An access to the β-anomer of 4′-thio-C-ribonucleosides: Hydroboration of 1-C-aryl- or 1-C-heteroaryl-4-thiofuranoid glycals and its regiochemical outcome

Article abstract of DOI:10.1021/jo201100n

We have developed a novel method for the synthesis of the β-anomer of 4′-thio-C-ribonucleosides from 3,5-O-(di-tert-butylsilylene)-4- thiofuranoid glycal. Palladium-catalyzed coupling of 1-tributylstannyl-4- thiofuranoid glycal with iodobenzene or a heter

Full text of DOI:10.1021/jo201100n

ARTICLE
pubs.acs.org/joc
An Access to the β-Anomer of 40-Thio-C-ribonucleosides:
Hydroboration of 1-C-Aryl- or 1-C-Heteroaryl-4-thiofuranoid
Glycals and Its Regiochemical Outcome
Kazuhiro Haraguchi,*,^ Chikafumi Horii,^ Yuichi Yoshimura,ξ Fumiko Ariga,^ Aya Tadokoro,^ and
Hiromichi Tanaka^
^School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
ξTohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
S Supporting Information
b
ABSTRACT: We have developed a novel method for the
synthesis of the β-anomer of 40-thio-C-ribonucleosides from
3,5-O-(di-tert-butylsilylene)-4-thiofuranoid glycal. Palladium-
catalyzed coupling of 1-tributylstannyl-4-thiofuranoid glycal
with iodobenzene or a heteroaryl halide gave 1-C-phenyl- or
1-C-heteroaryl-glycals. Hydroboration of these glycals pro-
ceeded at the α-face, and subsequent alkaline hydrogen per-
oxide treatment of the resulting 20-α-borane furnished the
respective β-anomer of 40-thio-C-ribonucleosides. These results demonstrate that this synthetic method has a wider scope in
terms of heterocyclic base structure. During this study, unexpected Markovnikov-oriented hydroboration has been observed to lead
to the respective 10-α-boranes. These 10-boranes were converted into either the ring-opened structure or the 20-deoxy derivatives
depending upon their stability.
’ INTRODUCTION
starting material in the present study. After converting 5 into the
1-tributylstannyl derivative 6, various types of aryl or heteroaryl
groups can be introduced through Stille coupling to give A.12 In
our previous study on electrophilic glycosidation using 5 and
NIS (or PhSeCl),9b a highly stereoselective formation of the
β-anomer was observed as a result of the presence of the 3,5-O-
DTBS (di-tert-butylsilylene) protecting group, which results in
NIS approaching from the α-face of 4-thiofuranoid glycal.13
Therefore, it might be reasonable to expect that hydroboration
of A would take place from its α-face to ensure β-glycosidic
stereochemistry in the product B. The depicted regiochemistry
of B can be anticipated from the reported hydroboration of 1-C-
aryl-furanoid glycals.14 Finally, treatment of B with alkaline
hydrogen peroxide should furnish the desired 40-thio-C-ribonu-
cleosides C.
Preparation of 1-C-Aryl (or Heteroaryl)-4-thiofuranoid
Glycals. Because our previously reported method for the synth-
esis of 5 has involved utilization of 2-deoxy-D-ribose, an expen-
sive starting material, and toxic mercuric acetate,9b a novel
method shown in Scheme 2 was developed. Thus, the synthetic
route utilized the cheaper starting material D-ribose, which was
then converted to 1,4-anhydro-4-thio-D-ribitol 7 utilizing non-
toxic reagents.15 Deprotection of the isopropylidene group of 7
with 80% AcOH and subsequent protection of the resulting triol
with the DTBS group gave 8 in 68% for 2 steps. Mesylation of
8 gave 9 in 98% yield. Finally, elimination of MsOH from 9 was
A class of compounds called “C-nucleosides” feature the
ribofuranosyl moiety linked to a heterocyclic base through a
carbonꢀcarbon bond.1 Besides naturally occurring C-nucleoside
antibiotics,1,2 several biologically active synthetic C-nucleosides
are well-known. One example is tiazofurin (1, Figure 1),3 which is
metabolically converted to a NAD mimic and consequently
strongly inhibits IMP-dehydrogenase.4 An additional example,
9-deazaadenosine (2),5 is highly cytotoxic against several lines of
murine and human tumor cells.6
In the meantime, it has been reported that simple replacement
of the furanose ring oxygen with a sulfur atom confers potent
antiviral and antitumor activities on naturally occurring nucleo-
sides, for example, 40-thiothymidine (3) and 20-deoxy-40-thiocy-
tidine (4) shown in Figure 2.7 Although this finding stimulated
the synthesis of thionucleosides of various types,8,9 only one
precedent10 is available so far for 40-thio-analogues of C-nucleo-
sides, wherein highly reactive five-membered heterocyclic bases
such as furan and thiophene derivatives were condensed with
1-O-acetyl-2,3,5-tri-O-benzyl-4-thio-D-ribofuranose.11 In this
context, we intended to develop a synthetic method for 40-
thio-C-ribonucleosides with a wider scope in terms of hetero-
cyclic base structure.
’ RESULTS AND DISCUSSION
Our synthetic plan is shown in Scheme 1. 3,5-O-(Di-tert-
butylsilylene)-4-thiofuranoid glycal 5, previously used for our
synthesis of 20-deoxy-40-thionucleosides,9b was selected as the
Received: May 28, 2011
Published: October 04, 2011
r
2011 American Chemical Society
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carried out by treatment with DBN in DMF at 150 ꢀC for 30 min
to furnish 5 in 56% yield.
1-C-pyridinyl-4-thiofuranoid glycals (13) could be obtained
(Figure 3).
Stannylation at the C-1 of 5 was performed by lithiation of 5
with BuLi and subsequent treatment of the resulting 1-lithiated
species with Bu3SnCl, giving 6 in 84% yield (Scheme 3).16 When
6 was reacted with iodobenzene in the presence of (Ph3P)4Pd
(10 mol %) and CuI (20 mol %) in THF under reflux con-
ditions, the desired cross-coupling product 1-C-phenyl-glycal
(10) could be obtained in 81% yield. Under the identical reac-
tion conditions, 1-C-naphthyl- (11) (88%), 1-C-quinolyl- (12), and
With the above result in mind, 5-iodoracil, which is the base
moiety of pseudouridine, was reacted with 6 under the above
reaction conditions (Figure 4). Unexpectedly, the coupling re-
action failed to give the desired 14, and instead 6 was recov-
ered. Although we have no reasonable explanation for the re-
sult at the moment, 5-iodo-2,4-dimethoxypyrimidine was next
reacted with 6. In contrast to the above result, the dimethoxy-
pyrimidine derivative successfully underwent coupling reaction
to give the desired 15 in 88% yield. Next, coupling with 2,4-
dibromothiazole17 was examined. Although 2,4-dibromothiazole
has two possible reaction sites, regioselective coupling at C-2
proceeded to give 1-C-(4-bromothiazol-2-yl)-4-thiofuranoid gly-
cal 16 in 48% yield.18
For the synthesis of 22, a precursor for 40-thio-9-deazaadeno-
sine, 7-iodinated 4-pivaloylamino-3H,5H-pyrrolo[3,2-d]pyrimidine
21, was prepared from 1719 (Scheme 4). Thus, 17 was chlorinated
with POCl3 to give 18 in 80% yield. The 4-chloro derivative 18
was subjected to ammonolysis to give 19 in 78% yield. After
protection of the amino group of 19 with the pivaloyl group (80%
isolated yield), the resulting 20 was iodinated by reaction with
N-iodosuccinmide (NIS) in DMF at 80 ꢀC to furnish 21 in 80%
yield. When 21 was reacted with 6 under the conditions
described for the synthesis of 10, the expected coupling reaction
proceeded to furnish 22 in 52% yield.
Figure 1. Synthetic C-nucleosides tiazofurine 1 and 9-deazaadenosine 2.
Hydroboration of 1-C-Phenyl- and 1-C-Heteroaryl-4-thio-
furanoid Glycal: Synthesis of β-Anomer of 40-Thio-C-nucleo-
sides. When 1-C-phenyl-4-thiofuranoid glycal 10 was reacted with
BH3 THF (5 equiv) in THF at 0 ꢀC for 18 h, the expected
3
hydroboration reaction proceeded to give an alkylborane 23
(Scheme 5).20 To elucidate the structure of 23, the reaction
Figure 2. 40-Thiothymidine 3 and 20-deoxy-40-thiocytidine 4.
Scheme 1. Synthetic Plan for 40-Thio-C-ribonucleoside C from 4-Thiofuranoid Glycal 5
Scheme 2. Preparation of 4-Thiofuranoid Glycal 5
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Scheme 3. Preparation of 1-C-Phenyl-4-thiofutanoid Glycal 10 by Stille Coupling of 1-Tributylstannyl Glycal 6 with PhI
pinacol to provide 33 and 34 in 26% and 17% yield, respec-
tively (Figure 6). The 10-boronic acid pinacol ester 34 is de-
rived from unusual Markovnikov-oriented hydroboration. On
the basis of the formation of 34, we postulated the mechanism
for the formation of 32 in Scheme 8. Thus, the initially formed
10-organoborane 35 is oxidized into 36 by treatment with alkaline
hydrogen peroxide. The hemithioacetal 36 was then transformed
into δ-ketothiol 37, and reduction of the keto groupꢀoxidation
of the thiol group furnished dimeric 38, which was isolated as the
acetate 32. The unexpected regiochemical outcome of the
hydroboration of 15 could be explained by coordination of
Figure 3. 1-C-Aryl- and 1-C-hereroaryl-4-thiofuranoid glycals 11ꢀ13.
BH3 to the oxygen atom of the methoxy group at the 2-position,
which is visualized as the transition state 39 (Figure 7). The
resulting 10-borane 40 might be stabilized by a five-membered
mixture was quenched with acetone pinacol. After chromatographic
coordination structure.
purification of the reaction mixture, the boronic acid pinacol
ester 24 was isolated in 25% yield as a single stereoisomer. The
A similar directing effect exerted by the heterocyclic base was
observed in the hydroboration of 16. Thus, 16 gave the target 40-
depicted stereochemistry of 24 was determined on the basis of
thiotiazofurin derivative 41 in 27% along with an anomeric
NOE experiments [H-10/H-40 (2.3%), H-20/ H-Ph (1.9%) and
mixture of 20-deoxy counterparts (42a and 42b, ratio of 1/1)
H-30/ H-Ph (1.4%)].21 When the reaction solution was treated
in 33% yield (Figure 8).
with 30% H2O2/1 M NaOH, a mixture of the desired 10-C-
As for the case of the hydroboration of 15, 10-organoborane 43
phenyl-40-thioribonucleoside derivative 25 and its partially desi-
would form from 16 (Scheme 9). In contrast to the case of 40, 43
lylated product was obtained. The crude products were treated
would not be stabilized by cyclic coordination with base moiety
with Bu4NF and then Ac2O in one pot to provide the tri-O-acetate
due to its unfavorable four-membered structure. Therefore, the
26 (90% from 10). The hydroboration reaction was found to be
borane 43 would release H2Bꢀ to give thionium ion 44, which is
successfully applicable to glycal 11ꢀ13 to provide the respective
then transformed into 42a,b by hydride reduction.
