New pyrano[3,4-b]indoles from 2-hydroxymethylindole and L-dehydroascorbic acid

Article abstract of DOI:10.1016/j.tet.2005.04.049

2-Hydroxymethylindole reacts with L-dehydroascorbic acid under mild conditions to give (3R,3aR,10cS)-3-[(1S)-1,2-dihydroxyethyl]-3a,10c-dihydroxy- 3a,5,6,10c-tetrahydrofuro[3′,4′:5,6]pyrano[3,4-b]indol-1(3H)-one. Its tosyl derivative undergoes cyclization to form a pentacyclic ketal derivative.

Full text of DOI:10.1016/j.tet.2005.04.049

Tetrahedron 61 (2005) 6610–6613
New pyrano[3,4-b]indoles from 2-hydroxymethylindole and
L-dehydroascorbic acid
Sergey N. Lavrenov,a Konstantin F. Turchin,b Alexander M. Korolev,a Olga S. Anisimovab
and Maria N. Preobrazhenskayaa,
*
aGause Institute of New Antibiotics, Russian Academy of Medical Sciences, B. Pirogovskaya 11, 119021 Moscow, Russia
bCenter for Drug Research, Russian Research Chimico-Pharmaceutical Institute, Zubovskaya 7, 119815 Moscow, Russia
Received 30 November 2004; revised 1 April 2005; accepted 21 April 2005
Available online 23 May 2005
Abstract—2-Hydroxymethylindole reacts with L-dehydroascorbic acid under mild conditions to give (3R,3aR,10cS)-3-[(1S)-1,2-
dihydroxyethyl]-3a,10c-dihydroxy-3a,5,6,10c-tetrahydrofuro[30,40:5,6]pyrano[3,4-b]indol-1(3H)-one. Its tosyl derivative undergoes
cyclization to form a pentacyclic ketal derivative.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
and their unique chemical and biological properties have
been investigated,3 but the reaction of isomeric 2-hydroxy-
methylindole with L-ascorbic acid poses synthetic
challenges and would help us to further elucidate the
synthetic potential of this unique compound and its
derivatives. The goal of our work was to study the
preparation of a compound isomeric to ascorbigen by the
reaction of 2-hydroxymethylindole 4 with L-ascorbic acid 1.
L-Ascorbic acid easily undergoes 2-C-alkylation by
3-hydroxymethylindole, 4-hydroxybenzyl alcohol, and
their analogues, which are able to produce quinone methide
type structures under mild acidic conditions.1,2 Ascorbigen,
which is 2-C-[(indol-3-yl)methyl]-a-L-xylo-hex-3-ulo-
furanosono-4-lactone 3 is a product of the reaction of
L-ascorbic acid 1 with the intermediate quinone methide
formed from 3-hydroxymethylindole 2.2 Ascorbigen 3 is the
main decomposition product of alkaloid glucobrassicin
from cruciferous vegetables, and animals and humans
receive it with meals. Recently, it was found that it is a
strong non-specific immunomodulator with valuable
properties (Scheme 1).3
2. Results and discussion
Unfortunately, 2-hydroxymethylindole 4a does not react
with 1 with the formation of an ascorbigen-like structure (5)
at pH 1–6. It can be explained by the inability of 4a to form
a quinone methide structure under these conditions.
However, on incubation of the reaction mixture (1C4a in
Several ascorbigens have been synthesized in our laboratory
Scheme 1.
Keywords: L-Ascorbic acid; L-Dehydroascorbic acid; Ascorbigen; Indolopyrane; 2-Hydroxymethylindole.
*
Corresponding author. Tel.: C7 095 245 37 53; fax: C7 095 245 02 95; e-mail: mnp@space.ru
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.04.049

S. N. Lavrenov et al. / Tetrahedron 61 (2005) 6610–6613
6611
Scheme 2.
Scheme 3.
H2O–MeOH mixture at pHw4.7) for more than two weeks,
we succeeded in the isolation of a new product in 20% yield.
