Simple synthesis of aromatic β-C-nucleosides via coupling of aryl grignard reagents with sugar fluorides

Article abstract of DOI:10.1055/s-1998-4487

The perbenzylated D-ribofuranosyl fluoride is allowed to react with Grignard reagents of aromatic heterocycles such as thiophene, pyrrole, and indole in THF to afford the corresponding β-C-nucleosides in moderate yields. The present process can be also applied to perbenzylated D- glucopyranosyl fluoride and perbenzylated 2-deoxy-D-ribofuranosyl fluoride as sugar donors.

Full text of DOI:10.1055/s-1998-4487

April 1998
SYNTHESIS
409
b
Simple Synthesis of Aromatic -C-Nucleosides via Coupling of Aryl Grignard Reagents
with Sugar Fluorides
Masataka Yokoyama,* Hirofumi Toyoshima, Miyuki Shimizu, Jun Mito, Hideo Togo
Department of Chemistry, Faculty of Science, Chiba University, Yayoi-cho, Inage-ku, Chiba 263, Japan
Fax +81(43)2902874; E-mail: yokoyama@science.s.chiba-u.ac.jp
Received 27 May 1997; revised 22 July 1997
Abstract: The perbenzylated D-ribofuranosyl fluoride is allowed Table 1. Reaction of Sugar Fluoride 1 with Various Arylmetal
to react with Grignard reagents of aromatic heterocycles such as Reagents 2
thiophene, pyrrole, and indole in THF to afford the corresponding
b-C-nucleosides in moderate yields. The present process can be Entry Ar-Metala Solvent Temp (°C) Prod-
Yield Ratio
also applied to perbenzylated D-glucopyranosyl fluoride and per-
benzylated 2-deoxy-D-ribofuranosyl fluoride as sugar donors.
uct
(%)
of a/b
l
ArMgBr THF
ArMgBr THF
ArMgBr Et2O
r.t.
50
r.t.
50
50
50
50
r.t.
3a
3a
3a
3a
3a
3a
3a
3b
65
52
64
67
51
53
41
54
8:92
0:100
6:94
18:82
12:88
58:42
32:68
0:100
Key words: sugar fluorides, Grignard reagents, C-nucleosides, b-
2
3
4
5
6
7
8
selectivity
ArZnCl
Ar2Zn
ArCdCl
Ar2Cd
THF
THF
THF
THF
Since the remarkable biological activity of naturally oc-
curring showdomycin was recognized, the synthesis of C-
nucleosides has attracted wide interest in the field of or-
ganic chemistry.1 In our study on the use of D-ribofurano-
syl fluoride as a sugar donor,2 we found that aryl Grignard
reagents reacted easily with perbenzylated D-ribofurano-
syl fluoride without Lewis acids to give the corresponding
C-nucleosides in a b-selective manner. Recently, Kool
and co-workers reported a procedure to prepare aromatic
C-nucleosides using protected D-deoxyribosyl chloride as
a sugar donor.3 We wish to report here a better and practi-
cal method for the b-selective synthesis of C-nucleosides
by utilizing the sugar fluorides in place of the unstable
sugar chlorides (Scheme 1).
ArMgBr THF
a For entries 4–7, Ar = 2-thienyl; for entry 8, Ar = N-methylpyrrol-2-yl.
Scheme 2
The reaction of arylmagnesium reagents with the sugar
fluoride 1 was also examined. The reaction took place at
room temperature to give the desired C-nucleosides with
b-selectivity, while the yield of 3 increased at 50°C to-
gether with perbenzylated D-ribofuranoid glycals 4 as
byproducts (Scheme 1, Table 2). From Entries 2–5 it is
clear that the electron-rich benzene derivatives afford
more glycals 4. The fact that the reaction with p-methoxy-
phenylmagnesium bromide gave glycal 4 in 44 % yield
without the desired C-nucleoside, and the result of Entry
6 support this result.
Scheme 1
In a typical experimental procedure, a mixture of 2,3,5-tri-
O-benzyl-D-ribofuranosyl fluoride (1), 2-thienylmagne-
sium bromide 2, and anhydrous THF was stirred at room
temperature to afford the corresponding C-nucleoside 3 in
65 % yield in a b-selective manner (a/b = 8:92) (Scheme
1 and Table 1).