40-thio-C-nucleosides 27-29 (Figure 5). The depicted structures
1-(2,4-Dimethoxypyrimidine-5-yl)-40-thio-C-ribonucleoside
of 27ꢀ29 were determined on the basis of NOE experiment as
31 could be successfully transformed to 40-thiopseudouridine 47
(Scheme 10). Thus, 31 was converted to tri-O-acetate 45, which
was then subjected to de-O-methylation by treatment with HI to
give 46.22 Deprotection of 46 with NH3/MeOH furnished 47 in
75% yield.
shown in Figure 5.
With the above result in mind, the glycal 22 was then subjected
to hydroboration under the same conditions as used for 10
(Scheme 6), and the expected 40-thio-9-deazaadenosine deriva-
tive 30 was obtained in 40% isolated yield as a single stereoisomer
along with recovered 22 (19%). The depicted stereochemistry
of 30 was determined on the basis of NOE experiments: H-10/
H-40 (2.0%), H-6/H-20 (0.6%), H-6/H-30 (1.9%), HO-20/H-40
(3.1%).
Finally, 20-O-triethylsilylated 1-(3-bromothiazol-2-yl)-40-thio-
C-ribonucleoside 48 obtained from 41 was converted into the
corresponding thiazole 4-carboxylic acid ethyl ester 49 by
halogenꢀlithium exchange reaction and subsequent treatment
of the resulting C4-lithio derivative with ClCO2Et. Ester 49 can
be transformed into 40-thiotiazofurin 50 using a published
procedure (Scheme 11).23
In contrast to these results, the hydroboration/oxidation of 15
gave two kinds of products after acetylation of the reaction
mixture (Scheme 7). The less polar compound was the desired
31 (isolated yield: 41%). NOE experiments revealed that 31 was
the depicted β-D-ribofuranosyl C-glycoside; H-10/H-40 (2.2%),
H-6/H-20 (2.9%) and H-6/H-30 (3.5%). On the other hand, the
more polar product was found unexpectedly to be dimer of ring-
opened furanose 32, which was isolated as an epimeric mixture
(major isomer/minor isomer = 5.5/1) in 16% isolated yield. A
HMBC spectrum showed correlations as follows: H-6/C-1 and
H-1/C(dO)CH3. Additional supporting data are molecular ion
peak 943 (M+ + H), fragment ion peaks 883 (M+ ꢀ OAc) and
824 (M+ ꢀ 2OAc) observed in the MS spectrum.
In conclusion, we have developed a novel method for the
synthesis of the β-anomer of 40-thio-C-ribonucleosides from 3,5-
O-(di-tert-butylsilylene)-4-thiofuranoid glycal 5. Pd-catalyzed
coupling of 1-tributylstannyl-4-thiofuranoid glycal 6 with aryl
halides or heteroaryl halides gave 1-C-aryl- 10 and 11 or 1-C-
heteroaryl-glycals 11ꢀ13, 15, and 16. Hydroboration of these
glycals proceeded at the α-face, and subsequent alkaline hydro-
gen peroxide treatment of the resulting 20-α-borane furnished
the respective β-anomer of 40-thio-C-ribonucleosides 26ꢀ31
and 41. These results demonstrate that this synthetic method has
a wider scope in terms of the heterocyclic base structure. During
this study, unexpected Markovnikov-oriented hydroboration has
To clarify the mechanism for the formation of 32, the inter-
mediate organoboranes in the reaction were trapped with acetone
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Figure 4. Structures of 1-C-hereroaryl-4-thiofuranoid glycals 14ꢀ16.
was stirred for 15 min. To the reaction mixture was added Bu3SnCl
(1.4 mL, 5.28 mL), and the mixture was stirred 15 min. The reaction
mixture was partitioned between CHCl3/saturated aqueous NH4Cl, and
silica gel column chromatography (hexane/AcOEt = 100/1) of the
organic layer gave 6 (1.49 g, 84%) as a syrup: UV (MeOH) λshoulder
262 nm (ε 1600), λmax 251 nm (ε 2000) and λmin 233 nm (ε 960); 1H
NMR (CDCl3) δ 0.88ꢀ1.07 (27H, m), 1.03 and 1.06 (18H, each as s),
Scheme 4. Preparation of 21 and Subsequent Coupling
Leading to 22
3.73 (1H, ddd, J3,4 = 12.4, J4,5a = 11.2, J4,5b = 5.1 Hz), 4.26 (1H, dd, J4,5a
=
11.2 and J5a,5b = 9.9 Hz), 4.32 (1H, dd, J4,5b = 5.1 and J5a,5b = 9.9 Hz),
5.09 (1H, dd, J2,3 = 1.7 and J3,4 = 12.4 Hz), 5.92 (1H, d, J2,3 = 1.7 Hz);
13C NMR (CDCl3) δ 10.1, 13.6, 13.7, 17.5, 20.0, 22.7, 27.2, 27.3, 27.51,
28.9, 55.9, 67.9, 87.4, 136.4, 138.7; FAB-MS (m/z) 561 (M+ + H). Anal.
Calcd for C25H50O2SSiSn: C, 53.47; H, 8.98. Found: C, 53.54; H, 9.28.
3,5-O-(Di-tert-butylsilylene)-1,4-anhydro-4-thio-D-ribitol
(8). An 80% AcOH (25 mL) solution of 7 (1.04 g, 5.47 mmol) was
stirred at 70 ꢀC for 8 h. The reaction mixture was evaporated to dryness
and coevaporated with toluene. The crude product was treated with
saturated methanolic ammonia (50 mL) at rt 10 h. The reaction mixture
was evaporated to dryness, and silica gel column chromatography (4%
MeOH in CH2Cl2) of the crude product gave the triol (821.6 mg, 100%)
as a syrup. To a DMF (20 mL) solution of the triol were added imidazole
(1.12 g, 16.41 mmol) and di-tert-butylsilyl bis-trifluoromethanesulfonate
(2.2 mL, 6.02 mmmol) at 0 ꢀC under Ar atmosphere, and the mixture
was stirred at rt for 16 h. The reaction mixture was partitioned between
AcOEt/H2O, and silica gel column chromatograpy (hexane/AcOEt = 10/1)
of the organic layer gave 8 (1.14 g, 68%) as a solid: mp 110ꢀ112 ꢀC; 1H
NMR (CDCl3) δ 1.03 and 1.06 (18H, each as s, t-Bu), 2.34 (1H, s, OH),
been observed to lead to the respective 10-α-boranes. These 10-
boranes were converted into ring-opened furanose 32 or 20-deoxyri-
bofuranosyl derivatives 42a,b, depending upon their stability.
’ EXPERIMENTAL SECTION
2.90 (1H, d, J1a,1b = 12.0 Hz), 3.08 (1H, ddd, J = 1.2, J1b,2 = 5.4 and J1a,1b
=
Melting points are uncorrected. 1H and 13C NMR spectra were
recorded either at 400 or 500 MHz. Chemical shifts are reported relative
to Me4Si. Mass spectra (MS) were taken in FAB mode with m-
nitrobenzyl alcohol as a matrix. Column chromatography was carried
out on silica gel. Thin-layer chromatography (TLC) was performed on
silica gel. When necessary, analytical samples were purified by high
performance liquid chromatography (HPLC). THF was distilled from
benzophenone ketyl.
1,4-Anhydro-2-deoxy-3,5-O-(di-tert-butylsilylene)-4-thio-
D-erythro-pento-1-enitol (5). To a DMF (15 mL) solution of 9
(1.78 g, 4.83 mmol) was added DBN (4.2 mL, 33.81 mmol) at rt, and the
reaction mixture was stirred at 150 ꢀC for 25 min. The reaction mixture
was partitioned between AcOEt/saturated aqueous NH4Cl, and silica
gel column chromatography (hexane/AcOEt = 40/1) of the organic
layer gave 5 (743.9 mg, 56%) as a solid: mp 68ꢀ69 ꢀC; UV (MeOH)
λmax 242 nm (ε 4100) and λmin 220 nm (ε 980); 1H NMR (CDCl3) δ
12.0 Hz), 3.60ꢀ3.67 (1H, m, H-4), 3.98ꢀ4.05 (1H, m, H-5a and H-5b),
4.34 (1H, dd, J2,3 = 4.8 and J3,4 = 10.0 Hz, H-3), 4.43 (1H, dd, J1b,2 = 5.4
and J2,3 = 4.8 Hz, H-2); 13C NMR (CDCl3) δ 20.2, 22.7, 27.2, 27.4, 32.7,
43.9, 68.7, 72.6, 76.7, 83.2; FAB-MS (m/z) 307 (M+ + H). Anal. Calcd
for C13H26O3SSi: C, 53.75; H, 9.02. Found: C, 53.98; H, 9.07.
3,5-O-(Di-tert-butylsilylene)-2-O-methanesulfonyl-1,4-
anhydro-4-thio-D-ribitol (9). To a pyridine (6 mL) solution of 8
(1.34 g, 4.37 mmol) was added MsCl (0.51 mL, 6.56 mmol) at 0 ꢀC
under Ar atmosphere, and the mixture was stirred at rt for 8 h. The reaction
mixture was partitioned between CHCl3/saturated NaHCO3, and silica
gel column chromatograpy (hexane/AcOEt = 7/1) of the organic layer
gave 9 (1.58 g, 98%) as a solid: mp 141ꢀ142 ꢀC; 1H NMR (CDCl3) δ
1.02 and 1.06 (18H, each as s), 3.09 (3H, s), 3.10 (1H, d, J1a,1b = 13.2
Hz), 3.22 (1H, dd, J1b,2 = 4.4 and J1a,1b = 13.2 Hz), 3.61ꢀ3.68 (1H, m,
H-4), 3.99 (1H, dd, J4,5a = 10.4 and J5a,5b = 11.0 Hz), 4.12 (1H, dd, J4,5b
=
3.6 and J5a,5b = 11.0 Hz), 4.34 (1H, dd, J2,3 = 5.2 and J3,4 = 10.2 Hz),
5.25 (1H, dd, J1b,2 = 4.4 and J2,3 = 5.2 Hz); 13C NMR (CDCl3) δ
20.1, 22.8, 26.9, 27.3, 32.2, 38.7, 43.9, 68.7, 81.0, 81.8; FAB-MS (m/z) 369
(M+ + H). Anal. Calcd for C14H28O5S2Si: C, 45.62; H, 7.66. Found: C,
45.57; H, 7.68.
1,4-Anhydro-2-deoxy-3,5-O-(di-tert-butylsilylene)-1-C-phenyl-
4-thio-D-erythro-pento-1-enitol (10). To a THF (10 mL) solution
of 6 (434.4 mg, 0.77 mmol) were added PhI (0.17 mL, 1.54 mmol),
(Ph3P)4Pd (89 mg, 0.077 mmol), and CuI (28.6 mg, 0.15 mmol), and the
mixture was stirred at 80 ꢀC under Ar atmosphere for 8 h. The reaction
mixture was chromatographed on silica gel (hexane/AcOEt = 150/1) to give
10 (218.3 mg, 81%) as a solid: mp 143ꢀ145 ꢀC; UV (MeOH) λmax 288 nm
1.03 and 1.06 (18H, each as s), 3.81ꢀ3.87 (1H, m), 4.29 (1H, t, J4,5a
=
J5a,5b = 10.1 Hz), 4.33 (1H, dd, J4,5b = 0.6 and J5a,5b = 10.1 Hz), 5.11 (1H,
ddd, J1,3 = 2.5, J2,3 = 2.7 and J3,4 = 12.2 Hz), 5.86 (1H, dd, J2,3 = 2.7 and
J1,2 = 6.1 Hz), 6.19 (1H, dd, J1,3 = 2.5 and J1,2 = 6.1 Hz); 13C NMR
(CDCl3) δ 20.0, 22.7, 27.2, 27.5, 55.0, 67.6, 86.1, 124.8, 127.8. FAB-MS
(m/z) 273 (M+ + H) and 215 (M+ ꢀ t-Bu). Anal. Calcd for C13H24O2SSi:
C, 57.30; H, 8.88. Found: C, 57.54; H, 9.10.
