
0 °C under argon was added 2,2,6,6-tetramethylpiperidine (1.2
mL, 7.2 mmol). The mixture was stirred at 0 °C for 30 min at
which time the pale yellow solution was cooled to -100 °C. A
solution of 2,6-dichloropyrazine (0.45 g, 3.0 mmol) in 30 mL
of dry THF was then added dropwise, and the mixture was
stirred at -100 °C for 1 h to give an orange colored solution.
Phenyl disulfide (0.655 g, 3.0 mmol) was added, and then the
reaction mixture was kept at -100 °C for 2 h. 2,3,5-Tri-O-
benzyl-D-ribono-1,4-lactone (1.26 g, 3.0 mmol) was dissolved
in 30 mL of dry THF and then transferred dropwise into the
lithiopyrazine solution at -100 °C. The mixture was stirred
at -100 °C under argon for 3 h and then warmed to room
temperature and stirred for an additional 10 h. The reaction
was quenched by the addition of a saturated ammonium
chloride solution. The reaction mixture was extracted with
diethyl ether (3 × 30 mL), and the combined organic phase
was dried over magnesium sulfate. After filtration, the solvent
was removed in vacuo, and the resultant yellow oil was
purified by silica gel flash chromatography (4 × 8 cm) and
eluted with ethyl acetate/hexane (1:6, Rf ) 0.4) to give 5d as
a clear oil (0.424 g, 35% yield). This oil was then dissolved in
60 mL of dry dichloromethane. To this solution at -78 °C,
under argon, were added boron trifluoride diethyl etherate
(1.90 mL, 15.8 mmol) and triethylsilane (2.00 mL, 8.70 mmol).
The mixture was allowed to stand at 5 °C for 72 h, quenched
with a saturated sodium bicarbonate solution, and extracted
with diethyl ether (3 × 30 mL). The combined extracts were
dried over magnesium sulfate, filtered, and evaporated in
vacuo. The residue was purified by silica gel flash chromatog-
raphy (2 × 10 cm) and eluted with ethyl acetate/hexane (1:19,
Rf ) 0.5) to give 6d as an oil (0.351 g, 84% yield). 1H NMR
(CDCl3) δ 7.41-7.10 (m, 30H), 5.40 (d, J ) 4.8 Hz, 1H), 4.50-
4.25 (m, 7H), 4.04 (dd, J ) 4.8 Hz, 1H), 3.68 (dd, J ) 5.7 Hz,
1H), 3.32-3.25 (m, 2H). 13C NMR (CDCl3) δ 152.9, 150.6, 149.2,
146.2, 138.6, 138.3, 138.2, 135.6, 135.2, 134.7, 130.2, 129.4,
129.3, 129.2, 129.1, 129.1, 128.6, 128.5, 128.4, 128.0, 127.9,
127.8, 81.5, 80.2, 79.8, 78.9, 77.6, 73.4, 72.2, 70.9. Anal. Calcd
for C48H42N2O4S3: C, 71.43; H, 5.25; N, 3.47. Found: C, 71.18;
H, 5.35; N, 3.33.
2-Ch lor o-5,6-bis-m eth ylth io-3-(â-D-r ibofu r a n osyl)p yr a -
zin e (7e). This was prepared following a similar procedure
1
described in 7b. H NMR (CDCl3) δ 5.37 (d, J ) 5.7 Hz, 1H),
4.57 (m, J ) 5.7 Hz, 1H), 4.44 (m, J ) 4.6 Hz, 1H), 4.21 (m,
1H), 3.92 (m, J ) 12.0, 2.7 Hz, 1H), 3.74 (ddd, J ) 11.8, 10.2,
2.0 Hz, 1H), 2.83 (dd. J ) 7.4, 2.6 Hz, 1H), 2.60 (s, 3H). 2.58
(s, 3H), 2.53 (m, 2H). 13C NMR (acetone-d6) δ 154.5, 153.5,
145.6, 143.3, 86.2, 81.8, 76.3, 73.3, 63.2, 13.5, 13.4. Anal. Calcd
for C11H15ClN2O4S2: C, 38.99; H, 4.46; N, 8.27. Found: C,
38.75; H, 4.36; N, 8.12.
Ack n ow led gm en t. The authors would like to thank
Mr. J ack Hinkley for the large-scale preparation of
compounds and Ms. Kimberly Barrett for assistance in
the preparation of this manuscript. This research was
supported by research grant 5-R01-AI-36872 from the
National Institute of Allergy and Infectious Diseases,
the National Institutes of Health.
2,3,5-Tr is-ph en ylth io-6-(â-D-r ibofu r an osyl)pyr azin e (7d).
This was prepared following a similar procedure described in
7b. 1H NMR (DMSO-d6) δ 7.56-7.21 (m, 15H), 4.96 (d, J )
5.2 Hz, 2H), 4.75 (d, J ) 5.7 Hz, 1H), 4.46 (dd, J ) 5.7 Hz,
1H), 3.95 (ddd, J ) 5.0 Hz, 1H), 3.67 (ddd, J ) 5.1 Hz, 1H),
3.55 (ddd, J ) 5.5 Hz, 1H), 3.00-3.21 (m, 2H). 13C NMR
J O001555F