From ascorbigens to indolocarbazoles

Article abstract of DOI:10.1016/S0014-827X(99)00026-9

New methods of L-ascorbic acid derivatization with the use of polyfunctional indole-3-cabinols are described. Reaction of β-hydroxy-N-methyltryptamine and L-ascorbic acid gave lactame derivatives; (indol-3-yl)gylcolic and L-ascorbic acids produced 2-hydroxy-4-hydroxymethyl-3-(indol-3-yl)-)-cylopen-2-enone. Similarly 4-hydroxy-3-methoxyphenylglycolic and L-ascorbic acids yielded 2-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-4-hydroxymethyl-cyclopen-2-enone. Properties of N-methoxyascorbigen (neoascorbigen) were investigated. Alkylation of L-ascorbic acid with polysubstituted pyrrolecarbinols led to pyrrole analogues of ascorbigen. Acidic transformation of 3-formylindole and 1-methyl-3-formylindole led to indolocarbazoles and triindolylmethane derivatives.

Full text of DOI:10.1016/S0014-827X(99)00026-9

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Il Farmaco 54 (1999) 265–274
From ascorbigens to indolocarbazoles
Maria N. Preobrazhenskaya a,*, Alexander M. Korolev a, Ilya I. Rozhkov a,
Larisa N. Yudina a, Eduard I. Lazhko a, Enrico Aiello b, Anna Maria Almerico b,
Francesco Mingoia c
a Institute of New Antibiotics, Russian Academy of Medical Sciences, B. Pirogo6skaya 11, Moscow 119867, Russia
b Uni6ersita` degli Studi, Istituto Farmacochimico 6ia Archirafi 32, 90123 Palermo, Italy
c Istituto di Chimica e Tecnologia dei Prodotti Naturali-CNR, Via Ugo La Malfa 153, 90123 Palermo, Italy
Received 30 December 1998; accepted 1 March 1999
Abstract
New methods of
b-hydroxy-N-methyltryptamine and
2-hydroxy-4-hydroxymethyl-3-(indol-3-yl)-cyclopen-2-enone. Similarly, 4-hydroxy-3-methoxyphenylglycolic and
yielded 2-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-4-hydroxymethyl-cyclopen-2-enone. Properties of N-methoxyascorbigen
(neoascorbigen) were investigated. Alkylation of -ascorbic acid with polysubstituted pyrrolecarbinols led to pyrrole analogues of
L
-ascorbic acid derivatization with the use of polyfunctional indole-3-cabinols are described. Reaction of
-ascorbic acid gave lactame derivatives; (indol-3-yl)glycolic and -ascorbic acids produced
-ascorbic acids
L
L
L
L
ascorbigen. Acidic transformation of 3-formylindole and 1-methyl-3-formylindole led to indolocarbazoles and triindolylmethane
derivatives. © 1999 Elsevier Science S.A. All rights reserved.
Keywords: Ascorbigen; L-Ascorbic acid; 3-Formylindole; Indolocarbazole; Neoascorbigen; Indolecarbinol; Pyrrolecarbinol
The facile 2-C-alkylation of ascorbic acid prompted
L
-Ascorbic acid is easily alkylated in mild conditions
us to study the interaction of polyfunctional indole-3-
carbinols with ascorbic acid. Indole-3-carbinols, with
functional groups in the neighbourhood of carbinol
hydroxyl, interact with ascorbic acid with the participa-
tion of the functional group. Earlier we investigated the
(room temperature, water–alcohol solution, pH 4–5)
with 3-hydroxymethylindole, with the formation of
ascorbigen (2-C-[(indol-3-yl)methyl]-a-L-xylo-3-hexulo-
furanosono-1,4-lactone (Asc), (Scheme 1) [1].
3-Hydroxymethylindole is formed in plants of the
cruciferous family from the alkaloid glucobrassicin, and
interaction of (indol-3-yl)ethandiol-1,2 with
L-ascorbic
acid, which yielded a mixture of products of the
L
-
its interaction with
L-ascorbic acid in plant tissues
ascorbic acid 2-C alkylation with the substituted skatyl
cation stabilized by the 3-CO hemiketal formation with
the participation of the CH2OH moiety of (indol-3-
yl)ethandiol-1,2 [6a,b]. The interaction of DL-N-methyl-
proceeds nonenzymatically [2]. For animals and hu-
mans Asc is a main source of 5H,11H-indolo[3,2-b]-
carbazole (ICZ), a natural potent Ah receptor agonist.
The Ah receptor is a widely occurring ligand-activated
transcription factor that mediates the activation of cy-
tochrome 4501A1, P4501A2, glutathione S-transferase,
and quinone reductase genes. The binding activity of
ICZ is only a factor of 3.7×10−2 lower than that of
the highly toxic environmental contaminant and cancer
promoter 2,3,7,8-tetrachlorodibenzo-p-dioxin [3–5].
b-hydroxytryptamine with
L-ascorbic acid proceeds
through the 2-C alkylation of the latter and the in-
tramolecular acylation of the methylamino group, to
yield diastereomeric 3-hydroxy-4-(indol-3-yl)-1-methyl-
3-(2,3,4-trihydroxybutyryl)-pyrrolid-2-ones (4a and 5b)
(Scheme 2), [7]. The 3-C–6-C moiety of ascorbic acid in
isomer 4a represents a cyclic hemiacetal (1%-C–4%-C),
whereas in isomer 5b it exists as an acyclic trihydroxy-
butyryl residue. Acetylation of compounds 4a and 5b
with acetic anhydride in pyridine at −16°C afforded 6a
and 6b, respectively, whose deacetylation (MeONa in
* Corresponding author. Tel.: +7-095-245-3753; fax: +7-095-245-
0295.
E-mail address: lcta@space.ru (M.N. Preobrazhenskaya)
0014-827X/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(99)00026-9