1,4-Anhydro-2-deoxy-3,5-O-(di-tert-butylsilylene)-1-tri-
butylstannyl-4-thio-D-erythro-pento-1-enitol (6). To a THF
(15 mL) solution of 5 (718 mg, 2.64 mmol) was added BuLi (2.6 M
hexane solution) (1.2 mL, 3.17 mmol) at ꢀ70 ꢀC, and the reaction mixture
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Scheme 5. Hydroboration of 10 with BH3 THF
3
Scheme 6. Hydroboration of 22
1,4-Anhydro-2-deoxy-3,5-O-(di-tert-butylsilylene)-1-C-(naph-
thalen-1-yl)-4-thio-D-erythro-pento-1-enitol (11). To a THF
(7 mL) solution of 6 (159.4 mg, 0.28 mmol) were added 1-iodonaphtha-
lene (82 μL, 0.56 mmol), (Ph3P)4Pd (32.4 mg, 0.028 mmol,) and CuI
(3.6 mg, 0.056 mmol), and the mixture was stirred at 80 ꢀC under Ar
atmosphere for 16 h. The reaction mixture was chromatographed on
silica gel (hexane/AcOEt = 150/1) to give 11 (102.7 mg, 92%) as a solid:
mp 108ꢀ110 ꢀC; 1H NMR (CDCl3) δ 1.08 and 1.12 (18H, each as s),
Figure 5. Structures of compounds 27ꢀ29.
1
(ε 4900), 230 nm (ε 15300) and λmin 264 nm (ε 2600); H NMR
(CDCl3) δ 1.05 and 1.09 (18H, each as s), 3.99 (1H, ddd, J3 ,4 = 11.9,
0
0
0
0
0
0
0
0
4.19 (1H, ddd, J3 ,4 = 11.9, J4 ,5 a = 10.0 and J4 ,5 b = 6.0 Hz), 4.39ꢀ4.43
0
0
0
0
0
0
0
0
J4 ,5 a = 10.6 and J4 ,5 b = 5.5 Hz), 4.35 (1H, t, J4 ,5 a = J5 a,5 b = 10.6 Hz),
0
0
0
0
0
0
(2H, m), 5.44 (1H, dd, J2 ,3 = 1.2 and J3 ,4 = 11.9 Hz), 6.05 (1H, d, J2 ,3
=
0
0
0
0
0
0
4.38 (1H, dd, J4 ,5 b = 5.5 and J5 a,5 b = 10.6 Hz), 5.30 (1H, dd, J2 ,3 = 1.8
1.2 Hz), 7.41ꢀ7.45, 7.48ꢀ7.54, 7.80ꢀ7.86 and 8.26ꢀ8.28 (7H, each as
m); 13C NMR (CDCl3) δ 20.1, 22.7, 55.9, 67.5, 86.6, 125.1, 125.4, 126.0,
126.3, 126.5, 127.1, 128.4, 129.0, 131.0, 132.8, 133.6, 138.2; FAB-MS
(m/z) 399 (M+ + H); FAB-HRMS (m/z) calcd for C23H31O2SSi:
399.1814, found: 399.1802 (M+ + H).
0
0
0
0
and J3 ,4 = 11.9 Hz), 6.23 (1H, d, J2 ,3 = 1.8 Hz), 7.30ꢀ7.36 and
7.44ꢀ7.46 (5H, each as m); 13C NMR (CDCl3) δ 20.1, 22.7, 27.2, 27.5,
54.6, 67.5, 86.3, 122.2, 126.0, 128.5, 128.7, 133.7, 139.5; FAB-MS (m/z)
349 (M+ + H). Anal. Calcd for C19H28O2SSi 1/3 H2O: C, 64.36; H,
8.15. Found: C, 64.28; H, 8.07.
3
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ARTICLE
Scheme 7. Hydroboration of 15
atmosphere for 17 h. The reaction mixture was chromatographed on
silica gel (hexane/AcOEt = 20/1) to give 13 (91.4 mg, 87%) as a solid:
mp 133ꢀ135 ꢀC; 1H NMR (CDCl3) δ 1.05 and 1.09 (18H, each as s),
0
0
0
0
0
0
4.02 (1H, ddd, J3 ,4 = 12.2, J4 ,5 a = 10.4 and J4 ,5 b = 5.6 Hz), 4.35 (1H, t,
0
0
0
0
0
0
0
0
J
4 ,5 a = J5 a,5 b = 10.0 Hz), 4.39 (1H, dd, J4 ,5 b = 5.6 and J5 a,5 b = 10.0 Hz),
0
0
0
0
0
0
5.31 (1H, dd, J2 ,3 = 1.6 and J3 ,4 = 12.2 Hz), 6.32 (1H, d, J2 ,3 = 1.6 Hz),
7.28ꢀ7.30, 7.69ꢀ7.72, 8.53ꢀ8.55 and 8.71ꢀ8.72 (4H, each as m); 13
C
NMR (CDCl3) δ 20.0, 22.7, 55.2, 67.2, 86.3, 123.2, 124.1, 129.6, 133.2,
136.4, 147.2, 149.6; FAB-MS (m/z) 350 (M+ + H); FAB-HRMS (m/z)
calcd for C18H28NO2SSi: 350.1610, found: 350.1604 (M+ + H).
1,4-Anhydro-2-deoxy-3,5-O-(di-tert-butylsilylene)-1-(2,4-
dimethoxypyrimidin-5-yl)-4-thio-D-erythro-pento-1-enitol
(15). To a THF (4 mL) solution of 6 (210.2 mg, 0.37 mmol) were added
5-iododimethoxypyrimidine (196.9 mg, 0.74 mmol), (Ph3P)4Pd (48.2
mg, 0.037 mmol), and CuI (14.1 mg, 0.074 mmol), and the mixture was
stirred at 80 ꢀC under Ar atmosphere for 8 h. The reaction mixture was
chromatographed on silica gel (hexane/AcOEt = 30/1) to give 15
(134.1 mg, 88%) as foam: UV (MeOH) λmax 291 nm (ε 7800), 249 nm
(ε 13700), 232 nm (ε 13500) and λmin 273 nm (ε 6700), 239 (ε 12200);
Figure 6. Structures of compounds 33 and 34.
1,4-Anhydro-2-deoxy-3,5-O-(di-tert-butylsilylene)-1-C-
(quinolin-3-yl)-4-thio-D-erythro-pento-1-enitol (12). To a THF
(7.0 mL) solution of 6 (176.4 mg, 0.31 mmol) were added 3-bromo-
quinoline (84 μL, 0.62 mmol), (Ph3P)4Pd (35.8 mg, 0.031 mmol), and
CuI (3.6 mg, 0.062 mmol), and the mixture was stirred at 80 ꢀC under Ar
atmosphere for 17 h. The reaction mixture was chromatographed on
silica gel (hexane/AcOEt = 40/1) to give 12 (117.8 mg, 95%) as a solid:
mp 211ꢀ213 ꢀC; 1H NMR (CDCl3) δ 1.06 and 1.10 (18H, each as s),
0
0
0
0
0
0
4.06 (1H, ddd, J3 ,4 = 12.0, J4 ,5 a = 10.0 and J4 ,5 b = 5.6 Hz), 4.38 (1H, t,
1H NMR (CDCl3) δ 1.04 and 1.09 (18H, each as s), 3.90 (1H, dt, J3 ,4
=
0
0
0
0
0
0
0
0
0
0
J4 ,5 a = J5 a,5 b = 10.0 Hz), 4.43 (1H, dd, J4 ,5 b = 5.6 and J5 a,5 b = 10.0 Hz),
0
0
0 0
J4 ,5 a = 11.2 and J4 ,5 b = 5.4 Hz), 4.01 and 4.08 (6H, each as s, OMe), 4.32
0
0
0
0
0
0
5.38 (1H, dd, J2 ,3 = 2.0 and J3 ,4 = 12.0 Hz), 6.49 (1H, d, J2 ,3 = 2.0 Hz),
7.54ꢀ7.58, 7.69ꢀ7.74, 7.81ꢀ7.83, 8.05ꢀ8.10 and 9.07ꢀ9.08 (6H, each
as m); 13C NMR (CDCl3) δ 20.1, 22.7, 54.7, 67.4, 86.5, 124.4, 126.8,
127.3, 127.5, 128.1, 129.3, 129.9, 132.8, 136.8, 147.7, 147.9; FAB-MS
(m/z) 400 (M+ + H); FAB-HRMS (m/z) calcd for C22H30NO2SSi:
400.1767, found: 400.1772 (M+ + H).
0
0
0
0
0
0
0
0
(1H, t, J4 ,5 a = J5 a,5 b = 11.2 Hz), 4.37 (1H, dd, J4 ,5 b = 5.4 and J5 a,5 b = 11.2
0
0
0
0
0 0
Hz), 5.27 (1H, dd, J2 ,3 = 2.0 and J3 ,4 = 11.2 Hz), 6.52 (1H, d, J2 ,3
=
2.0Hz), 8.23(1H, s, H-6);13CNMR(CDCl3) δ20.1, 22.7, 27.2, 27.4, 53.8,
54.3, 55.0, 67.3, 86.4, 109.7, 126.9, 130.4, 157.2, 164.3, 167.6; FAB-MS
(m/z) 411(M+ +H) and353(M+ ꢀ t-Bu). Anal. Calcd for C19H30O4N2SSi:
C, 55.58; H, 7.36; N, 6.82. Found: C, 55.80; H, 7.50; N, 6.78.
1,4-Anhydro-2-deoxy-3,5-O-(di-tert-butylsilylene)-1-C-
(pyridin-3-yl)-4-thio-D-erythro-pento-1-enitol (13). To a THF
(7.0 mL) solution of 6 (169.6 mg, 0.30 mmol) were added 3-iodopyr-
idine (123.0 mg, 0.60 mmol), (Ph3P)4Pd (34.7 mg, 0.03 mmol), and CuI
(11.4 mg, 0.06 mmol), and the mixture was stirred at 80 ꢀC under Ar
1,4-Anhydro-2-deoxy-3,5-O-(di-tert-butylsilylene)-1-(4-bro-
mothiazol-2-yl)-4-thio-D-erythro-pento-1-enitol (16). To a THF
(6.0 mL) solution of 6 (490.3 mg, 0.87 mmol) were added 2,4-dibro-
mothiazole (318.2 mg, 1.31 mmol), (Ph3P)4Pd (100.5 mg, 0.087 mmol),
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ARTICLE
Scheme 8. Plausible Mechanism for the Formation of 32
Scheme 9. Plausible Mechanism for the Formation of 42a,b
Figure 7. Transition state 39 for Markovnikov-oriented hydroboration
of 15 leading to 10-borane 40.
neutralized with NaHCO3. The mixture was evaporated to dryness and
the residual solid was collected by suction filtration to give 18 (1.23 g,
80%) as a solid: mp 195ꢀ197 ꢀC; UV (MeOH) λmax 275 nm (ε 7100)
and λmin 241 nm (ε 1500); 1H NMR (DMSO-d6) δ 6.73 (1H, s), 3.70
(1H, t, J = 2.8 Hz), 8.62 (1H, s), 12.44 (1H, br); 13C NMR (CDCl3) δ
102.3, 124.0, 134.4, 141.7, 149.1, 150.9; FAB-MS (m/z) 154 and 156
(M+ + H). Anal. Calcd for C6H4ClN3 1/10H2O: C, 46.33; H, 2.72; N,
3
27.01. Found: C, 46.46; H, 2.63; N, 27.34.
4-Amino-3H,5H-pyrrolo[3,2-d]pyrimidine (19). Ethanolic
ammonia (200 mL) was added to 18 (1.23 g, 8.0 mmol) placed in
sealed tube, and the suspension was heated under reflux for 24 h. The
reaction mixture was evaporated to dryness, and the residue was
chromatographed on silica gel (15% MeOH in CH2Cl2) to give 19
(829.9 mg, 78%) as a solid: mp 226ꢀ228 ꢀC; UV (MeOH) λmax 275 nm
(ε 7100) and λmin 241 nm (ε 1500); 1H NMR (DMSO-d6) δ 6.42 (1H,
d, J6,7 = 3.3 Hz), 7.67 (1H, d, J6,7 = 3.3 Hz), 7.86 (2H, br), 8.31 (1H, s),
11.95 (1H, br); 13C NMR (CDCl3) δ 98.8, 113.0, 129.7, 140.5, 147.5,
151.4; FAB-MS (m/z) 135 (M+ + H); FAB-HRMS (m/z) calcd for
C6H7N4: 135.0671, found: 135.0650 (M+ + H).
