Synthetic transformations of higher terpenoids. XXVI. 16- acetylaminomethyllabdanoids and their cytotoxicity

Article abstract of DOI:10.1134/S1068162011060082

Coupling of methyl 16-aminomethyllambertianate with N-Boc-protected ω-amino acids resulted in 16-(N-Boc-aminononan)- and 16-(N-Boc- aminoundecan)amidomethyllabdanoids. Interaction of methyl aminomethyllambertianate with bicyclo[2.2.1]hept-5-en-2,3-dicarboxylic acid anhydride led to the amide of bicyclo[2.2.1]heptan-1,2-dicarboxylic acid with a labdanoid substituent. Reaction of methyl 16-aminomethyllambertianate with chloroacetyl chloride resulted in methyl 16-(chloroacetylaminomethyl) lambertianate; coupling of the latter with methyl esters of amino acids gave the corresponding amides of methyl lambertianate. The compounds obtained were more cytotoxic toward CEM-13, MT-4, and U-937 tumor cell lines as compared with lambertianic acid; the dose inhibiting tumor cell viability by 50% (CCID ₅₀) of the more active compounds was 3.9-9.9 μM. Pleiades Publishing, Ltd. 2012.

Full text of DOI:10.1134/S1068162011060082

ISSN 1068ꢀ1620, Russian Journal of Bioorganic Chemistry, 2012, Vol. 38, No. 1, pp. 107–115. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © Yu.V. Kharitonov, E.E. Shul’ts, M.M. Shakirov, M.A. Pokrovsky, A.G. Pokrovsky, G.A. Tolstikov, 2012, published in Bioorganicheskaya Khimiya, 2012,
Vol. 38, No. 1, pp. 127–136.
Synthetic Transformations of Higher Terpenoids.1
XXVI. 16ꢀAcetylaminomethyllabdanoids
and Their Cytotoxicity
, 2
Yu. V. Kharitonova, E. E. Shul’tsa , M. M. Shakirova, M. A. Pokrovskyb,
A. G. Pokrovskyb, and G. A. Tolstikova
aNovosibirsk Institute of Organic Chemistry of the Siberian Branch of the Russian Academy of Sciences,
pr. Lavrent’eva 9, 630090 Novosibirsk
bNovosibirsk State University
Received April 11, 2011; in final form, May 4, 2011
Abstract—Coupling of methyl 16ꢀaminomethyllambertianate with
NꢀBocꢀprotected ωꢀamino acids resulted
in 16ꢀ( ꢀBocꢀaminononan)ꢀ and 16ꢀ( ꢀBocꢀaminoundecan)amidomethyllabdanoids. Interaction of
N
N
methyl aminomethyllambertianate with bicyclo[2.2.1]heptꢀ5ꢀenꢀ2,3ꢀdicarboxylic acid anhydride led to the
amide of bicyclo[2.2.1]heptanꢀ1,2ꢀdicarboxylic acid with a labdanoid substituent. Reaction of methyl
16ꢀaminomethyllambertianate with chloroacetyl chloride resulted in methyl 16ꢀ(chloroacetylaminomeꢀ
thyl)lambertianate; coupling of the latter with methyl esters of amino acids gave the corresponding amides of
methyl lambertianate. The compounds obtained were more cytotoxic toward CEMꢀ13, MTꢀ4, and Uꢀ937
tumor cell lines as compared with lambertianic acid; the dose inhibiting tumor cell viability by 50% (CCID50)
of the more active compounds was 3.9–9.9 μM.
Keywords: plant diterpenoids, lambertianic acid, methyl 16ꢀaminomethyllambertianate,
cells
ωꢀamino acids, tumor
DOI: 10.1134/S1068162011060082
2 1
INTRODUCTION
the study of cytotoxic properties of the compounds
obtained toward CEMꢀ13, MTꢀ4, and Uꢀ937 tumor
cells.
Lambertianic acid produced by Siberian cedar
Pinus sibirica R. Mayr.) is of interest as a source for a
(
number of natural products [2–4] and pharmaceutiꢀ
cally valuable agents [5–7]. Previous studies of the
pharmacological activity of lambertianic acid (I), its
RESULTS AND DISCUSSION
ester (II), and their amino derivatives revealed the
antidepressant and neurotropic activity of these comꢀ
pounds [8, 9]. Vinylꢀ16ꢀcarbamoylbenzamides of
methyl lambertianate obtained from azlactone of
methyl 16ꢀformyllambertianate showed the properties
of cytostatic polychemotherapy correctors [10, 11].
Recently, an active search for immunomodulating and
antitumor agents among the diterpenoid derivatives
containing the fragments of various amino acids has
been conducted [12].
Reaction of methyl 16ꢀformyllambertianate (III
with hydroxylamine hydrochloride gave ( )ꢀoxime
IV) in quantitative yield; reduction of compound (IV
resulted in methyl 16ꢀaminomethyllambertianate (
)
E
(
)
)
V
in 97% yield. The corresponding acetamide derivatives
VI) and (VII) of labdanoids were obtained in 81–88%
yields in the reaction of amine ( ) with acetyl or chloꢀ
(
V
roacetyl chlorides in dichloromethane in the presence
of triethylamine. Amides (VIII) and (IX) (57 and 77%
yield, respectively) were synthesized by coupling
This paper describes the synthesis of the derivatives
of methyl 16ꢀaminomethylambertianate and methyl
16ꢀchloroacetylaminomethyllambertianate, the prodꢀ
ucts of their modification with various amino acid
substituents in the side chain, and also the results of
amine (V) with NꢀBocꢀprotected ωꢀamino acids in the
presence of dicyclohexylcarbodiimide (DCC) and
1ꢀhydroxybenzotriazole (HOBt). The interaction of
methyl 16ꢀaminomethyllambertianate (
5ꢀnorbornenꢀ2,3ꢀdicarboxylic acid anhydride (
V) with endoꢀ
X)
resulted in labdanoids containing fragments of 3ꢀcarꢀ
bamoylbicyclo[2.2.1]ꢀheptꢀ5ꢀenꢀ2ꢀcarboxylic acid
Abbreviations: CCID —dose inhibiting tumor cell viability by
50
50%).
1
2
(
XI) (76% yield) or imide of endoꢀnorbornylꢀ5ꢀenꢀ
Communication XXV see [1].
Corresponding author: phone: +7(383) 330ꢀ85ꢀ33; fax:
+7(383) 330ꢀ97ꢀ52; eꢀmail: schultz@nioch.nsc.ru.
2,3ꢀdicarboxylic acid (XII) (97% yield) depending on
the reaction conditions.
107

108
KHARITONOV et al.
OH
N
NH2
O
CHO
O
12
7
13
11
9
16
15
O
O
14
H /Ni–Ra
2
NH OH
2
⋅
HCl
1
4
EtOH
NaOH
⋅ H O, 1 : 1
2
3
5
H
CO2R
H
H
H
CO2CH3
CO2CH3
CO2CH3
R=H (
I
), Me (II
)
(III
)
(
IV)
(V)
H
R
(CH2)nNHBoc
NH
2'
3'
N
3'
2'
1'
1'
O
O
O
R
Cl
Et N, CH Cl
2
BocNH(CH ) CO H
2
n
2
O
O
(V)
HOBt, DCC,
3
2
CH Cl , 0
2
°C
2
H
H
CO2CH3
(
VI), (VII
)
(VIII), (IX)
CO2CH3
R=CH3 (VI), CH2Cl (VII),
n
= 8 (VIII), 10 (IX)
O
N
O
H
2'
3'
1'
7'
O
6'
NH
O
O
5'
4'
H
H
O
O
O
(X)
(X)
(
V
)
HO C
H
2
CH CO H,
3 2
20°C, 24 h
CH CO H
3
20°C, 6 h
2
H
H
CO2CH3
CO2CH3
(XI)
(XII)
Scheme 1.
To obtain
danoids, we used the reaction of
nomethyllambertianate (VII) with the derivatives of
various amino acids. Coupling of compound (VII
with methyl esters of amino acids hydrochlorides
(3ꢀaminoꢀ3ꢀphenylpropionic, 8ꢀaminononaic, and
10ꢀaminoundecanoic acids) was carried out in THF in
N
'ꢀsubstituted aminoacetamides of labꢀ
The composition and structures of the compounds
obtained were confirmed by elemental analyses, mass
spectrometry, IR, UV, and NMR spectroscopy. IR specꢀ
tra of the synthesized acetamides (VI)–(IX), (XI) and
amino acetamides (XIII)–(XVII) had absorption bands
at 1673–1680 cm–1 (amide I and conjugated carbonyl
bands), 3265–3368 cm–1 (transꢀassociated form of NH),
and 3380 cm–1 (OH groups for compound (XI)). The
1H and 13C NMR spectra of the compounds obtained are
in complete agreement with their structure. The configuꢀ
ration of oxime (IV) was determined using the 1H NMR
stereochemical parameter, i.e., by chemical shift of the
Nꢀchloroacetylamiꢀ
)
the presence of K2CO3. Corresponding
amides of labdanoids (XIII)–(XV) were obtained in
61–67% yields. The interaction of compound (VII
Nꢀsubstituted
)
with D,Lꢀvaline methyl ester hydrochloride proꢀ
ceeded under reflux in acetonitrile in the presence of
K2CO3 and gave compound (XVI) in a 44% yield.