266
M.N. Preobrazhenskaya et al. / Il Farmaco 54 (1999) 265–274
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Scheme 1.
MeOH) gave again individual 4a and 5b to show that in
the course of the acetylation no racemization occurred.
Among chiral atoms of 4a and 5b, there are two (3-C
and 4-C of the lactam cycle) whose stereochemistry is
not pre-assigned by the stereochemistry of
acid.
The absolute configuration of the 3-C atom is deter-
mined by the direction of the electrophilic attack of the
L-ascorbic
Scheme 2.

M.N. Preobrazhenskaya et al. / Il Farmaco 54 (1999) 265–274
267
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can be explained by the small size of the methyl group
[9]. This suggests the S configuration at the 3-C of
compounds 4a and 5b.
The absolute configuration at 4-C of the 4a and 5b
isomers was determined for their tri-O-acetyl deriva-
tives 6a and 6b. 1H and 13C NMR data showed that the
frameworks of 6a and 6b are the same as that of 5b.
The presence of a sharp signal of the unsubstituted
3-OH group in 1H NMR spectra of 6a and 6b in
DMSO-d6 allowed us to use NOE-difference experi-
ments to determine the disposition of the substituents
at 4-C. The selective saturation of the 3-OH proton at
6.73 ppm gave rise to 8% signal enhancement of the
4-H multiplet at 3.87 ppm in 6b, whereas the saturation
of the 3-OH proton in 6a did not affect the 4-H signal.
Based on these data, we assigned the indole residue at
4-C and the carbohydrate moiety at 3-C, a cis-arrange-
ment in 6b and therefore in 5b, and a trans-arrange-
ment in 6a and therefore in 4a. This led to the
conclusion that the absolute configuration at 4-C is S in
5b and R in 4a (Scheme 3).
Scheme 3.
Compounds 4a and 5b contain the same indolyl
g-lactame backbone as alkaloid staurosporine (Scheme
4), [10].
The reaction of N-alkylindolylglycolic acids (7) with
-ascorbic acid in methanol–HCl solution unexpectedly
Scheme 4.
L
led to 3-(1-alkylindolyl)-2-hydroxy-4-hydroxymethylcy-
clopent-2-en-ones (9, Scheme 5) in 30–40% yields.
Bright fluorescence of cyclopentenone derivatives 9
in UV light helped to isolate these compounds by
chromatography methods. Formation of the intermedi-
ate 2%-carboxyascorbigens (8) in this reaction is postu-
lated.
substituted skatyl cation at the 2-C atom of the L-ascor-
bic acid lactone ring [2]. In all the ascorbic acid 2-C-
alkylations reported to date, such an attack was
directed from the site opposite the CHOH–CH2OH
fragment [8], except for the 2-C methylation of
L-ascor-
bic acid yielding a mixture of 2S and 2R isomers, which
Scheme 5.