4-Pivaloylamino-3H,5H-pyrrolo[3,2-d]pyrimidine (20). To
a CH3CN (20 mL) solution of 19 (827 mg, 6.17 mmol) were added
i-Pr2NEt (4.3 mL, 24.68 mmol) and (CH3)3COCl (2.3 mL, 18.51 mmol)
at 0 ꢀC under Ar atmosphere, and the mixture was stirred for 20 h. The
reaction mixture was quenched with MeOH and evaporated to dryness.
Silica gel column chromatography (1% MeOH in CH2Cl2) of the residue
gave 20 (1.08 g, 80%) as foam: UV (MeOH) λshoulder 296 nm (ε 8200),
λmax 280 nm (ε 9400), 238 nm (ε 14700) and λmin 253 nm (ε 3000),
Figure 8. 40-Thiotiazofurin derivative 41 and the 20-deoxy counterparts
42a,b.
and CuI (32.4 mg, 0.17 mmol), and the mixture was stirred at 80ꢀC under
Ar atmosphere for 10 h. The reaction mixture was chromatographed on
silica gel (hexane/AcOEt = 100/1) to give 16 (181.6 mg, 48%) as a solid:
mp 157ꢀ159 ꢀC; UV (MeOH) λmax 391 nm (ε 6200), 289 (ε 6000) and
λmin 306 nm (ε 5700), 255 (ε 2200); 1H NMR (CDCl3) δ 1.03 and 1.07
0
0
0
0
0
0
(18H, each as s), 4.04 (1H, ddd, J3 ,4 = 12.2, J4 ,5 a = 10.0 and J4 ,5 b = 6.0
0
0
0
0
0
0
Hz), 4.33 (1H, t, J4 ,5 a = J5 a,5 b = 10.0 Hz), 4.37 (1H, dd, J4 ,5 b = 6.0 and
0
0
0
0
0
0
J5 a,5 b = 10.0 Hz), 5.31 (1H, dd, J2 ,3 = 2.0 and J3 ,4 = 12.2 Hz), 6.57 (1H,
d, J2 ,3 = 2.0Hz), 7.20(1H, s);13C NMR(CDCl3) δ 20.0, 22.7, 27.1, 27.4,
55.0, 67.1, 86.0, 117.6, 126.0, 128.4, 132.8, 162.2; FAB-MS (m/z) 434 and
435 (M+ + H). Anal. Calcd for C16H24Br NO2S2Si: C, 44.23; H, 5.57; N,
3.22. Found: C, 44.13; H, 5.48; N, 3.03.
0
0
4-Chloro-3H,5H-pyrrolo[3,2-d]pyrimidine (18). A mixture of
17 (1.35 g, 10.0 mmol) and POCl3 (18.6 mL, 200 mmol) was heated
at 100 ꢀC for 4 h. The reaction mixture was quenched with ice chips and
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ARTICLE
Scheme 10. Synthesis of 40-Thiopseudouridine 47 from 45
Scheme 11. Synthesis of 40-Thiotiazofurin 50
224 nm (ε 8300); 1H NMR (CDCl3) δ 1.40 (9H, s), 6.72 (1H, t, J6,7 = J7,
NH = 2.0 Hz), 7.56 (1H, t, J6,7 = J6,NH = 2.0 Hz), 8.51 (1H, br), 8.59 (1H,
s); 13C NMR (CDCl3) δ 27.5, 39.9, 102.8, 115.4, 130.4, 142.0, 149.6,
152.4, 178.1; FAB-MS (m/z) 219 (M+ + H). Anal. Calcd for
stirred 18 h at rt. To the reaction mixture was added a THF (1.5 mL)
solution of acetone cathecol (260 mg, 2.20 mmol), and the mixture stirred
at 0 ꢀC for 22 h at rt. ICN silica gel column chromatography (hexane/
AcOEt = 300/1) of the reaction mixture gave 24 (13.2 mg, 25%) as a
solid: mp 120ꢀ122 ꢀC; UV (MeOH) λshoulder 221 nm (ε 5400); 1H NMR
(500 MHz) (DMSO-d6) δ 1.01 and 1.02 (18H, each as s), 1.23 and 1.24
C11H14N4OSSi 1/5CH3OH: C, 59.88; H, 6.64; N, 24.94. Found: C,
3
59.71; H, 6.54; N, 24.64.
0
0
0
0
(12H, each as s), 2.16 (1H, dd, J1 ,2 = 4.1 and J2 ,3 = 8.6 Hz), 3.66 (1H,
4-Pivaloylamino-7-iodo-3H,5H-pyrrolo[3,2-d]pyrimidine
(21). To a DMF (20 mL) solution of 20 (1.07 g, 4.90 mmol) was added
N-iodosuccinimide (1.32 g, 5.88 mmol) at rt under Ar atmosphere, and
the mixture was stirred at 80 ꢀC for 1 h. The reaction mixture was
partitioned between AcOEt/H2O, and silica gel column chromatogra-
phy (hexane/AcOEt = 2/1) of the organic layer gave 21 (1.35 g, 80%) as
foam: UV (MeOH) λmax 306 nm (ε 6140), 283 nm (ε 10200), 247 nm
(ε 16500) and λmin 297 nm (ε 6050), 261 nm (ε 5200), 231 nm (ε
8100); 1H NMR (CDCl3) δ 1.40 (9H, s, t-Bu), 7.64 (1H, d, J6,NH = 2.4
Hz), 8.29 (1H, br), 8.68 (1H, s), 11.25 (1H, br); 13C NMR (CDCl3) δ
27.5, 40.0, 57.9, 115.6, 134.1, 142.4, 150.5, 152.3, 178.3; FAB-MS (m/z)
0
0
0
0
0
0
0
0
ddd, J3 ,4 = 10.8, J4 ,5 a = 9.8 and J4 ,5 b = 4.6 Hz), 3.95 (1H, dd, J4 ,5 a = 9.8
0
0
0
0
0
0
and J5 a,5 b = 10.3 Hz), 4.31 (1H, dd, J4 ,5 b = 4.6 and J5 a,5 b = 10.3 Hz),
0
0
0
0
0
0
4.49 (1H, d, J1 ,2 = 4.1 Hz), 4.61 (1H, dd, J2 ,3 = 8.6 and J3 ,4 = 10.8 Hz),
7.21ꢀ7.25 and 7.30ꢀ7.36 (5H, each as m, Ph); NOE experiment: H-10/
H-40 (2.3%), H-20/ H-Ph (1.9%) and H-30/ H-Ph (1.4%); 13C NMR
(DMSO-d6) δ 19.7, 22.3, 24.0, 25.3, 26.8, 27.3, 48.3, 49.7, 68.2, 82.1,
83.4, 127.1, 127.2, 128.6, 143.8. FAB-MS (m/z) 476 and 477 (M+ + H).
Anal. Calcd for C25H41BO4SSi: C, 63.01; H, 8.67. Found: C, 63.33; H, 8.78.
1-[2,3,5-Tri-O-acetyl-4-thio-β-D-ribofuranosyl]benzene
(26). To a THF (2.5 mL) solution of 10 (42.9 mg, 0.12 mmol) was
345 (M+ + H). Anal. Calcd for C11H13IN4O 3/4H2O: C, 36.94; H,
added BH3 THF (1 M THF solution) (0.6 mL, 0.60 mmol) at 0 ꢀC
3
3
under Ar atmosphere, and the reaction mixture was stirred for 15 h. To
the reaction mixture was added MeOH (89 μL, 2.2 mmol), and the
mixture stirred at 0 ꢀC. After 1 h, 10% NaOH (0.18 mL, 0.44 mmol) and
30% H2O2 (37 μL, 0.33 mmol) was added at 0 ꢀC, and the mixture was
stirred for 24 h at rt. The reaction mixture was partitioned between
CHCl3/H2O and the organic layer was evaporated to dryness and dried
in vacuo overnight. To a stirred THF (3.0 mL) solution of the crude
product was added Bu4NF (1 M THF solution) (0.33 mL, 0.33 mmol) at
0 ꢀC under Ar atmosphere. After stirring for 11 h, Ac2O (52 μL, 0.55
mmol) was added to the reaction mixture, and the mixture was stirred for
10 h at rt. The reaction mixture was partitioned between CHCl3/saturated
aqueous NaHCO3 and column chromatography (hexane/AcOEt = 7/1)
of the organic layer gave 26 (34.8 mg, 90%) as a syrup: UV (MeOH)
8.37; N, 15.66. Found: C, 37.22; H, 3.69; N, 15.26.
1,4-Anhydro-2-deoxy-3,5-O-(di-tert-butylsilylene)-1-(4-N-
pivaloylamino-pyrrolo[3,2-d]pyrimidin-7-yl)-4-thio-D-ery-
thro-pento-1-enitol (22). To a THF (25.0 mL) solution of 6 (2.12 g,
3.78 mmol) were added 21 (1.69 g, 4.91 mmol), (Ph3P)4Pd (566.2 mg,
0.49 mmol), and CuI (186.6 mg, 0.98 mmol), and the mixture was
stirred at 80 ꢀC under Ar atmosphere for 20 h. The reaction mixture
was chromatographed on silica gel (hexane/AcOEt = 5/1) to give 22
(966.2 mg, 52%) as a solid: mp 179ꢀ180 ꢀC; UV (MeOH) λmax
323 nm (ε 4400), 264 nm (ε 22900), 237 nm (ε 21500) and λmin 303 nm
(ε 3700), 247 nm (ε 18100), 231 nm (ε 20100); 1H NMR (CDCl3) δ
1.04 and 1.09 (18H, each as s), 1.40 (9H, s), 3.96ꢀ4.03 (1H, m), 4.36
0
0
0
0
0
0
0
0
(1H, t, J5 a,5 b = J4 ,5 a = 10.0 Hz), 4.40 (1H, dd, J5 a,5 b = 10.0 and J4 ,5 b
1
0
0
0
0
5.6 Hz), 5.39 (1H, dd, J2 ,3 = 1.8 and J3 ,4 = 11.6 Hz), 6.92 (1H, d, J =
1.8 Hz), 7.53 (1H, d, J = 2.4 Hz), 8.23 (1H, br), 8.66 (1H, s), 11.05
(1H, br); 13C NMR (CDCl3) δ 20.1, 22.7, 27.2, 27.47, 27.49, 27.8,
40.0, 53.9, 67.6, 86.5, 111.6, 116.4, 123.0, 128.4, 129.5, 142.4, 149.2, 150.1,
178.2; FAB-MS (m/z) 489 (M+ + H). Anal. Calcd for C24H36O3N4-
SSi: C, 58.98; H, 7.42; N, 11.46. Found: C, 59.05; H, 7.49; N, 11.37.
