Eleuthesides and their analogs: V. Medium- and large-ring lactones based on levoglucosenone

Article abstract of DOI:10.1134/S1070428014010229

Ozonolysis of the bridging double bond in bicyclic enol ethers obtained by the Michael reaction and subsequent intramolecular etherification afforded chiral decanolides fused to a tetrahydropyran ring. Three-step procedures were developed for the synthesis of chiral lactones with medium and large rings via oxidative cleavage with pyridinium chlorochromate of mixed bicyclic ketals which were prepared by treatment with methanolic HCl of Michael adducts derived from levoglucosenone and cyclopenta-, cyclohexa-, cyclohepta-, and cyclododecanone.

Full text of DOI:10.1134/S1070428014010229

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 1, pp. 117–127. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © Yu.A. Khalilova, L.V. Spirikhin, Sh.M. Salikhov, F.A. Valeev, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50,
No. 1, pp. 125–135.
Eleuthesides and Their Analogs: V.* Medium- and Large-Ring
Lactones Based on Levoglucosenone
Yu. A. Khalilova, L. V. Spirikhin, Sh. M. Salikhov, and F. A. Valeev
Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: sinvmet@anrb.ru
Received July 31, 2013
Abstract—Ozonolysis of the bridging double bond in bicyclic enol ethers obtained by the Michael reaction and
subsequent intramolecular etherification afforded chiral decanolides fused to a tetrahydropyran ring. Three-step
procedures were developed for the synthesis of chiral lactones with medium and large rings via oxidative
cleavage with pyridinium chlorochromate of mixed bicyclic ketals which were prepared by treatment with
methanolic HCl of Michael adducts derived from levoglucosenone and cyclopenta-, cyclohexa-, cyclohepta-,
and cyclododecanone.
DOI: 10.1134/S1070428014010229
Taking into account anticancer activity of eleuthe-
sides [2–4] and some medium- and large-ring lactones
[5], an important aspect of studying structure–activity
relations in this series of compounds is the synthesis of
both eleutheside analogs possessing a lactone function-
ality in the B ring and lactones modified according to
the eleutheside type.
We made an attempt to use levoglucosenone as
a chiral source in the synthesis of medium-ring
lactones with a view to obtain eleutheside oxa analogs
possessing a ten-membered lactone ring. There are two
synthetic strategies ensuring approach to medium-ring
lactones. The first strategy involves closure of linear
chain termini to a ring of appropriate size, and the
second is based on oxidative cleavage of bridging C–C
bond in bicyclic systems by the action of ozone [6, 7],
3-chloroperoxybenoic acid, CrO3 [5, 8], Pb(OAc)4
[9, 10], HgO–I2 [11, 12], or PhI(OAc)2 [13, 14].
It is known that levoglucosenone adduct with dime-
done is capable of undergoing spontaneous cyclization
with formation of mixed ketal II having a bridging
double C=C bond [15]. We tried to synthesize the
corresponding lactone starting from compound II.
Hemiketal II was synthesized by ultrasonic irradiation
of a solution of levoglucosenone (I) and dimedone in
toluene in the presence of K2CO3 (Scheme 1). In the
next steps, a difficult problem was to stabilize ketal II
as dihydropyran derivative. The conversion of II into
methanesulfonate III or p-toluenesulfonate IV,
followed by reductive elimination of the corresponding
group by the action of nickel borohydride (prepared in
situ), afforded conjugated cyclohexenone V.
Following an alternative route, hemiketal II was
treated with methanol in the presence of p-toluenesul-
fonic acid. Methoxy derivative VI was thus obtained
with high efficiency and was subjected to ozonolysis in
methylene chloride. As a result, a mixture of products
which were difficult to separate was formed, presum-
ably due to intermediacy of labile α-diketone. When
the ozonolysis was carried out in methanol and the
peroxide ozonolysis products were treated with sodium
tetrahydridoborate, we isolated in good yield diastereo-
isomeric lactones VIIa and VIIb as products of intra-
molecular transesterification of intermediate lactone
(Scheme 2). Treatment of VI with a solution of HCl in
methanol produced trimethyl ketal VIII and stereo-
isomeric dimethyl ketals IXa and IXb.
