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New Journal of Chemistry
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on the uracil ring. After several unsuccessful trials with N-
protecting groups on uracil of 2’-deoxypseudouridine (
opted to protect the oxygens of uracil for subsequent glycosylation with ribofuranoid glycal
Thus, 2,4-dimethoxy-5-iodopyrimidine (
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), we protected equivalent of uracil, was suDbOjeI:c1t0e.d103t9o/Ct9hNeJ01H0e12cBk
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. In a continuous
screening of palladium catalyst and phosphine ligand
combinations, the silyl enol ether adduct from Heck
transformation.
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glycosylation was obtained as a single diastereomer in good
yields (76%) when the reaction was carried out in DMF at 70 °C
with Pd2(dba)3 as the catalyst and PPh3 as the ligand (entries 3
and 5 in Table S2 in Supporting Information). In contrast, when
the reaction was carried out with Pd(OAc)2 and PPh3, only a
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minimum yield of the silyl enol ether
9 was obtained
accompanied with the formation of the corresponding
desilylated adduct 10 in 83% yield (Table S2). Our investigation
showed that the use of Pd(OAc)2 as the catalyst resulted in
partial desilylation of the immediate Heck adduct
product mixtures of Regardless, the overall yield
for the C-C bond formation is excellent and the condition is
more suitable for multi-gram synthesis. Although and 10 can
be readily separated by column chromatography for
characterization purpose, in our later work, the mixture of
and 10 was treated with TBAF and AcOH for global desilylation
to give 5-(2’-deoxy-3’-oxoribofuranosyl)-2,4-
9 to form a
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reagents and conditions:
(a) Pd2dba3 (0.1 equiv), XantPhos (0.2 equiv), 5-iodouracil (3, 2 equiv), glycal 4 (1
equiv), n-Bu3N (1.5 equiv), DMF (0.05 M), 70 °C, 15 h, 83%; (b) AcOH (2 equiv),
TBAF (1M in THF, containing ca. 5% water, 2 equiv), THF (0.2 M), 0 °C~rt, 8 h, 85%;
(c) NaB(OAc)3H (1.5 equiv), AcOH/CH3CN (12 mL, v/v = 1 : 1, 0.066 M), 0 °C~rt, 3 h,
92%
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dimethoxypyrimidine (11) in an excellent yield.
Scheme 3. Synthesis of 2’-deoxypseudouridine (dΨ, 2)
As a result, instead of elaborating the silyl enol ether 9, we
decided to derive the 3’-keto adduct 11 into the targeted
molecule. After protecting the 5’-hydroxy group of 11 with
TBDPS, the 3’-keto group was reduced with NaBH4 to form an
epimeric mixture of 13. Subsequently, mesylation of the
mixture 13 followed by elimination and concomitant removal
of TBDPS group with DBU in CH3CN furnished the 2’,3’-
dideoxydidehydro-C-nucleoside 15. cis-Dihydroxylation of 15
with OsO4 gave a mixture of lyxofuranosyl and ribofuranosyl
adducts (16 and 17, respectively) in the ratio of 1 to 6.4.31
Fortunately, the desired product 17 is predominant and can be
readily separated.32 Finally, O-demethylation of 17 was
accomplished by treatment with NaI in acetic acid at reflux
temperature to afford pseudouridine (
data of our synthesized pseudouridine (
1
1
).11 The spectroscopic
) is in accordance with
data previously reported in the literature (Tables S3~S6 in
Supporting Information). 11,15,33-35
Conclusion
In summary, we herein reported a facile and practical
synthesis for pseudouridine ), which provides a
(
1
complementary access to this important biological molecule.
Further application of this approach to manipulate the Heck-
type glycosylation adducts into ribonucleosides would be
amenable to the synthesis of versatile C-nucleosides.
reagents and conditions:
(a) Pd(OAc)2 (0.1 equiv), PPh3 (0.2 equiv), 2,4-dimethoxy-5-iodopyrimidine (8, 2
equiv), glycal 4 (1 equiv), Et3N (1.5 equiv), DMF (0.1 M), 70 °C, 15 h; (b) TBAF (1M
in THF, containing ca. 5% water, 2.0 + 1.0 equiv), AcOH (2.0 equiv), THF (0.1 M), 0
°C~rt, overnight, 88% from 4; (c) TBDPSCl (1.2 equiv), imidazole (2.2 equiv), DCM
(0.1 M), rt, overnight, 97%; (d) NaBH4 (1.5 equiv), MeOH (0.1 M), rt, 1 h, 96%
(diastereoisomeric mixture); (e) MsCl (1.3 equiv), Et3N (1.5 equiv), DCM (0.1 M),
rt, 1 h (quantitative); (f) DBU (18 equiv), CH3CN (0.1 M), 75 °C, 48 h, 49% from 13;
(g) OsO4 (0.05 equiv), NMO (3.0 equiv), acetone (0.1 M), -20 °C~rt, overnight, 76%
(16 : 17 = 1 : 6.4); (h) NaI (4 equiv), AcOH (0.04 M), reflux, 45 min, 90%
Experimental section
General chemical procedures
The chemical shift values are reported in δ values (parts per
million, ppm) relative to the standard chemical shift for the
hydrogen residue peak and carbon-13 peak in the deuterated
Scheme 4. Synthesis of pseudouridine (Ψ, 1)
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