3-O and 2-C Alkylation of L-ascorbates with benzyl halides and N-substituted indolemethanol derivatives

Article abstract of DOI:10.1007/s11172-010-0101-8

Coupling of alkali metal ascorbates with benzyl halides and 2and 3-hydroxymethylindole methanesulfonates resulted in L-ascorbic acid 3-Oand 2-C-derivatives. In contrast to 3-Obenzyl L-ascorbate, its indole analogs are unstable compounds, which underwent decomposition or rearrangement during isolation to give thermodynamically stable 2-C-isomers.

Full text of DOI:10.1007/s11172-010-0101-8

Russian Chemical Bulletin, International Edition, Vol. 59, No. 2, pp. 457—462, February, 2010
457
3ꢀO and 2ꢀC Alkylation of Lꢀascorbates with benzyl halides and
Nꢀsubstituted indolemethanol derivatives
A. M. Korolev, Yu. N. Luzikov, M. I. Reznikova, and M. N. Preobrazhenskaya
G. F. Gause Institute of New Antibiotics, Russian Academy of Medical Sciences,
11 ul. Bolshaya Pirogovskaya, 119021 Moscow, Russian Federation.
Fax: +7 (499) 245 0295. Eꢀmail: korolev_am@mail.ru
Coupling of alkali metal ascorbates with benzyl halides and 2ꢀ and 3ꢀhydroxymethylindole
methanesulfonates resulted in Lꢀascorbic acid 3ꢀOꢀ and 2ꢀCꢀderivatives. In contrast to 3ꢀOꢀ
benzyl Lꢀascorbate, its indole analogs are unstable compounds, which underwent decomposiꢀ
tion or rearrangement during isolation to give thermodynamically stable 2ꢀCꢀisomers.
Key words: ascorbigen, Lꢀascorbic acid, 3ꢀOꢀ and 2ꢀCꢀalkylation, regioselectivity.
Derivatives of Lꢀascorbic acid (1) substituted at the
positions O(3), O(5), and O(6) are well known, some of
them are commercially available products.1,2 Derivatives
of 1 substituted at the position C(2) are also of interest.
The most wellꢀknown is ascorbigen, 2ꢀCꢀ[(indolꢀ3ꢀyl)ꢀ
methyl]ꢀαꢀLꢀxyloꢀhexꢀ3ꢀulofuranosonoꢀ1,4ꢀlactone (2),
a very active immunomodulator, which is formed in the
reaction of 1 with 3ꢀhydroxymethylindole (3) (Scheme 1).
Ascorbigen (2) was also isolated from Brassicacae.3 A large
range of 2ꢀCꢀderivatives of 1 are known. Some of them posꢀ
sess valuable biological properties.4 They were isolated
from natural sources or synthesized on the base of unsaturꢀ
ated aldehydes, ketones, and some alkyl aromatic alcohols,
for example, 4ꢀhydroxybenzyl alcohol (4) and its analogs.
A characteristic feature of the 2ꢀC alkylation of 1 in
acidic media is the involvement of stable intermediate catꢀ
Scheme 1
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 447—452, February, 2010.
1066ꢀ5285/10/5902ꢀ0457 © 2010 Springer Science+Business Media, Inc.

458
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 2, February, 2010
Korolev et al.
ions, which can be generated by two pathways.3 Protonaꢀ
tion of the compounds bearing electronꢀwithdrawing
groups (formyl, keto, nitro, or cyano groups), which are
conjugated with unsaturated radicals affords electrophilic
species. The latter undergo 1,4ꢀconjugate addition of the
Michael type or aldol condensation giving 2ꢀCꢀderivatives
of 1. Protonation and dehydration of a molecule of an
alkyl aromatic alcohol of type 3 or 4 leads to stable elecꢀ
trophilic species such as quinonemethides, for example,
3ꢀmethylideneindoleninium cation or pꢀhydroxybenzyl
cation. Under weakly acidic conditions (pH 4—5), such
cations stereospecifically and regioselectively alkylate 1
following an SE1 mechanism affording exclusively 2ꢀCꢀdeꢀ
rivatives (Scheme 1). However, under these conditions,
no reactions of 1 with electrophilic reagents that cannot
produce stable cations were observed. Thus no formation
of structural analogs of ascorbigen was observed from
2ꢀhydroxymethylꢀ1ꢀmethylindole5 (5) and 1ꢀ(tertꢀbutꢀ
oxycarbonyl)ꢀ3ꢀhydroxymethylindole (6). Low reactivity
of alcohols 5 and 6 can apparently be explained by instaꢀ
bility of the corresponding carbocations due to violation
of the aromatic stabilization or a decrease in the ability of
the nitrogen atom for positive charge delocalization.6,7
Like ethyl acetoacetate, Lꢀascorbic acid gives an ambiꢀ
dent anion under basic conditions, which is an electroꢀ
philic Oꢀ and Cꢀalkylation agent. The position C(2) of
compound 1 is more nucleophilic as compared with the
position O(3) and, as a result, 2ꢀCꢀderivatives are more
thermodynamically stable. However, the ratio of the Oꢀ
and Cꢀstructural isomers depends on the reaction condiꢀ
tions, the nature of the electrophilic agents, and their strucꢀ
tural features.3
found. Thus the ratio of the 2ꢀC and 3ꢀO alkylation prodꢀ
ucts is 1 : 2 and remained practically unchanged with
a decrease in the DMSO content in the solvent mixture
from 50% to 10%. The nature of benzyl halide also affectꢀ
ed the product ratio insignificantly, although benzyl broꢀ
mide (7b) accelerated the reaction considerably. No noꢀ
ticeable increase in the yields of the final products 8 and 9
was found with the increase in the reaction time and temꢀ
perature. The ratios of the 3ꢀO and 2ꢀC alkylation prodꢀ
ucts were determined by 1H NMR spectroscopy, since
great difference in their molar extinction did not allow
the use of HPLC with UV detection.