Table 2. Reaction of Sugar Fluoride 1 with Various Aryl Grignard
Reagents (ArMgBr)
Entry Ar
Temp (°C)
Product(s)
Yield (%)
3a
4
The solvent effect of the reaction was examined by chang-
ing diethyl ether to tetrahydrofuran as the solvent. Al-
though diethyl ether was found to be a little better than
THF in b-selectivity (Entry 3), THF was employed as the
solvent due to easier handling. The b-selectivity was di-
minished when other metal reagents of heterocycles such
as zinc and cadmium were used4 (Entries 4–7). It is no-
ticeable that Entry 6 shows a-selectivity (Scheme 2).
1
2
3
4
5
6
7
Ph
Ph
r.t.
50
50
50
50
50
50
23
57
29
45
34
70
54
0
29
0
51
36
0
2-MeC6H4
4-MeC6H4
3-MeOC6H4
4-ClC6H4
1-naphthyl
0
a Only b-selectivity was observed.

410
Papers
SYNTHESIS
Table 3. IR and MS Data of Compounds 3–8 Prepared
Prod-
ucta
Molecular
Formula
IR (Neat)
HRMS (FAB/NBA), m/z
n (cm–1)
calc.
found
3ab
3b
3c
3d
3e
3f
C30H30O4S
(486.6)
C31H33NO4
(483.6)
C32H32O4
(480.6)
C33H34O4
(494.6)
C33H34O4
(494.6)
C33H34O5
(510.6)
32H31ClO4
(515.1)
C36H34O4
(530.7)
C39H41NO5
(603.8)
C37H40O5
(564.7)
C23H24O3S
(380.5)
C27H26O3S
(430.6)
1080, 2830
509.1763
(M + Na+)
484.2488
(M + 1)
509.1763
(M + Na+)
484.2501
(M + 1)
910, 1460, 1500, 2860, 3030
700, 1460, 1500, 2940, 3020
740, 1120, 2860, 2920, 3030
700, 1100, 1150, 2950, 3010
1090, 1130, 1460, 2880, 3030
1450, 1490, 1720, 2880, 3030
1090, 1130, 1460, 2880, 3030
700, 1060, 2910, 3030, 3450
1100, 2870, 2900, 3030, 3060
740, 1100, 1460, 2860, 3030
730, 1100, 2880, 2930, 3030
519.1938
(M + K+)
533.2094
(M + K+)
533.2094
(M + K+)
549.2043
(M + K+)
515.1989
(M + 1)
569.2094
(M + K+)
603.3063
(M)
565.2954
(M + 1)
519.1954
(M + K+)
533.2111
(M + K+)
533.2106
(M + K+)
549.1997
(M + K+)
515.1986
(M + 1)
569.2104
(M + K+)
603.3052
(M)
565.2944
(M + 1)
3g
3h
6a
6b
8a
8b
419.1083
(M + K+)
430.1603
(M)
419.1079
(M + K+)
430.1602
(M)
a All compounds are oils, except 3e: mp 78–79°C; 3g: mp 54–56°C; 6a: mp 109–110°C; and 8b: mp 56–57°C.
b Anal. calc. for C30H30O4S (486.6): C, 74.05; H, 6.21. Found: C, 73.90; H, 6.07.
Furthermore, the pyrrolylation and allylation of D-glu-
copyranose were successful by using the present proce-
dure. 2,3,4,6-Tetra-O-benzyl-D-glucopyranosyl fluoride
(5)5 was allowed to react with N-methylpyrrol-2-ylmag-
nesium bromide to give the corresponding product 6a in
45 % yield as only b-epimer, and allylmagnesium bro-
mide gave the corresponding product, 6b in 77 % yield (a/
b = 35:65).
