Synthesis of 4- or 3-Substituted Phenyl C-Nucleosides
SHORT COMMUNICATION
omer 3 or 5 (1 mmol) in dichloromethane (50 mL) (in case of 5,
1 mL of H2SO4 was also added). The mixture was stirred at 40°C
for 24 h and then poured onto ice containing NaHCO3. Products
were extracted to chlorophorm and chromatographed as above.
fully characterized and molecular structure of 8c was also
determined by X-ray diffraction (Figure ).[13]
Suzuki–Miyaura Cross-Coupling of 2 or 4: Toluene (15 mL) was
added to an argon-purged flask containing bromo derivative 2 or
4 (255 mg, 0.5 mmol), arylboronic acid (1 mmol), K2CO3 (100 mg),
and Pd(PPh3)4 (30 mg, 0.025 mmol) and the mixture was stirred at
100°C for 12 h. After filtration and evaporation the mixture was
chromatographed as above.
Stille Cross-Coupling of 2: DMF (10 mL) was added to an argon-
purged flask containing bromo derivative 2 (255 mg, 0.5 mmol), 2-
thienyl(tributyl)stannane (1 mmol), and Pd(PPh3)4 (30 mg,
0.025 mmol) and the mixture was stirred at 100°C for 12 h. After
evaporation, the mixture was chromatographed as above.
Cross-Coupling of 2 with Organozinc or Organoaluminium Rea-
gents: THF (10 mL) was added to an argon-purged flask contain-
ing bromo derivative 2 (255 mg, 0.5 mmol), and Pd(PPh3)4 (30 mg,
0.025 mmol) and the mixture was stirred until a clear solution was
formed. Then a commercial solution of triethylaluminium or ben-
zylzinc chloride (1 mmol) was added and the mixture was stirred
at 70°C for 12 h. Then it was poured onto ice containing NH4Cl
and EDTA and extracted to ethyl acetate. After evaporation, the
mixture was chromatographed as above.
Figure 1. ORTEP drawing of 8c with the atom numbering scheme.
Thermal ellipsoids are drawn at the 50% probability level.
This modular and facile methodology was shown to be
a very good alternative to the synthesis of substituted
phenyl and biaryl C-nucleosides. It avoids the use of toxic
and harmful organocadmium compounds commonly used
in the synthesis of this type of nucleosides. There is also
no need of optimization of the coupling and isomerization
conditions for each arylorganometal reagent. In our meth-
odology, the bromophenylnucleosides are prepared in
multigram amounts from very cheap starting compounds
(2-deoxyribose and dibromobenzenes) and the subsequent
cross-couplings are standard established reactions generally
proceeding very well with a variety of commercially avail-
able organometallics. As the proof of principle, it was dem-
onstrated on 1,4- and 1,3-dibromobenzene but most likely
also other types of dihaloaromatics and heteroaromatics
could be in the same way converted to mono-Grignard rea-
gent, coupled with halogenose and eventually used in cross-
coupling reaction and thus generate a large series of diverse
novel C-nucleosides. Due to its modularity in the choice of
the bromoarylmagnesium reagent and organometallic rea-
gent for the cross-coupling, this method could be used even
for the construction of libraries of C-nucleosides. Hopefully,
it will enable preparation of new types of C-nucleosides for
the use in chemical biology and extension of genetic alpha-
bet.
Deprotection of 6 or 7: NaOMe (1 solution in MeOH, 0.1 mL,
0.1 mmol) was added to a solution of 6 or 7 (0.2 mmol) in MeOH
(100 mL) and the resulting solution was allowed to stand overnight
at room temp. Then it was evaporated and the residue chromato-
graphed on a silica gel column [EA/hexanes (2:1) to EA/MeOH
(9:1)]. Products were crystallized from ethyl acetate/heptane.
Supporting Information: Full experimental details and spectral and
analytical data for all new compounds (see also the footnote on the
first page of this article).
Acknowledgments
This work is a part of the Institute’s research project Z4 055 905.
It was supported by the Centre of Biomolecules and Complex Mo-
lecular Systems (LC 512) and by NIH, Fogarty International
Center (grant R03TW007372, PI Prof. Robert D. Kuchta).
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Experimental Section
Coupling of Halogenose 1 with Organomagnesium Reagents: 1,4- or
1,3-Dibromobenzene (4.4 mmol) was added dropwise to magne-
sium turnings (128 mg, 5.2 mmol) activated by one drop of ethylene
bromide in THF (10 mL). The mixture was stirred at 65°C for 1 h
and the resulting solution was added to a solution of 1 (1.2 g,
3 mmol) in THF (50 mL). The mixture was stirred at room temp.
for 12 h, poured onto ice containing NH4Cl, exctracted to ethyl
acetate (2×100 mL), evaporated, and chromatographed on a silica
gel column (hexanes/EA, 10:1) to get products 2 and 3 or 4 and 5.
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Isomerization of α-Anomers: A mixture of BSA (550 mg, 3.5 mmol)
and TFA (1.25 mL, 16.8 mmol) was added to a solution of α-an-
Eur. J. Org. Chem. 2005, 4525–4528
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