Scheme 2
The aim of the present work was the study of the reacꢀ
tions of ascorbates 1a,b with benzyl halides and inꢀ
dolemethanol derivatives that do not form stable carbocaꢀ
tions. It has previously been shown8 that alkylation of
sodium ascorbate (1a) with benzyl chloride (7a) in aqueꢀ
ousꢀorganic solutions led to 3ꢀOꢀbenzylascorbic acid (8)
along with the 2ꢀC alkylation product, 2ꢀCꢀbenzylꢀαꢀLꢀ
xyloꢀhexꢀ3ꢀulofuranosonoꢀ1,4ꢀlactone (9). In the present
work, this reaction was studied in detail, the resulting
products were isolated and characterized; other Oꢀ and
Cꢀalkylation reaction of sodium and potassium ascorbates
were studied as well.
X = Cl (a), Br (b);
M = Na (a), K (b)
Isolation of structural isomers 8 and 9 by chromatogꢀ
raphy (TLC or HPLC) failed. For the isolation of these
compounds in the individual state, other methods were
developed (Scheme 3). Hydrogenolysis of the product mixꢀ
ture in the presence of Pd/C led to decomposition of 3ꢀOꢀ
benzyl ether 8, and lactone 9 was isolated in 30% yield.
Treatment of the product mixture with acetone in the presꢀ
ence of TsOH resulted in the conversion of 3ꢀOꢀbenzyl
ether 8 into isopropylidene derivative 10, while compound
9 remaines virtually unaffected. Chromatography of the
resulting mixture afforded ketal 10 in 66% yield. Subseꢀ
quent removal of the isopropylidene protecting group by
acid hydrolysis furnished 3ꢀOꢀbenzylꢀLꢀascorbic acid (8).
2ꢀHydroxymethylꢀ1ꢀmethylindole (5), which was obꢀ
tained by reduction of ethyl 1ꢀmethylindoleꢀ2ꢀcarboxylate
(11) in the presence of LiAlH4 in 70% yield, was convertꢀ
ed in methane sulfonate (12) (Scheme 4). The reaction of
12 with sodium ascorbate (1a) in DMSO resulted in
(1ꢀmethylindolꢀ2ꢀyl)methyl derivatives 13 and 14. Preꢀ
Results and Discussion
In alkylation of ascorbates 1a,b with benzyl halides
7a,b (Scheme 2), the product ratio depended on the reacꢀ
tion conditions. 3ꢀOꢀAlkylation proceeded mainly in aproꢀ
tic polar solvents (acetone, DMSO). Mixtures of 3ꢀOꢀ
and 2ꢀCꢀderivatives 8 and 9 were obtained in water—orꢀ
ganic media containing acetone, THF, or DMSO. No
noticeable influence of the aprotic solvent content in the
mixture on the ratio of the resulting structural isomers was

3ꢀOꢀ and 2ꢀCꢀAlkylation of Lꢀascorbic acid
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 2, February, 2010
459
Scheme 3
was synthesized by acylation of 3ꢀformylindole with subseꢀ
quent reduction with NaBH4 and sulfonylation (Scheme 5).
The reaction of methanesulfonate 15 with ascorbate 1a
resulted mainly in 2ꢀCꢀderivative of 1, viz. NꢀBocꢀascorꢀ
bigen (16). Treatment with trifluoroacetic acid led to
cleavage of the Bocꢀprotecting group and elimination of
the skatole moiety furnishing a mixture of di(indolꢀ3ꢀyl)ꢀ
methane (17) and ascorbigen (2).
