Direct glycosylation: Synthesis of α-indoline ribonucleosides

Article abstract of DOI:10.1016/j.tetlet.2005.01.164

A selective synthesis of α-anomers of indoline nucleosides is described. Ribonucleosides of indoline, dimethylindoline and 5-bromoindoline are readily prepared in good yield by reacting indoline bases directly with the protected sugar, 2,3-O-(1-methylethylidene) 5-O-(triphenylmethyl)-D-ribofuranose in dry ethanol or methylene chloride in presence of molecular sieves at 40-60°C.

Full text of DOI:10.1016/j.tetlet.2005.01.164

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2071–2074
Direct glycosylation: synthesis of a-indoline ribonucleosides
Tilak Chandra and Kenneth L. Brown*
Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701-3132, United States
Received 28 December 2004; revised 24 January 2005; accepted 25 January 2005
Abstract—A selective synthesis of a-anomers of indoline nucleosides is described. Ribonucleosides of indoline, dimethylindoline and
5-bromoindoline are readily prepared in good yield by reacting indoline bases directly with the protected sugar, 2,3-O-(1-methyl-
ethylidene) 5-O-(triphenylmethyl)-D-ribofuranose in dry ethanol or methylene chloride in presence of molecular sieves at 40–60 ꢀC.
ꢁ 2005 Elsevier Ltd. All rights reserved.
R1
R2
R1
R2
1. Introduction
(i)
a-Ribonucleosides1,2 are rare in nature, but occur, for
example, as the lower axial ligand (5,6-dimethyl-a-D-
ribofuranosylbenzimidazole)3 in coenzyme B12. Analogs
of coenzyme B12 with altered axial nucleoside ligands
are of interest as probes of the function of the axial
ligand in the enzymatic activation of the coenzyme for
carbon–cobalt bond homolysis.4–7 As such, a-indole
nucleosides, which lack a coordinating nitrogen but
otherwise maintain the structural integrity of the co-
enzyme, can probe the importance of axial coordination
to enzymatic activation. However, the necessary syn-
thetic routes to a-ribonucleosides are rare. We recently
reported the successful synthesis of the a-ribonucleo-
sides of indoline and 5,6-dimethylindoline and corre-
sponding indole ribonucleosides8,9 via a multistep
route requiring protection of the indoline and the use
of an expensive coupling reagent, 2-fluoro-1-methylpy-
ridinium tosylate.10 Here we report an alternative route
in which an unprotected indoline may be directly cou-
pled to 2,3-O-(1-methylethylidene)5-O-(triphenylmethyl)-
D-ribofuranose11 in dry ethanol/methylene chloride, in
N
H
N
H
4: R1, R2 = H
5: R1, R2 = CH3
6: R1 = Br, R2 = H
1: R1, R2 = H
2: R1, R2 = CH3
3: R1 = Br, R2 = H
H
O
O
TrO
TrO
OH
(ii)
(4 - 6)
N
R2
R1
55-70%
O
O
O
O
H3C
CH3
H3C
CH3
7
8: R1, R2 = H
9: R1, R2 = CH3
10: R1 = Br, R2 = H
H
O
TrO
(
iii)
N
R2
8-10
O
O
H3C
CH3
R1
(indole ribonucleosides)
˚
the presence of Type 4 A molecular sieves to give the
a-ribonucleoside in 55–70% yield without any detectable
b-ribonucleosides.
Scheme 1. Reagents and conditions: (i) sodium cyanoborohydride,
AcOH, 10–15 ꢀC; (ii) molecular seives, ethanol/methylene chloride, 40–
60 ꢀC, 4–6 h; (iii) MnO2, benzene or methylene chloride, molecular
sieves.
The dimethylindole12,13 bases were prepared by stan-
dard procedures from 5-nitropseudocumene in three
steps. For the coupling reaction the dimethylindole base
was converted in to dimethylindoline14,15 (Scheme 1) in
excellent yield by sodium cyanoborohydride reduction14
at 12 ꢀC. 2,3-O-(1-Methylethylidene)-5-O-(triphenyl-
methyl)-D-ribofuranose was prepared from D-ribose in
two steps in fairly good yield. A dry solution of 2,3-O-
(1-methylethylidene)5-O-(triphenylmethyl)-D-ribofura-
nose11 in ethanol was added directly dimethylindoline
*
Corresponding author. E-mail: brownk3@ohio.edu
0040-4039/$ - see front matter ꢁ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.164

2072
T. Chandra, K. L. Brown / Tetrahedron Letters 46 (2005) 2071–2074
Table 1. Reaction conditions and yields of glycosylation of different bases with 2,3-O-(1-methylethylidene)5-O-(triphenylmethyl)-D-ribofuranose