It was identified as (3R,3aR,10cS)-3-[(1S)-1,2-dihydroxy-
ethyl]-3a,10c-dihydroxy-3a,5,6,10c-tetrahydrofuro[30,40:
5,6]pyrano[3,4-b]indol-1(3H)-one 7a (Scheme 2).
previously observed dominant mode of alkylation in such
systems.1,3,5 An isomeric structure with a different type of
annelation of the pyranoindole and furanone rings than in
compound 7 could be proposed for the product of reaction of
4 with 6. A double resonance experiment allowed the
identification in the 1H NMR spectrum of 8a of the signal of
the OH-group (10c-OH), which is nearest to the carbonyl
group. In the 1H coupled 13C NMR spectrum of compound
8a a coupling constant 3J1C,10c-OHz4 Hz was observed. The
NOE for this 10c-OH proton was determined (h10c-OH{10-
H}z3.5%) by saturation of 10-H. An analogous effect was
observed in the reverse experiment (h10-H{10c-OH}) in
accordance with structure 7 and 8.
It is suggested that 7a is a product of the reaction of
L-dehydroascorbic acid 6 with 4a. When L-ascorbic acid was
oxidized to L-dehydroascorbic acid by the action of oxygen
in the presence of activated charcoal in H2O–MeOH4
before addition of 4a, the yield of compound 7a increased to
50% and the reaction time was reduced to seven days.
Similarly, compound 7b was obtained in 60% yield from
1-methyl-2-hydroxymethyindole 4b and L-dehydroascobic
acid 6. It suggests that the nucleophilic attack of 3-C indole
atom on carbonyl group at 2-C of dehydroascorbic acid
takes place followed by hemiacetal formation with the
participation of 3-CO of dehydroascorbic acid and hydroxy
group of 4. The reaction of 7a or 7b with acetone 0in0 the
presence of p-toluenesulfonic acid gave crystalline 1 ,2 -O-
isopropylidene derivatives 8a or 8b, respectively. By the
reaction of 7a with an excess of p-toluenesulfonyl chloride
in pyridine 20-O-monotosyl derivative 9 was obtained. On
purification by preparative TLC, 9 partially underwent
cyclization into acetal 10 (Scheme 3).
The stereochemistry of compounds 7a,b was suggested by
NOE experiments and appears to be in accord with the
Figure 1. NOE experiments for 8b.

6612
S. N. Lavrenov et al. / Tetrahedron 61 (2005) 6610–6613
1
The reciprocal orientation of two hydroxyl groups (10c-OH
and 3a-OH) was elucidated based on rather high NOE
values h3-H{5-Ha}z9% and h5-Ha{3-H}z6%), in com-
pound 8b 5-Ha is the highfield doublet of AB system 5-H2
(Fig. 1). Molecular modeling of compounds 7 and 8 led to a
conclusion, that the distance between atoms 5-Ha and 3-H
may be !2 A only in the structure in, which the two
hydroxyl groups in the tetrahydrofuranone cycle are cis-
oriented.
321.0849. Found: 321.0830; H NMR: d (DMSO-d6) 3.54
(m, 2H, 20-HAHB); 3.91 (m, 1H, 10-H); 4.52 (d, JZ3.8 Hz,
1H, 3-H); 4.82 (d, JZ15.4 Hz, 1H, 5-HB); 4.90 (br s, 1H,
20-OH); 4.96 (d, JZ15.4 Hz, 1H, 5-HA); 5.97 (br s, 1H,
10-OH); 6.50 (br s, 1H, 10-OH); 7.01 (ddd, JZ7.8, 7.0,
1.0 Hz, 1H, 9-H); 7.08 (ddd, JZ8.1, 7.0, 1.2 Hz, 1H, 8-H);
7.19 (br s, 1H, 3a-OH); 7.35 (ddd, JZ8.1, 1.0, 0.7 Hz, 1H,
7-H); 7.73 (ddd, JZ7.8, 1.2, 0.7 Hz, 1H, 10-H); 11.14 (s,
1H, 6-H); 13C NMR: d (DMSO-d6) 58.0 (5-C); 61.5 (20-C);
68.8 (10-C); 70.9 (10c-C); 81.2 (3-C); 99.4 (3a-C); 104.1
(10b-C); 111.4 (7-C); 119.2 (9-C); 120.6 (10-C); 121.4
(8-C); 125.8 (10a-C); 134.3 (5a-C); 136.5 (6a-C); 174.3
(1-C).