The 1H NMR spectra of carbohydrate fragments of
derivatives 9, 13, and 16 are similar to those of indoleꢀ
containing bicyclic ascorbigens.10 A characteristic feature
1
of the H NMR spectra of the carbohydrate moieties of
the ascorbigen analogs is the spinꢀspin coupling constant
J4,5 = 0 Hz. Thus, the signal for the H(4) proton is
a singlet, and the signals for the H(5), Ha(6), and Hb(6)
protons are doublets with characteristic coupling constants
(geminal coupling constant J6a,6b = 9.7 Hz, transꢀvicinal
coupling constant J5,6a =5.9 Hz and cisꢀvicinal coupling
constant J5,6b = 3.3 Hz), giving the threeꢀspin systems
AMX. The spectral parameters of the carbohydrate moiꢀ
ety of 3ꢀOꢀderivative 14 were established by comparing
them with those for benzyl ether 8.11
parative TLC on silica gel was used for the isolation of the
individual compounds. During chromatography, 3ꢀOꢀ[(inꢀ
dolꢀ2ꢀyl)methyl]ꢀLꢀascorbic acid (14), which is apparently
a kinetic reaction product, converted partially into 2ꢀC
isomer (13). The latter is a structural isomer and homolog
of ascorbigen (2) (see Scheme 4).
To date, only one example of such isomerization has
been known: upon refluxing in toluene, 3ꢀOꢀallylꢀ5,6ꢀOꢀ
isopropylideneꢀLꢀascorbic acid converted into the 2ꢀC isoꢀ
mer by a mechanism of pericyclic [3,3]ꢀsigmatropic rearꢀ
rangement.9
The mass spectra (ESI) of compounds 8—10, 13, 14,
and 16 revealed the peaks of low abundances (20—50%)
that were attributed to the molecular ion ([M]+) and fragment
ions ([M – CO2]+ , [M – CO2 – H2O]+, [M – CO]+, and
[M – But – CO]+), as well as the ion peaks of the benzyl
and skatyl radicals. Furthermore, the mass spectra of all
ascorbic acid derivatives exhibited characteristic ion fragꢀ
ment peaks of ascorbic acid (m/z = 77, 55). Highꢀresoluꢀ
tion mass spectra revealed the peaks corresponding to the
lactone molecular ions [M]+, [M + Na]+, and [M + K]+.
The IR spectra of compounds 8—10, 13, and 16 conꢀ
tained the absorption bands characteristic of the lactone
The alkylating reagent (1ꢀBocꢀindolꢀ3ꢀyl)methyl meꢀ
thanesulfonate (15), which is an analog of compound 12,
fragment in the range of 1790 cm–1
.
Scheme 4

460
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 2, February, 2010
Korolev et al.
Scheme 5
taining compounds were visualized in the UV light and by sprayꢀ
ing with the Ehrlich reagent (2% 4ꢀdimethylaminobenzaldehyde
in EtOH—HCl) or the van Urk reagent (2% 4ꢀdimethylamiꢀ
nobenzaldehyde in EtOH : 50% H2SO4, 1 : 1). The mass spectra
(EI) were obtained on a Finnigan SAQ 710 spectrometer (70 eV,
direct inlet, the ion source temperature 150 °C). The highꢀresoꢀ
lution mass spectra (ESI) were recorded on a Finnigan MAT
900S spectrometer. Analytical HPLC was performed on a Shiꢀ
madzu LC10 vp instrument equipped with a Kromasilꢀ100 C18
column (4×250 mm, 5 μm, Knauer, Germany). The injection
volume is 20 μL. The UV detection was performed at 254 nm
(λ
of ascorbigen). The column was eluted with a MeCN —
max
0.01 M H3PO4 mixture, pH 2.6, in a gradient mode, where the
percentage of MeCN increased from 20 to 22% within 15 min,
then to 90% within 15 min at a flow rate 1 mL min–1. The
optical rotation was measured on a Perkin—Elmer 241 polarimꢀ
eter. The IR spectra were obtained on a NicoletꢀiS10 Fourier
transform IR spectrometer (DTGS detector, splitter — KBr)
with a Smart Performer module equipped with a ZnSeꢀcrystal.
The spectra were run in the range of 3000—650 cm–1 with
a resolution of 4 cm–1. The spectra were processed using the
OMNICꢀ7.0 program package.