H
O
TrO
methylene chloride/
ethanol, base
O
TrO
OH
B
O
O
O
O
H3C
CH3
H3C
CH3
S. no.
Base (B)
Solvent
Reaction temp (ꢀC)
Reaction time (h)
Yielda
1
2
3
4
5
6
Indoline
Ethanol
Ethanol
Ethanol
60–70
60–70
60–70
40
5–6
4–5
6–7
4
60
65
55
65
70
60
Dimethylindoline
5-Bromoindoline
Indoline
Methylene chloride
Methylene chloride
Methylene chloride
Dimethylindoline
5-Bromoindoline
40
40
4
5
a Isolated yields.
˚
and 4 A molecular sieves at room temperature and the
mixture was heated for 5–6 h under an argon atmo-
sphere while the reaction progress was monitored by
TLC and NMR. The reaction proceeded smoothly,
and after completion the mixture was cooled to room
temperature and filtered, and thoroughly washed with
ethanol. By using methylene chloride as a solvent, the
observed yield was higher and there was no decompo-
sition of the sugar, as the ethanol method resulting a
sluggish reaction and decomposition of 2,3-O-(1-
methylethylidene)5-O-(triphenylmethyl)-D-ribofuranose
at higher temperature. The reaction mixture showed
only one isomer in NMR after workup. The reaction
of dimethylindoline and 2,3-O-(1-methylethylidene)5-
O-(triphenylmethyl)-D-ribofuranose proceeds faster
(Table 1) than the reaction with the other indoline bases.
5-Bromoindoline16 is less reactive and the longer heating
time results in lower yields of the corresponding
ribonucleoside.
The identity and a-configuration of these ribonucleo-
sides were confirmed based on the previous characteriza-
tion8 of the corresponding a-indoline ribonucleosides,
which were prepared by the 2-fluoro-1-methylpyridi-
nium tosylate10 method and fully characterized by X-
ray and 2D NMR spectroscopy. The structure of these
indoline ribonucleosides, prepared by direct glycosyla-
tion, was also confirmed by 1H NMR, 13C NMR,
and as well as 2D NMR (COSY, HMQC, and NOESY).
The signals for the methyl protons of the isopropylidene
in 8 were present at d 1.38 and 1.60 ppm and the ano-
meric proton signal was visible at d 5.44 ppm (Table
2), the same as reported for the indoline ribonucleo-
sides8 prepared by the 2-fluoro-1-methylpyridinium tos-
ylate method. The indoline methylene protons in
dimethylindoline ribonucleoside 9 showed a strong
NOE with one of the isopropylidene methyls, which fur-
ther supports the a-anomeric configuration. For further
use as a precursor for B3-deazacobalamins (Fig. 1),
Table 2. 1H NMR/13C NMR comparison of indoline ribonucleosides prepared by direct glycosylationb/2-fluoro-1-methylpyridinium tosylatea
method (chemical shifts, ribose protons, d ppm)
5'
H
O
TrO
1'
4'
3'
2'
R2
R1
N
R1 = R2 = H (indoline)
R1 = R2 = Me (dimethylindoline)
R1 = Br, R2 = H (5-bromoindoline)
O
O
H3C
CH3
S. no.
Compound (ribonucleosides)
Me1
1.39
Me2
1.61
50
3.28
50 0
40
4.19
30
4.72
20
4.85
10
5.455
1
2
Indolinea (1H NMR)
Indolineb
3.35
3.35
—
1.38
25.56
25.57
1.38
1.59
27.48
27.49
1.60
3.28
63.89
63.92
3.26
4.17
82.00
82.03
4.19
4.69
80.67
80.72
4.64
4.84
81.49
81.52
4.80
5.44
92.83
92.89
5.41
3
Indolinea
Indolineb
(
13C NMR)
4
5
Dimethylindolinea (1H NMR)
Dimethylindolineb
3.32
3.33
—
6
1.39
1.62
3.29
4.21
4.67
4.83
5.43
7
Dimethylindolinea
Dimethylindolineb
5-Bromoindolinea
5-Bromoindolineb
(
13C NMR)
25.56
25.58
1.38
27.51
27.51
1.60
64.02
64.05
3.24
81.93
81.94
4.14
80.91
80.92
4.64
81.58
81.58
4.77
93.20
93.22
5.32
8
9
10
3.41
3.36
1.38
1.60
3.28
4.18
4.69
4.81
5.36
a Reported 1H NMR values in (d ppm), Ref. 8.
b Prepared by direct glycosylation.