Compound (VII) was coupled with methyl 3ꢀ(9ꢀamiꢀ
nononanoyl)aminoꢀ3ꢀphenylpropionate hydrochloꢀ
ride under the same conditions. The corresponding
product (XVII) was isolated with a yield of 39%.
proton (СН=NOH). In the spectrum of (
furanꢀ2ꢀcarbaldehyde, the signal of the above proton is a
singlet at 7.47 ppm, and that for its ( )ꢀisomer is at
8.00 ppm [13]. The signal of the corresponding proton in
compound (IV) was observed at 7.94 ppm, which conꢀ
firms the ꢀconfiguration of the oxime.
Z)ꢀoxime of
Е
δ
Е
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
No. 1
2012

SYNTHETIC TRANSFORMATIONS OF HIGHER TERPENOIDS
109
CO2Me
O
N2' 3'
1'H
O
CH
Ph
4'
5'
N
H
CH2NH(CH2)nCO2Me
NH
CO2Me
H
C
C
H2N
H2
Ph
NH (CH ) Me
2 2 n
O
O
(VII)
K CO ,
2
K CO ,
2
3
3
THF, 20°C
THF, 20°C
H
H
(
XIII), (XIV
)
(XV)
CO2CH3
CO2CH3
MeO2C
CH
Pri
O
H2N
H2N(CH2)8C
N
H
CH(Ph)CH2CO2Me
K CO ,
2
3
K CO ,
2
3
MeCN, 80°C
MeCN, 80°C
O
O
H
N
O
N
CO2Me
H
CH2NHCH
CO2Me
CH2NH(CH2)8 C N C
H
H Ph
O
O
H
H
(
XVI
)
(XVII
)
CO2CH3
CO2CH3
n
= 8 (XIII); 10 (XIV
)
Scheme 2.
1
In the H NMR spectra of 16ꢀaminomethyllamꢀ following coupling constants:
bertianate (
XVII) we observed the characteristic chemical shifts
J
2'3' = 5.5, J2'1' = 2.9, and
V
) and its derivatives (VI)–(IX) and (XI)– J3'4' = 3.0 Hz; the nodal H1',4' protons appear as the
broadened doublets at 3.07 and 3.21 ppm (J2'1' = 2.9 and
J3'4' = 3.0 Hz); the signals of H5' and H6' were observed
(
and splitting of the protons of the aminomethyl substitꢀ
uent at the C1' atom depending on the substituent at the
nitrogen atom. Thus, in the spectrum of amine (V)
these protons resonate as a singlet at 4.03 ppm, and in
the H NMR spectra of derivatives (VII)–(IX) and
XIII)–(XVII) with a substituent at the nitrogen
atom, they are magnetically nonequivalent and
appear as the doublets at 4.30–4.36 ppm with a couꢀ
pling constant of 4.5–5.0 Hz. The protons at C4' atoms
of chloroacetylaminomethyllambertianate (VII) resoꢀ
nate in 1H NMR spectra as a singlet at 4.02 ppm, and the
signals of the above protons in compounds (VIII),
IX), and (XI)–(XVII) shift upfield (Δδ 0.61–
1.06 ppm). The structure of compounds (XI) and
XII) is characterized by the presence of cyclic substitꢀ
uents in the side chain, such as norbornene and
as the doublets at 3.13 and 3.26 ppm (J = 9.9 Hz). The
distinguishing feature of the H NMR spectrum of
1
compound (XII) is a upfield shift of the protons at the
C2' and C3' atoms (δ 5.89 and 5.92 ppm, respectively).
1
(
Table 1 shows the cytotoxicity of labdanoids (VI),
VIII), (IX), (XII), and (XIV)–(XVI). Compounds
VIII) and (IX) with the fragments of longꢀchain
(
(
amino acids in the amide substituent, and compound
XII) containing the fragments of methyl lambertianꢀ
(
ate and conformational rigid imide of endoꢀnorꢀ
bornylꢀ5ꢀenꢀ2,3ꢀdicarboxylic acid, exhibited the
highest cytotoxicity toward three types of tumor cells.
Special attention should be given to the selective cytoꢀ
toxicity of a series of compounds toward the type of
tumor cells. Thus, compound (XVI) exhibited high
cytotoxicity toward Uꢀ937 tumor cells (CCID50
(
(
1
phthalimide. H NMR spectral data of the terpene
derivative of norbornene (XI) indicate that the bicyclic
substituent in the side chain has an endoꢀconfiguraꢀ
3.9
μM). As compared with lambertianic acid, the
cytotoxicity of the derivatives increased 3–10 times;
tion: the protons of olefinic bond appear as the double compound (IX) was the most toxic toward MTꢀ4 and
doublets with centers at 6.13 and 6.38 ppm with the CEMꢀ13 lymphoid tumor cells, and compounds
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
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2012

110
KHARITONOV et al.
Cytotoxicity of the derivatives of lambertianic acid containing amide and
N
'
ꢀ
aminoacetamide substituents in furan cycle
MTꢀ4 tumor cells,
CEMꢀ13 tumor cells, Uꢀ937 tumor cells,
Compound
CCID50,
µM
CCID50,
µM
CCID50, µM
(
(
(
(
VI
VIII
IX
XII
)
37.4
9.9
7.5
4.2
111.9
11.1
9.2
)
)
6.2
12.5
8.3
)
9.9
67.2
60.2
77.7
64.1
92.1
(XIV)
9.4
15.9
37.1
3.9
(XV
)
13.4
28.0
69.1
(XVI
)
Lambertianic acid (
I)
43.2
(
VIII) and (XVI) exhibited the highest toxicity toward
(1S,4aR,5S,8aR)ꢀMethylꢀ5ꢀ(2ꢀ{2ꢀ[(E)ꢀ(hydroxyꢀ
Uꢀ937 tumor cells. The results obtained show the imino)methyl]furanꢀ3ꢀyl}ethyl)ꢀ1,4aꢀdimethylꢀ6ꢀmethylꢀ
promise of modification of lambertianic acid by introꢀ enedecahydronaphthaleneꢀ1ꢀcarboxylate (IV). Hydroxꢀ
ducing the amide and peptide substituents at the C16 ylamine hydrochloride (0.20 g, 2.8 mmol) and NaOH
position, since such a transformation makes it possible (0.12 g, 2.8 mmol) were added to a stirred solution of
to obtain compounds with an orderꢀofꢀmagnitude aldehyde (III) (1.00 g, 2.8 mmol) in aqueous ethanol
higher cytotoxicity toward tumor cells as compared
with the minor cytotoxicity of the parent compound ( ). room temperature for 5 h, then 50 ml of water was
To establish the mechanism of cytotoxicity of the new added and the product was extracted with chloroform
(EtOH–H2O 1 : 1). The reaction mixture was stirred at
I
compounds, further investigation of their effect on the
expression of genes involved in the development of
apoptosis will be performed.
(
(
3
3
×
×
50 ml). The organic layer was washed with water
40 ml), dried over MgSO4, and evaporated to give
compound (IV) (1.04 g, 100%) as an oil.