˚
The S-configuration at 10c atom follows from analysis of
relevant literature, as there are no examples of attack on the
2C atom of L-ascorbic acid from the side cis to the bulky
substituent at C-4 (CHOH–CH2OH).3
3.1.2. (3R,3aR,10cS)-3-[(1S)-1,2-Dihydroxyethyl]-3a,10c-
dihydroxy-6-methyl-3a,5,6,10c-tetrahydrofuro[30,40:
5,6]pyrano[3,4-b]indol-1(3H)-one (7b). Compound 7b
was obtained from 4b (1 g, 6.25 mmol) and purified by
the same way as 7a, as a light-brown powder (1.25 g, 60%);
Rf 0.44 (A); [a]2D0 C6.5 (MeOH); nmax: 3368, 1786, 1455,
1031, 759 cmK1; HRMS Calcd for C16H17NO7: 335.1005.
Found: 335.0998; 1H NMR: d (CD3OD) 3.64 (s, 3H,
6-CH3); 3.81 (m, 2H, 20-HAHB); 4.08 (m, 1H, 10-H); 4.63 (d,
JZ5.3 Hz, 1H, 3-H); 5.04 (d, JZ15.6 Hz, 1H, 5-HB); 5.13
(d, JZ15.6 Hz, 1H, 5-HA); 7.10 (ddd, JZ7.9, 7.1, 1.0 Hz,
1H, 9-H); 7.19 (ddd, JZ8.3, 7.1, 1.2 Hz, 1H, 8-H); 7.37
(ddd, JZ8.3, 1.0, 0.7 Hz, 1H, 7-H); 7.88 (ddd, JZ7.9, 1.2,
0.7 Hz, 1H, 10-H); 13C NMR: d (CD3OD) 29.9 (N–CH3);
59.8 (5-CH2); 63.3 (20-C); 70.9 (10-C); 72.5 (10c-C); 81.2
(3-C); 100.9 (3a-C); 104.3 (10b-C); 110.1 (7-C); 121.0
(9-C); 121.6 (10-C); 123.0 (8-C); 126.7 (10a-C); 136.3
(5a-C); 139.8 (6a-C); 175.9 (1-C).
The compounds obtained have a structural fragment of
1,3,4,9-tetrahydropyrano[3,4-b]indole, which represents a
framework of some anti-inflammatory drugs such as
etodolac.6
3. Experimental
3.1. General
NMR spectra were recorded on a Varian Unity C400
1
instrument (400 MHz for H, 100.6 MHz for 13C). NOE
values (hHi{Hj, %) were measured as an increase of Hi
signal intensity when Hj signal was saturated. Analytical
TLC was performed on Kieselgel F254 plates (Merck),
preparative TLC chromatography on plates (20!20 cm,
0.5 mm) with Kieselgel 60 F254 (Merck), and column
chromatography on Kieselgel 60 (Merck), using the
following systems of solvents: CHCl3/MeOH 5:1 (A);
10:1 (B) and EtOAc/petroleum ester, 1:1 (C). Optical
rotations were measured on a Perkin-Elmer 241 polarimeter.
Infrared spectra were recorded with a Nicolet Avatar 330
FT-IR spectrometer using KBr discs.