Unlike compounds VI and IXa/IXb, trimethyl ketal
VIII derived from primary alcohol is more stable.
Ozonolysis of the double C=C bond in VIII and subse-
quent treatment of intermediate ozonide with NaBH4
afforded stable substituted decanolide Xa/Xb as a mix-
ture of two diastereoisomers (Scheme 3).
The structure of decanolides Xa/Xb follows from
* For communication IV, see [1].
the structure of their precursors and is confirmed by
117

KHALILOVA et al.
118
Scheme 1.
O
Me
Me
H
O
K2CO3, 18-crown-6
PhMe, ultrasonic activation
O
O
O
O
+
Me
Me
O
OH
O
O
I
II
O
O
O
O
H
MsCl, Et3N, CH2Cl2, DMAP
or TsCl, pyridine, 0°C
NiCl2·6H2O, NaBH4, EtOH
LiAlH4, Et3N, Et2O
O
O
O
H
Me
Me
Me
Me
O
OR
III, IV
V
III, R = Ms; IV, R = Ts.
Scheme 2.
O
O
O
H
(1) O3, MeOH, –78°C
(2) NaBH4, –40°C
O
O
O
O
MeOH, TsOH
H
II
Me
Me
OMe
OMe
Me
Me
O
H
OMe
OH
VI
VIIa, VIIb
Scheme 3.
OH
O
O
H
O
H
O
Me
Me
HCl–MeOH
+
VI
OMe
H
Me
OMe
OMe
OMe
O
O
Me
OMe
VIII
IXa, IXb
H
O
O
MeO
O
12
(1) O3, MeOH, –78°C
(2) NaBH4, –40°C
11
1
12a
2
3
10
7
9
8
4a
VIII
MeO
MeO
4
Me
Me
5
6
H
O
OH
Xa, Xb
1
the H and 13C NMR spectra. Three methoxy groups
give singlets at δ 3.24, 3.38, and 3.40 ppm for Xa and
at δ 3.20 and 3.40 ppm for Xb. Both stereoisomers
displayed in the 13C NMR spectrum coinciding signals
from C12 and C6 at δC 62.70 and 69.37 ppm, respec-
tively, ketal and acetal (δC 97.60 and 97.65 ppm,
lactone carbonyl (C10, δC 172.85 ppm), and ketone
carbonyl carbon atoms (δC 211.35 ppm).
Michael adducts XIa/XIb and XIIIa/XIIIb prepared
previously [16] from levoglucosenone and cycloalka-
nones (Scheme 4). Individual compounds XIIa, XIIb,
XIVa, and XIVb were isolated by column chromatog-
raphy. In the 13C NMR spectrum of trimethyl ketal
XIVa, the C12 signal appeared at δC 38.14 ppm. Tetra-
methyl ketal XIVb whose formation also involved ace-
talization with the primary hydroxy group displayed in
13
the C NMR spectrum a signal at δC 28.38 ppm from
Methyl ketals XIIa, XIIb, XIVa, and XIVb were
synthesized in a similar way from stereoisomeric
C1 which corresponds to C12 in XIVa.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 1 2014

ELEUTHESIDES AND THEIR ANALOGS: V.
119
Scheme 4.