T. Chandra, K. L. Brown / Tetrahedron Letters 46 (2005) 2071–2074
2073
NH2
NH2
O
O
O
O
NH2
NH2
O
O
O
O
O
O
H2N
NH2
H2N
NH2
A
B
C
A
B
C
CN N
CN N
N
N
Co
N
Co
N
N
N
OH
2
D
D
H2N
O
O
H2N
O
O
NH2
NH2
NH
NH
O
O
Me
-O
P
O
Me
-O
P
O
N
N
O
OH
O
N
OH
Me
Me
HO
HO
O
O
Cyanocobalamin
B3-deaza-cyanocobalamin
Figure 1.
these indoline ribonucleosides were converted to the cor-
responding indole ribonucleosides and all spectroscopic
data were compared with previously prepared indole
ribonucleosides9 as described earlier (Scheme 1).
atmosphere, the progress of the reaction mixture was
monitored by TLC (ether: benzene 20:80). After com-
plete conversion of the sugar, the reaction mixture was
cooled and silica gel (5 g) was added, and the solvent
was removed under reduced pressure. The silica gel pow-
der was loaded on to a silica gel column packed in benz-
ene. After elution with benzene it afforded the pure
dimethylindoline ribonucleoside in 70% yield.
2. General procedure for the synthesis of indoline
nucleosides 8–10
2.1. Method a: synthesis of 1-(5-O-triphenylmethyl-2,
3-O-isopropylidene-a-D-ribofuranosyl) indoline17 (8)
Acknowledgements
To a solution of indoline 4 (0.336 g, 2.8 mmol) in freshly
distilled dry ethanol (15 mL) was added 2,3-O-(1-me-
thylethylidene)5-O-(triphenylmethyl)-D-ribofuranose, 7
This research was supported by the National Institute of
General Medical Sciences, Grant GM 48858.
˚
(1.0 g, 2.3 mmol) and type 4A molecular sieves (5 g).
The reaction mixture was stirred at 50–60 ꢀC for 5–6 h
under an argon atmosphere and the progress of the reac-
References and notes
1
tion was monitored by TLC and H NMR. After com-
1. Mikhailov, S. N.; Pfleiderer, W. Synthesis 1985, 4, 397–
399.
2. Stevens, J. D.; Ness, R. K.; Fletcher, H. G., Jr. J. Org.
Chem. 1968, 33(5), 1806–1810.
3. Holly, F. W.; Shunk, C. H.; Peel, E. W.; Cahill, J. H.;
Lavigne, J. B.; Folkers, K. J. Am. Chem. Soc. 1952, 74,
4521–4525.
4. Brown, K. L.; Li, J. J. Am. Chem. Soc. 1998, 120, 9466–
9474.
5. Brown, K. L.; Cheng, S.; Zou, X.; Li, J.; Chen, G.;
Valente, E. J.; Zubkowski, J. D.; Marques, H. M.
Biochemistry 1998, 37, 9704–9715.
6. Hay, B. P.; Finke, R. G. J. Am. Chem. Soc. 1986, 108,
4820–4829.
plete conversion of the sugar, the reaction mixture was
filtered and thoroughly washed with methylene chloride
(3 · 10 mL). The solvent was then removed under re-
duced pressure and the residue was extracted with meth-
ylene chloride (2 · 50 mL). The organic layer was dried
over anhydrous sodium sulfate and evaporated under
reduced pressure. The viscous oil was then passed
through a silica gel column and eluted with methylene
chloride:hexane (1:1) to give the desired product in
60% yield. The reaction was also repeated in methylene
chloride as a solvent which afforded the desired ribonu-
cleoside in higher yield (70%).
7. Hay, B. P.; Finke, R. G. J. Am. Chem. Soc. 1987, 109,
8012–8018.
2.2. Method b: synthesis of 1-(5-O-triphenylmethyl-2, 3-
O-isopropylidene-a-D-ribofuranosyl) 5,6-dimethylindoline
(9)
8. Brown, K. L.; Chandra T.; Zou, S.; Valente, E. J.
Nucleosides, Nucleotides and Nucleic Acids (communi-
cated). The indoline nucleosides were synthesized by
coupling freshly prepared, silylated dimethylindoline/
indoline base to an anomeric mixture of the protected
sugar 2,3-O-(1-methylethylidene)5-O-(triphenylmethyl)a/b-
D-ribo- furanose by using 2-fluoro-1-methylpyridinium-
p-toluenesulfonate as a condensing agent in 90–96%
yield.