Hydroboration of 10 and Quenching with Acetone Pina-
col: Formation of 24. To a THF (2.5 mL) solution of 10 (38.3 mg,
λshoulder 250 nm (ε 370); H NMR (CDCl3) δ 1.97, 2.14, and 2.14
(18H, each as s), 3.66 (1H, ddd, J3 ,4 = 3.2, J4 ,5 a = 6.8 and J4 ,5 b = 6.0
Hz), 4.27 (1H, dd, J4 ,5 a = 6.8 and J5 a,5 b = 11.4 Hz), 4.36 (1H, dd,
4 ,5 b = 6.0 and J5 a,5 b = 11.4 Hz), 4.63 (1H, d, J1 ,2 = 8.1 Hz), 5.41 (1H, dd,
J1 ,2 = 8.1 and J2 ,3 = 3.2 Hz), 5.52 (1H, t, J2 ,3 = J3 ,4 = 3.2 Hz),
7.27ꢀ7.36 and 7.45ꢀ7.47 (5H, each as m, Ph); NOE experiment: H-10/
H-40 (1.1%) and H-20/ H-50a (2.0%); 13C NMR (CDCl3) δ 20.5, 20.8,
46.5, 50.8, 65.0, 74.3, 78.3, 128.0, 128.1, 128.7, 136.7, 169.7, 169.8, 170.5.
FAB-MS (m/z) 353 (M+ + H). Anal. Calcd for C17H20O6S: C, 57.94; H,
5.72. Found: C, 57.83; H, 5.77.
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0 0
J
0
0
0
0
0
0
0
0
0.11 mmol) was added BH3 THF (1 M THF solution) (0.55 mL,
3
0.55 mmol) at 0 ꢀC under Ar atmosphere, and the reaction mixture was
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ARTICLE
1-[3,5-O-(Di-tert-butylsilylene)-4-thio-β-D-ribofuranosyl]-
naphthalene (27). To a THF (6.0 mL) solution of 11 (105.3 mg, 0.26
7.98ꢀ7.99, 8.52ꢀ8.54, 8.69 (6H, each as m); NOE experiment: H-10/
H-40 (2.0%), HO-20/H-40 (3.0%); 13C NMR (CDCl3) δ 20.2, 22.8, 27.2,
27.3, 46.2, 51.3, 67.9, 79.3, 81.5, 125.2, 138.8, 139.2, 146.5, 147.3; FAB-
MS (m/z) 368 (M+ + H); FAB-HRMS (m/z) calcd for C18H30NO3SSi:
368.1716, found: 368.1717 (M+ + H).
mmol) was added BH3 THF (1 M THF solution) (1.3 mL, 1.30 mmol)
3
at 0 ꢀC under Ar atmosphere, and the reaction mixture was stirred 4 h.
To the reaction mixture was added MeOH (0.20 mL, 5.2 mmol), and the
mixture stirred at 0 ꢀC for 1 h. The reaction mixture was evaporated to
dryness, and silica gel column chromatography (hexane/AcOEt = 20/1)
of the residue gave the organoborane. To a THF (5.0 mL) solution of
the organoborane was added 9.9% NaOH (0.42 mL, 1.04 mmol) and
30% H2O2 (88 μL, 0.78 mmol) was added at 0 ꢀC, and the mixture was
stirred for 7 h. The reaction mixture was partitioned between AcOEt/
H2O and the organic layer was washed with saturated NH4Cl and
saturated NaHCO3. Silica gel column chromatography (hexane/AcOEt =
40/1) of the organic layer gave 27 (67 mg, 62%) as a solid: mp 102ꢀ
104 ꢀC; 1H NMR (CDCl3) δ 1.02 and 1.05 (18H, each as s), 2.06 (1H,
7-[3,5-O-(Di-tert-butylsilylene)-4-thio-β-D-ribofuranosyl]-
4-pivaloylamino-3H,5H-pyrrolo[3,2-d]pyrimidine (30). To a
THF (2.5 mL) solution of 22 (48.9 mg, 0.1 mmol) was added BH3
3
THF (1 M THF solution) (0.5 mL, 0.5 mmol) at 0 ꢀC under Ar
atmosphere, and the reaction mixture was stirred 18 h. To the reaction
mixture was added MeOH (81 μL, 2.0 mmol), and the mixture stirred at
0 ꢀC for 1 h. The reaction mixture was evaporated to dryness, and silica
gel column chromatography (hexane/AcOEt = 2/1) of the residue gave
19 (9.4 mg, 19%) and the organoborane. To a THF (2.5 mL) solution of
the organoborane (26.8 mg) were added 9.9% NaOH (40 μL, 0.10
mmol) and 30% H2O2 (8.7 μL, 0.015 mmol) at 0 ꢀC, and the mixture
was stirred for 2 h. The reaction mixture was partitioned between
AcOEt/H2O, and the organic layer was washed with saturated NH4Cl
and saturated NaHCO3. Silica gel column chromatography (hexane/
AcOEt = 1/1) of the organic layer gave 30 (20 mg, 40%, syrup): UV
(MeOH) λshoulder 301 nm (ε 6100), λmax 283 nm (ε 9500), 243 nm (ε
20000) and λmin 260 nm (ε 4500), 227 nm (ε 8900); 1H NMR (CDCl3)
δ 1.04 and 1.06 (18H, each as s), 1.39 (9H, s), 3.02 (1H, br), 3.84 (1H,
0
0
0
0
0
0
br), 3.89 (1H, ddd, J3 ,4 = 9.8, J4 ,5 a = 10.0 and J4 ,5 b = 3.6 Hz), 4.18 (1H,
0
0
0
0
0
0
0
0
t, J4 ,5 a = J5 a,5 b = 10.0 Hz), 4.21 (1H, dd, J4 ,5 b = 3.6 and J5 a,5 b = 10.0
0
0
0
0
Hz), 4.40ꢀ4.42 (1H, m), 4.47 (1H, dd, J2 ,3 = 5.2 and J3 ,4 = 9.8 Hz),
5.31 (1H, s), 7.45ꢀ7.49, 7.51ꢀ7.54, 7.57ꢀ7.62, 7.77ꢀ7.79, 7.87ꢀ7.90,
8.22ꢀ8.24 (7H, each as m); NOE experiment: H-10/H-40 (1.7%) and
HO-20/H-40 (3.3%); 13C NMR (CDCl3) δ 20.5, 23.0, 27.5, 27.6, 45.1,
51.0, 68.9, 79.3, 81.7, 123.4, 125.52, 125.53, 126.2, 126.9, 128.4, 129.1,
131.6, 134.0, 136.0; FAB-MS (m/z) 417 (M+ + H); FAB-HRMS (m/z)
calcd for C23H33O3SSi: 417.1920, found: 417.1932 (M+ + H).
0
0
0
0
0
0
0
0
ddd, J3 ,4 = 11.2, J4 ,5 a = 10.0 and J4 ,5 b = 4.8 Hz), 4.16 (1H, dd, J4 ,5 a
=
0
0
0
0
0
0
10.0 and J5 a,5 b = 11.2 Hz), 4.41 (1H, dd, J4 ,5 b = 4.8 and J5 a,5 b = 11.2
3-[3,5-O-(Di-tert-butylsilylene)-4-thio-β-D-ribofuranosyl]-
quinoline (28). To a THF (5.0 mL) solution of 12 (80.9 mg, 0.034
0
0
0
0
0
0
Hz), 4.57 (1H, d, J2 ,3 = 3.6 Hz), 4.65 (1H, dd, J2 ,3 = 3.6 and J3 ,4 = 11.2
Hz), 4.84 (1H, s), 7.55 (1H, d, JNH,6 = 2.8 Hz), 8.25 (1H, br), 8.59 (1H,
s), 10.84 (1H, br); NOE experiment: H-10/H-40 (2.0%), H-6/H-20
(0.6%), H-6/H-30 (1.9%), HO-20/H-40 (3.1%); 13C NMR (CDCl3) δ
20.2, 22.7, 27.2, 27.4, 27.5, 39.9, 44.9, 45.0, 68.8, 78.5, 81.3, 116.5, 116.6,
129.2, 142.2, 149.2, 149.3, 178.2; FAB-MS (m/z) 507 (M+ + H). Anal.
mmol) was added BH3 THF (1 M THF solution) (1.0 mL, 1.00 mmol)
3
at 0 ꢀC under Ar atmosphere, and the reaction mixture was stirred 6 h.
To the reaction mixture was added MeOH (0.15 mL, 4.0 mmol), and the
mixture stirred at 0 ꢀC for 1 h. The reaction mixture was evaporated to
dryness, and silica gel column chromatography (hexane/AcOEt = 3/1)
of the residue gave the organoborane. To a THF (5.0 mL) solution of
the organoborane were added 9.9% NaOH (0.32 mL, 0.80 mmol) and
30% H2O2 (68 μL, 0.60 mmol) at 0 ꢀC, and the mixture was stirred for
8 h. The reaction mixture was partitioned between AcOEt/H2O, and the
organic layer was washed with saturated NH4Cl and saturated NaHCO3.
Silica gel column chromatography (hexane/AcOEt = 3/1) of the organic
layer gave 28 (36.7 mg, 44%) as a syrup: 1H NMR (CDCl3) δ 1.05 and
1.07 (18H, each as s), 2.63 (1H, br), 3.83ꢀ3.90 (1H, m), 4.20 (1H, dd,
Calcd for C24H38N4O4SSi 1/4CH3CO2C2H5: C, 56.78; H, 7.62; N,
3
10.60. Found: C, 57.00; H, 7.60; N, 10.60.
Hydroboration of 15: Formation of 31 and 32. To a THF
(2.0 mL) solution of 15 (41.9 mg, 0.10 mmol) was added BH3 THF
3
(1 M THF solution) (0.5 mL, 0.50 mmol) at 0 ꢀC under Ar atmosphere,
and the reaction mixture was stirred for 4 h. To the reaction mixture was
added MeOH (76 μL, 2.0 mmol), and the mixture stirred at 0 ꢀC. After
2 h of stirring, 10% NaOH (0.16 mL, 0.4 mmol) and 30% H2O2 (34 μL,
0.3 mmol) were added at 0 ꢀC, and the mixture was stirred for 4 h. The
reaction mixture was partitioned between CHCl3/H2O, and the organic
layer was evaporated to dryness. The crude product was reacted with
Ac2O (28 μL, 0.3 mmol), i-PrNEt2 (70 μL, 0.4 mmol), and DMAP (2.4
mg, 0.02 mmol) in CH2Cl2 (2.5 mL) for 3 h at rt. The reaction mixture
was partitioned between CHCl3/saturated NaHCO3, and column
chromatography (hexane/AcOEt = 7/1) of the organic layer gave 31
(19.5 mg, 41%, syrup) and 32 (15.0 mg, 16%, syrup).