OH
O
O
OMe
OMe
O
H
MeO
O
O
HCl–MeOH
+
H
OMe
O
OMe
O
H
OMe
OMe
O
XIa, XIb
XIIa
XIIb
O
OH
O
MeO
O
H
5
6
H
O
6a
O
4a
4
10b
HCl–MeOH
7
8
5
2
10a
+
7
6
3
H
OMe
8
6a
O
3
12
O
2
10
9
1
9
10a
H
10
1
OMe
OMe
OMe
O
OMe
OMe
XIVa
XIIIa, XIIIb
XIVb
Oxidative cleavage of the C6a–C10a bridge in XIVa
with Jones’ reagent [9] was accompanied by consider-
able tarring of the reaction mixture, while only a small
amount of compound XVI was formed. The use of
a milder oxidant, pyridinium chlorochromate (PCC),
ensured smooth formation of lactone XVI in 24 h.
Under analogous conditions, tetramethyl ketal XIVb
was also converted into lactone XVI. Therefore, there
is no need of separating compounds XIVa and XIVb;
oxidative cleavage of mixture XIVa/XIVb was equally
efficient. Likewise, treatment of XIIb with PCC
afforded nonanolide XV (Scheme 5).
The structure of the isolated medium-ring lactones
was proved using various NMR techniques. As
an example, structure determination of decanolide XVI
is described below. The configuration of some chiral
centers in molecules XV and XVI is set by the struc-
ture of the initial Michael adduct, and it does not
change in the course of its transformations. The vicinal
3
coupling constant J12a, 4a = 10.0 Hz indicates anti
orientation of the 4a-H proton. The C2 atom was
assigned S configuration on the basis of the observed
nuclear Overhauser effect (NOE) between 2-H and
4a-H. The HMBC spectrum revealed coupling between
12-H and lactone carbonyl carbon atom (C10) resonat-
ing at δC 172.58 ppm), and the position of the ketone
carbonyl group follows from the presence of a cross
peak between 4a-H and C5. The 13C NMR spectrum of
Presumably, the formation of lactone XVI involves
initial transformation of trimethyl ketal XIVa into
hemiketal A (Scheme 6) whose oxidative fragmenta-
tion produces medium-ring lactone XVI [20].
Scheme 5.
O
H
MeO
MeO
PCC, CH2Cl2
4a
12a
( )n
O
XIIb or XIVa, XIVb
2
MeO
O
O
H
XV, XVI
XV, n = 1; XVI, n = 2.
Scheme 6.
HO
HO
O
H
O
O
H
O
Cl
Cr
Py+ ClCrO3
–HOCr(O)Cl
O
O
XIVa
XVI
–O
OMe
OMe
H
H
OMe
OMe
OMe
OMe
A
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 1 2014

KHALILOVA et al.
120
O
O
H
H
MeO
MeO
MeO
MeO
6
5
4
4a
12a
12
3
2
8
9
7
10
O
1
O
11
O
MeO
O
MeO
O
H
H
O
XV
XVI
XVI contained signals from the acetal (δC 97.35 ppm)
and ketal carbon atoms (δC 96.54 ppm) and the corre-
sponding methoxy groups (δC 55.30, 48.24, 47.85 ppm).
The lactone and ketone carbonyl signals appeared as
δC 172.58 and 208.11 ppm, respectively. The two ketal
methoxy groups gave singlets at δ 3.16 and 3.18 ppm
by heating compound I with cycloalkenylmorpholines
XVII and XVIII in boiling benzene for 2 h, followed
by hydrolysis. As a result, we isolated diastereoisomer
mixtures XIXa/XIXb and XXa/XXb (Scheme 7).
Treatment of the latter with a solution of HCl in
MeOH and subsequent oxidation of intermediate
methyl ketal mixtures with pyridinium chlorochromate
smoothly afforded substituted undecanolide XXI and
lactone XXII (Scheme 7). The hexadecanolide ring in
XXII is the key structural fragment of a number of
natural macrocycles [23].
1
in the H NMR spectrum, and protons in the acetal
methoxy group resonated as a singlet at δ 3.40 ppm. In
addition, signals from the C12H2 methylene group were
2
observed at δ 4.05 and 4.30 ppm (d.d, J = 10.5 Hz),
and the 12a-H signal was a double doublet of doublets
at δ 4.15 ppm (J = 10.3, 10.0, 4.2 Hz).