(
(
[
α]D +20.06
): 276 (3.98). IR
, cm–1): 891, 1642, 2938 (C=CH2), 954, 3492
°
c 17.16, СНCl3). UV, λmax, nm (logε
ν
(=NOH), 1154, 1227, 1725 (CO2Me). Found, %:
C 70.03, H 8.21, N 3.34. C22H31NO4. Calculated, %:
C 70.75, H 8.37, N 3.75. 1H NMR: 0.46 (3 H, s, H20),
EXPERIMENTAL
The H and 13C NMR spectra were recorded on
1
0.91 (1 H, dt,
1.23 (1 H, dd, J5 12.7, J5 2.9, H5
J
13.2, 3.9, H1
α
), 1.13 (3 H, s, H19),
), 1.45 (1 H,
14.2, H2), α1.54 (1 H,αbαr. s, H9), 1.59 (1 H, m,
H11), 1.66–1.80 (4 H, m, H11,6,1 ,2), 1.84 (1 H, dt,
13.2, 3.9, Н7 , 1.94 (1 H, dm, 12.5, H6), 2.11 (1 H,
dm, Jgem 13.2, H3 ), 2.33–2.38 (1 H, m, H12), 0.98
(1H, dt, 13.2, 3.9, H3 ); 2.39 (1 H, td, gem 13.2, 2.9,
H7 ), 2.56–2.61 (1 H, m, H12), 3.57 (3 H, s, OCH3),
4.54 and 4.89 (2 H, 2 s, H17,17), 6.29 (1 H, d, 14,15 1.5,
Bruker AVꢀ300 (300.13 and 75.47 MHz, respectively)
and Bruker DRXꢀ500 (500.13 and 125.76 MHz,
respectively) instruments (Germany). Editing of the
signals in 13C NMR spectra was performed using stanꢀ
dard techniques, such as Jꢀmodulation and offꢀresoꢀ
nance decoupling. The highꢀresolution mass spectra
were recorded on a DFS mass spectrometer (the
Netherlands). Optical rotations were measured on a
poLAAr 3005 polarimeter (Germany) at room temꢀ
α
6β
6
dm,
J
β
J
α)
J
β
J
α
J
β
J
H14), 7.36 (1 H, d, J14,15 1.5, H15), 7.94 (1 H, s,
CH=). 13C NMR: 12.19 (C20), 19.44 (C2), 22.56
(C12), 23.71 (C11), 25.78 (C6), 28.28 (C19), 37.65
(C3), 38.13 (C7), 38.54 (C1), 39.67 (C4), 43.82
(C10), 50.72 (OCH3), 54.27 (C9), 55.70 (C5), 106.17
(C17), 112.22 (C14), 128.69 (C13), 138.39 (CH=),
142.37 (C16), 143.36 (C15), 147.23 (C8), 177.37 (C18).
perature (20–23°С). The IR spectra were recorded in
KBr pellets on a VECTORꢀ22 spectrometer (Russia).
The UV spectra were recorded on an HP 8453 UV Vis
spectrophotometer (United States) from ethanol soluꢀ
tions (C
10–4 M).
The progress of reactions and the purity of the
compounds obtained were monitored by TLC on Siluꢀ
fol UVꢀ254 plates eluted in chloroform–ethanol (3 : 1)
and petroleum ether–ethyl acetate (10 : 1) solvent sysꢀ
tems. Spots were visualized in UV light or by spraying
with a 10% aqueous solution of sulfuric acid followed
(1S,4aR,5S,8aR)ꢀMethylꢀ5ꢀ{2ꢀ[2ꢀ(aminomethyl)
furanꢀ3ꢀyl]ethyl}ꢀ1,4aꢀdimethylꢀ6ꢀmethylenedecahyꢀ
dronaphthaleneꢀ1ꢀcarboxylate (V). 2 N NaOH (10 ml)
and Raney nickel (1 g) were added to a solution of
oxime (IV) (1.00 g, 2.8 mmol) in ethanol. The reaction
mixture was stirred at room temperature under a
by heating to 100°C.
Methyl 16ꢀformyllambertianate (III) was obtained hydrogen atmosphere for 5 h. The catalyst was filtered
according to the procedure reported in [14]. Synthesis off, and the solvent was evaporated. A saturated soluꢀ
of bicyclo[2.2.1]heptꢀ5ꢀenꢀ2,3ꢀdicarboxylic acid tion of oxalic acid in diethyl ether (15 ml) was added
anhydride (X) is described in [15].
to the residue. The precipitate was filtered off to give
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
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2012

SYNTHETIC TRANSFORMATIONS OF HIGHER TERPENOIDS
111
amine (
33.21
(2.55), 212 (2.30), 226 (2.37), 242 (2.39). IR (
893, 1642, 2946 (C=CH2), 1156, 1230, 1724 Triethylamine (0.24 g, 2.4 mmol) was added dropwise
(CO2Me), 3431 (NH2). Highꢀresolution MS, to a stirred solution of amine ( ) (0.58 g, 1.6 mmol)
359.2450 [
]+. C22H33NO3. Calculated:
1H NMR: 0.49 (3 H, s, H20), 1.01 (1 H, dt,
H1 ), 1.01 (1 H, dt, 13.5, 3.2, H3
H19), 1.28 (1 H, d, J5 11.2, H5
V
) (1.17 g, 97%); mp 165–168°C.
0.29, EtOH). UV, λmax, nm (log ): 193 acetyl)aminomethyl]furanꢀ3ꢀyl}ethyl)ꢀ1,4ꢀdimethylꢀ
, cm–1): 6ꢀmethylenedecahydronaphthaleneꢀ1ꢀcarboxylate (VII).
[
α D
]
(1S,4aR,5S,8aR)ꢀMethylꢀ5ꢀ(2ꢀ{2ꢀ[2ꢀ(2ꢀchloroꢀ
+
°
(
c
ε
ν
m
/
z
:
V
M
M
J
359.2457. and 2ꢀchloroacetyl chloride (0.22 g, 1.9 mmol) in
13.5, 3.2, dichloromethane (20 ml) under an argon atmosphere.
α
J
α
α)
), 1.16 (3 H, s, The reaction mixture was stirred at room temperature
, 1.51 (3 H, m, for 6 h and left overnight. The solvent was removed
H2,9,11), 1.57 (1 H, m, H11), 1.74–1.82 (3 H, m, under reduced pressure, diethyl ether (20 ml) was
Н2,6,1 , 1.87 (1 H, m, Н7 , 1.98 (1 H, m, H6), 2.13 added to the residue, and the precipitate (Et3N HCl
(1 H, dm, Jgem 13.2, H3 ), 2.28 (1 H, m, H12), 2.40 was filtered off. The mother liquor was evaporated
(1 H, d, Jgem 11.1, H7 ), 2.53 (1 H, m, H12), 3.60 under reduced pressure, and the residue was subjected
α6β
β)
α)
⋅
)
β
β
(3 H, s, OCH3), 4.03 (2 H, br. s, CH2N), 4.56 and 4.90 to column chromatography on silica gel using chloroꢀ
(2 H, 2 s, H17,17), 4.76 (2 H, br. s, NH2), 6.28 (1 H, form as eluent to give compound (VII) (0.79 g, 81%)
13
s, H14), 7.24 (1 H, s, H15). C NMR: 11.65 (C20), as an oil.
[
α D
): 203 (3.70), 220 (2.82), 279 (2.39). IR (
27.81 (C19), 33.01 (CH2N), 37.20 (C3), 37.77 (C7), 893, 1668, 2946 (C=CH2), 1154, 1722 (CO2Me),
38.14 (C1), 39.30 (C4), 43.89 (C10), 50.32 (OCH3), 1214, 1532, 3297 (NHCO). Highꢀresolution MS,
]
+27.73° (
c
5.65, CHCl3). UV, λmax, nm
19.01 (C2), 21.93 (C12), 23.33 (C11), 25.43 (C6), (log
ε
ν
, cm–1):
m/z:
54.11 (C9), 55.35 (C5), 105.67 (C17), 110.86 (C14), 435.2166 [
124.49 (C13), 141.08 (C16), 142.46 (C15), 146.86 1H NMR: 0.45 (3 H, s, H20), 0.93 (1 H, dt,
(C8), 177.54 (C18). H1 ), 0.98 (1 H, dt, 13.2, 4.1, H3
H19), 1.22 (1 H, dd, J5 β 12.3, J5 α 2.9, H5
M
]+. C24H34NO4Cl. Calculated:
M
J
435.2171.
13.9, 4.1,
α
J
α
), 1.13 (3 H, s,
, 1.48
(1 H, m, H2), 1.53 (1 Hα,6m, H9), 1.663 (1 H, m, H11),
1.72, 1.76, 1.80, and 1.84 (5 H, 4 m, H11,2,6,1 ,6),
gem 13.0, H3 ),
), 2.49
α)
α
(1 ,4a ,5 ,8aR)ꢀMethylꢀ5ꢀ{2ꢀ[2ꢀ(acetylaminoꢀ
S
R
S
methyl)furanꢀ3ꢀyl]ethyl}ꢀ1,4ꢀdimethylꢀ6ꢀmethyleneꢀ
decahydronaphthaleneꢀ1ꢀcarboxylate (VI). Triethyꢀ
lamine (0.25 g, 2.5 mmol) was added dropwise to a
β
1.93 (1 H, m, H7
2.24 (1 H, m, H12), 2.38 (1 H, dm,
α
), 2.11 (1 H, dm,
J
β
J
10.7, H7β
stirred solution of amine (V) (0.67 g, 1.9 mmol) and
(1 H, m, H12), 3.57 (3 H, s, OCH3), 4.02 (2 H, s,
CH2Cl), 4.36 (2 H, d, 5.6, CH2N), 4.54 and 4.88
acetyl chloride (0.20 g, 2.5 mmol) in dichloromethane
(20 ml) under an argon atmosphere. The reaction
mixture was stirred at room temperature for 6 h and
left overnight. The solvent was removed under reduced
pressure, diethyl ether (20 ml) was added to the resiꢀ
due, and the precipitate (Et3N.HCl) was filtered off.