Scheme 3
The allylation of D-glucopyranose reported before gave
the corresponding product in an a-selective manner.6
Therefore, the sugar lactones have been employed in a
two step procedure in order to obtain the corresponding b-
glucosides.7
The reaction is considered to proceed via an oxocarbeni-
um ion, and show b-selectivity because of the steric hin-
drance of 2-alkoxy group. These are explained by the
following facts:
The structure determination of aromatic C-nucleosides
was carried out by the comparison of their spectral data
with those of authentic samples.8 The stereochemistries of
3, 6 and 8 were determined mainly by the result of differ-
ential NOE (1-H « 4-H) and J1¢ 2¢ values in NMR mea-
surements. Particularly, the structure of 6b was
determined by the following NMR data; J1¢ 2¢ values (a:
5.6 Hz, b: 12.5 Hz) and d values in 13C NMR of g-position
carbons to C-3 (a: 3¢-C, d = 82.4; 5¢-C, d = 71.2. b: 3¢-C,
(1) The a-epimer of 1 gave the same result as its b-
epimer; (2) 2,3,5-tri-O-benzylribofuranose was observed
in the first stage of the reaction by TLC monitoring; and
(3) the use of 2,3,5-tri-O-methyl-D-ribofuranosyl fluoride
in place of 1 gave the corresponding thiophenyl C-nucle-
oside in 49% yield with higher a-selectivity (a/b = 41:59)
than that of 1; (4) the use of 7 gave the corresponding
product with a-selectivity.
1
d = 87.3 ; 5¢ -C, d = 79.1). The IR, Mass, and H NMR
spectroscopic data are summarized in Tables 3 and 4.
The decrease of b-selectivity with softer zinc and cadmi-
um reagents than a magnesium reagent9 may be explained
by the bulkiness of the nucleophilic species solvated
The reaction of 3,5-di-O-benzyl-2-deoxy-D-ribofuranosyl
fluoride (7) with 2-thienylmagnesium bromide and 2-ben-
zothienylmagnesium bromide afforded the corresponding
products 8a and 8b in 37 (a/b = 67:33) and 54 % (a/b = strongly by THF even if the ionic adius of magnesium is
smaller (Entries 1–7 in Table 1).10
55:/45) yields, respectively (Scheme 3).

April 1998
SYNTHESIS
411
Table 4. 1H NMR Data of Compounds 3-8 Prepared
Product
1H NMR (CDCl3/TMS)h
d, J (Hz)
3a
a-form 3.59–3.77 (m, 2 H, 5¢-Ha, 5¢-Hh), 4.03 (dd, 1 H, 2¢-H, J1¢,2¢ = 3.3, J2¢.3¢ = 3.7), 4.24–4.28 (m, 2 H, 3¢-H, 4¢-H),