Lactone XIV was subjected to modification with
N-methylurocanic acid (XXIV). The reduction of XIV
with NaBH4 in EtOH was accompanied by cleavage of
the lactone ring and esterification of the carboxy group
to produce ethyl ester XXIII, and treatment of XXIII
with N-methylurocanic acid (XXIV) [24] gave bis-
ester XXV as a result of esterification with the primary
hydroxy group in XXIII (Scheme 8). The structure of
XXV was proved by H and C NMR spectroscopy.
Nuclear Overhauser effect was observed between
1′′′-H and 4-H, so that the C1′′′ carbon atom was
assigned R configuration; the 1′′′-H and 4-H signals
were multiplets. The HMBC spectrum of XXV con-
tained a cross peaks between 1′-H and ester carbonyl
carbon atom (δC 167.71 ppm), the 1″-CH3 and C4″
signals were observed in the 13C NMR spectrum at
Thus, the synthesis of nonanolide XV fused to
a trimethoxy-substituted pyran ring and of decanolide
XVI may be regarded as the first step toward oxa
analogs of eleuthesides. The developed procedure for
the synthesis of medium-ring lactones is promising
from the viewpoint of preparation of macrolides. For
this purpose we examined analogous transformations
with cycloheptanone and cyclododecanone derivatives.
4-(Cyclohept-1-en-1-yl)morpholine (XVII) was
synthesized according to the procedure described in
[15–19] using toluene instead of benzene, and 4-(cy-
clododec-1-en-1-yl)morpholine (XVIII) was prepared
according to [19]. Unlike dimedone adducts
(Scheme 1), Michael adducts of levoglucosenone with
cycloheptanone and cyclododecanone were obtained
1
13
Scheme 7.
O
O
O
H
MeO
MeO
(1) PhH, reflux
(2) H2O
(1) HCl–MeOH
(2) PCC, CH2Cl2
H
I
+
N
O
O
O
H
MeO
O
H
O
O
XVII
XIXa, XIXb
XXI
OMe
O
OMe
OMe
O
O
H
H
(1) PhH, reflux
(2) H2O
(1) HCl–MeOH
(2) PCC, CH2Cl2
O
O
O
I
+
N
O
H
H
O
O
XVIII
XXa, XXb
XXII
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 1 2014

ELEUTHESIDES AND THEIR ANALOGS: V.
121
Scheme 8.
OH
H
H
MeO
MeO
OEt
NaBH4, EtOH
XIV
OH
O
MeO
O
XXIII
Me
OH
COOH
9'''
Me
N
H
7'''
5'''
3'''
4'
MeO
MeO
(XXIV)
1'''
O
4
3
6'''
5
N
8'''
2'''
4'''
5'
2
6
DCC, DMAP, CHCl3, reflux
1
O
O
1'
3'N'
4''
MeO
2''
1''
N
H
O2'
3'
Me
5''
O
XXV
δC 33.63 and 138.38 ppm, respectively, and the
position of the C2H5O group followed from the pres-
ence of a cross peak between 8′′′-H and C6′′′.
was obtained with the following parameters: 4 K data
points, 512 increments, spectral width 5.0 kHz; the
data were processed using a sine bell-shaped function
for the F1 and F2 projections (ssb 2). The gsHSQC
spectra were recorded with a pulse delay optimized for
a JCH value of 145 Hz; 2 K data points, 256 in-
crements. The gsHMBC spectra were measured with
a small constant evolution delay of 71.4 ms for
1H–13C; 2 K data points, 256 increments. The NOESY
spectra were acquired using 2 K data points, 256 incre-
ments, spectral width 5.0 kHz, mixing time 0.5 s. All
NMR spectra were recorded from solutions in CDCl3
unless otherwise stated.
In summary, we have developed procedures for
four-atom ring expansion of cycloalkanones into chiral
medium- and large-ring lactones on the basis of levo-
glucosenone.