Alkylation of alkali metal ascorbates with benzyl halides (genꢀ
eral procedure). To a solution of 1 (5.6 g, 0.035 mol) in water
(30 mL) equimolar amount of NaOH or KOH was added. After
short stirring, to the resulting solution of ascorbate (pH~7.0),
a solution of benzyl halide 7a,b in acetone or DMSO (30 mL)
was added. The mixture was stirred until complete consumption
of 7 (TLC monitoring), diluted with water, the aqueous layꢀ
er was saturated with NaCl, and the mixture was extracted
with EtOAc. The combined organics was washed with water,
dried with Na2SO4, and the solvent was removed in vacuo. Flash
column chromatography of the residue (eluent — CHCl3,
CHCl3—MeOH, 50 : 1→10 : 1) afforded several fractions conꢀ
taining benzyl derivatives of the ascorbic acid (1). The fraction
with Rf 0.45 (CHCl3—MeOH, 5 : 1) contained a mixture of 3ꢀO
and 2ꢀCꢀderivatives 8 and 9. This mixture was subjected to hydrꢀ
ogenolysis in EtOAc with 5% Pd/C. After 30 min, the catalyst
was filtered off, the solvent was removed in vacuo, and 2ꢀCꢀ
derivative 9 was isolated by column chromatography, eluent —
CHCl3—MeOH, 10 : 1.
Similar to ascorbigen (2),10 the electrophilic addition
of benzyl halides 7a,b and 2ꢀ and 3ꢀhydroxymethylindole
methanesulfonates 12 and 15 proceeded from the side that
is opposite that where the chain is involved in ring closure
to hemiketal. Therefore, the chiral C(2) atom has the
Sꢀconfiguration, which is confirmed by the positive optiꢀ
cal rotation of compounds 9, 13, and 16.
Analysis of the reaction products demonstrated the inꢀ
fluence of the structural factors on regioselectivity of alkyꢀ
lation of ascorbates with benzyl halides and hydroxymeꢀ
thylindole sulfonates, as well as on the stability of the
resulting 3ꢀOꢀ and 2ꢀCꢀascorbic acid derivatives.
2ꢀCꢀBenzylꢀαꢀLꢀxyloꢀhexꢀ3ꢀulofuranosonoꢀ1,4ꢀlactone (9)
was obtained by the reaction of sodium ascorbate (1a) (0.035 mol)
with benzyl chloride (7a) (2.2 g, 2 mL, 0.017 mol) or with benzyl
bromide (7b) (2.88 g, 2 mL, 0.017 mol) in a yield of ~1.1 g
(24%), colorless crystals, Rf 0.52 (CHCl3—MeOH, 7 : 1), Rt =
= 8.48 min (98.2%, sample concentration 1—2 mg mL–1), m.p.
Experimental
20
190—196 °C (decomp.), [α]D +8 (c 0.05, MeOH). IR (powꢀ
der), ν/cm–1: 1781 (CO lactone). 1H NMR (CD3OD), δ: 3.22
(d, 1 H, PhCH2, J = 13.0 Hz); 3.27 (d, 1 H, PhCH2, J = 13.0 Hz);
3.75 (s, 1 H, H(4)); 4.05 (dd, 1 H, H(6a), J = 9.7 Hz, J = 3.4 Hz);
4.14 (d, 1 H, H(6b), J = 5.7 Hz); 4.25 (m, 1 H, H(5)); 6.27
(s, 1 H, H (3´)); 6.88 (t, 1 H, H(6´), J = 7.1 Hz); 7.09 (t, 1 H,
H(5´), J = 7.1 Hz); 7.22—7.33 (m, 5 H, Ph). 13C NMR (CD3OD),
δ: 41.94; 75.50; 75.74; 81.23; 88.09; 108.45; 128.19; 129.03;
131.94; 135.32; 177.58. MS (EI, 70 eV), m/z (Irel (%)): 266 [M]+
(39). Found: m/z 289.0670 [M + Na]+. C13H14O6Na. Calculatꢀ
ed: M = 289.0688.