4.34–4.60 (m, 6 H, benzyl-H), 5.33 (d, 1 H, 1¢-H, J1¢.2¢ = 3.3), 6,96–7.08 (m, 1 H, thiophene 4-H), 7.16 (d, 1 H,
thiophene 3-H, J3¢,4¢ = 2.2), 7.18–7.20 (m, 1 H, thiophene 5-H), 7.22–7.33 (m, 15 H, benzyl Ph-H)
b-form 3.60 (m, 2 H, 5¢-Ha, 5¢-Hb), 3.91 (dd, 1 H, 2¢-H, J1¢,2¢ = 6.6, J2¢,3¢ = 5.0), 4.01 (dd, 1 H, 3¢-H, J2¢,3¢ = 5.0,
J3¢,4¢ = 3.8), 4.31 (dd, 1 H, 4¢-H, J3¢,4¢ = 3.8, J4¢,5¢ = 4.4), 4.49–4.63 (m, 6 H, benzyl-H), 5.26 (d, 1 H, 1¢-H, J1¢,2¢ = 6.6),
6.95 (m, 1 H, thiophene 4-H), 7.05 (m, 1 H, thiophene 3-H), 7.21–7.34 (m, 16 H, thiophene 5-H, benzyl Ph-H)
b-form 3.52 (d, 2 H, 5¢-Ha, 5¢-Hb, 4¢,5¢ = 4.4), 3.58 (brs, 3 H, pyrrole NCH3), 4.02 (dd, 1 H, 3¢-H, J2¢,3¢ = 5.6),
4. 12 (dd, 1 H, 2¢-H, J1¢.2¢ = 7.1, J2¢,3¢ = 5.6), 4.25–4.28 (m, 1 H, 4¢-H), 4.46–4.66 (m, 6 H, benzyl-H), 5.02 (d, 1 H, 1¢-H,
1¢,2¢ = 7.1), 6.02–6.05 (m, 2 H, pyrrole 3-H, 4-H), 6.57–6.58 (m, 1H, pyrrole 5-H), 7.22–7.34 (m, 15 H, benzyl Ph-H)
b-form 3.61–3.69 (m, 2 H, 5¢-Ha, 5¢-Hb), 3.81 (dd, 1 H, 2¢-H, J1¢,2¢ = 6.6, J2¢,3¢ = 5.4), 4.01 (dd, 1 H, 3¢-H, J2¢,3¢ = 5.4,
3¢,4¢ = 4.6), 4.33–4.37 (m, 1 H, 4¢-H), 4.44–4.63 (m, 6 H, benzyl-H), 5.02 (d, 1 H, 1¢-H, J1¢,2¢ = 6.6), 7.17–7.40 (m, 20 H,
benzene 2-H, 3-H, 4-H, 5-H, 6-H, benzyl Ph-H)
b-form 2.37 (s, 3 H, Ar-CH3), 3.65 (dd, 1 H, 5¢-Ha, 4¢,5¢ = 3.9, Jgem = 10.5), 3.73 (dd, 1 H, 5¢-Hb, J4¢,5¢= 3.9, Jgem = 10.5),
3b
3c
3d
J
J
J
J
3.88 (dd, 1 H, 2¢-H, J1¢,2¢ = 6.1, J2¢,3¢ = 5.6), 4.07 (t, 1 H, 3¢-H, J2¢,3¢ = 5.6), 4.34 (q, 1 H, 4¢-H, J4¢,5¢ = 3.9),
4.43–4.69 (m, 6 H, benzyl-H), 5.28 (d, 1 H, 1¢-H, J1¢,2¢ = 6.1), 7.09–7.36 (m, 17 H, benzyl Ph-H, toluene-H),
7.50 (d, 2 H, toluene-H, J = 3.3)
3e
3f
b-form 2.34 (s, 3 H, Ar-CH3), 3.61–3.68 (m, 2 H, 5¢-Ha, 5¢-Hb), 3.80 (dd, 1 H, 2¢-H, J1¢,2¢ = 6.6, J2¢,3¢ = 5.4), 4.00 (dd, 1H, 3¢-H,
J
2¢,3¢ = 5.4, J3¢,4¢ = 4.6), 4.33 (dd, 1 H, 4¢-H, J3¢,4¢ = 4.6, J4¢,5¢ = 4.0), 4.47–4.62 (m, 6 H, benzyl-H), 5.00 (d, 1 H, 1¢-H,
J1¢.2¢ = 6.6), 7.09–7.34 (m, 19 H, toluene 2-H, 3-H, 5-H, 6-H, benzyl Ph-H)
b-form 3.61–3.68 (m, 5 H, 5¢-Ha, 5¢-Hb, Ar–OCH3), 3.80–3.84 (m, 1 H, 2¢-H, J1¢,2¢ = 6.3), 4.02 (t, 1 H, 3¢-H), 4.33–4.36
(m, 1 H, 4¢-H), 4.50–4.64 (m, 6 H, benzyl-H), 5.01 (d, 1 H, l¢-H, J1¢,2¢ = 6.3), 6.79–6.82 (m, 1 H, anisole-H),
6.93–6.99 (m, 1 H, anisole-H), 7.19–7.66 (m, 17 H, benzyl Ph-H, anisole-H)