EXPERIMENTAL
The 1H, 13C, and 15N NMR spectra were recorded at
298 K on a Bruker Avance-III pulse spectrometer at
500.13, 125.47, and 50.58 MHz, respectively, using
a 5-mm PABBO Z-gradient probe. The chemical shifts
in the 13C and 1H NMR spectra were measured relative
to tetramethylsilane as internal reference. Digital reso-
lution was enhanced by zero-filling and multiplication
of the Fourier image by the exponential function
The IR spectra were recorded from films or Nujol
mulls on Shimadzu IR Prestige-21 and Bruker Tensor
27 instruments. The mass spectra were obtained on
a Hewlett Packard HP 5973 mass-selective detector
coupled with an HP 6890 gas chromatograph. Analyti-
cal TLC was performed using Sorbfil PTSKh-AF-A
plates manufactured by Sorbpolimer closed corpora-
tion (Krasnodar, Russia). The melting points were
measured on a Boetius PHMK 05 melting point ap-
paratus. The elemental compositions were determined
with a Euro 2000 CHNS(O) analyzer. The optical
rotations were measured on a Perkin Elmer 341
polarimeter.
1
(lb 0.1 Hz for H and 1 Hz for 13C). The 13C NMR
spectra with power-gated decoupling were recorded
with the use of composite WALTZ-16 sequence with
the following parameters: spectral width 29.8 kHz,
64 K data points, pulse duration (30°) 3.2 μs, relaxa-
tion delay 2 s, number of scans 512–2048. The
13C NMR spectra were edited on the basis of DEPT-90
and DEPT-135 experiments. The coupling constants
JCH were determined from the 13C NMR spectra
recorded with the use of gated decoupling sequence
in order to conserve NOE: spectral width 29.8 kHz,
64 K data points, accumulation time 1.1 s, pulse
duration (30°) 3.2 μs, relaxation delay 2 s, number of
scans 4096.
(2R,3R,6S,7R)-3,6-Epoxy-2-hydroxy-10,10-di-
methyl-2,7-methano-2,3,5,6,7,9,10,11-octahydro-
8H-1,4-benzodioxonin-8-one (II). Levoglucosenone
(I), 2.0 g (16.0 mmol), was dissolved in 50.0 mL of
toluene, 2.0 g (16.0 mmol) of 5,5-dimethylcyclohex-
ane-1,3-dione, 13.8 g (100.0 mmol) of potassium car-
bonate, and 0.3 g (a catalytic amount, 5%) of dicyclo-
hexano-18-crown-6 were added at room temperature,
The two-dimensional spectra were recorded using
standard multipulse sequences. The gsCOSY spectrum
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 1 2014

KHALILOVA et al.
122
and the mixture was subjected to ultrasonic irradiation
for 6 h. When the reaction was complete (TLC), the
mixture was concentrated, and the residue was purified
by chromatography. Yield 2.5 g (60%), colorless crys-
tals, mp 73°C, [α]D20 = –123.2° (c = 1.0, CHCl3), Rf 0.2
(petroleum ether–EtOAc, 1:1). IR spectrum, ν, cm–1:
Compound II, 0.400 g (1.5 mmol), was dissolved in
10.0 mL of pyridine, 0.573 g (3.0 mmol) of p-toluene-
sulfonyl chloride was added under stirring at 0°C, and
the mixture was stirred for two weeks (TLC). The