3.1.3. (3R,3aR,10cS)-3-[(4S)-2,2-Dimethyl-1,3-dioxolan-
4-yl]-3a,10c-dihydroxy-3a,5,6,10c-tetrahydrofuro[30,
40:5,6]pyrano[3,4-b]indol-1(3H)-one (8a). To a solution of
7a (500 mg, 1.56 mmol) in dry acetone (10 mL) was added
p-toluenesulfonic acid (10 mg). The reaction mixture was
stirred for 40 min at rt, diluted with 100 mL of 10%
NaHCO3 solution, extracted with EtOAc (2!30 mL).
After drying (Na2SO4) of the extract, evaporating, and
recrystallization from acetone 8a (500 mg, 90%) was
obtained as colorless crystals. Mp 190–196 8C (decomp.);
Rf 0.16 (C); [a]2D0 C6.7 (MeOH); nmax: 3329, 1785, 1085,
1059, 753 cmK1; HRMS Calcd for C18H19NO7: 361.1161.
High resolution mass spectra were registered on a MAT
8430 Finnigan instrument (USA) with data operating system
SS-300 (EI, 70 eV, direct introduction, temperature of ion
source 250 8C). Electron impact (EI) mass-spectra were
registered on a SSQ 710 Finnigan MAT instrument (USA),
(EI: 70 eV, direct introduction). Melting points were
determined on a Buchi SMP-20 apparatus and are
uncorrected.
1
Found: 361.1143; H NMR: d (DMSO-d6) 1.29 and 1.33
(2 s, 2!3H, 10,20-OC(CH3)2); 3.90 (dd, JZ8.9, 6.5 Hz, 1H,
20-HB,); 4.14 (dd, JZ8.9, 6.3 Hz, 1H, 20-HA); 4.34 (m, 1H,
10-H); 4.39 (dd, JZ8.0, 1.0 Hz, 1H, 3-H); 4.96 (d, JZ
15.8 Hz, 1H, 5-HB); 5.02 (d, JZ15.8 Hz, 1H, 5-HA); 6.44 (s,
1H, 10c-OH); 6.96 (d, JZ1.0 Hz, 1H, 3a-OH); 7.02 (ddd,
JZ7.9, 7.2, 1.1 Hz, 1H, 9-H); 7.10 (ddd, JZ8.1, 7.2,
1.3 Hz, 1H, 8-H); 7.36 (ddd, JZ8.1, 1.1, 0.8 Hz, 1H, 7-H);
7.72 (ddd, JZ7.9, 1.3, 0.8 Hz, 1H, 10-H); 11.26 (s, 1H,
3.1.1. (3R,3aR,10cS)-3-[(1S)-1,2-Dihydroxyethyl]-3a,10c-
dihydroxy-3a,5,6,10c-tetrahydrofuro[30,40:5,6]-
pyrano[3,4-b]indol-1(3H)-one (7a). To a solution of 4a
(1.2 g, 7.36 mmol) in CH3OH (10 mL) was added buffer
solution prepared by dissolving of 2.7 g of citric acid and
6 g of Na2HPO4 in 300 mL of H2O and solution of
L-dehydroascorbic acid (6), obtained from 1 (6.5 g,
36.8 mmol) in 100 mL of CH3OH. The reaction mixture
was stirred for seven days at rt, saturated with NaCl,
extracted with CHCl3 (1!50 mL) and then with EtOAc
(3!40 mL). EtOAc extract was dried (Na2SO4), evaporated
and after column chromatography (A) gave 7a (1.2 g, 50%)
as a light-brown powder (as minimum 96% purity by NMR
data); Rf 0.26 (A); [a]2D0 C4 (MeOH); nmax: 3266, 1767,
1455, 1104, 741 cmK1; HRMS Calcd for C15H15NO7:
13
6-H); C NMR: d (DMSO-d6) 25.5 and 26.6 (10,20-
OC(CH3)2); 59.6 (5-C); 65.1 (20-C); 70.7 (10c-C); 74.7
(10-C); 79.3 (3-C); 99.7 (3a-C); 104.0 (10b-C); 108.8 (10,20-
OC(CH3)2); 111.5 (7-C); 119.4 (9-C); 120.2 (10-C); 121.8
(8-C); 125.4 (10a-C); 134.0 (5a-C); 136.8 (6a-C); 173.3
(1-C).