The mother liquor was evaporated under reduced
pressure, and the residue was subjected to column
chromatography on silica gel using chloroform as eluꢀ
ent to give compound (VI) (0.66 g, 88%); mp 106–
J
(2 H, 2 s, H17,17), 6.20 (1 H, d, J14,15 1.8, H14), 6.76
(1 H, br. s, NH), 7.27 (1 H, d, J14,15 1.8, H15).
13C NMR: 12.45 (C20), 19.75 (C2), 21.89 (C12),
24.33 (C11), 26.09 (C6), 28.60 (C19), 34.63 (CH2N),
37.97 (C3), 38.54 (C7), 38.86 (C1), 39.97 (C4), 42.32
(CH2Cl), 44.09 (C10), 50.97 (OCH3), 54.79 (C9),
56.04 (C5), 106.39 (C17), 111.51 (C14), 122.72
(C13), 141.72 (C15), 145.16 (C16), 147.57 (C8),
165.38 (C=O), 177.57 (C18).
110°C.
(log ): 203 (3.62), 220 (2.40). IR (
2938 (C=CH2), 1149, 1164, 1722 (CO2Me), 1282, ycarbonyl)amino]nonanamido}methyl)furanꢀ3ꢀyl]ethyl}ꢀ
1544, 3265 (NHCOCH3). Highꢀresolution MS, 1,4aꢀdimethylꢀ6ꢀmethylenedecahydronaphthaleneꢀ1ꢀ
401.2558 [ 401.2561. carboxylate (VIII). HOBt (0.38 g, 2.79 mmol) and
]+. С24Н35O4N. Calculated:
1H spectrum: 0.46 (3 H, s, H20), 0.95 (1 H, dt,
12.7, DCC (0.57 g, 2.79 mmol) were added to a stirred soluꢀ
3.8, H1 ), 0.99 (1 H, dt, 12.9, 3.8, H3 ), 1.14 (3 H, tion of 9ꢀ(tertꢀbutoxycarbonyl)ꢀ9ꢀaminononaic acid
s, H19), 1.23 (1 H, dd, J5 β 12.3, J5 α 3.0, H5 , 1.48 (0.80 g, 2.79 mmol) in dichloromethane (20 ml) at
(1 H, m, H2), 1.54 (1 H,αm, H9), 1.66 (1 H, m, H11), under an argon atmosphere. The reaction mixture was
1.72, 1.77, 1.80, and 1.84 (5 H, 4 m, Н11,2,6,1 ,7 stirred at 0°C for 30 min and at room temperature for
1.93 (1 H, m, H6), 1.94 (3 H, s, COCH3), 2.12 (1 H, 5 h, then cooled to 0°C, and compound ( ) (1.00 g,
dm, Jgem 13.2, H3 ), 2.25 (1 H, m, H12), 2.39 (1 H, 2.23 mmol) and triethylamine (0.31 g, 3.02 mmol)
m, H7 ), 2.49 (1 H, m, H12); 3.57 (3 H, s, OCH3), were added. The reaction mixture was heated to room
4.39 (2 H, d, 5.0, CH2N), 4.55 and 4.88 (2 H, 2 s, temperature and kept under occasional stirring for
H17,17), 5.81 (1 H, br. s, NH), 6.19 (1 H, d, 14,15 2.1 1 day, then cooled to ; the precipitate was filtered
[
α D
]
+29.74° (
c
1.17, EtOH). UV, λmax, nm
ε
ν
, cm–1): 901, 1637,
(1S,4aR,5S,8aR)ꢀMethylꢀ5ꢀ{2ꢀ[2ꢀ({9ꢀ[(tertꢀbutoxꢀ
m/z:
M
M
J
α
J
α
α)
0°С
6
α6
β
α),
V
β
β
J
J
,
0°С
13
H14), 7.25 (1 H, d, J14,15 2.0, H15). C NMR: 12.47 off and washed with cold dichloromethane. The comꢀ
(C20), 19.76 (C2), 22.90 (C12), 24.36 (C11), 26.11 bined filtrates were washed with 10% hydrochloric
(C6), 28.61 (C19), 34.46 (СН2N), 38.00 (C3), 38.57 acid, water, 5% sodium bicarbonate, and water, and
(C7), 38.88 (C1), 39.99 (C4), 44.12 (C10), 50.95 dried over MgSO4. The solvent was evaporated; the
(OCH3), 54.83 (C9), 56.08 (C5), 106.42 (C17), residue was dissolved in dichloromethane (3 ml),
111.47 (C14), 122.14 (C13), 141.35 (C15), 146.12 cooled to –10
°
С
; the precipitate of dicyclohexylurea
(C16), 147.60 (C8), 169.48 (C=O), 177.58 (C18).
was filtered off and washed with cold dichloꢀ
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
No. 1
2012

112
KHARITONOV et al.
1
romethane; the combined filtrate was evaporated. This H 9.72, N 4.36. H NMR: 0.48 (3 H, s, H20), 0.97
procedure was repeated twice. The residue was subꢀ (1 H, td, 13.3., 4.0, H1 , 1.01 (1 H, dt, 13.3, 4.3,
jected to column chromatography on silica gel using H3 , 1.16 (3 H, s, H19), 1.25 (15 H, m, 7СН2, H5
chloroform as eluent to give compound (VIII) (0.78 g, 1.43 (12 H, m, С(СН3)3, СН2, H2), 1.56 (1 H, m, H9),
57%) as an oil. α D +15.80° ( 10.34, CHCl3). UV, 1.60 (1 H, m, H11), 1.74, 1.78, 1.82, and 1.89 (5 H,
λmax, nm (log ): 202 (4.01), 220 (3.74), 282 (1.97). IR 4 m, Н11,2,6,1 ,7 , 1.97 (1 H, m, H6), 2.14 (3 H,
, cm–1): 892, 2932 (C=CH2), 1166, 1229, 1722 dm,
8.0, СОСН2, Н3 , 2.26 (1 H, m, H12), 2.41
(CO2Me), 1651, 3310 (CONH). Found, %: C 70.63, (1 H, dm, 12.1, Н7 , 2.51 (1 H, m, H12), 3.06 (1 H,
H 9.21, N 4.25. C36H58N2O6. Calculated, %: C 70.32, d, 6.3, NНСН2), 3.10 (1 H, d, 6.3, NНСН2), 3.59
H 9.51, N 4.56. H NMR: 0.46 (3 H, s, H20), 0.96 (3 H, s, OCH3), 4.33 (1 H, d, 5.0, CH2N), 4.33 (1 H,
(1 H, m, H1), 0.98 (1 H, dt, 13.2, 3.9, H3), 1.14 d, 5.0, CH2N), 4.57 and 4.90 (2 H, 2 s, H17,17), 5.67
(3 H, s, H19), 1.25 (11 H, m, 5СН2, H5), 1.40 (12 H, (1 H, t, NH), 6.21 (1 H, d, J14,15 2.0, H14), 7.27 (1 H,
m, С(СН3)3, СН2, H2), 1.54 (1 H, m, H9), 1.58 (1 H, d,
14,15 2.0, H15). 13C NMR: 12.46 (C20), 19.76 (C2),
m, H11), 1.73, 1.76, 1.80, and 1.85 (5 H, 4 m, 22.92 (C12), 24.44 (C11), 25.49 (CH2), 26.09 (C6),
H11,2,6,1,7), 1.97 (1 H, m, H6), 2.12 (3 H, dm, 8.1, 26.60 (CH2), 28.26 (С(СН3)3), 28.60 (C19), 29.07
СОСН2, H3), 2.24 (1 H, m, H12), 2.39 (1 H, dm, (CH2), 29.09 (CH2), 29.13 (CH2), 29.19 (CH2), 29.28
J
α)
J
α)
α),
[
]
c
ε
β α)
(
ν
J
β)
J
β)
J
J
1
J
J
J
J
J
J
11.7, H7), 2.48 (1 H, m, H12), 3.05 (2 H, d,
J
J
5.6, (CH2), 29.86 (CH2), 34.23 (CH2NH), 36.29 (COH2),
4.6, 37.98 (C3), 38.55 (C7), 38.84 (C1), 39.96 (C4), 40.43
NН2СН2), 3.57 (3 Н, c, OCH3); 4.30 (2 H, d,
СН2N), 4.55 and 4.88 (2 H, 2 s, H17,17), 5.90 (1 H, (CH2NH2), 44.09 (C10), 50.93 (OCH3), 54.84 (C9),
br. s, NH), 6.19 (1 H, s, H14), 7.24 (1 H, s, H15). 56.04 (C5), 106.42 (C17), 111.42 (C14), 122.93
13C NMR: 12.50 (C20), 19.81 (C2), 22.94 (C12), (C13), 141.17 (C15), 146.39 (C16), 147.52 (C8),
24.41 (C11), 24.41 (CH2), 24.84 (CH2), 25.43 (CH2), 172.65 (СО), 177.52 (C18).
