Regio- and stereoselective glycosylation: Synthesis of 5-haloimidazole α-ribonucleosides

Article abstract of DOI:10.1021/jo060087s

We describe the synthesis of novel 5-haloimidazole ribonucleosides as precursors of modified cobalamins. A regio- and stereoselective glycosylation of protected ribose with silylated 4(5)-haloimidazoles produces 5-haloimidazole ribonucleosides predominant

Full text of DOI:10.1021/jo060087s

Supporting Information
Regio- and stereo-selective glycosylation: Synthesis of 5-haloimidazole
α-ribonucleosides
Tilak Chandraa, Xiang Zoua, Edward J. Valenteb and Kenneth L. Browna*
a Department of Chemistry & Biochemistry, Ohio University, Athens, Ohio 45701, USA.
b Department of Chemistry, Mississippi College, Clinton, Mississippi 39085
Table of Contents
General methods
S1
Preparation and characterization data of compound 2
Preparation and characterization data of compound 4
Preparation and characterization data of compound 5
Crystal data and structure refinement for compound 8
Selected Bond Length and Angles for Compound 8
Selected Torsion Angles for Compound 8
19F spectrum of compound 2
S2
S3
S4
S5
S6
S7
S8
19F spectrum of compound 8
S9
1H spectrum of compound 8
S10
S11
S12
S13
S14
S15
S16
1H spectrum of reaction mixture of 8 &12
13C spectrum of compound 8
COSY of compound 8
HMQC of compound 8
NOESY of compound 8
Down field region NOESY of compound 8
1

S-17
nOe’s of / 5-haloimidazole ribonucleosides
ORTEP diagram of compound 8
1H spectrum of 9
S-18
S19
S20
S21
S22
S23
S24
S25
S26
S27
S28
S29
S30
S31
S32
NOESY of compound 9
COSY of compound 9
HMQC of compound 9
13C spectrum of compound 9
1H spectrum of compound 10
13C spectrum of compound 10
NOESY of compound 10
1H spectrum of compound 11
HMQC of compound 11
COSY of compound 11
13C spectrum of compound 11
NOESY of compound 11
Down field region NOESY of compound 11 showing nOe between anomeric
proton and C-5 imidazole proton
1H spectrum of compound 13
13C spectrum of compound 13
HMQC of compound 13
S33
S34
S35
S36
S37
NOESY of compound 13
1H spectrum of compound 15
2

General methods (S1)
Experimental Section
All reactions were carried out in oven or flame-dried glassware under a nitrogen
atmosphere. Solvents were distilled prior to use. Dichloromethane, benzene and ether
were distilled from calcium hydride. Purification of reaction products was carried out by
flash chromatography using silica gel (230-400 mesh). All reagents were commercially
available and used without further purification. All reactions were monitored by thin-
layer chromatography (TLC) using silica gel 60, F-254. Column chromatography was
conducted using flash silica gel. 1H NMR and 13C NMR spectra were recorded on 500 or
400 NMR spectrometers using the residual proton resonance of the solvent as an internal
reference at 25 oC. Two-dimensional NMR (COSY, NOESY) spectra were obtained at 25
oC on a NMR spectrometer using TMS as an internal reference. The multiplicities of the
13C NMR signals were determined by HMQC and DEPT techniques.
4-Fluoroimidazole17, 18 (2) S2: A solution of 4-nitroimidazole (4.5 g., 39 mmol) in 50%
tetrafluoroboric acid (200 mL) was cooled to -10 oC. The solution stirred rapidly and was
aerated with argon. Zinc dust (8.2 g., 125 mmol) was added to it slowly maintaining the
o
temperature -5 C. Complete reduction was monitored by UV. Finally, a solution of
sodium nitrite (3.0 g., 43 mmol) in water (10 mL) was added dropwise to it in 30
minutes. The resulting solution was diluted with 50% cold tetrafluoroboric acid (200 mL)
and then photolysed. The photolysis reactions were carried out in in a glass vessel using a
high pressure Xe-Hg photolysis lamp (254 nm principal wavelength) for 2-3 hr at
ambient temperature. After complete conversion of the reactant, the reaction mixture was
o
cooled to 0 C and neutralized with cold concentrated sodium hydroxide solution. The
3

