Low temperature dehydrogenation of α-indoline nucleosides

Article abstract of DOI:10.1016/j.tetlet.2004.08.110

A variety of α-indole nucleosides are easily prepared from α-indoline nucleosides in excellent yield and at moderate temperature using manganese dioxide and molecular sieves in benzene or methylene chloride.

Full text of DOI:10.1016/j.tetlet.2004.08.110

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7783–7786
Low temperature dehydrogenation of a-indoline nucleosides
Tilak Chandra, Shawn Zou and Kenneth L. Brown*
Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701-3132, USA
Received 15 July 2004; revised 4 August 2004; accepted 5 August 2004
Abstract—A variety of a-indole nucleosides are easily prepared from a-indoline nucleosides in excellent yield and at moderate tem-
perature using manganese dioxide and molecular sieves in benzene or methylene chloride.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
There are few reports of the dehydrogenation of the
related b-indoline nucleosides to corresponding b-indole
nucleosides. Preobrazhenskaya et al.5 reported the dehy-
drogenation of 1-(2,3,5-O-tri-O-benzoyl-b-D-ribofuran-
osyl)indoline to the corresponding indole nucleoside
using manganese dioxide in benzene at reflux for 15h.
However, the a-nucleosides are thermodynamically
unstable and may isomerize to the corresponding b-
nucleosides. Consequently, harsh reaction conditions
for the dehydrogenation of the a-indoline nucleosides
are problematic. The desired a-nucleosides do not
survive these drastic conditions and undergo polymeri-
zation. Dehydrogenation by 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ)6 does not give the desired
nucleosides and gives charred products instead. In view
of the above, we have developed a mild, high yield dehy-
drogenation method for these unstable a-indoline nucleo-
sides using different solvents and molecular sieves. To
compare the reactivity of these a-nucleosides, the indole
and dimethylindoline bases were also dehydrogenated
under similar condition and produce the indoles in sim-
ilar yields.
Semi-synthesis/partial synthesis of cobalamins1 (vitamin
B12 derivatives, Fig. 1) modified in the axial base
requires the synthesis of the lower axial ligand for the
nucleotide loop. Among others, B3-deaza derivatives
(Fig. 1) are of interest because they lack the coordinat-
ing nitrogen of the axial base but maintain the remain-
ing structural features of the coenzyme. While many
B12 analogs with altered axial nucleotides can be
obtained by Ôguided biosynthesisÕ,2 via fermentation of
Propionibacterium shermanni on media supplemented
with the desired axial base, indoles are not incorporated
into the synthesized B12 due to their lack of reactivity
with the necessary ribosyltransferase, which catalyzes
formation of the axial nucleoside.3 Consequently, the
synthesis of such deaza cobalamins requires the develop-
ment of a robust method for the synthesis of a-indole
nucleosides. In previous work4 we prepared and fully
characterized the desired dimethylindoline nucleoside
with the a-N-configuration in excellent yield, the most
critical step being the coupling of the indoline to the
ribose to give the unusual a-N-glycosidic bond configu-
ration. For the semi-synthesis of the indole derivative of
cyanocobalamin, we have now prepared the a-indole
nucleoside by reacting 1-(5-O-triphenylmethyl-2,3-O-
isopropylidene-a-D-ribofuranosyl)5,6-dimethylindoline4
with manganese dioxide in benzene or methylene chlo-
ride in presence of molecular sieves at slightly elevated
temperature.
The dimethylindoline and indoline nucleosides were pre-
pared in good yield by coupling silylated indoline bases
to the protected sugar, 2,3-O-(1-methylethylidene)-5-O-
(triphenylmethyl)-D-ribofuranose in presence of 2-
fluoro-1-methylpyridinium-p-toluenesulfonate7 as
a
condensing agent. 1-(5-O-triphenylmethyl-2,3-O-isoprop-
ylidene-a-D-ribofuranosyl)indoline, 1, was dehydrogen-
ated in either benzene or methylene chloride using
MnO2 in presence of type 4A molecular sieves. The reac-
tion, which was monitored by TLC and NMR, proceeds
rapidly and without decomposition or isomerization of
*
Corresponding author. Tel.: +1 740593 1737; fax: +1 740593
0148; e-mail: brownk3@ohio.edu
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.110