26.14 (C6), 28.26 (С(СН3)3), 28.60 (C19), 28.90
(1S,4aR,5S,8aR)ꢀMethylꢀ5ꢀ(2ꢀ{[((2R,3S)ꢀ3ꢀcarboxyꢀ
(CH2), 28.99 (CH2), 29.02 (CH2), 34.48 (CH2NH),
36.37 (COH2), 38.04 (C3), 38.60 (C7), 38.91 (C1),
40.03 (C4), 40.43 (CH2NH2), 44.16 (C10), 50.99
(OCH3), 54.90 (C9), 56.11 (C5), 106.44 (C17),
111.50 (C14), 122.14 (C13), 141.35 (C15), 146.28
(C16), 147.61 (C8), 169.78 (CO), 172.57 (С=О),
177.60 (C18).
bicyclo[2.2.1]heptꢀ5ꢀenꢀ2ꢀcarboxamido)methyl]furanꢀ
3ꢀyl} ethyl)ꢀ1,4aꢀdimethylꢀ6ꢀmethylenedecahydronaphꢀ
thaleneꢀ1ꢀcarboxylate (XI). Bicyclo[2.2.1]heptꢀ5ꢀenꢀ
2,3ꢀdicarboxylic acid anhydride
1.34 mmol) was added to a solution of amine (
(X) (0.22 g,
V)
(0.50 g, 1.11 mmol) in acetic acid (10 ml). The reacꢀ
tion mixture was stirred for 6 h. The solvent was
(1
carbonyl)amino]undecanamido}methyl)furanꢀ3ꢀyl]ethyl}ꢀ (10 ml) was added to the residue. The precipitate was
1,4aꢀdimethylꢀ6ꢀmethylenedecahydronaphthaleneꢀ1ꢀ filtered off and dried in vacuum to give compound (XI
carboxylate (IX). HOBt (0.22 g, 1.6 mmol) and DCC (0.44 g, 76%); mp 130–131°C. α D +29.39° ( 4.11,
(0.33 g, 1.6 mmol) were added to a stirred solution of CHCl3). UV, λmax, nm (log ): 203 (3.85), 241 (3.40),
11ꢀ(tertꢀbutoxycarbonyl)ꢀ11ꢀaminoundecanoic acid 280 (2.98). IR (
, cm–1): 893, 1646, 2946 (C=CH2),
(0.50 g, 1.6 mmol) in anhydrous dichloromethane 1163, 1250, 1707 (CO2Me), 1772 (CO2H). Found, %:
(20 ml) at under an argon atmosphere. The reacꢀ C 70.63, H 7.81, N 2.27. C31H41NO6. Calculated, %:
tion mixture was stirred at
for 30 min and at room C 71.10, H 7.89, N 2.67. 1H NMR: 0.48 (3 H, s, H20),
temperature for 5 h, then cooled to 0оС, and comꢀ 0.97 (1 H, td,
13.3, 4.0, H1 ), 1.01 (1 H, dt, 13.2,
pound ( ) (0.60 g, 1.3 mmol) and triethylamine 4.0, H3 ), 1.15 (3 H, s, H19), 1.25 (1 H, dd, J5
(0.17 g, 1.7 mmol) were added. The reaction mixture 12.5, J5 2.9, H5 J
8α.5β,
S,4aR,5S,8aR)ꢀMethylꢀ5ꢀ{2ꢀ[2ꢀ({9ꢀ[(tertꢀbutoxyꢀ removed under reduced pressure and diethyl ether
)
T
[
]
c
ε
ν
0°С
0°С
J
α
J
V
α
6
α)
, 1.31 and 1.45 (2 H, 2 d,
was heated to room temperature and kept under occaꢀ СН2), 1α.49 (1 H, m, H2), 1.56 (2 H, m, H11,9), 1.66
sional stirring for 1 day, then cooled to ; the precipꢀ (1 H, m, H11), 1.75 and 1.78 (3 H, 2 m, H2,6,1 , 1.83
itate was filtered off and washed with cold dichloꢀ (1 H, m, Н7 , 1.97 (1 H, m, H6), 2.14 (1 H, dm,
romethane. The combined filtrates were washed with 13.0, H3), 2.23 (1 H, m, H12), 2.40 (1 H, td, Jgem
10% hydrochloric acid, water, 5% sodium bicarbonꢀ 12.1, 2.9, H7 ), 2.48 (1 H, m, H12), 3.07 (1 H, br. s,
6α
0°С
β)
α)
J
J
β
ate, and water, and dried over MgSO4. The solvent was H1'), 3.13 (1 H, dd, J6 5' 9.9,
J
3.1, H6'), 3.21 (1 H, br.
J 2.9, H5'), 3.58 (3 H, s,
evaporated; the residue was dissolved in dichloꢀ s, H4'), 3.26 (1 H, dd, J' 5 6' 9.9,
'
romethane (3 ml), cooled to –10°C; the precipitate of OCH3), 4.25–4.30 (2 H, m, CH2Fu), 4.55 and 4.89
dicyclohexylurea was filtered off and washed with cold (2 H, 2 s, H17,17), 6.13 (1 H, dd, J3 2' 5.5,
J
3'4' 3.0, H3'),
dichloromethane; the combined filtrate was evapoꢀ 6.20 (1 H, d,
rated. This procedure was repeated twice. The residue H2'), 7.28 (1 H, d,
was subjected to column chromatography on silica gel (C20), 19.47 (C2), 22.61 (C12), 24.10 (C11), 25.78
using chloroform as eluent to give compound (IX (C6), 28.33 (C19), 34.32 (СН2), 37.70 (C3), 38.25
(0.66 g, 77%) as an oil. α D +24.70° ( 9.56, CHCl3). (C7), 38.58 (C1), 39.71 (C4), 43.82 (C10), 46.64*
IR (
, cm–1): 892, 2930 (C=CH2), 1167, 1230, 1714 (C1'), 47.58* (C4'), 48.48 (CH2Fu), 49.01* (C3'),
J
1.8, H14), 6.38 (1 H,'dd,
J
2'3'
5.5,
J
2'1' 2.9
,
J
1.8, H15). 13C NMR: 12.17
)
[
]
c
ν
(CO2Me), 1651, 3320 (CONH). Found, %: C 70.92, 49.49* (C2'), 50.71 (OCH3), 54.59 (C9), 55.74 (C5),
H 9.38, N 4.35. C38H62N2O6. Calculated, %: C 70.99, 106.13 (C17), 112.12 (C14), 121.89 (C13), 133.43*
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
No. 1
2012

SYNTHETIC TRANSFORMATIONS OF HIGHER TERPENOIDS
113
(C5'), 135.86* (C6'), 141.12 (C16), 145.39 (C15), 147.31 (1 H, dt,
(C8), 172.68 (CO2H), 175.65 (CO), 177.34 (C18). (11 H, m, H5
(1 H, m, H2), 1.55 (1 H, m, H9), 1.67 (1 H, m, H11),
J
13.1, 4.0, H3
α
), 1.14 (3 H, s, H19), 1.25
α
, 5 CH2), 1.39 (2 H, t, J 6.6, CH2), 1.46
(1 ,4a ,5 ,8a )ꢀMethylꢀ5ꢀ(2ꢀ{2ꢀ[(1,3ꢀdioxoꢀ
S
R
S
R
1.74, 1.77, 1.80, and 1.83 (5 H, 4 m, H11,2,6,1
1.95 (1 H, m, H6), 2.12 (1 H, dm, Jgem 13.2, H3
2.23 (1 H, m, H12), 2.27 (2 H, t,
(1 H, td, 12.1, 3.0, H7 ), 2.53 (3 H, t,
C1'H2), 3.23 (2 H, s, COСН2N), 3.58 (3 H, s, OCH3),
3.64 (3 H, s, CO2CH3), 4.34 (2 H, d, 5.5, CH2N),
4.56 and 4.88 (2 H, 2 s, H17,17), 6.19 (1 H, d, 14,15 1.8
H14), 7.26 (1 H, d, 14,15 1.8, H15), 7.41 (1 H, br. s,
β
,7
α
β
),
),
3a,4,7,7aꢀtetrahydroꢀ1 ꢀ4.7ꢀmethanoisoindolꢀ2(3 )ꢀyl)
H
H
methyl]furanꢀ3ꢀyl}ethyl)ꢀ1,4aꢀdimethylꢀ6ꢀmethyleneꢀ
decahydronaphthaleneꢀ1ꢀcarboxylate (XII). Comꢀ
J
7.5, С8'Н2), 2.39
J
β
J
7.2, H12,
pound (
of amine (
X) (0.22 g, 1.34 mmol) was added to a solution
V
) (0.50 g, 1.11 mmol) in acetic acid
J
(10 ml). The reaction mixture was stirred for 24 h. The
solvent was removed under reduced pressure and
diethyl ether (10 ml) was added to the residue. The
precipitate was filtered off and dried in vacuum to give
compound (XII) (0.71 g, 97%); Tmp 129–123°C.