0
0
0
0
0
0
0
0
J4 ,5 a = 10.0 and J5 a,5 b = 11.2 Hz), 4.30 (1H, dd, J4 ,5 b = 6.4 and J5 a,5 b
=
=
0
0
0
0
0
0
11.2 Hz), 4.29 (1H, d, J2 ,3 = 4.4), 4.46 (1H, dd, J2 ,3 = 4.4 and J3 ,4
10.0 Hz), 4.69 (1H, s), 7.54ꢀ7.59, 7.72ꢀ7.76, 7.82ꢀ7.84, 8.09ꢀ8.12,
8.18ꢀ8.19, 8.97ꢀ8.98 (6H, each as m); NOE experiment: H-10/H-40
(1.5%), HO-20/H-40 (3.5%); 13C NMR (CDCl3) δ 20.2, 22.8, 25.8, 27.2,
27.4, 46.0, 52.2, 68.3, 68.3, 79.7, 81.6, 127.2, 127.6, 127.8, 129.2, 129.7,
133.3, 134.8, 147.4, 150.7; FAB-MS (m/z) 418 (M+ + H); FAB-HRMS
(m/z) calcd for C22H32NO3SSi: 418.1863, found: 418.1863 (M+ + H).
3-[3,5-O-(Di-tert-butylsilylene)-4-thio-β-D-ribofuranosyl]-
pyridine (29). To a THF (5.0 mL) solution of 13 (78.8 mg, 0.23
Physical data of 31: UV (MeOH) λmax 267 nm (ε 5100) and λmin
245 nm (ε 2800); 1H NMR (CDCl3) δ 1.00 and 1.02 (18H, each as s),
2.16 (3H, s), 3.72ꢀ3.79 (1H, m), 3.99 and 4.02 (6H, each as s), 4.07
mmol) was added BH3 THF (1 M THF solution) (1.2 mL, 1.15 mmol)
3
0
0
0
0
0
0
0
0
at 0 ꢀC under Ar atmosphere, and the reaction mixture was stirred 8 h.
To the reaction mixture was added MeOH (0.17 mL, 4.6 mmol), and the
mixture stirred at 0 ꢀC for 1 h. The reaction mixture was evaporated to
dryness, and silica gel column chromatography (hexane/AcOEt = 1/1)
of the residue gave the organoborane. To a THF (5.0 mL) solution of
the organoborane were added 9.9% NaOH (0.37 mL, 0.19 mmol) and
30% H2O2 (78 μL, 0.69 mmol) at 0 ꢀC, and the mixture was stirred for 8
h. The reaction mixture was partitioned between AcOEt/H2O, and the
organic layer was washed with saturated NH4Cl and saturated NaHCO3.
Silica gel column chromatography (hexane/AcOEt = 3/1) of the organic
(1H, t, J4 ,5 a = J5 a,5 b = 10.0 Hz), 4.25 (1H, dd, J2 ,3 = 3.8 and J3 ,4 = 10.0
0
0
0
0
Hz), 4.38 (1H, dd, J4 ,5 b = 4.8 and J5 a,5 b = 10.0 Hz), 4.43 (1H, s), 5.51
(1H, d, J2 ,3 = 3.8 Hz), 8.38 (1H, s); NOE experiment: H-10/H-40
(2.2%), H-6/H-20 (2.9%) and H-6/H-30 (3.5%); 13C NMR (CDCl3) δ
20.0, 21.1, 22.7, 26.9, 27.2, 44.7, 45.3, 54.3, 54.9, 68.4, 77.7, 79.7, 113.6,
157.3, 164.9, 168.2, 169.3; FAB-MS (m/z) 471 (M+ + H). Anal. Calcd
for C21H34N2O6SSi: C, 53.59; H, 7.28; N, 5.95. Found: C, 53.91; H,
7.40; N, 5.62.
0
0
Physical data of 32: UV (MeOH) λmax 263 nm (ε 5600) and λmin
241 nm (ε 2700); 1H NMR (CDCl3) (major isomer) δ 0.93 and 0.99
(18H, each as s), 2.06 (3H, s), 2.00ꢀ2.10 (1H, m, H-20a), 2.70 (1H, dt,
1
layer gave 29 (43 mg, 51%) as a solid: mp 129ꢀ131 ꢀC; H NMR
0
0
0
0
0
0
0
0
0
0
(CDCl3) δ 1.04 and 1.07 (18H, each as s), 2.62 (1H, br), 3.82 (1H, ddd,
J1 ,2 b = J2 a,2 b = 8.6 and J1 ,2 b = 5.2 Hz), 2.76 (1H, dd, J3 ,4 = 1.5, J4 ,5 a =
0
0
0
0
0
0
0
0
0
0
0
0
0
0
J3 ,4 = 10.0, J4 ,5 a = 10.4 and J4 ,5 b = 4.8 Hz), 4.20ꢀ4.23 (1H, m), 4.42
11.0 and J4 ,5 b = 4.4 Hz), 3.70 (1H, dt, J2 a,3 = J2 b,3 = 8.2 and J3 ,4 = 1.5
0
0
0
0
0
0
0
0
(1H, dd, J2 ,3 = 4.8 and J3 ,4 = 10.0 Hz), 4.49 (1H, s), 7.48ꢀ7.52,
Hz), 3.96 (1H, t, J4 ,5 a = J5 a,5 b = 11.0 Hz), 3.99 and 4.00 (6H, each as s),
8666
dx.doi.org/10.1021/jo201100n |J. Org. Chem. 2011, 76, 8658–8669

The Journal of Organic Chemistry
ARTICLE
0
0
0
0
0
0
0
0
0
0
0
0
4.21 (1H, dd, J4 ,5 b = 4.4 and J5 a,5 b = 11.0 Hz), 6.12 (1H, dd, J1 ,2 a = 5.2
(18H, each as s), 2.32 (1H, dt, J1 ,2 = 8.8, J2 a,3 = J2 a,2 b = 12.4 Hz), 2.70
0
0
0
0
0
0
0
0
and J1 ,2 b = 8.6 Hz), 8.24 (1H, s); (minor isomer) δ 1.00 and 1.02 (18H,
(1H, dd, J2 b,3 = 5.2 and J2 a,2 b = 12.8 Hz), 3.43 (1H, ddd, J3 ,4 = 9.8,
0
0
0
0
0
0
0
0
0
0
0
0
each as s), 2.13 (3H, s), 6.01 (1H, dd, J1 ,2 a = 4.4 and J1 ,2 b = 7.4 Hz);
HMBC experiment: C-10/H-6 and H-10/ C(=O)CH3; 13C NMR
(CDCl3) δ 19.7, 21.2, 22.5, 26.9, 27.2, 39.5, 54.1, 54.6, 54.9, 67.5,
67.7, 73.4, 112.7, 157.8, 165.1, 168.9, 169.9; FAB-MS (m/z) 943 (M+ +
H). Anal. Calcd for C42H70N4O12S2Si2: C, 53.48; H, 7.48; N, 5.94.
Found: C, 53.64; H, 7.55; N, 5.60.
J4 ,5 a = 11.0 and J4 ,5 b = 4.8 Hz), 4.32 (1H, ddd, J2 a,3 = 12.4, J2 b,3 = 5.2
0
0
0
0
0
0
and J3 ,4 = 9.8 Hz), 4.36 (1H, dd, J4 ,5 b = 4.8 and J5 a,5 b = 10.8 Hz), 4.75
(1H, d, J1 ,2 a = 8.8 Hz), 7.19 (1H, s); NOE experiment: H-10/H-40
(1.1%) and H-10/ H-20a (5.7%); 13C NMR (CDCl3) δ 19.9, 22.7, 27.0,
27.3, 42.5, 42.5, 49.3, 68.7, 78.6, 118.0, 125.2, 177.1; FAB-MS (m/z) 436
0
0
and 438 (M+ + H). Anal. Calcd for C16H26BrNO2S2Si 1/2AcOEt: C,
3
44.99; H, 6.29; N, 2.91. Found: C, 44.62; H, 6.10; N, 2.86.
Hydroboration of 15 and Quenching with Acetone Cathe-
col: Formation of 33 and 34. To a THF (2.5 mL) solution of 15
(35.3 mg, 0.086 mmol) was added BH3 THF (1 M THF solution)
Physical data of 42b: mp 103ꢀ105 ꢀC; UV (MeOH) λmax 335 nm (ε
1370), 257 nm (ε 3440) and λmin 298 nm (ε 510) and 230 nm (ε 2230);
1H NMR (CDCl3) δ 1.01 and 1.07 (18H, each as s), 2.06 (1H, dd,
3
(0.43 mL, 0.43 mmol) at 0 ꢀC under Ar atmosphere, and the reaction
mixture was stirred for 7 h at rt. To the reaction mixture was added a
THF (2.0 mL) solution of acetone cathecol (203.3 mg, 1.72 mmol), and
the mixture stirred for 18 h at rt. Silica gel column chromatography
(hexane/AcOEt = 40/1) of the reaction mixture gave a mixture of 33
and 34. Preparative TLC of the mixture gave 33 (12.2 mg, 26%, solid)
and 34 (7.8 mg, 17%, solid).
0
0
0
0
0
0
0
0
J1 ,2 a = 10.8 and J2 a,2 b =12.2Hz), 2.92(1H, ddd, J1 ,2 b =7.2, J2 b,3 =5.2and
0
0
0
0
0
0
0
0
J2 a,2 b = 12.2 Hz), 3.58 (1H, ddd, J3 ,4 = 9.4, J4 ,5 a = 11.1 and J4 ,5 b = 4.8
0
0
0
0
Hz), 3.99 (1H, dd, J4 ,5 a = 11.0 and J5 a,5 b = 10.0 Hz), 4.25ꢀ4.30 (1H,
0
0
0
0
0
0
m), 4.30 (1H, dd, J4 ,5 b = 4.8 and J5 a,5 b = 10.0 Hz), 4.77 (1H, dd, J1 ,2 a
=
10.8 and J1 ,2 b = 7.2 Hz), 7.18 (1H, s); NOE experiment: H-10/H-20 β
(4.7%), H-10/ H-30 (4.7%) and H-20α/H-40(4.0%); 13C NMR (CDCl3)
δ 19.9, 22.7, 27.0, 27.4, 42.1, 43.6, 49.5, 68.3, 80.4, 117.4, 124.7, 175.0;
0
0
1
Physical data of 33: mp 84ꢀ86 ꢀC; H NMR (CD3Cl) δ 1.03 and
FAB-MS (m/z) 436 and 438 (M+
+ H). Anal. Calcd for
0
0
1.04 (18H, each as s), 1.31 and 1.32 (12H, each as s), 2.21 (1H, dd, J1 ,2
=
=
=
0
0
0
0
0
0
0
0
C16H26BrNO2S2Si: C, 44.03; H, 6.00; N, 3.21. Found: C, 44.37; H,
5.98; N, 3.02.
2.4 and J2 ,3 = 8.0 Hz), 3.73 (1H, ddd, J3 ,4 = 10.8, J4 ,5 a = 9.8 and J4 ,5 b
4.6 Hz), 3.98 and 4.00 (6H, each as s, OMe), 4.00 (1H, t, J4 ,5 a = J5 a,5 b
0
0
0
0
0
0
0
0
10.2 Hz), 4.34 (1H, dd, J4 ,5 b = 4.8 and J5 a,5 b = 10.2 Hz), 4.47 (1H, dd,
5-[2,3,5-Tri-O-acetyl-4-thio-β-D-ribofuranosyl]-2,4-dimeth-
oxypyrimidine (45). To a stirred THF (2.0 mL) solution of 31 was
added Bu4NF (1 M THF solution) (0.12 mL, 0.12 mmol) at 0 ꢀC under
Ar atmosphere. After 7.5 h of stirring, Ac2O (25 μL, 0.27 mmol) was
added to the reaction mixture, and the mixture was stirred overnight at rt.