3g
3h
b-form 3.60 (dd, 1 H, 5¢-Ha, J4¢,5¢ = 3.8 Hz, Jgem = 10.3), 3.66 (dd, 1 H, 5¢-Hb, J4¢,5¢ = 3.8, Jgem = 10.3), 3.74 (dd, 1 H, 2¢-H,
J
1¢,2¢ = 7.=, J2¢,3¢ = 5.3), 3.99 (dd, 1 H, 3¢-H, J2¢,3¢ = 5.3, J3¢,4¢ = 3.8), 4.34 (dd, 1 H, 4¢-H, J3¢,4¢ = 3.8, J4¢,5¢ = 3.8), 4.38–4.69
(m, 6 H, benzyl-H), 4.97 (d, 1 H, 1¢-H, J1¢,2¢ = 7.0), 6.98–7.37 (m, 19 H, chlorobenzene 2-H, 3-H, 5-H, 6-H, benzyl Ph-H),
b-form 3.74 (dd, 1 H, 5¢-Ha, J4¢,5¢ = 3.8 Hz, Jgem = 10.7), 3.86 (dd, 1 H, 5¢-Hb, J4¢,5¢ = 3.4, Hz, Jgem = 10.7), 4.08
(t, 1 H, 2¢-H, J1¢,2¢ = 4.8), 4.13–4.15 (m, 1 H, 3¢-H), 4.43–4.68 (m, 7 H, 4¢-H, benzyl-H), 5.78–5.79 (d, 1 H, 1¢-H, J1¢.2¢ = 4.8),
7.19–7.42 (m, 18 H, naphthalene-H, benzyl Ph-H), 7.47 (dd, 1 H, naphthalene-H, J = 6.7, 7.0), 7.77 (dd, 1 H, naphthalene-H,
J = 6.3, 6.8), 7.85 (d, 1 H, naphthalene-H, J = 8.7), 8.12 (d, 1 H, naphthalene-H, J = 8.5)
6a
6b
b-form 3.55–3.58 (m, 1 H, 5¢-H), 3.61 (s, 3 H, pyrrole NCH3), 3.67–3.74 (m, 2 H, 2¢-H, 4¢-H), 3.75–3.79 (m, 3 H, 3¢-H, 6¢-H), 3.99
(d, 1 H, benzyl-H), 4.34 (d, 1 H, 1¢-H, J1¢.2¢ = 9.5), 4.44–4.64 (m, 4 H, benzyl-H), 4.85–4.98 (m, 3 H, benzyl-H), 6.12–6.13
(m, 1 H, pyrrole 4-H), 6.24–6.26 (m, 1 H, pyrrole 3-H), 6.59–6.60 (m, 1 H, pyrrole 5-H), 7.01–7.36 (m, 20 H, benzyl Ph-H)
a-formb 2.42–2.54 (m, 2 H, 3-H), 3.59–3.66 (m, 3 H, 4¢-H, 5¢-H, 6¢-Ha), 3.70 (dd, 1 H, 6¢-Hb, J5¢,6¢= 3.5, Jgem = 10.5), 3.75 (dd,
1 H, 2¢-H, J1¢,2¢ = 5.6, J2¢,3¢ = 9.5), 3.79 (dd, 1 H, 3¢-H, J2¢,3¢ =9.5, J3¢,4¢ = 8.1), 4.14 (ddd, 1 H, 1¢-H, J1¢,2¢ = 5.6, J1¢,3a = 11.0,
J1¢,3h = 4.6), 4.46–4.94 (m, 8H, benzyl-H), 5.07 (dd, 1 H, J1,2 = 10.8, Jgem = 1.5), 5.15 (dd, 1 H, 1-Hb, J1b,2= 17.1,
Jgem = 1.5), 5.81 (dddd, 1 H, 2-H, J1a,2 = 10.8, J1b,2 = 17.1, J2,3a = 6.4, J2,3b = 7.3), 7.11–7.37 (m, 20 H, benzyl Ph-H)
b-formc 2.32 (ddd, 1 H, 3-Ha, J2,3a = 7.1 Hz, Jgem = 14.6, J1¢,3a = 7.3), 2.60 (ddd, 1 H, 3-Ha, J2,3b= 6.4, Jgem = 14.6,
J1¢,3b = 3.2), 3.33 (dd, 1 H, 2¢-H, J1¢,2¢ = 12.5, J2¢,3¢ = 8.3), 3.34 (ddd, 1 H, 1¢-H, J1¢,2¢ = 12.5, J1¢,3a = 7.3, J1¢,3b = 3.2),
3.41 (ddd, 1 H, 5¢-H, J4¢,5¢ = 9.6, J5¢,6¢a = 4.5, J5¢,6¢b = 2.0), 3.60 (dd, 1 H, 4¢-H, J3¢,4¢ = 9.2, J4¢,5¢ = 9.6), 3.68 (dd,
1 H, 6¢-Ha, J5¢,6¢a = 4.5, Jgem = 10.6), 3.70 (dd, 1 H, 3¢-H, J2¢,3¢ = 8.3, J3¢,4¢ = 9.2), 3.73 (dd, 1 H, 6¢-Hb, J5¢,6¢b= 2.0,