J
,
J
NHCO). 13C NMR: 12.38 (C20), 19.70 (C2), 22.86
(C12), 24.39 (C11), 24.63 (CH2), 26.03 (C6), 26.79
(CH2), 28.51 (C19), 28.78 (CH2), 28.91 (CH2), 28.99
(CH2), 29.69 (CH2), 33.66* (C8'H2), 33.73* (CH2N),
37.91 (C3), 38.46 (C7), 38.76 (C1), 39.87 (C4), 43.98
(C10), 49.86 (C1'H2), 50.82 (OCH3), 51.11
(COCH3), 52.16 (СОСН2N), 54.76 (C9), 55.95 (C5),
106.31 (C17), 111.33 (C14), 121.80 (C13), 141.18
(C15), 146.23 (C16), 147.44 (C8), 171.14 (СО),
173.80 (CO2CH3), 177.30 (C18).
[α]D +24.50° (c 1.53, CHCl3). IR (ν
, cm–1): 907,
1642, 2948 (C=CH2), 1165, 1231, 1716 (CO2Me),
1771 (CO). Found, %: C 73.24, H 7.71, N 2.27.
C31H39NO5. Calculated, %: C 73.63, H 7.77, N 2.77.
1H NMR: 0.48 (3 H, s, H20), 0.94–1.05 (2 H, m,
H1
α,3α), 1.15 (3 H, s, H19), 1.26 (1 H, dd, J5 β 12.5,
α6
J5 α 3.2, H5
α
)
, 1.49 (1 H, d,
(1αH, m, H2), 1.58 (2 H, m, H11,9), 1.65 (1 H, m,
H11), 1.74–1.82 (3 H, 2 m, H2,6,1 , 1.83 (1 H, dd,
12.5, 4.2, Н7 , 1.97 (1 H, m, H6), 2.13 (1 H, dm,
Jgem 11.7, H3), 2.29–2.36 (1 H, m, H12), 2.40 (1 H,
td, Jgem 12.5, 2.9, H7 ), 2.52–2.58 (1 H, m, H12),
3.21* (1 H, d, 2.9, H5'), 3.22* (1 H, d, 2.9, H6'),
3.33 (2 H, br. s, H4',1'), 3.58 (3 H, s, OCH3), 4.35
(1 H, d, 14.9, CH2Fu), 4.40 (1 H, d, 14.9, CH2Fu),
4.62 and 4.90 (2 H, 2 s, H17,17), 5.89 (1 H, dd,
J3'2' 6.5, 2.9, H3'), 5.92* (1 H, dd, J2'3' 6.5, 2.9, H2'),
J 9.3, СН2), 1.41–1.56
6
β)
(1S,4aR,5S,8aR)ꢀMethylꢀ5ꢀ{2ꢀ[2ꢀ({2ꢀ[((11ꢀmethoꢀ
J
α)
xycarbonyl)undecyl)amino]acetylamino}methyl)furanꢀ3ꢀ
yl]ethyl}ꢀ1,4aꢀdimethylꢀ6ꢀmethylenedecahydronaphthaꢀ
leneꢀ1ꢀcarboxylate (XIV). K2CO3 (0.60 g, 4.36 mmol)
J
β
J
J
was added to a stirred solution of compound (VII
)
(0.95 g, 2.18 mmol) and methyl 11ꢀaminoundecanoyl
hydrochloride (0.52 g, 2.4 mmol) in THF (15 ml). The
reaction mixture was stirred at room temperature for
6 h and left overnight, then diluted with diethyl ether
J
J
J
J
6.14 (1 H, d, J14,15 1.7, H14), 7.21 (1 H, d, J14,15, H15).
13C NMR: 12.17 (C20), 19.49 (C2), 22.64 (C12),
24.04 (C11), 25.81 (C6), 28.31 (C19), 34.07 (СН2),
37.70 (C3), 38.25 (C7), 38.51 (C1), 39.67 (C4), 43.76
(C10), 44.43 (C1',4'), 45.20 (C3',2'), 50.61 (ОСН3),
51.40 (СН2Fu), 54.69 (C9), 55.71 (C5), 106.17 (C17),
110.87 (C14), 122.86 (C13), 133.62* (C5'), 133.66*
(C6'), 141.03 (C15), 143.80 (C16), 147.27 (C8),
176.41 (CO, CO), 177.11 (C18).
(50 ml), washed with water (3
× 50 ml), dried over
MgSO4, and evaporated. The residue was subjected to
column chromatography on silica gel using chloroꢀ
form as eluent to give compound (XIV) (0.94 g, 67%)
as an oil. UV, λmax, nm (log
IR (
, cm–1): 892, 2929 (C=CH2), 1165, 1726
(CO2Me), 1674, 3350 (CONH). Highꢀresolution MS,
614.4270 Calculated:
]+. С36Н58O6N2
614.4289. 1H NMR: 0.43 (3 H, s, H20), 0.92 (1 H,
13.2, H1 ), 0.96 (1 H, dt, 13.0, 3.5, H3 ), 1.11
carbonyl)nonyl)amino]acetylamino}methyl)furanꢀ3ꢀ (3 H, s, H19), 1.25 (15 H, m, H5 , 7 CH2), 1.35 (2 H,
yl]ethyl}ꢀ1,4aꢀdimethylꢀ6ꢀmethylenedecahydronaphthaꢀ t, 5.8, CH2), 1.45 (1 H, m, H2), 1.52 (1 H, m, H9),
leneꢀ1ꢀcarboxylate (XIII). K2CO3 (0.67 g, 4.9 mmol) 1.58 (1 H, m, H11), 1.70, 1.74, 1.79, and 1.84 (5 H,
was added to a stirred solution of compound (VII 4 m, H11,2,6,1 ,7 ), 1.92 (1 H, m, H6), 2.09 (1 H,
(0.71 g, 1.6 mmol) and methyl 9ꢀaminononainate dm, gem 13.2, H3 ), 2.19 (1 H, m, H12), 2.24 (2 H, t,
hydrochloride (0.55 g, 2.5 mmol) in THF (15 ml). The 7.6, C8'H2), 2.36 (1 H, dm, 12.3, H7 ), 2.49 (3 H,
reaction mixture was stirred at room temperature for t, 7.0, H12, C1'H2), 3.19 (2 H, s, COСН2N), 3.55
6 h and left overnight. The reaction mixture was (3 H, s, OCH3), 3.60 (3 H, s, CO2CH3), 4.31 (2 H, d,
diluted with diethyl ether (50 ml) and washed with 5.6, CH2N), 4.53 and 4.85 (2 H, 2 s, H17,17), 6.16
water ( 50 ml); the organic layer was dried over (1 H, d, 14,15 1.8, H14), 7.23 (1 H, d, 14,15 1.8, H15),
MgSO4 and evaporated. The residue was subjected to 7.38 (1 H, t, 4.0, NHCO). C NMR: 12.17 (C20),
ε): 2.03 (4.08), 220 (1.80).
ν
m/z:
[
M
.
M
J
(1S
,4a
R
,5
S
,8a
R)ꢀMethylꢀ5ꢀ{2ꢀ[2ꢀ({2ꢀ[((9ꢀmethoxyꢀ t,
α
J
α
α
J
)
β α
J
β
J
J
β
J
J
3
×
J
J
13
J
column chromatography on silica gel using chloroꢀ 19.48 (C2), 22.67 (C12), 24.18 (C11), 24.48 (CH2),
form as eluent to give compound (XIII) (0.60 g, 64%) 25.81 (C6), 26.66 (CH2), 28.33 (C19), 28.67 (CH2),
as an oil.