3.1.4. (3R,3aR,10cS)-3-[(4S)-2,2-Dimethyl-1,3-dioxolan-
4-yl]-3a,10c-dihydroxy-6-methyl-3a,5,6,10c-tetrahydro-

S. N. Lavrenov et al. / Tetrahedron 61 (2005) 6610–6613
6613
furo[30,40:5,6]pyrano[3,4-b]indol-1(3H)-one (8b). Com-
pound 8b was obtained and purified by the same way as 8a
from 7b (500 mg, 1.5 mmol) as colorless crystals (517 mg,
92%). Mp 161–165 8C (decomp.); Rf 0.19 (C); [a]2D0 C5 (c
2.5, MeOH); HRMS Calcd for C19H21NO7: 375.1318.
8.1, 7.0, 1.0 Hz, 1H, 9-H); 7.06 (s, 1H, 3a-OH); 7.12 (ddd,
JZ8.1, 7.0, 1.2 Hz, 1H, 8-H); 7.38 (ddd, JZ8.1, 1.0,
0.8 Hz, 1H, 7-H); 7.52 (d, JZ9.6 Hz, 2H, Ts) 7.70 (ddd, JZ
8.0, 1.2, 0.8 Hz, 1H, 10-H); 7.84 (d, JZ9.6 Hz, 2H, Ts);
11.25 (s, 1H, 6-H).
1
Found: 375.1324; H NMR: d (DMSO-d6) 1.29 and 1.33
(2 s, 2!3H, 10,20-OC(CH3)2); 3.62 (s, 3H, 6-CH3); 3.88 (dd,
JZ8.8, 6.8 Hz, 1H, 20-HB,); 4.15 (dd, JZ8.8, 6.5 Hz, 1H,
20-HA); 4.32 (m, 1H, 10-H); 4.43 (dd, JZ8.0, 1.2 Hz, 1H,
3-H); 5.04 (d, JZ15.8 Hz, 1H, 5-HB); 5.11 (d, JZ15.8 Hz,
1H, 5-HA); 6.47 (s, 1H, 10c-OH); 6.98 (d, JZ1.2 Hz, 1H,
3a-OH); 7.06 (ddd, JZ8.0, 7.1, 1.0 Hz, 1H, 9-H); 7.17 (ddd,
JZ8.2, 7.1, 1.2 Hz, 1H, 8-H); 7.48 (ddd, JZ8.2, 1.0,
0.8 Hz, 1H, 7-H); 7.73 (ddd, JZ8.0, 1.2, 0.8 Hz, 1H, 10-H);
11.26 (s, 1H, 6-H); 13C NMR: d (DMSO-d6) 25.4 and 26.5
(10,20-OC(CH3)2); 29.7 (N–CH3); 59.1 (5-C); 65.0 (20-C);
70.5 (10c-C); 74.7 (10-C); 79.0 (3-C); 99.8 (3a-C); 103.3
(10b-C); 108.8 (10,20-OC(CH3)2); 109.6 (7-C); 119.6 (9-C);
120.2 (10-C); 121.6 (8-C); 125.0 (10a-C); 135.2 (5a-C);
137.5 (6a-C); 173.1 (1-C).