Jgem = 10.6), 4.55–4.90 (m, 8 H, benzyl-H), 5.07 (dd, 1 H, 1-Ha, J1a,2= 10.3, Jgem = 1.0), 5.10 (dd, 1 H, 1-Hb, J1b,2= 7.2,
Jgem = 1.0), 5.93 (dddd, 1 H, 2-H, J1a,2 = 10.3, J1b,2 = 17.2, J2,3a = 6.4, J2,3b = 7. 1), 7.20–7.30 (m, 20 H, benzyl Ph-H)
8a
8b
a-form 2.04–2.11 (m, 1 H, 2¢-Ha, J1¢,2¢= 5.2), 2.41–2.44 (m, 1 H, 1-Hb, J1¢,2¢= 5.2), 3.53 (dd, 1 H, 5¢-Ha, Jgem = 5.6, J4¢.5¢ = 4.6),
3.65 (dd, 1 H, 5¢-Hb, Jgem =5.6, J4¢,5¢ = 4.6), 4.17–4.19 (m, 1 H, 3¢-H), 4.26–4.30 (m, 1 H, 4¢-H), 4.52–4.62 (m, 4 H,
benzyl-H), 5.39 (dd, 1 H, l¢-H, J1¢,2¢ = 5.2), 6.94–7.01 (m, 3 H, thiophene 3-H, 4-H, 5-H)
7.23–7.36 (m, 10 H, benzyl Ph-H)
b-form 2.17–2.26 (m, 1 H, 2¢-Ha, J1¢,2¢= 6.7), 2.63–2.69 (m, 1 H, 2¢-Hb, J1¢,2¢= 6.7), 3.59–3.67 (m, 2 H, 5¢-Ha, 5¢-Hb), 4.24–4.33
(m, 2 H, 3¢-H, 4¢-H), 4.47–4.62 (m, 4 H, benzyl-H), 5.34 (t, 1 H, 1¢-H, J1¢,2¢ = 6.7), 6.94–7.02 (m, 3 H, thiophene
3-H, 4-H, 5-H), 7.24–7.37 (m, 10 H, benzyl Ph-H)
a-form 2.27–2.33 (m, 1 H, 2¢-Ha, J1¢,2¢= 6.7), 2.65–2.72 (m, 1 H, 2¢-Hb, J1¢,2¢ = 6.7), 3.59–3.67 (m, 2 H, 5¢-Ha, 5¢-Hb), 4.28 (q, 1 H,
J
3¢,4¢ = 4.2, 3¢-H), 4.37 (q, 1 H, J3¢,4¢ = 4.2, J4¢,5¢ = 8.4, 4¢-H), 4.46–4.63 (m, 4 H, benzyl-H), 5.43 (t, 1 H, 1¢-H, J1¢,2¢ = 6.7), 7.21–
7.37 (m, 13 H, benzothiophene-H, benzyl Ph-H), 7.69 (d, 1 H, J=8.2, benzothiophene-H), 7.79 (d, 1 H, J=7.5, benzothiophene-H)
b-form 2.11–2.18 (m, 1 H, 2¢-Ha, J1¢,2¢= 5.3), 2.44–2.49 (m, 1 H, 2¢-Hb, J1¢,2¢= 5.3), 3.54–3.58 (dd, 1 H, 5¢-Ha, J4¢,5¢= 5.5,
Jgem = 10.0), 3.68 (dd, 1 H, 5¢-Hb, J4¢,5¢= 4.6, Jgem = 10.0), 4.20–4.22 (m, 1 H, 3¢-H), 4.32–4.35 (m, 1 H, 4¢-H, J4¢,5¢ = 5.5,
4.6), 4.54–4.65 (m, 4 HJ, benzyl-H), 5.45–5.49 (dd, 1 H, 1¢-H, J1¢,2¢ – 5.3), 7.21–7.47 (m, 13 H, benzothiophene-H,
benzyl Ph-H) 7.68–7.70 (dd, 1 H J = 7.4, benzothiophene-H), 7.79 (d, 1 H, J = 7.7, benzothiophene-H)
a 1H NMR spectra were recorded at 400 MHz for 3b-h, 6a, 8a, b and at 500 MHz for 3a, 6b.
b 13C NMR (CDCl3/TMS): d = 29.8 (3-C), 69.0 (6¢-C), 71.52 (5¢-C), 73.7 (1¢-C), 78.2 (4¢-C), 80. 1 (2¢-C), 82.4 (3¢-C), 116.8 (1-C), 134.8 (2-C)
c 13C NMR (CDCl3/TMS): d = 36.0 (3-C), 69.1 (6¢-C), 78.70 (4¢-C), 78.74 (1¢-C), 79.1 (5¢-C), 81.6 (2¢-C), 87.3 (3¢-C), 117.0 (1-C), 134.8 (2 C).