Indolemethanols 5 and 6 were synthesized from the comꢀ
mercially available compounds, ethyl indoleꢀ2ꢀcarboxylate
(Aldrich) and 3ꢀformylindole (Fluka). Compound 11 was obꢀ
tained by the known procedure.5
The 1H and 13C NMR spectra were recorded on a VXRꢀ400
instrument at 400 MHz in CDCl3 or CD3OD. Chemical shifts
are given in the δ scale relative to the residual solvent signals
(CDCl3, δH 7.25, δC 77.00; CD3OD, δH 3.32, δC 49.00). Analytꢀ
ical TLC was performed on precoated silica gel F254 plates
(0.2 mm, Merck), preparative TLC was carried out on the plates
(20×20 cm×0.5 mm) with silica gel 60 F254 (Merck), silica gel 60
(Merck) was used for column chromatography. The indoleꢀconꢀ
3ꢀOꢀBenzylꢀ5,6ꢀOꢀisopropylideneꢀLꢀascorbic acid (10). To
a solution of the mixture of 8 and 9 (500 mg, 1.56 mmol) in dry
acetone (10 mL), TsOH (10 mg) was added. The mixture was

3ꢀOꢀ and 2ꢀCꢀAlkylation of Lꢀascorbic acid
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 2, February, 2010
461
stirred for 40 min, diluted with 10% NaHCO3 (100 mL), extractꢀ
ed with EtOAc (2×30 mL), the combined organics was dried
with Na2SO4, and the solvent was removed in vacuo. Purificaꢀ
tion by column chromatography afforded compound 9 (150 mg)
and 3ꢀOꢀbenzyl derivative 10 (250 mg), yellowish oil, Rf 0.34
(petroleum ether—EtOAc, 3 : 1). 1H NMR(CDCl3), δ: 1.47
(s, 3 H, C—Me); 1.50 (s, 3 H, C—Me); 4.22—4.10 (m, 2 H,
Ha(6), Hb(6)); 4.36 (m, 1 H, H(5)); 4.67 (s, 1 H, H(4)); 5.62
(d, 1 H, PhCH2, J = 11.9 Hz); 5.67 (d, 1 H, PhCH2, J = 11.9 Hz)
7.55—7.35 (m, 5 H, Ph). 13C NMR (CD3OD), δ: 14.0; 22.55;
61.59; 65.14; 73.33; 73.96; 78.49; 121.40; 127.50; 128.55; 128.56;
135.35; 155.22; 172.75. MS (EI, 70 eV), m/z (Irel (%)): 306 [M]+
(40). Found: m/z 329.0992 [M + Na]+. C16H18O6Na. Calculatꢀ
ed: M = 329.1001.
3ꢀOꢀBenzylꢀLꢀascorbic acid (8). A solution of isopropylidene
derivative 10 (0.1 g, 0.32 mmol) in a mixture of 1 M HCl and
THF (1 : 1) was stirred until complete consumption of the startꢀ
ing compound. The reaction mixture was neutralized with 10%
NaHCO3 and extracted with BuOH (2×20 mL). The combined
organics was washed with water and the solvent was removed
in vacuo. Purification of the residue by column chromatography
(eluent — CH2Cl2—MeOH, 20 : 1) afforded compound 8 in
a yield of 0.07 g (80%), Rt = 12.84 min (sample concentration
0.1—0.4 mg mL–1). IR (powder), ν/cm–1: 1781 (CO lactone).
1H NMR (CD3OD), δ): 3.64—3.68 (m, 2 H, Ha(6), Hb(6)); 3.88
(m, 1 H, H(5)); 4.90 (s, 1 H, H(4)); 5.50 (d, 1 H, PhCH2,
J = 11.9 Hz); 5.57 (d, 1 H, PhCH2, J = 11.9 Hz); 7.46—7.32
(m, 5 H, Ph). 13C NMR (CD3OD), δ: 61.59; 70.60; 73.96; 78.49;
121.40; 129.12; 129.55; 129.78; 137.86; 150.90; 172.75. MS (EI,
70 eV), m/z (Irel (%)): Found: m/z 289.0684 [M + Na]+.
C13H14O6Na. Calculated: M = 289.0688.
2ꢀHydroxymethylꢀ1ꢀmethylindole (5). To a suspension of Liꢀ
AlH4 (0.2 g, 0.005 mmol) in diethyl ether (10 mL), ethyl
1ꢀmethylindoleꢀ2ꢀcarboxylate (11) (1.0 g, 0.005 mol) was added
and the reaction mixture was stirred for 30 min until complete
consumption of the starting ester. The excess of LiAlH4 was
decomposed by addition of aqueous MeOH, the product was
extracted with Et2O, the combined organics was washed with
water (3×50 mL), and dried with Na2SO4. Removal of the solꢀ
vent in vacuo furnished alcohol 5 in a yield of 0.55 g (70%), darkꢀ
brown powder, Rf = 0.20 (petroleum ether—EtOAc, 3 : 1).
1H NMR (CDCl3), δ): 3.73 (s, 3 H, Me); 4.72 (s, 2 H, CH2OH);
7.09 (t, 1 H, H(6´), J = 7.1 Hz); 7.22 (t, 1 H, H(5´), J = 7.21 Hz);
7.29 (d, 1 H, H(7´), J = 7.3 Hz); 7.57 (d, 1 H, H(4´), J = 7.6 Hz).
13C NMR (CDCl3), δ: 29.62; 57.26; 101.16; 109.06; 119.35; 120.49;
121.34; 126.97; 137.92; 138.47. Found (%): C, 74.45; H, 6.95;
N, 8.79. C10H11NO. Calculated (%): C, 74.51; H, 6.88; N, 8.69.