To a solution of 5,6-dimethyl-2,3-dihydro-1H-indole,15
5 (0.200 g, 1.3 mmol) in dry methylene chloride (4 mL)
was added 2,3-O-(1-methylethylidene)5-O-(triphenyl-
methyl)-D-ribofuranose 7 (0.30 g, 0.7 mmol) and the
mixture was heated at 40 ꢀC for 4 h under an argon

2074
T. Chandra, K. L. Brown / Tetrahedron Letters 46 (2005) 2071–2074
9. Chandra, T.; Zou, X.; Brown, K. L. Tetrahedron Lett.
2004, 45, 7783–7786.
10. Mukaiyama, T.; Hashimoto, Y.; Hayashi, Y.; Shoda, S. I.
Chem. Lett. 1984, 557–560.
11. Klein, R. S.; Ohrui, H.; Fox, J. J. J. Carbohydr. Nucleos.
Nucleot. 1974, 1(3), 265–269.
12. Tyson, F. T. J. Am. Chem. Soc. 1941, 63, 2024–2025.
13. Leo, M. O.; Catharine, O. W. Can. J. Res. 1947, 25B, 1–
13.
(s, 3H, CH3, isopropylidene), 2.91–2.97 (m, 2H, CH2,
indoline), 3.28 (dd, J = 4.5, 5.0 Hz, 1H, 50), 3.35 (dd,
J = 4.5, 5 Hz, 1H, 50 0), 3.52–3.55 (m, 1H, CH of NCH2,
indoline), 3.59 (q, 1H, CH, indoline), 4.17–4.21 (m, 1H,
CH, 40), 4.67–4.69 (m, 1H, CH, 30), 4.83–4.85 (m, 1H,
CH, 20), 5.44 (d, J = 3.78 Hz, 1H, CH, 10), 6.76 (d,
J = 7.5 Hz, 1H, CH, Ar), 6.80 (d, J = 8 Hz, 1H, Ar),
7.06–7.12 (m, 2H, Ar), 7.25–7.46 (m, 15H, Ar, trityl); 13C
NMR (CDCl3): d 25.57 (CH3), 27.49 (CH3), 28.28 (CH2),
47.35 (CH2), 63.92 (CH2, 50), 80.72 (C 30), 81.52 (C 20),
82.03 (C 40), 86.72 (Cquat), 92.89 (C 10), 108.95 (CH,
Ar), 114.03 (Cquat), 119.20 (CH), 124.61 (CH), 127.00
(CH), 127.77 (CH), 127.91, 128.73, 130.44 (Cquat),
143.78 (Cquat); HRMS: m/z: 534.2644 (calcd for
C35H36NO4: 534.2643) (M+H); MS: (FAB) m/z 534,
491, 430, 355, 281, 243, 165. Compound 9: yield: 70%.