412
Papers
SYNTHESIS
(2) Yokoyama, M.; Nomura, M.; Tanabe, T.; Togo, H. Heteroatom
Chem. 1995, 6, 189.
In conclusion, the present method is very useful for the
preparation of b-C-nucleosides, because sugar fluorides
are very stable sugar donors and their glycosylation pro-
ceeds by simple operation and, furthermore, with b-selec-
tivity.
Yokoyama, M.; Nomura, M.; Togo, H.; Seki, H. J. Chem. Soc.,
Perkin Trans. 1 1996, 2145.
(3) Schweitzer, B. A.; Kool, E. T. J. Org. Chem. 1994, 59, 7238.
Chaudhuri, N. C.; Kool, E. T. Tetrahedron Lett. 1995, 36, 1795.
(4) This reagent was prepared by the same method as that of diphe-
nylzinc or -cadmium according to the literature.3
(5) Posner, G. H.; Haines, S. R. Tetrahedron Lett. 1985, 26, 5.
(6) Nicolaou, K. C.; Dolle, R. E.; Chucholowski, A.; Randall, J. L.
J. Chem. Soc., Chem. Comm. 1984, 1153.
2-(2,3,5-Tri-O-benzyl-D-ribofuranosyl)thiophene (3a); Typical
Procedure:
A mixture of 2,3,5-tri-O-benzyl-D-ribofuranosyl fluoride (1; 85 mg,
0.2 mmol), 2-thienylmagnesium bromide (2a; 1.0 M THF solution,
2 mL, 2 mmol), and anhyd THF (2 mL) was stirred at r.t. for 3 h. The
resulting mixture was quenched with H2O, neutralized with aq NH4Cl
solution and extracted with CHCl3 (4 ´ 10 mL). The organic phase
was dried (Na2SO4) and concentrated under reduced pressure to give
a yellow oil, which was purified by preparative TLC on silica gel (elu-
ent: hexane/EtOAc, 4:1) to afford the corresponding C-nucleoside 3a
in 65 % yield (a/b = 8:/92). When 5 equiv of 2a was used, the yield
of 3a decreased to 45 %. Thus 10 equiv of Grignard reagent was used
in the reaction of 2a and 2b. In the cases of 2c–h, the reaction was
carried out with 5 equiv of the metal reagents.
(7) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
4976.
Lancelin, J.-M.; Zollo, P. H. A.; Sinay, P. Tetrahedron Lett.
1983, 24, 4833.
Kraus, G. A.; Molina, M. T. J. Org. Chem. 1988, 53, 752.
Czernecki, S.; Ville, G. J. Org. Chem. 1989, 54, 610.
Krohn, K.; Heins, H.; Wielckens, K. J. Med. Chem. 1992, 35,
511.
(8) Yokoyama, M.; Tanabe, T.; Toyoshima, A.; Togo, H. Synthesis
1993, 517.
Yokoyama, M.; Toyoshima, H.; Shimizu, M.; Togo, H. J.
Chem. Soc., Perkin Trans. 1 1997, 29.
Financial supportfrom a Grant-in-Aid (No. 07554085) for Scientific
Research from Ministry of Education, Science, and Culture of Japan
is gratefully acknowledged.
(9) Fleming, I. Frontier Orbitals and Organic Chemical Reactions,
John Wiley & Sons: New York, 1976; pp 34-40.
(10) msley J. The Elements, 2nd Ed.; Clarendon Press: Oxford,
1991, pp 38, 110, and 218 (Ionic radius of atom: Mg2+, 0.78 A;
Zn2+, 0.83 Å; Cd2+, 1.03 Å).
(1) Watanabe, K. A. In Chemistry ofNucleosides and Nucleotides;
Townsend, L. B., Ed.; Plenum Press: New York, 1994; Vol. 3;
pp 421-535.