2ꢀCꢀ[(1ꢀMethylindolꢀ2ꢀyl)methyl]ꢀαꢀLꢀxyloꢀhexꢀ3ꢀulofuraꢀ
nosonoꢀ1,4ꢀlactone (13) and 3ꢀOꢀ(1ꢀmethylindolꢀ2ꢀyl)methylꢀLꢀ
ascorbic acid (14). To a solution of alcohol 5 (0.5 g, 0.003 mol) in
THF (5 mL), a solution of the MsCl—DMAP complex (preꢀ
pared from MsCl (0.43 g, 0.29 mL, 0.003 mol) and DMAP (0.46 g,
0.0038 mol)) in DMF (10 mL) was slowly added. The reaction
mixture was stirred for 16 h, the volatiles were removed in vacuo,
and the residue was diluted with DMSO. In a separate flask,
sodium ascorbate (1a) was prepared from Lꢀascorbic acid (1.5 g,
0.0085 mol) and NaOH (0.34 g, 0.0085 mol) in a DMSO—H2O
(4 : 1) mixture, then the above solution was slowly added. The
resulting clear solution was stirred until complete consumption
of the starting mesylate. The reaction mixture was diluted with
saturated aqueous NaCl (30 mL), extracted with ethyl acetate
(2×30 mL), the combined organics was washed with aqueous
NaCl, dried with Na2SO4, and the solvent was removed in vacꢀ
uo. Purification of the residue (350 mg) by flash column chroꢀ
matography and preparative TLC (silica gel, eluents — petroꢀ
leum ether—EtOAc, 3 : 1; CHCl3—MeOH, 10 : 1) afforded comꢀ
pound 13 (100 mg, 20%), pale pink amorphous powder, Rf = 0.36
(CHCl3—MeOH, 7 : 1) and ether 14 (50 mg, ~10%), Rf = 0.24
(CHCl3—MeOH, 7 : 1).
Compound 13, Rt = 23.60 min (96.8%, sample concentraꢀ
tion 0.1—0.4 mg•mL–1), [α]D20 +12 (c 0.05, MeOH). IR (powꢀ
der), ν/cm–1: 1781 (CO lactone). 1H NMR (DMSOꢀd6), δ: 3.21
(d, 1 H, CH2ꢀInd, J = 15.0 Hz); 3.24 (d, 1 H, CH2ꢀInd, J =
= 15.0 Hz); 3.69 (s, 3 H, N—Me); 3.88 (dd, 1 H, H(6b), J1 = J2 =
= 5.7 Hz); 4.15 (dd, 1 H, H(6a), J = 9.7, J = 3.4 Hz); 4.24
(s, 1 H, 4ꢀH); 4.22 (m, 1 H, H(5)); 6.27 (c, 1 H, H(3´)); 6.88
(t, 1 H, H(6´), J = 7.1 Hz); 7.09 (t, 1 H, H(5´), J = 7.1 Hz); 7.38
(d, 1 H, H(7´), J = 8.1 Hz); 7.46 (d, 1 H, H(4´), J = 8.1 Hz).
13C NMR (DMSOꢀd6), δ: 29.40; 31.85; 75.53; 75.54; 80.90; 88.32;
103.50; 108.67; 110.10; 119.40; 120.25; 121.50; 126.59; 137.53;
138.49; 178.75. MS (EI, 70 eV), m/z (Irel (%)): 319 [M]+ (48).
Found: m/z 342.0946 [M + Na]+. C16H17NO6Na. Calculated:
M = 342.0954. Found: m/z 358.0686 [M + K]+. C16H17NO6K.
Calculated: M = 358.0693.
3ꢀOꢀ(1ꢀMethylindolꢀ2ꢀyl)methylꢀLꢀascorbic acid (14). IR
(powder), ν/cm–1: 1756 (CO lactone). 1H NMR (DMSOꢀd6), δ:
3.65 (s, 3 H, N—Me); 3.78—3.83 (m, 2 H, Ha(6), Hb(6)); 4.10
(m, 1 H, H(5)); 4.80 (s, 1 H, H(4)); 5.62 (d, 2 H, CH2ꢀInd,
J = 15.0 Hz); 5.69 (d, 2 H, CH2ꢀInd, J = 15.0 Hz); 6.64 (s, 1 H,
H(3´)); 7.08 (t, 1 H, H(6´), J = 7.1 Hz); 7.20 (t, 1 H, H(5´),
J = 7.1 Hz); 7.48 (d, 1 H, H(7´), J = 8.1 Hz); 7.56 (d, 1 H, H(4´),
J = 8.1 Hz). 13C NMR (CD3OD), δ: 29.62; 61.59; 63.26; 70.60;
73.96; 101.16; 108.68; 109.06; 119.35; 120.49; 121.40; 126.97;
137.40; 137.92; 138.47; 171.15. MS (EI, 70 eV), m/z (Irel (%)):
319 [M]+ (43). Found: m/z 320.1126 [M + H]+. C16H18NO6.