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T. Chandra et al. / Tetrahedron Letters 45 (2004) 7783–7786
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
N
CN
Co
N
N
N
Co
N
N
OH2 N
D
D
H2N
O
O
H2N
O
O
NH2
NH2
NH
NH
Me
Me
O
N
O
Me
Me
O P O
O
N
O P O
O
N
OH
OH
HO
O
HO
O
B3-deaza-cyanocobalamin
Cyanocobalamin
Figure 1.
Table 1. Comparison of dehydrogenation of protected nucleoside by using benzene/methylene chloride in presence of MnO2 and molecular sieves
S. No.
Reactant
Solvent
Rexn. temp (ꢁC)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
Indoline nucleoside
Benzene
Benzene
Benzene
40–50
40–50
40–50
30–40
30–40
30–40
40–50
40–50
1–1.5
1–1.5
1.5–3
2–3
90
94
90
92
95
86
90
91
Dimethylindoline nucleoside
Br-indoline nucleoside
Indoline nucleoside
Methylene chloride
Methylene chloride
Methylene chloride
Benzene
Dimethylindoline nucleoside
Br-indoline nucleoside
Indoline base
2–3
2–3
1–2
1–2
Dimethylindoline base
Benzene
a Isolated yields.
the starting material. Dehydrogenation of dimethylindo-
line and indoline nucleosides is complete within 1h in
benzene at 40–50ꢁC whereas the 5-bromoindoline takes
1.5–3.0h (Table 1). After completion, the reaction
mixture was cooled to room temperature and filtered
through Celite, and after the usual work up, the solvent
was removed under reduced pressure and the product
had a clean NMR spectrum without any purification.
The crude product was just passed through a small silica
gel column to remove the inorganic impurities. The reac-
tion was repeated in methylene chloride at 30–40ꢁC
using MnO2 and molecular sieves and proceeded
smoothly without any decomposition, in 95% yield
(dimethylindoline). The reaction proceeds much faster
(1–1.5h) in benzene than methylene chloride. Without
molecular sieves, the reaction was sluggish and required
higher temperature and more time (Scheme 1).
isopropylidene methyls, which further supports the a-
anomeric configuration (Fig. 2). Other spectroscopic
data were compared with literature8–10 assignments for
the a-N-configuration.
2. General method for dehydrogenation of compound
1, 2, and 3
Method a. To a solution of indoline nucleoside 1
(0.700g, 1.3mmol) in benzene (20mL) was added acti-
vated manganese(IV) oxide (0.879g, 10mmol) and type
4A molecular sieves (5g) at room temperature. The
reaction mixture was stirred at 40–50ꢁC for 1–1.5h
and the reaction progress was monitored by TLC and
1H NMR. The reaction mixture was filtered and thor-
oughly washed with methylene chloride (3 · 10mL).
The solvent was then removed under reduced pressure
and the residue was extracted with methylene chloride
(100mL). The organic layer was dried over anhydrous
sodium sulfate and evaporated under reduced pressure.
The residue was then passed through a small silica gel
column and eluted with methylene chloride–hexane
(1:1) to give the desired product in 90% isolated yield11
(Table 1).
The structures of the indole nucleosides were confirmed
based on previous characterization4 of the correspond-
1
ing indoline nucleosides and confirmed by H NMR,
13C NMR, high resolution mass spectroscopy, and as
well as 2D NMR (COSY and NOESY). The proton
spectra of compound 611 showed two sharp singlets at
d 1.384 and d 1.610with a separation of 0.22ppm for
the methyl protons of isopropylidene. The anomeric
proton was visible at d 6.854 with a coupling constant
of 4.0Hz, consistent with the a-configuration. The two
indole proton showed a strong NOE with one of the
Method b. To a solution of nucleoside 1 (0.5g,
0.93mmol) in methylene chloride (20mL) activated
manganese(IV) oxide (0.85g, 9.7mmol) and type 4A