The reaction mixture was partitioned between CHCl3/saturated aque-
ous NaHCO3, and silica gel column chromatography (hexane/AcOEt =
3/1) of the organic layer gave 45 (20.4 mg, 93%) as a syrup: UV
(MeOH) λmax 266 nm (ε 5200) and λmin 246 nm (ε 3000); 1H NMR
0
0
0
0
0
0
J2 ,3 = 8.0 and J3 ,4 = 9.4 Hz), 4.59 (1H, d, J1 ,2 = 2.4 Hz), 8.38 (1H, s);
NOE experiment: H-10/H-40 (1.8%), H-20/ H-2 (5.6%) and H-30/ H-2
(3.0%); 13C NMR (CD3Cl) δ 20.1, 22.8, 24.6, 25.4, 27.1, 39.2, 48.7,
54.0, 54.8, 69.3, 81.7, 83.7, 118.0, 155.8, 164.3, 168.3; FAB-MS (m/z)
539 (M+ + H); FAB-HRMS (m/z) calcd for C25H44BN2O6SSi:
539.2782, found: 539.2729 (M+ + H).
Physical data of 34: mp 159ꢀ161 ꢀC; 1H NMR (CD3Cl) δ 0.98 and
0
0
1.00 (18H, each as s), 1.24 and 1.26 (12H, each as s), 2.26 (1H, dd, J2 a,3
0
0
0
0
0
0
= 5.2 and J2 a,2 b = 12.4 Hz), 2.40 (1H, dd, J2 b,3 = J2 a,2 b = 12.4 Hz), 3.32
0
0
(CDCl3) δ 2.03 and 2.12 (9H, each as s), 3.68 (1H, dt, J3 ,4 = 4.4 and
0
0
0
0
0
0
(1H, ddd, J3 ,4 = 11.7, J4 ,5 a = 7.8 and J4 ,5 b = 4.4 Hz), 3.98 and 3.99 (6H,
0
0
0
0
J4 ,5 = 6.0 Hz), 3.99 and 4.04 (6H, each as s), 4.28 (2H, d, J4 ,5 = 6.0 Hz),
0
0
0
0
each as s), 3.95ꢀ4.05 (2H, m), 4.33 (1H, dd, J4 ,5 b = 4.8 and J5 a,5 b
=
0
0
0
0
0
0
4.65 (1H, d, J1 ,2 = 6.8 Hz), 5.46 (1H, dd, J2 ,3 = 3.6 and J3 ,4 = 4.4 Hz),
12.4 Hz), 8.61 (1H, s); NOE experiment: H-20/H-2 (1.0%) and H-30/
H-2 (1.4%); 13C NMR (CD3Cl) δ 19.9, 22.7, 24.3, 27.1, 27.4, 29.7, 43.3,
48.7, 53.8, 54.7, 69.0, 79.4, 84.1, 118.6, 156.9, 164.2, 167.9; FAB-MS (m/
z) 539 (M+ + H); FAB-HRMS (m/z) calcd for C25H44BN2O6SSi:
539.2782, found: 539.2729 (M+ + H).
5.71 (1H, dd, J1 ,2 = 6.8 and J2 ,3 = 3.6 Hz), 8.34 (1H, s); 13C NMR
(CDCl3) δ 20.6, 20.7, 43.3, 46.2, 54.2, 54.9, 64.5, 74.2, 75.2, 110.9, 157.6,
165.0, 168.8, 169.7, 169.8, 170.5; FAB-MS (m/z) 415 (M+ + H). Anal.
Calcd for C17H22N2O8S: C, 49.27; H, 5.35; N, 6.76. Found: C, 49.06; H,
5.42; N, 6.48.
0
0
0
0
Hydroboration of 16: Formation of 41, 42a, and 42b. To a
THF (2.5 mL) solution of 16 (35.9 mg, 0.083 mmol) was added
5-[2,3,5-Tri-O-acetyl-4-thio-β-D-ribofuranosyl]uracil (46).
To an AcOH (32.0 mL) solution of 45 (168.2 mg, 0.41 mmol) was
added NaI (121.6 mg, 0.82 mmol) at rt under Ar atmosphere, and the
reaction mixture was stirred under reflux for 45 min. The reaction
mixture was evaporated to dryness, and silica gel column chromatogra-
phy (CHCl3/MeOH = 20/1) of the residue gave 46 (135.8 mg, 87%) as
a solid: mp 94ꢀ96 ꢀC; UV (MeOH) λmax 264 nm (ε 6600) and λmin
235 nm (ε 2300); 1H NMR (CD3OD) δ 1.94, 1.97, and 1.99 (9H, each
BH3 THF (1 M THF solution) (0.42 mL, 0.42 mmol) at 0 ꢀC under Ar
3
atmosphere, and the reaction mixture was stirred for 8 h at rt. To the
reaction mixture was added MeOH (63 μL, 1.66 mmol), and the mixture
stirred at 0 ꢀC. After be stirring for 1 h, 9.9% NaOH (0.13 mL, 0.33 mmol)
and 30% H2O2 (28 μL, 0.25 mmol) was added at 0 ꢀC, and the mixture
was stirred for 14 h at rt. The reaction mixture was partitioned between
CHCl3/H2O and column chromatography (hexane/AcOEt = 30/1ꢀ20/1)
of the organic layer gave 41 (10 mg, 27%, syrup) and 42a,b (12 mg, 33%,
solid). Compounds 42a (solid, tR 10.6 min) and 42b (solid, tR 11.1 min)
were separated by HPLC (hexane/ethyl acetate =20/1).
0
0
0
0
as s) 3.54ꢀ3.62 (1H, m), 4.16 (1H, dd, J4 ,5 a = 5.7 and J5 a,5 b = 11.7 Hz),
0
0
0
0
0
0
4.25 (1H, dd, J4 ,5 b = 6.8 and J5 a,5 b = 11.7 Hz), 4.38 (1H, d, J1 ,2 = 6.4
0
0
0
0
0
0
Hz), 5.30 (1H, dd, J2 ,3 = 3.7 and J3 ,4 = 4.2 Hz), 5.58 (1H, dd, J1 ,2 = 3.7
and J2 ,3 = 3.7 Hz), 7.51 (1H, d, J6,1 = 0.7 Hz); 13C NMR (CDCl3) δ
20.8, 20.9, 42.9, 45.8, 65.2, 74.5, 75.9, 111.5, 140.4, 152.3, 163.1, 169.99,
170.05, 171.06; FAB-MS (m/z) 287 (M+ + H). Anal. Calcd for
C15H18N2O8S: C, 46.62; H, 4.69; N, 7.25. Found: C, 46.89; H, 4.61;
N, 6.98.
0
0
0
Physical data of 41: UV (MeOH) λmax 256 nm (ε 4000) and λmin
233 nm (ε 2700); 1H NMR (CDCl3) δ 1.03 and 1.04 (18H, each as s),
0
0
0
0
0
0
2.48 (1H, br), 3.83 (1H, ddd, J3 ,4 = 4.8, J4 ,5 a = 10.0 and J4 ,5 b = 11.2
0
0
0
0
0 0
Hz), 4.12 (1H, dd, J4 ,5 a = 10.0 and J5 a,5 b = 11.2 Hz), 4.26 (1H, dd, J4 ,5 b
=
0
0
0
0
0
0
3.6 and J5 a,5 b = 11.2 Hz), 4.40 (1H, dd, J2 ,3 = 4.8 and J3 ,4 = 10.0 Hz),
5-[4-Thio-β-D-ribofuranosyl]uracil (47). Compound 46 (100.2
mg, 0.26 mmol) was treated with methanolic ammonia (15 mL) at rt for
12 h. The reaction mixture was evaporated to dryness, and silica gel
column chromatography ((CHCl3/MeOH = 5/1) of the residue gave
crude product, which was purified by reversed pase HPLC (H2O/
CH3CN = 98/2; tR 20 min) to give 47 (50.9 mg, 75%) as a solid: mp
0
0
0
0
4.57 (1H, d, J2 ,3 = 4.8 Hz), 4.71 (1H, d, J1 ,2 = 0.4 Hz), 7.20 (1H, s),
7.26 (1H, s); NOE experiment: H-10/H-40 (1.3%) and HO-20/ H-40
(1.6%); 13C NMR (CDCl3) δ 20.2, 22.7, 27.2, 27.3, 44.9, 50.8, 68.4,
78.8, 81.0, 118.4, 125.6, 173.1; FAB-MS (m/z) 451 and 453 (M+ + H).
Anal. Calcd for C16H26BrNO3S2Si 1/2CH3CO2C2H5: C, 43.54; H,
6.09; N, 2.82. Found: C, 43.81; H, 5.79; N, 3.10.
3
256ꢀ259 ꢀC (dec.); UV (MeOH) λmax 264 nm (ε 6600) and λmin
1
0
0
Physical data of 42a: mp 110ꢀ112 ꢀC; UV (MeOH) λmax 257 nm
236 nm (ε2500); HNMR(D2O) δ3.28 (1H, m), 3.58 (1H, dd, J4 ,5 a =6.1
(ε 3470) and λmin 231 nm (ε 1950); 1H NMR (CDCl3) δ 1.02 and 1.05
and J5 a,5 b = 11.7 Hz), 3.71 (1H, dd, J4 ,5 b = 6.4 and J5 a,5 b = 11.7 Hz),
0
0
0
0
0
0
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0
0
0
0
0
0
4.04 (1H, t, J2 ,3 = J3 ,4 = 4.1 Hz), 4.13 (1H, d, J1 ,2 = 6.3 Hz), 4.26 (1H,
’ REFERENCES
dd, J1 ,2 = 6.3 and J2 ,3 = 3.9 Hz), 7.61 (1H, s); 13C NMR (CDCl3) δ
46.5, 52.9, 64.7, 76.2, 78.7, 113.1, 141.9, 153.1, 165.9; FAB-MS (m/z)
261 (M+ + H). Anal. Calcd for C9H12N2O5S: C, 41.53; H, 4.65; N,
10.76. Found: C, 41.70; H, 4.65; N, 10.40.
0
0
0
0
(1) Watanabe, K. A. In Chemistry of Nucleosides and Nucleotides;
Townsend, L. B., Ed.; Plenum Press: New York, 1994; Vol. 3, Chapter 5.
(2) For a review of nucleoside antibiotics, see: Isono, K. J. Antibiot.
1988, 41, 1711–1739.
4-Bromo-2-[2-(triethylsilyl)-3,5-O-(di-tert-butylsilylene)-
4-thio-D-erythro-pentofuranosyl]thiazole (48). To a DMF
(2.0 mL) solution of 41 (13.2 mg, 0.029 mmol) were added imidazole
(8.2 mg, 0.12 mmol) and Et3SiCl (15.2 μL, 0.087 mmol) at 0 ꢀC under
Ar atmosphere, and the mixture was stirred at rt for 12 h. The reaction
mixture was partitioned between AcOEt/H2O, and silica gel column
chromatography (hexane/AcOEt = 100/1) of the organic layer gave
48 (16.3 mg, 99%) as a syrup: UV (MeOH) λmax 258 nm (ε 3700) and
λmin 233 nm (ε 2000); 1H NMR (CDCl3) δ 0.73 (6H, q, J = 4.4 Hz,
(3) (a) Fuertes, M.; García-Lꢀopez, T.; García-Mun~oz, G.; Stud, M.