Calculated: M = 320.1134.
1ꢀ(tertꢀButoxycarbonyl)ꢀ3ꢀformylindole. To a cooled to 0 °C
suspension of NaH (1.44 g, 0.025 mol) in anhydrous DMF
(50 mL), a solution of 3ꢀformylindole (3.6 g, 0.025 mol) in DMF
(30 mL) was added dropwise. The reaction mixture was stirred at
the same temperature for 30 min, and a solution of Boc2O (5.75 g,
0.025 mol) in THF (10 mL) was added. Then the reaction mixꢀ
ture was acidified with a solution of 1 M HCl in THF to pH 9.0,
diluted with petroleum ether (30 mL) and with water (pH 3.0,
30 mL). The organic layer was separated, washed with water
(pH 3.0, 3×50 mL), 5% NaHCO3 (3×50 mL), and brine until
neutral. The organic layer was dried with Na2SO4, the solvent
was removed in vacuo to give 1ꢀBocꢀ3ꢀformylindole in a yield of
7.2 g (85%), lightꢀbrown powder, Rf = 0.89 (CHCl3—MeOH,
10 : 1). 1H NMR (CDCl3), δ: 1.87 (s, 9 H, Boc); 7.26 (t, 1 H,
H(6), J = 7.1 Hz); 7.34 (t, 1 H, H(5), J = 7.1 Hz); 7.64 (d, 1 H,
H(7), J = 8.0 Hz); 7.72 (s, 1 H, H(2)); 8.37 (d, 1 H, H(4), J = 8.1
Hz); 10.61 (s, 1 H, 3ꢀCHO). MS (EI, 70 eV), m/z (Irel (%)): 245
[M]+ (80). Found (%): C, 68.50; H, 6.09; N, 5.62. C14H15NO3.
Calculated (%): C, 68.55; H, 6.16; N, 5.71.
1ꢀ(tertꢀButoxycarbonyl)ꢀ3ꢀhydroxymethylindole (6). To a soꢀ
lution of 1ꢀBocꢀ3ꢀformylindole (2.0 g, 0.008 mol) in EtOH,
NaBH4 (0.16 g, 0.004 mol) was added and the reaction mixture
was stirred for 30 min until complete consumption of the starting
aldehyde. The reaction mixture was diluted with water, extractꢀ
ed with Et2O (30 mL), the combined organics was washed with
water (3×50 mL), and dried with Na2SO4. Removal of the solꢀ

462
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 2, February, 2010
Korolev et al.
vent in vacuo furnished compound 6 (1.7 g, 85%), lightꢀbrown
powder, Rf = 0.73 (CHCl3—MeOH, 10 : 1). 1H NMR (CDCl3),
δ: 1.66 (s, 9 H, Boc); 4.83 (s, 2 H, CH2OH); 7.26 (t, 1 H, H(6´),
J = 7.1 Hz); 7.34 (t, 1 H, H(5´), J = 7.1 Hz); 7.57 (s, 1 H,
H(2´)); 7.64 (d, 1 H, H(7´), J = 8.0 Hz); 8.15 (d, 1 H, H(4´),
J = 8.1 Hz). Found (%): C, 67.82; H, 6.68; N, 5.49. C14H17NO3.
Calculated (%): C, 67.70; H, 6.93; N, 5.67.
the extracts was washed with water until neutral, dried with
Na2SO4. Removal of the solvent in vacuo afforded a mixture of
compounds 2 and 17 identified by HPLC with the known samꢀ
ples with Rt = 9.86 and Rt = 7.21 min, respectively.
This work was financially supported by the Russian
Foundation for Basic Research (project No 06ꢀ03ꢀ32233).
2ꢀCꢀ(1ꢀBocꢀIndolꢀ3ꢀyl)methylꢀαꢀLꢀxyloꢀhexꢀ3ꢀulfuranosonoꢀ
1,4ꢀlactone (16). To a solution of 3ꢀhydroxymethylindole (6)
(0.6 g, 0.0024 mol) in THF (5 mL), a solution of the MsCl—DMAP
complex (prepared from MsCl (0.35 g, 0.24 mL, 0.003 mol) and
DMAP (0.42 g, 0.0034 mol)) in DMF (10 mL) was slowly added.