Compound 10. Colourless crystals. Mp 201–205 8C; Rf 0.61
(A); nmax: 3416, 1778, 1477, 1087, 1038, 747 cmK1; HRMS
Calcd for C15H13NO6: 303.0743. Found: 303.0738; 1H
NMR: d (DMSO-d6–benzene-d6, 3:1) 4.26 (dd, JZ9.3,
4.1 Hz, 1H, 2-HA); 4.52 (dd, JZ9.3, 6.1 Hz, 1H, 2-HB);
4.60 (dd, JZ6.1, 4.1 Hz, 1H, 1-H); 5.06 (s, 1H, 12a-H); 5.20
(d, JZ15.6 Hz, 1H, 5-HA); 5.31 (d, JZ15.6 Hz, 1H, 5-HB);
6.05 (br s, 1H, 1-OH); 6.25 (s, 1H, 10c-OH); 7.15 (t, JZ
7.5 Hz, 1H, 9-H); 7.22 (t, JZ7.5 Hz, 1H, 8-H); 7.53 (d, JZ
7.9 Hz, 1H, 7-H); 8.05 (d, JZ7.9 Hz, 1H, 10-H); 11.50 (s,
1H, 6-H); 13C NMR: d (DMSO-d6–benzene-d6, 3:1) 61.4
(20-C); 70.5 (10c-C); 73.6 (10-C); 75.9 (5-C); 82.1 (12a-C);
104.9 (10b-C); 110.2 (3a-C); 111.5 (7-C); 119.5 (9-C);
120.1 (10-C); 121.8 (8-C); 124.9 (10a-C); 134.1 (5a-C);
136.7 (6a-C); 172.9 (11-C).
3.1.5. (3R,3aR,10cS)-3a,10c-Dihydroxy-1-oxo-1,3,3a,5,
6,10c-hexahydrofuro[30,40:5,6]pyrano[3,4-b]indol-3-yl]-
2-hydroxyethyl tosylate (9), and (1S,3aS,10cS,12aR)-
1,10c-dihydroxy-1,6,10c,12a-tetrahydro-2H-furo[200,
300:40,50]furo[30,40:5,6]pyrano[3,4-b]indol-11(5H)-one
(10). To a stirred solution of 7a (500 mg, 1.56 mmol) in dry
pyridine (10 mL) was added tosylchloride (305 mg,
1.6 mmol) and after 4 h incubation the reaction mixture
was diluted by citric acid solution and extracted by EtOAc
(2!30 mL). After evaporation 600 mg of brown oil was
obtained. It consisted of 80% of 9 and not contained 10.
After preparative TLC chromatography (system B) 60 mg
of 9 (8% yield,) and 300 mg of 10 (63% yield) were
obtained. The latter was formed during chromatography.
Acknowledgements
This study was supported by Russian Foundation for Basic
Research, grant No. 03-03-32090.
References and notes
1. Poss, A. J.; Belter, R. K. J. Org. Chem. 1988, 53, 1535–1540.
2. Piironen, E.; Virtanen, A. I. Acta Chem. Scand. 1962, 16,
286–287.
Compound 9. Colourless oil; Rf 0.52 (B); HRMS Calcd for
C22H21NO9S: 475.0937. Found: 475.0930; 1H NMR: d
(DMSO-d6) 2.48 (s, 3H, CH3 of Ts); 4.04 (m, 1H, 10-OH);
4.16 (dd, JZ9.6, 6.4 Hz, 1H, 20-HA); 4.31 (dd, JZ9.6,
3.2 Hz, 1H, 20-HB); 4.38 (d, JZ8.1 Hz, 1H, 3-H); 4.97 (d,
JZ15.1 Hz, 5-HA); 5.00 (d, JZ15.1 Hz, 5-HB); 5.98 (d, JZ
6.4 Hz, 1H, 10-OH); 6.52 (s, 1H, 10c-OH); 7.02 (ddd, JZ
3. Preobrazhenskaya, M. N.; Korolev, A. M. Russ. J. Bioorg.
Chem. 2000, 26, 85–97.
4. Ohmori, M.; Takagi, M. Agric. Biol. Chem. 1978, 42, 170–174.
5. Preobrazhenskaya, M. N.; Lazhko, E. I.; Korolev, A. M.
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Pedrocchi-Fantoni, G. Tetrahedron 1997, 53, 17769–17780.