J. Org. Chem. 1976, 41, 4074–4077. (b) Srivastava, P. C.; Pickering,
M. V.; Allen, L. B.; Streeter, D. G.; Campbell, M. T.; Witkowski, J. T.;
Sidwell, R. W.; Robins, R. K. J. Med. Chem. 1977, 20, 256–262.
(4) Cooney, D. A.; Jayaram, H. N.; Gebeyehu, G.; Betts, C. R.; Kelly,
J. A.; Marquez, V. E.; Johns, D. G. Biochem. Pharmacol. 1982, 31, 2133–2136.
(5) Lim, M.-I.; Klein, R. S. Tetrahedron Lett. 1981, 22, 25–28.
(6) Glazer, R. I.; Hartman, K. D.; Knode, M. C. Mol. Pharmacol.
1983, 24, 309–315 and references cited therein.
(7) (a) Secrist, J. A., III; Tiwari, K. N.; Riordan, J. M.; Montgomery,
J. A. J. Med. Chem. 1991, 34, 2361–2366. (b) Dyson, M. R.; Coe, P. L.;
Walker, R. T. J. Chem. Soc., Chem. Commun. 1991, 741–742.
(8) For a review of synthesis and biological activity of various types
of thionucleosides, see: Yokoyama, M. Synthesis 2000, 1637–1655.
(9) For the synthesis of 40-thionucleosides, see the following and
also references cited therein: (a) Femandez-Bolanos, J. G.; al-Masoudi,
N. A.; Maya, I. Adv. Carbohydr. Chem. Biochem. 2001, 57, 21–98. (b)
Haraguchi, K.; Takahashi, H.; Tanaka, H. Tetrahedron Lett. 2002,
43, 5657–5660. (c) Haraguchi, K.; Takahashi, H.; Shiina, N.; Horii, C.;
Yoshimura, Y.; Nishikawa, A.; Sasakura, E.; Nakamura, K. T.; Tanaka, H. J.
Org. Chem. 2002, 67, 5919–5927. (d) Haraguchi, K.; Shiina, N.; Yoshimura,
Y.; Shimada, H.; Hashimoto, K.; Tanaka, H. Org. Lett. 2004, 6, 2645–2648.
(e) Yoshimura, Y.; Kuze, T.; Ueno, M.; Komiya, F.; Haraguchi, K.; Tanaka,
H.; Kano, F.; Yamada, K.; Asami, K.; Kaneko, N.; Takahata, H. Tetrahedron
Lett. 2006, 47, 591–594. (f) Kumamoto, H.; Nakai, T.; Haraguchi, K.;
Nakamura, K. T.; Tanaka, H.; Baba, M.; Cheng, Y.-C. J. Med. Chem. 2006,
49, 7861–7867. (g) Haraguchi, K.; Shimada, H.; Tanaka, H.; Hamasaki, T.;
Baba, M.; Gullen, E. A.;Dutschman, G. E.; Cheng, Y.-C.J. Med. Chem. 2008,
51, 1885–1893. (h) Haraguchi, K.; Matsui, H.; Takami, S.; Tanaka, H. J. Org.
Chem. 2009, 74, 2616–2619.
0
0
0
0
SiCH2), 1.01ꢀ1.04 (27H, m), 3.86 (1H, ddd, J3 ,4 = 4.8, J4 ,5 a = 11.0
0
0
0
0
0
0
and J4 ,5 b = 11.2 Hz), 4.08 (1H, dd, J4 ,5 a = 9.6 and J5 a,5 b = 11.4 Hz),
0
0
0
0
0
0
4.14 (1H, dd, J4 ,5 b = 3.2 and J5 a,5 b = 11.4 Hz), 4.36 (1H, dd, J2 ,3
=
=
0
0
0
0
0
0
4.8 and J3 ,4 = 10.0 Hz), 4.43 (1H, d, J1 ,2 = 0.8 Hz), 4.54 (1H, d, J2 ,3
4.8 Hz), 7.17 (1H, s), 7.26 (1H, s); 13C NMR (CDCl3) δ 4.8, 6.7, 20.1,
22.7, 27.0, 27.3, 27.4, 4.1, 53.1, 68.7, 79.7, 80.3, 118.3, 125.6, 173.9; FAB-
MS (m/z) 566 and 568 (M+ + H). Anal. Calcd for C22H40BrNO3S2Si2
1/2CH3CO2C2H5: C, 47.19; H, 7.26; N, 2.29. Found: C, 47.56; H,
7.11; N, 2.19.
3
2-[2-(Triethylsilyl)-3,5-O-(di-tert-butylsilylene)-4-thio-D-
erythro-pentofuranosyl]-4-ethoxycarbonylthiazole (49). To
a THF (1.5 mL) solution of 48 (16.7 mg, 0.029 mmol) was added tert-
BuLi (1.55 M, hexane solution) (21 μL, 0.032 mmol) at ꢀ70 ꢀC under
Ar atmosphere, and the mixture was stirred for 5 min. To the reaction
mixture was added ClCO2Et (8.3 μL, 0.087 mmol), and the mixture was
stirred for 10 min. The reaction mixture was partitioned between
CHCl3/saturated aqueous NH4Cl, and preparative TLC (hexane/
AcOEt = 20/1) of the organic layer gave 49 (3.6 mg, 22%) as a syrup:
1H NMR (CDCl3) δ 0.72 (2H, q, JCH ,CH = 8.0 Hz), 1.01 and 1.02
(18H, each as s), 1.02 (3H, t, JCH ,CH = 28.0 Hz), 1.38 (3H, t, JCH ,CH
=
3
2
3
2
3
(10) (a) Francheti, P.; Marchetti, S.; Cappellacci, L.; Grifantini, M.;
Goldstein, B. M.; Dukhan, D.; Barascut, J.-L.; Imbach, J.-L. Nucleosides,
Nucleotides Nucleic Acids 1999, 18, 679–680. (b) Franchetti, P.; Marchetti,
S.; Cappellacci, L.; Jayaram, H. N.; Yalowitz, J. A.; Goldstein, B. M.;
Barascut, J.-L.; Dukhan, D.; Imbach, J.-M.; Grifantini, M. J. Med. Chem.
2000, 43, 1264–1270.
0
0
0
0
7.2 Hz), 3.87ꢀ3.92(1H, m), 4.10 (1H, dd, J4 ,5 a = 10.0 and J5 a,5 b = 10.0
0
0
0
0
Hz), 4.17 (1H, dd, J4 ,5 b = 3.2 and J5 a,5 b = 10.0 Hz), 4.33ꢀ4.40 (3H, m),
4.44 (1H, s), 4.56 (1H, d, J2 ,3 = 3.2 Hz), 7.26 (1H, s); 13C NMR
(CDCl3) δ 4.8, 6.7, 14.1, 14.3, 20.2, 22.7, 27.0, 27.3, 29.7, 44.4, 53.3,
61.6, 68.6, 79.6, 80.4, 130.2, 131.0, 149.3, 161.4, 178.9; FAB-MS (m/z)
560 (M+ + H). FAB-HRMS (m/z) calcd for C25H46NO5S2Si2: 560.2356,
found: 560.2375 (M+).
0
0
(11) Synthesis of 40-thio-D-erythrofuraosyl furans has been reported:
(a) Lꢀopez Aparicio, F. L.; Zorrilla Benítez, F.; Santoyo Gonzꢀalez, F.;
Asensio Rosell, J. L. Carbohydr. Res. 1986, 155, 151–159. (b) Ulgar, V.;
Lopez, O.; Maya, I.; Fernandez-Bolanos, J. G.; Bols, M. Tetrahedron
2003, 59, 2801–2809.
(12) Pd-catalyzed cross-coupling reaction of 1-tributylstanny-
lated furanoid glycal with halogenated arene has been reported:
Zhang, H.-C.; Brackta, M.; Daves, G. D., Jr. Tetrahedron Lett. 1993,
34, 1571–1574.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra of
compounds. This material is available free of charge via the Internet
S
b
at http://pubs.acs.org.
’ AUTHOR INFORMATION
(13) A possible effect of the 30,50-O-DTBS protecting group for the
remarkable stereochemical outcome has recently been described in
electrophilic glycosidation employing 3,5-O-DTBS-erythro-furanoid gly-
cal: Haraguchi, K.; Konno, K.; Yamada, K.; Kitagawa, Y.; Nakamura,
K. T.; Tanaka, H. Tetrahedron 2010, 66, 4587–4600.
Corresponding Author
*E-mail: harakazu@pharm.showa-u.ac.jp.
(14) Parker, K. A.; Su, D.-S. J. Org. Chem. 1996, 61, 2191–2194.
(15) Haraguchi, K.; Shimada, H.; Kimura, K.; Akutsu, G.; Tanaka,
H.; Abe, H.; Hamasaki, T.; Baba, M.; Gullen, E. A.; Dutschman, G. E.;
Cheng, Y.-C.; Balzarini, J. ACS Med. Chem. Lett. 2011, 2, 692–697.
(16) We have already described the synthesis of 1-C-carbon-sub-
stituted 4-thiofuranoid glycal by means of LDA-mediated lithiation of
4-thiofuranoid glycal: Haraguchi, K.; Takahashi, H.; Tanaka, H. Tetra-
hedron Lett. 2002, 43, 5657–5660.
(17) Reynaud, P.; Robba, M.; Moreau, R. C. Bull. Soc. Chim. Fr.
1962, 1735.
(18) It has been described that dihalogenated thiazoles underwent
C2-selective coupling: (a) Bach, T.; Heuser, S. Angew. Chem., Int. Ed.
’ ACKNOWLEDGMENT
Financial support from Japan Society for the Promotion of
Science (KAKENHI No. 21590123 to K.H. and No. 17590094
to H.T.), the Research Foundation of Pharmaceutical Sciences
(to K.H.), and the Japan Health Sciences Foundation (SA
14804 to H.T.) is gratefully acknowledged. The authors are
also grateful to Mrs. K. Shiohara, Miss Y. Odanaka, and Mrs.
Matsubayashi (Center for Instrumental Analysis, Showa Uni-
versity) for technical assistance with NMR, MS, and elemental
analyses.
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2001, 40, 3184–3185. (b) Bach, T.; Heuser, S. J. Org. Chem. 2002,
67, 5789–5795. (c) Delgado, O.; Heckmann, G.; M€uller, H. M.; Bach, T.
J. Org. Chem. 2006, 71, 4599–4608. (d) Pereira, R.; Furst, A.; Iglesias, B.;
Bermain, P.; Gronemeyer, H.; de Lera, A. R. Org. Biomol. Chem. 2006,
4, 4514–4525.
(19) Furneaux, R. H.; Tyler, P. C. J. Org. Chem. 1999, 64, 8411–8412.
(20) Hydroboration of dihydrothiophene has been reported:
O’Neil, I. A.; Hamilton, M.; Miller, J. A. Synlett 1995, 1053.
(21) Of the two protons at the 50-position, the one that appears at a
higher field is designated as H-50a, and the other as H-50b, throughout
the text and experimental section. The same was applied to H-20.
(22) Grohar, P. J.; Chow, C. S. Tetrahedron Lett. 1999, 40, 2049–2052.
(23) Haraguchi, K.; Matsui, H.; Takami, S.; Tanaka, H. J. Org. Chem.
2009, 74, 2616–2619.
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