White foam. Rf; 0.6 (methylene chloride), 1H NMR
(CDCl3): d 1.39 (s, 3H, CH3, isopropylidene), 1.62 (s, 3H,
CH3, isopropylidene), 2.18 (s, 3H, CH3, Ar), 2.21 (s, 3H,
CH3, Ar), 2.86–2.992 (m, 2H, CH2, indoline), 3.29 (dd,
J = 4.5, 5 Hz, 2H, 50), 3.33 (dd, J = 4.5, 5 Hz, 2H, 50 0),
3.46–3.44 (m, 1H, indoline), 3.55 (q, 1H, indoline), 4.21
(q, J = 4.5 Hz, 1H, 40), 4.66–4.68 (m, 1H, 30), 4.82–4.84
(m, 1H, H 20), 5.43 (d, J = 3.5 Hz, 1H, 10), 6.63 (s, 1H,
Ar), 6.89 (s, 1H, Ar), 7.23–7.29 (m, 9H, trityl), 7.46 (d,
6H, trityl); 13C NMR (CDCl3): d 19.17 (CH3, Ar), 20.20
(CH3, Ar), 25.58 (CH3, isopropylidene), 27.51 (CH3,
isopropylidene), 28.11 (CH2, indoline), 47.29 (CH2,
indoline), 64.050 (CH2, 50), 80.92 (C 30), 81.58 (C 20),
81.94 (C40), 86.68 (Cquat), 93.22 (C10), 110.61 (CH),
113.91 (Cquat), 125.87 (CH), 126.98, 127.76, 127.911
(CH), 128.63 (CH), 128.72 (CH), 135.04 (Cquat), 143.81
(Cquat), 148.16 (Cquat), HRMS: m/z: 561.2882 (calcd for
C37H39NO4: 561.2868); MS: (FAB) m/z 561, 318, 244,
243, 165. Compound 10: white foam. Rf: 0.7 (methylene
chloride), 1H NMR (CDCl3): d 1.385 (s, 3H, CH3,
isopropylidene), 1.602 (s, 3H, CH3, isopropylidene),
2.90–2.96 (m, 2H, CH2, indoline), 3.28 (dd,J = 4.5 Hz,
1H, 50), 3.36 (dd, 1H, 50 0), 3.53–3.56 (q, 1H, NCH2,
indoline), 3.58 (q, 1H, NCH2, indoline), 4.17–4.20 (m,
1H, CH, 40), 4.68–4.70 (m, 1H, CH, 30), 4.80–4.83 (m,
1H, CH, 20), 5.36 (d, J = 3.8 Hz, 1H, CH, 10), 6.67 (d,
J = 8.5 Hz, 1H, Ar), 7.14 (d, J = 8.5 Hz, 1H, Ar), 7.19 (s,
1H, Ar), 7.24–7.28 (m, 9H, trityl), 7.41 (d, J = 7 Hz, 6H,
trityl).
14. Gribble, G. W.; Hoffman, J. H. Synthesis 1997, 859–860.
15. 5,6-Dimethyl-2,3-dihydro-1H-indole (5): A solution of
dimethylindole (2) (1.1 g, 7.5 mmol) in acetic acid
(20 mL) was stirred for 10 min at 12 ꢀC and sodium
cyanoborohydride (1.6 g, 25 mmol) was added portion
wise under a nitrogen atmosphere at the same tempera-
ture. The reaction mixture was further stirred for 2 h at
12 ꢀC and was monitored by TLC. After completion of the
reaction, the mixture was neutralized with 50% sodium
hydroxide (30 mL). Finally ether (100 mL) was added and
the mixture was stirred for 30 min. The ether layer was
separated, the extraction was repeated two more times,
and the combined ether layers were washed with brine.
The organic layer was dried over anhydrous potassium
carbonate, and finally the ether layer was removed under
reduced pressure to afford a viscous oil. The oil was finally
1
purified on silica gel column. Yield: 95%; white solid; H
NMR (CDCl3): d 2.14 (s, 3H, CH3), 2.17 (s, 3H, CH3),
2.98 (t, J = 8.4 Hz, 2H, CH2), 3.53 (t, J = 8.8 Hz, 2H,
CH2), 6.54 (s, 1H, Ar), 6.93 (s, 1H, Ar); 13C NMR
(CDCl3): d 19.19 (CH3), 19.93 (CH3), 29.67 (CH2), 47.53
(CH2), 111.52 (CH), 125.82 (CH), 126.86 (Cquat), 127.05
(Cquat), 135.10 (Cquat), 149.16 (Cquat); MS (EI) m/z: 147
(M+), 132, 117.
16. 5-Bromo-2,3-dihydro-1H-indole (6): 5-Bromo-2,3-dihydro-
1H-indole was similarly prepared from 5-bromoindole as
described for 5,6-dimethylindoline (5), above. Yield: 90%;
1
low melting solid. H NMR (CDCl3): d 2.99 (t, J = 8 Hz,
2H, CH2), 3.53 (t, J = 8.5 Hz, 2H, NCH2), 3.7 (br s, 1H,
NH), 6.46 (d, J = 8.5 Hz, 1H, Ar), 7.06 (d, J = 6.5 Hz, 1H,
Ar), 7.17 (s, 1H, Ar); 13C NMR (CDCl3): d 29.62 (CH2),
47.47 (CH2), 110.01 (Cquat), 110.50 (Cquat), 127.44 (CH),
129.68 (CH), 131.71 (CH), 150.55 (Cquat); MS (EI) m/z:
198 (M+), 118 (MꢀBr).
17. Selected data for 8: yield: 90%; Rf 0.6; white foam; 1H
NMR (CDCl3): d 1.38 (s, 3H, CH3, isopropylidene), 1.59