(log ): 218 (1.74). IR (
1164, 1229, 1725 (CO2Me), 1637, 3350 (CONH). (C3), 38.27 (C7), 38.57 (C1), 39.69 (C4), 43.81
[α]D +23.32° (c 3.69, CHCl3). UV, λmax, nm 28.77 (CH2), 28.91 (CH2), 28.99 (CH2), 29.03 (CH2),
ε
ν
, cm–1): 892, 2932 (C=CH2), 29.62 (CH2), 33.49* (C10'H2), 33.62* (CH2N), 37.72
Highꢀresolution MS,
С34Н54O6N2. Calculated:
(3 H, s, H20), 0.96 (1 H, td,
m
/
z
:
586.3986
[M
]+. (C10), 49.77 (C1'H2), 50.67 (OCH3), 50.96
M
586.3976. 1H NMR: 0.46 (COCH3), 52.07 (СОСН2N), 54.57 (C9), 55.78 (C5),
13.8, 3.5, H1 ), 0.99 106.08 (C17), 111.13 (C14), 121.66 (C13), 141.00
J
α
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
No. 1
2012

114
KHARITONOV et al.
(C15), 145.98 (C16), 147.28 (C8), 171.08 (СО), 202 (4.19), 220 (1.90). IR (
173.81 (CO2CH3), 177.25 (C18). (C=CH2), 1153, 1229, 1724 (CO2Me), 1680, 3368
(CONH). Highꢀresolution MS, : 530.3358 [
]+.
ν
, cm–1): 893, 2961
m
/
z
M
(1 ,4a ,5 ,8a )ꢀMethylꢀ5ꢀ{2ꢀ[2ꢀ({2ꢀ[(3ꢀmethoxyꢀ
S
R
S
R
С30Н46O6N2. Calculated:
530.3350. 1H NMR: 0.47
(3 H, s, H20), 0.86 and 0.88 (6 H, 2 d, 6.8,
СН(СН3)2), 0.96 (1 H, dt, 13.2, 3.2, H1 , 0.99 (1 H,
dt, 13.3, 3.9, H3 , 1.14 (3 H, s, H19), 1.24 (1 H, dd,
J5 11.9, J5 2.9, H5 , 1.48 (1 H, m, H2), 1.55
(1αH, m, H9), 1.64 (1 H, m, H11), 1.75 (1 H, dd,
11.7, 3.7, СН(СН3)2), 1.80, 1.86, 1.89, and 1.95 (6 H,
4 m, Н11,2,6,1 ,7 ,6), 1.95 (1 H, m, H6), 2.13 (1 H,
dm, Jgem 13.2, H3 ), 2.25 (1 H, m, H12), 2.39 (1 H,
dt, 12.2, 3.0, H7 ), 2.50 (1 H, m, H12), 2.90 (1 H,
d, J 5.6, СНСО2Ме), 2.96 (1 H, d, 17.4, СОСН2)
3.41 (1 H, d, 17.4, СОСН2), 3.58 (3 H, s, OCH3),
3.68 (3 H, s, CHCO2CH3), 4.28 (1 H, dd, 15.5, 5.0,
CH2N), 4.39 (2 H, dd, 15.5, 5.9, CH2N), 4.55 and
4.88 (2 H, 2 s, H17,17), 6.20 (1 H, d, 14,15 1.7, H14),
7.26 (1 H, d,
14,15 1.7, H15), 7.36 (1 H, br. s, NH). 13C
M
carbonyl)ꢀ1ꢀphenylpropyl)amino]acetylamino}methyl)
furanꢀ3ꢀyl]ethyl}ꢀ1,4aꢀdimethylꢀ6ꢀmethylenedecahydroꢀ
naphthaleneꢀ1ꢀcarboxylate (XV). K2CO3 (0.32 g,
2.30 mmol) was added to a stirred solution of compound
J
J
α)
J
α)
α)
6β
α6α
(
VII) (0.5 g, 1.15 mmol) and methyl 3ꢀaminoꢀ3ꢀphenylꢀ
propionate hydrochloride (0.25 g, 1.38 mmol) in THF
(15 ml). The reaction mixture was stirred at room temꢀ
perature for 6 h and left overnight, then diluted with
J
β
α
β
β
diethyl ether (50 ml), washed with water (3 × 50 ml),
dried over MgSO4, and evaporated. The residue was
subjected to column chromatography on silica gel
J
J
,
J
using chloroform as eluent to give compound (XV
(0.94 g, 67%) as an oil. α D +26.73° ( 1.11, CHCl3).
UV, λmax, nm (log ): 203 (4.34), 230 (3.88). IR
, cm–1): 892, 2948 (C=CH2), 1154, 1229, 1724
(CO2Me), 1674, 3368 (CONH). 1H NMR: 0.47 (3 H,
s, H20), 0.96 (1 H, dt, 13.1, 3.0, H1 , 0.99 (1 H, dt,
13.1, 3.0, H3 , 1.14 (3 H, s, H19), 1.24 (1 H, dd,
J5 11.8, J5 3.0, H5 , 1.47 (1 H, m, H2), 1.56
(1αH, m, H9)6,α1.62–1.80 (5 H, m, Н11,11,2,6,1
1.85 (1 H, m, Н7 , 1.95 (1 H, m, H6), 2.12 (1 H, dm,
Jgem 13.1, H3 ), 2.26 (1 H, m, H12), 2.39 (1 H, dt,
11.8, 2.8, H7 ), 2.52 (1 H, m, H12), 2.62 (2 H, m,
CH2), 3.05 (1 H, d, 17.3, COCH2), 3.12 (1 H, d,
17.3, COCH2), 3.57 (3 H, s, OCH3), 3.60 (3 H, s,
CHCO2CH3), 3.98 (1 H, dd, 8.2, 5.6, CH), 4.25–
4.41 (2 H, m, СН2N), 4.57 and 4.88 (2 H, 2 s,
H17,17), 6.21 (1 H, d, 14,15 1.8, H14), 7.18 (2 H, m,
14,15 1.8, H15), 7.26–7.30 (3 H, m,
5.1, NH). 13C NMR: 12.51 (C20),
)
J
[
]
c
J
ε
J
(
ν
J
NMR: 12.50 (C20), 17.92 (CH3), 19.29 (CH3), 19.81
(C2), 23.00 (C12), 24.50 (C11), 26.15 (C6), 28.66
(C19), 31.21 (СН(СН3)2), 33.84 (СОСН2), 38.05 (C3),
38.60 (C7), 38.92 (C1), 40.02 (C4), 44.15 (C10), 50.98
(СО2СН3), 51.62 (ОСН3), 54.96 (C9), 56.12 (C5),
67.29 (СНСО2СН3), 106.42 (C17), 111.47 (C14),
122.07 (C13), 141.37 (C15), 146.08 (C16), 147.64
(C8), 170.63 (CO), 174.73 (СОСН3), 177.59 (C18).
J
α)
J
α)
α)
6β
α
β),
α)
β
β
J
J
J
(1S,4aR,5S,8aR)ꢀMethylꢀ1,4ꢀdimethylꢀ6ꢀmethyleneꢀ
J
5ꢀ{2ꢀ[2ꢀ(3,14,18ꢀtrioxoꢀ16ꢀphenylꢀ19ꢀoxaꢀ2,5,15ꢀ
triazaicosyl)furanꢀ3ꢀyl]ethyl}decahydronaphthaleneꢀ
1ꢀcarboxylate (XVII). K2CO3 (0.32 g, 2.3 mmol) was
added to a stirred solution of compound (VII) (0.5 g,
1.1 mmol) and methyl 3ꢀ(9ꢀaminononanoyl)aminoꢀ
3ꢀphenylpropionate hydrochloride (0.43 g, 1.1 mmol)
in acetonitrile (15 ml). The reaction mixture was
refluxed for 20 h, cooled to room temperature; water
(50 ml) was added to the reaction mixture and the
J
Ph), 7.28 (1 H, d,
Ph), 7.47 (1 H, t,
J
J
19.82 (C2), 23.07 (C12), 24.53 (C11), 26.16 (C6),
28.67 (C19), 33.87 (СН2N) 38.05 (C3), 38.60 (C7),
,
38.68 (C1), 40.03 (C4), 42.10 (СН2), 44.15 (С10),
49.61 (СОСН2), 51.00 (СО2СН3), 51.62 (ОСН3), 55.01
(C9), 56.09 (C5), 59.02 (CH), 106.44 (C17), 111.44
(C14), 122.08 (C13), 126.62 (C2',6'), 127.76 (C4'),
128.69 (C3'5'), 141.01 (C1'), 141.29 (C15), 146.35
(C16), 147.64 (C8), 170.85 (CO), 171.94 (СОСН3),
product was extracted with chloroform (
The organic layers were washed with water (
dried over MgSO4, and evaporated. The residue was
subjected to column chromatography on silica gel
using chloroform as eluent to give compound (XVII
(0.84 g, 39%) as an oil. α D +17.29° ( 0.67, CHCl3).