T. Chandra et al. / Tetrahedron Letters 45 (2004) 7783–7786
7785
H
H
O
O
TrO
TrO
R2
R1
R2
R1
N
N
(i)
O
O
O
O
H3C
H3C
CH3
CH3
1: R1 = R2 = H
6: R1 = R2 = H
7: R1 = R2 = CH3
8: R1 = Br, R2 = H
9: Indole base
2: R1 = R2 = CH3
3: R1 = Br, R2 = H
4: Indoline base
10: dimethylindole base
5: dimethylindoline base
Scheme 1. Reagents and conditions: (i) MnO2, molecular sieves, benzene, 40–50ꢁC or MnO2, molecular sieves, methylene chloride, 30–40ꢁC.
Figure 2. NOESY spectrum of compound 6.
protected sugar 2,3-O-(1-methylethylidene)5-O-(triphenyl-
methyl)a/b-D-ribofuranose by using 2-fluoro-1-methylpy-
ridinium-p-toluenesulfonate as a condensing agent in 90–
96% yield.
molecular sieves (5g) was added and the mixture was
heated slowly at 40ꢁC for 2h. The progress of the reac-
tion was monitored by TLC. After completion, the mix-
ture was cooled to room temperature, filtered, and
washed thoroughly with methylene chloride, and then
concentrated under reduced pressure and passed
through a small silica gel column to remove the inor-
ganic impurities.
5. Preobrazhenskaya, M. N.; Yartseva, I. V.; Ektova, L. V.
Nucleic Acid Chem. 1978, 2, 623–721.
6. Preobrazhenskaya, M. N.; Vigdorchik, M. N.; Suvorov,
N. N. Tetrahedron 1967, 23, 4653–4660.
7. Mukaiyama, T.; Hashimoto, Y.; Hayashi, Y.; Shoda, S. I.
Chem. Lett. 1984, 557–560.
References and notes
8. Tapiero, C.; Imbach, J. L.; Townsend, L. B.; Stuart, T. R.
Nucleic Acid Chem. 1978, 2, 1055.
9. Imbach, J. L.; Barascut, J. L.; Kam, B. L.; Rayner, B.;
Tamby, C.; Tapiero, C. J. Heterocycl. Chem. 1973, 10(6),
1069–1070.
1. Brown, K. L.; Zou, X.; Li, J.; Chen, G. Inorg. Chem. 2001,
40, 5942–5947.
2. Krautler, B.; Konrat, R.; Stupperich, E.; Faber, G.;
Gruber, F.; Kratky, C. Inorg. Chem. 1994, 33, 4128–4139.
3. Cheong, C.-J.; Escalante-Semerena, J. C.; Rayment, I. J.
Biol. Chem. 2002, 277, 41120–41127.
10. Rayner, B.; Tapiero, C.; Imbach, J. L. Carbohydr. Res.
1976, 47(2), 195–202.
1
11. Selected data for 6. Rf 0.8; H NMR (CDCl3): d 1.384 (s,
3H, CH3), 1.610(s, 3H, CH 3), 3.329 (dd, J = 3, 7.5Hz, 1H,
50), 3.679 (dd, J = 2.5, 7.5Hz, 1H, 500), 4.468 (br t, 1H, 40),
4.937 (d, J = 6Hz, 1H, 30), 5.086–5.107 (m, 1H, 20), 6.66
(d, J = 3.5Hz, 1H, indole), 6.854 (d, J = 4Hz, 1H, 10),
4. Brown, K. L.; Chandra, T.; Zou, S.; Valente, E. J. Chem.
Commun., communicated. The indoline nucleosides were
synthesized by coupling freshly prepared, silylated dimeth-
ylindoline/indoline base to an anomeric mixture of the