viscous mixture was extracted with ethyl acetate (3x100 mL). The ethyl acetate was dried
over Na2SO4, concentrated and finally passed through a silica gel plug column to remove
1
the inorganic salts. Yield: 20-30%; white crystalline solid; Rf. 0.6; H NMR (CDCl3):
6.39 (dd, J = Hz, 1H), 7.07 (s, 1H), 13C NMR (CDCl3): 93.9 (d, J = 37.87 Hz), 128.5 (d,
J = 15.87 Hz), 155.6 (d, J = 233.5 Hz); 19F NMR (CDCl3): -136.61 (d, J = 8 Hz).
1-(Trimethylsilanyl)-4- Bromoimidazole (4) S3:
A mixture of 4- bromoimidazole (1.0 g., 7 mmol) and hexamethyldisilazane (1.0 g., 29
mmol) was refluxed for 6 hr. Excess HMDS was removed under reduced pressure and
1
the residue was dried under high vacuum for 3 h. Yield: 95%; white solid; H NMR
(CDCl3): 0.47 (s, 9H), 6.90 (s, 1H), 7.43 (s, 1H); HRMS: m/z: 218.9961 (calcd. for
C6H12BrSiN2; 218.9952) (M +H).
1-(Trimethylsilanyl)-4- Iodooimidazole (5) S4:
This compound was prepared similarly to 4, starting from 4-iodoimidazole. Yield: 97%;
1
13
white solid; H NMR (CDCl3): 0.57 (s, 9H), 6.97 (s, 1H), 7.40 (s, 1H), C NMR
(CDCl3): -0.70 (SiMe3), 83.65 (Cquat), 125.69 (CH), 141.35 (CH ); HRMS: m/z:
266.9661 (calcd. for C6H12ISiN2; 266.9773) (M +H).
4

TABLE 1. Crystal data and structure refinement for compound 8 (S-5)
empirical formula
C30H29F1N2O4
formula weight
color of crystal
crystal system
space group
a, Å
500.55
colorless
orthorhombic
P212121
8.2594(4)
14.7704(8)
20.8394(9)
90.058(4)
89.990(4)
89.935(2)
2542.3(2)
4
b, Å
c, Å
α, deg.
β, deg.
γ, deg.
V, Å3
Ζ
ρ
calcd, g/cm3
1.308
T, K
100
λ, Å
0.71073
0.994
a
2
Goodness-of-fit on F
Final R indicesb
[I>2sigma(I)]
R indicesc (all data)
R1 = 0.0378,
wR2 = 0.0924
R1 = 0.0463,
wR2 = 0.0953
-3
Largest diff. peak and hole
0.471 and -0.195 e.Å
aGoodness-of-fit = [Σ[w(Fo2 − Fc2)2]/Nobservns − Nparams)]1/2, all data.
bR1 = Σ(|Fo| − |Fc|) / Σ |Fo|. cwR2 = [Σ[w(Fo2 − Fc2)2] / Σ [w(Fo2)2]]1/2.
5

TABLE 2. Selected Bond Length and Angles* for Compound 8, (S-6)
Bond
Length (Å)
1.446
Bond angle
C1-O1-C10
C3-N2-C4
O1-C1-C5
F1-C2-N1
O1-C10-C11
C1-N1-C4
Angle (deg)
107.60
N1-C1
N1-C2
C1-H1
C1-C5
O1-C1
O1-C10
1.373
106.05
0.961
105.75
1.528
119.21
1.421
111.87
1.445
128.91
Errors in bond distances are estimated at about 0.001 Å, and in inter bond angles about
0.05 - 0.08 degrees
6

TABLE 3. Selected Torsion Angles for Compound 8 (S-7)
Torsion
C2-N1-C1-O1 115.62
C2-N1-C1-H1 -3.23
angle (°)
Torsion
angle (°)
65.98
Torsion
angle (°)
C4-N1-C1-C5
C1-N1-C2-F1
C10-O1-C1-N1 161.37
C10-O1-C1-H1 83.73
C10-O1-C1-C5 36.41
C1-O1-C10C9 -28.93
C1-C5-C9-C10 10.79
10.27
C2-N1-C1-C5 -125.84
C4-N1-C1-O1 -52.55
C4-N1-C1-H1 -171.40
C1-N1-C2-C3 -170.95
C4-N1-C2-F1 -179.22
C4-N1-C2-C3
-0.45
Errors in torsion angles are estimated at about 0.6 - 0.9 degrees
7

S-8, 19F spectrum of compound 2
8

S-9 19F spectrum of compound 8
9

S-10 1H spectrum of compound 8
10

S-11 1H spectrum of compound 8&12 (reaction mixture)
11

S-12 13C spectrum of compound 8
12

S-13 COSY of compound 8
13

S-14 HMQC of compound 8
14

S-15 1NOESY spectrum of compound 8
15

S-16 Down field region NOESY of compound 8
16

H
O
TrO
H
O
TrO
F
H
H
H
H
H
H
N
N
N
N
H
H
O
O
O
O
H
H3C
CH3
H3C
CH3
8
11
H
N
N
H
Br
O
TrO
H
H
O
O
H3C
CH3
13
S-17 nOe’s of / 5-haloimidazole ribonucleosides
17

S-18 ORTEP diagram of compound 8
18

S-19 1H spectrum of compound 9
19

S-20 NOESY of compound 9
20

S-21 COSY for compound 9
21

S-22 HMQC
22

S-23 13C spectrum of compound 9
23

S-24 1H spectrum of compound 10
24

S-25 13C spectrum of compound 10
25

S-26 NOESY of compound 10
26

S-27 1H spectrum of compound 11
27

S-28 HMQC of compound 11
28

S-29
29

S-30 13C spectrum of compound 11
30