, cm–1): 1165, 1228, 1722 (CO2Me), 1651, 1656,
3
3
×
50 ml).
× 40 ml),
177.61 (C18). Highꢀresolution MS,
]+. С34Н46O6N2. Calculated:
578.3350.
(1 ,4a ,5 ,8a )ꢀMethylꢀ5ꢀ{2ꢀ[2ꢀ({2ꢀ[(1ꢀmethoxyꢀ IR (ν
m/z: 578.3358
)
[
M
M
[
]
c
S
R
S
R
carbonylꢀ3ꢀmethylbutanꢀ2ꢀyl)amino]acetylamino}methyl) 3301 (CONH). Found, %: C 69.89, H 8.34, N 5.36.
furanꢀ3ꢀyl]ethyl}ꢀ1,4aꢀdimethylꢀ6ꢀmethylenedecahyꢀ C43H63N3O7. Calculated, %: C 70.36, H 8.65, N 5.72.
dronaphthaleneꢀ1ꢀcarboxylate (XVI). Methyl D,Lꢀ 1H NMR: 0.46 (3 H, s, H20), 0.97 (1 H, dt,
J
13.4, 3.9,
, 1.16 (3 H, s,
, 1.46 (1 H, m, H2),
pound (VII) (0.83 g, 1.9 mmol) in acetonitrile (10 ml). 1.56 (1 H, m, H9), 1.67 (1 H, m, H11), 1.75–1.88
The reaction mixture was refluxed for 20 h, cooled to (5 H, m, H11,2,6,1 ,7 ), 1.98 (1 H, m, H6), 2.14
), 2.18–2.29 (3 H, m, H12,
7.2, С1'Н2, Н12,7 , 2.82
15.7, 5.9,
40 ml), dried over MgSO4, and СH2Ph), 3.13 (2 H, s, COСН2N), 3.60 (6 H, s,
evaporated. The residue was subjected to column 2 OCH3), 4.33 (2 H, d, 5.4, CH2N), 4.57 and 4.90
chromatography on silica gel using chloroform as eluꢀ (2 H, 2 s, H17,17), 5.43 (1 H, m, CH), 6.20 (1 H, d,
ent to give compound (XVI) (0.44 g, 44%) as an oil. J14,15 2.0, H14), 6.62 (1 H, d, 8.6, CONHСН2), 6.89
α D +25.00° ( 1.83, CHCl3). UV, λmax, nm (log ): (1 H, t, 5.1, СН2NHCO), 7.25 (1 H, d, 14,15 2.0
valinate hydrochloride (0.38 g, 2.3 mmol) and K2CO3 H1
α), 1.01 (1 H, dt, J 13.5, 3.9, H3α)
(0.58 g, 4.2 mmol) were added to a solution of comꢀ H19), 1.25 (11 H, m, 5СН2, H5
α)
β
α
room temperature; water (50 ml) was added to the (1 H, dm, Jgem 13.2, H3
reaction mixture and the product was extracted with С8'Н2), 2.39–2.55 (3 H, t,
β
J
β)
chloroform (
washed with water (
3 × 50 ml). The organic layers were (1 H, dd, J 15.7, 5.9, СH2Ph), 2.92 (1 H, dd, J
3
×
J
J
[
]
c
ε
J
J
,
RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
No. 1
2012

SYNTHETIC TRANSFORMATIONS OF HIGHER TERPENOIDS
115
2. Vlad, P.F. and Ungur, N.D., Khim. Prir. Soed., 1970,
H15), 7.28, 7.30, 7.32, and 7.33 (5 H, 4 m, Ph).
13C NMR: 12.52 (C20), 19.70 (C2), 22.98 (C12),
24.42 (C11), 25.39 (CH2), 26.16 (C6), 26.92 (CH2),
28.67 (C19), 28.84 (CH2), 28.89 (CH2), 29.10 (CH2),
29.57 (CH2), 33.77* (C8'H2), 34.30* (CH2N), 36.52
(CH2), 38.04 (C3), 38.58 (C7), 38.90 (C1), 40.04
(C4), 44.17 (C10), 48.96 (C1'H2), 49.28 (CH), 51.03
(OCH3), 51.73 (COCH3), 51.96 (СОСН2N), 54.88
(C9), 56.07 (C5), 106.44 (C17), 111.49 (C14), 122.34
(C13), 126.11 (C2',6'), 127.48 (C4'), 128.57 (C3',5'),
140.51 (C1'), 141.50 (C15), 145.86 (C16), 147.65
(C8), 171.64 (NHСОCH2), 174.19 (CH2CONH),
1777.62 (СО2Ме), 177.69 (C18).
pp. 541–542.
3. Shults, E.E., Velder, J., Schmalz, H.ꢀG., Chernov, S.V.,
Rubalova, T.V., Gatilov, Y.V., Henze, G., Tolstikov, G.A.,
and Prokop, A., Bioorg. Med. Chem. Lett., 2006, vol. 16,
pp. 4228–4232.
4. Mironov, M.E., Kharitonov, Yu.V., Shul’ts, E.E., Shaꢀ
kirov, M.M., Bagryanskaya, I.Yu., and Tolstikov, G.A.,
Khim. Prir. Soed., 2010, pp. 194–200.
5. Tolstikova, T.G., Sorokina, I.V., Dolgikh, M.P., Khariꢀ
tonov, Yu.V., Chernov, S.V., Shul’ts, E.E., and Tolꢀ
stikov, G.A., Khim. Farm. Zh., 2004, vol. 39, pp. 46–49.
6. Kharitonov, Yu.V., Shul’ts, E.E., Sorokina, I.V., Tolꢀ
stikova, T.G., Baev, D.S., Zhukova, N.A., and Tolꢀ
stikov, G.A., RF Patent No. 2346940, 2009.
Cell cultures. MTꢀ4, CEM (Tꢀcell human leukeꢀ
mia cells), and Uꢀ937 (human monocytes) human
tumor cell lines were used in the present work. Cell
lines were maintained in RPMIꢀ1640 medium suppleꢀ
mented with 10% fetal bovine serum, 2 mmol/l
7. Morozova, E.A., Tolstikova, T.G., Shul’ts, E.E., Cherꢀ
nov, S.V., Kharitonov, Yu.V., Mironov, M.E., and Tolꢀ
stikov, G.A., Khim. Interesah Ustoich. Razvit., 2010,
vol. 18, pp. 489–494.
8. Tolstikova, T.G., Sorokina, I.V., Voevoda, T.V.,
Lꢀglutamine, 80
mycin at 37 in a CO2 incubator. The compounds
μg/l gentamycin, and 30 μg/l lincoꢀ
Shul’ts, E.E., and Tolstikov, G.A., Dokl. Akad. Nauk
2001, vol. 376, pp. 271–273.
,
°С
under investigation were dissolved in DMSO and
added to a cell line at an appropriate concentration
(three wells per concentration). The cells incubated
without the studied compounds were used as a control.
9. Tolstikova, T.G., Voevoda, T.V., Dolgikh, M.P., and
Sorokina, I.V., Eksp. Klin. Farmakol., 2002, vol. 65,
pp. 9–12.
10. Kharitonov. Yu.V., Shul’ts, E.E., Shakirov, M.M.,
Bagryanskaya, I.Yu., and Tolstikov, G.A., Zh. Org.
Khim., 2007, vol. 43, pp. 843–854.
MMT assay. To determine CCID50, we used a stanꢀ
dard MTT assay described in [16, 17].
11. Sorokina, I.V., Tolstikova, T.G., Baev, D.S., Zhuꢀ
kova, N.A., and Kharitonov, Yu.V., Khim. Interesah
Ustoich. Razvit., 2010, vol. 18, pp. 499–504.
ACKNOWLEDGMENTS
12. Hanson, J.R., Nat. Prod. Rep., 2009, vol. 26, pp. 1156–
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 09ꢀ03ꢀ
00183) and the Council on Grants at the President of
the Russian Federation (Program of State Support for
Leading Scientific Schools of the RF, Grant NShꢀ
7005.2010.03).
1171.
13. Giichi, G., Kenji, K., Tetsuya, O., and Takuichi, M.,
Chem. Pharm. Bull., 1986, vol. 34, p. 3202.
14. Klok, D.A., Shakirov, M.M., Grishko, V.V., and Ralduꢀ
gin, V.A., Izv. Akad. Nauk, Ser. Khim., 1995, pp. 2514–
2516.
15. Levchenko, N.K., Segal, G.M., and Torgov, I.V., Khim.
Prir. Soed., 1981, pp. 347–350.
16. Mosmann, T., J. Immunol. Methods, 1983, vol. 16,
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RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 38
No. 1
2012