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T. Chandra et al. / Tetrahedron Letters 45 (2004) 7783–7786
7.18–7.25 (m, 2H, Ar, indole), 7.35–7.43 (m, 9H, Ar,
(s, 1H, Ar), 7.401 (s, 1H, Ar), 7.46 (d, J = 6Hz, 6H, trityl);
13C NMR (CDCl3): d 20.00 (CH3), 20.60 (CH3), 25.47
(CH3), 27.34 (CH3), 63.70(CH 2, 50), 81.05 (C30), 83.77
(C40), 84.29 (C20), 86.92 (Cquat), 91.26 (C10), 102.60
(CH), 110.63 (CH), 114.41 (Cquat), 121.05 (CH), 123.72
(CH), 127.08 (CH), 127.85 (CH), 127.85 (CH), 128.71
(CH), 128.90, 131.13 (Cquat), 134.60 (Cquat), 143.59
trityl), 7.51 (d, J = 6.5Hz, 1H, indole), 7.54 (d, 6H, trityl),
7.67 (d, J = 3.0Hz, 1H, indole), 7.704 (d, J = 7.5Hz, 1H,
indole); 13C NMR (CDCl3): d 24.42 (CH3), 26.00 (CH3),
65.97 (CH2, 50), 80.44 (C20), 81.39 (C40), 82.61 (C30), 87.11
(10), 87.71 (Cquat), 102.41 (C3 indole), 109.02 (CH,
indole), 113.25 (Cquat), 119.92 (C2, indole), 120.98
(Cquat), 121.66 (CH, indole), 126.97 (Cquat), 127.02
(Cquat), 127.36 (CH), 127.89 (CH), 128.09 (CH), 128.59
(CH), 128.71 (CH), 136.03 (CH), 143.40 (Cquat); MS
(FAB) m/z: 532 (M+ +1), 243; HRMS: m/z: 532.2488
(calcd for C35H34NO4: 532.2486) (M+H); IR (KBr cmꢀ1):
2902, 2362, 1495, 1462, 1383, 1318, 1220, 1117, 1081, 996,
749, 706. Selected data for 7. The dimethylindoline
nucleoside, 7, was similarly dehydrogenated as described
for the indole nucleoside 6. Yield: 95%, white foam, 1H
NMR (CDCl3): d 1.365 (s, 3H, CH3), 1.646 (s, 3H, CH3),
2.327 (s, 3H, CH3, Ar), 2.357 (s, 3H, CH3, Ar), 3.334 (m,
2H, CH2, 5 and 500), 4.351–4.377 (m, 1H, 40), 4.826–4.847
(m, 1H, 30), 4.929–4.949 (m, 1H, 20), 6.076 (d, J = 3.5Hz,
1H, 10), 6.369 (d, J = 2.5Hz, 1H, indole), 7.072 (d,
J = 3.5Hz, 1H, indole), 7.242–7.295 (m, 9H, trityl), 7.387
+
(Cquat); MS (FAB) m/z: 560(M +1), 459, 443, 374, 341,
313, 244, 243; HRMS: m/z: 560.2800 (calcd for
C37H38NO4: 560.2854) (M+H); IR (KBr cmꢀ1): 2946,
2376, 2338, 1472, 1458, 1380, 1279, 1211, 1081, 761, 703,
674. Selected data for 8. Yield: 90%, white foam, 1H NMR
(CDCl3): d 1.364 (s, 3H, CH3), 1.638 (s, 3H, CH3), 3.33
(dd, J = 3.9, 6.5Hz, 1H, CH2, 50), 3.42 (dd, J = 3.9, 6.5Hz,
1H, 500), 4.364–4.388 (m, 1H, 40), 4.847–4.878 (m, 1H, 30),
4.909–4.929 (m, 1H, 20), 6.02 (d, J = 3.3Hz, 1H, 10), 6.41
(d, J = 2.8Hz, 1H, indole), 7.24 (d, 1H, indole), 7.26–7.30
(m, 9H, trityl), 7.38 (s, 1H, indole), 7.41 (d, J = 6Hz, 6H,
trityl), 7.47 (d, 2H, indole), 7.74 (d, 1H, indole); MS
(FAB) m/z: 612 (M+ +1), 613, 615, 616, 611, 548, 447, 394,
337, 245, 244, 243, 197, 149; HRMS: m/z: 610.1593 (calcd
for C35H33NO4Br: 610.1591) (M+H).