268
M.N. Preobrazhenskaya et al. / Il Farmaco 54 (1999) 265–274
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Scheme 8.
the skatyl position facilitating cyclopentenone
formation.
Scheme 6.
Among alkaloids isolated from plants of the crucifer-
ous family indole glucosinolate alkaloids glucobrassicin
and neoglucobrassicin (N-methoxyglucobrassicin) pre-
dominate; the first is a source of indole-3-carbinol and
hence ascorbigen, and the latter is a source of 1-
methoxyindole-3-carbinol and hence neoascorbigen (N-
methoxyascorbigen). The level of neoascorbigen in
cruciferous vegetables in most cases is lower than that
of Asc, though there are vegetables in which the neoglu-
cobrassicin level is higher than that of glucobrassicin
[14]. We obtained the data presented in Table 1 by the
HPLC method using synthetic neoascorbigen and
ascorbigen as standards.
Neoascorbigen and its N-alkoxy homologues were
prepared from N-hydroxyindole, which was obtained
by the methods described in (Schemes 7 and 8) and
Refs. [15–17], and their properties were compared with
the properties of ascorbigen. Similarly to ascorbigen,
N-methoxy- and N-ethoxyascorbigen form O-glyco-
sides (15a,b), amides (17a,b), or were reduced by
A similar reaction proceeds between L-ascorbic acid
and vanilomandelic acid (11) in MeOH–HCl mixture
on heating (Scheme 6), [11]. Vanilomandelic acid is a
major metabolite of adrenaline. The structures of cy-
clopentenone derivatives 9a–c and 12 were confirmed
by NMR and HR mass spectrometry (HR-MS) meth-
ods and through transformations into reduced (10) or
per-O-silylated (13) compounds.
Formation of cyclopentenone derivatives represents
an example of a domino reaction, which is a process
involving two or more bond-forming transformations
(usually C–C bonds) taking place under the same reac-
tion conditions without adding additional reagents and
catalysts, and in which the subsequent reactions result
as a consequence of the functionality formed in the
previous step. Tandem reaction sequence, cascade reac-
tions, or domino reactions, involve two or more consec-
utive reactions, each dependent on the formation of a
reactive functionality in the preceding step [12,13]. In
these reactions C-alkylation of ascorbic acid by the
skatyl cation, which takes place in strong acids, is
followed by the opening of the lactone ring in ascorbi-
gen-type compounds, decarboxylation, dehydration, al-
dole-type cyclization of the pentenone cycle, and again
decarboxylation, the presence of the carboxyl group in
NaBH4 to 2-C-[(1-methoxyindol-3-yl)methyl]-L-gulonic
acid 1,4-lactone (16a) (Scheme 9). Stereochemistry of
the 4-C centre of 16a was confirmed by NOE differen-
tial NMR spectroscopy.
However, neoascorbigen and its ethoxy homologue
are more stable in acidic conditions than Asc (Table 2).
When heated in acidic media they produced 3-(1-
alkoxyindolyl)-2-hydroxy-cyclopent-2-en-ones (19a,b)
isolated in ꢀ15% yields. The structures of compounds
19a,b were confirmed by HR-MS and NMR spec-
troscopy methods. Additionally, small amounts of di(1-
alkoxyindol-3-yl)methanes (20) and 2,3-di(1-alkoxy-
Table 1
Level of ascorbigen content in cohlrabi cabbage
Ascorbigen
Neoascorbigen
22.30 mg/kg fresh weight
3.50 mg/kg fresh weight
Scheme 7.