The resulting suspension was stirred for 16 h, the volatiles were
removed in vacuo, the residue containing mesylate 15 was dilutꢀ
ed with DMSO (5 mL). In a separate flask, sodium ascorbate
(1a) was prepared from Lꢀascorbic acid (0.86 g, 0.0049 mol) and
NaOH (0.19 g, 0.0048 mol) in a DMSO—H2O (4 : 1) mixture,
then the above solution of mesylate 15 was slowly added. The
resulting clear solution was stirred until complete consumption
of mesylate 15. The reaction mixture was diluted with brine
(30 mL), extracted with ethyl acetate (2×30 mL), the combined
organics was washed brine, dried with Na2SO4, and the solvent
was removed in vacuo. Purification of the residue (350 mg) by
flash column chromatography (silica gel, eluents — CHCl3;
CHCl3—MeOH, 10 : 1, 7 : 1) afforded compound 16 (250 mg,
25%), pale pink amorphous powder, Rf = 0.48 (CHCl3—MeOH,
References
1. Y. Nihro, S. Sogawa, T. Sudo, T. Miki, H. Matsumoto,
T. Satoh, Chem. Pharm. Bull., 1991, 39, 1731.
2. K. Yagi, Lipid Peroxidation in Biology and Medicine, Acaꢀ
demic Press, New York, London, 1982.
3. M. N. Preobrazhenskaya, A. M. Korolev, Bioorg. Khim.,
2000, 26, 97 [Russ. J. Bioorg. Chem. (Engl. Transl.), 2000,
26, 85].
4. M. N. Preobrazhenskaya, I. L. Plikhtyak, Khim.ꢀFarm. Zh.,
1993, 27, 22 [Pharm. Chem. J. (Engl. Transl.), 1993, 27, 25].
5. S. N. Lavrenov, A. M. Korolev, K. F. Turchin, M. N. Preoꢀ
brazhenskaya, Khimiya i biologicheskaya activnost´ sintetꢀ
icheskikh i prirodnykh soedineniy. Kislorodꢀ i serosoderzhashꢀ
chie getericycly [Chemistry and biological activity of synꢀ
thetic and natural substances. Oxygenꢀ and sulfurꢀcontaining
heterocycles], Ed. V. G. Kartsev, Moscow, 2003, 1, 324
(in Russian).
7 : 1), Rt
= 27.41 min (96.8%, sample concentration
0.1—0.2 mg mL–1). IR (powder), ν/cm–1: 1792 (CO lactone);
[α]D20 +13 (c 0.05, MeOH). 1H NMR (CD3OD), δ: 1.67 (s, 9 H,
Boc); 3.20 (d, 1 H, CH2ꢀInd, J = 15.0 Hz); 3.26 (d, 1 H,
CH2ꢀInd, J = 15.0 Hz); 4.03 (dd, 1 H, H(6b), J1 = J2 = 5.7 Hz);
4.15 (s, 1 H, H(4)); 4.18 (dd, 1 H, H(6a), J = 9.7 Hz, J = 3.4 Hz);
4.29 (m, 1 H, H(5)); 7.18 (t, 1 H, H(6´), J = 7.1 Hz); 7.26
(t, 1 H, H(5´), J = 7.1 Hz); 7.57 (s, 1 H, H(2´)); 7.62 (d, 1 H,
H(7´), J = 8.1 Hz); 8.07 (d, 1 H, H(4´), J = 8.1 Hz).
13C (CD3OD), δ: 27.65; 29.40; 75.60; 76.05; 81.90; 88.05; 106.06;
108.50; 112.10; 119.99; 121.25; 122.40; 123.50; 131.09; 137.59;
142.53; 152.2; 178.75. MS (EI, 70 eV), m/z (Irel (%)): 405 [M]+
(53). Found: m/z 428.1323 [M + Na]+. C20H23NO8Na. Calcuꢀ
lated: M = 428.1321.
6. E. Leete, J. Am. Chem. Soc., 1959, 81, 6023.
7. L. I. Belen'kiy, Khim. Geterosikl. Soedin., 1980, 1587 [Chem.
Heterocycl. Compd. (Engl. Transl.), 1980, 1195].
8. E. Buncel, K. G. A. Jackson, J. K. N. Jones, Chem. Ind.,
1965, 89.
9. K. Wimalasena, M. P. D. Mahindaratne, J. Org. Chem., 1994,
59, 3427.
10. E. I. Lazhko, A. M. Korolev, M. N. Preobrazhenskaya, Khim.
Geterosikl. Soedin., 1993, 353 [Chem. Heterocycl. Compd.
(Engl. Transl.), 1993, 295].
11. H. Tahir, O. Hindsgaul, J. Org. Chem., 2000, 65, 911.
Ascorbigen (2) and di(indolꢀ3ꢀyl)methane (17). A solution of
compound 16 (0.05 g, 0.12 mmol) in CHCl3 (2 mL) was acidiꢀ
fied with trifluoroacetic acid (0.1 mL) and stirred for 10 min.
The reaction mixture was poured onto ice, extracted with CHCl3,
Received March 17, 2009;
in revised form October 20, 2009