mixture was then treated with 3% aqueous HCl and
with water and extracted with ethyl acetate. The
organic phase was separated and repeatedly washed
with water to remove pyridine, the aqueous phase was
extracted with ethyl acetate (3×10 mL), the extracts
were combined with the organic phase, dried over
MgSO4, and evaporated, and the residue was purified
by chromatography. Yield 0.500 g (83%), colorless
oily substance, Rf 0.5 (EtOAc). IR spectrum, ν, cm–1:
1
3138, 2924, 2852, 1581, 1112. H NMR spectrum, δ,
ppm: 1.04 s (3H, CH3), 1.08 s (3H, CH3), 1.64 d.d (1H,
12-H, J = 1.9, 12.9 Hz), 2.23 s and 2.26 s (1H each,
11-H), 2.33 s and 2.35 s (1H each, 9-H), 2.38 d.d (1H,
12-H, J = 3.2, 12.9 Hz), 3.08 m (1H, 7-H), 3.88 d.d
(1H, 5-exo-H, J = 4.4, 7.2 Hz), 4.11 d (1H, 5-endo-H,
J = 7.2 Hz), 4.36 br.s (1H, 6-H), 5.18 d (1H, 3-H, J =
13
1
1.9 Hz), 5.70 br.s (OH). C NMR spectrum, δC, ppm:
2935, 2870, 1732, 1614, 1196, 1169, 1105. H NMR
28.09 (CH3), 28.29 (CH3), 28.73 (C12), 31.07 (C7),
31.07 (C10), 41.87 (C11), 49.84 (C9), 68.71 (C5), 76.10
(C6), 99.76 (C2), 103.57 (C3), 112.70 (C7a), 174.66
(C11a), 196.79 (C8). Mass spectrum: m/z 265 [M + H]+.
Found, %: C 63.16; H 6.78. C14H18O5. Calculated, %:
C 63.15; H 6.81. M 266.2897.
spectrum, δ, ppm: 1.02 s (3H, CH3), 1.08 s (3H, CH3),
2.05–2.40 m (4H, CH2), 2.37 d (1H, 9-H, J = 15.8 Hz),
2.42 c (3H, C6H4CH3), 2.67 d (1H, 9-H, J = 15.8 Hz),
3.21 d (1H, 7-H, J = 8.8 Hz), 3.84 m (1H, 5-exo-H),
4.32 br.s (1H, 6-H), 4.35 m (1H, 5-endo-H), 5.01 s
(1H, 3-H), 7.40–7.80 m (4H, Harom). 13C NMR spec-
trum, δC, ppm: 21.42 (CH3), 27.57 (CH3), 27.63 (CH3),
33.92 (C12), 35.42 (C7), 42.89 (C11), 51.27 (C9), 67.87
(C5), 76.57 (C6), 101.04 (C3), 101.99 (C2), 113.35
(C7a); 127.73, 130.09, 133.15, 144.52 (Carom); 162.61
(C11a), 196.70 (C8). Mass spectrum: m/z 421 [M + H]+.
Found, %: C 60.00; H 5.78; S 7.63. C21H24O7S. Cal-
culated, %: C 59.99; H 5.75; S 7.63. M 420.47771.
(2R,3R,6S,7R)-3,6-Epoxy-10,10-dimethyl-8-oxo-
2,7-methano-2,3,5,6,7,9,10,11-octahydro-8H-1,4-
benzodioxonin-2-yl methanesulfonate (III). Com-
pound II, 1.00 g (3.76 mmol), was dissolved in
20.0 mL of methylene chloride, 0.65 g (5.64 mmol) of
methanesulfonyl chloride, 1.14 g (11.28 mmol) of
triethylamine, and a catalytic amount (5%) of DMAP
were added at room temperature, and the mixture was
stirred for 1 h (TLC). The mixture was treated with
water and extracted with methylene chloride
(3×20 mL), and the extract was dried over CaCl2 and
evaporated. Yield 0.70 g (60%), colorless crystals,
mp 158°C, Rf 0.6 (EtOAc), [α]D20 = –66.4° (c = 1.0,
CHCl3). IR spectrum, ν, cm–1: 2947, 2852, 1649, 1622,
(1S,2R,5R)-2-(4,4-Dimethyl-6-oxocyclohex-1-en-
1-yl)-6,8-dioxabicyclo[3.2.1]octan-4-one (V). Sodium
tetrahydridoborate, 0.36 g (9.6 mmol), was added
under argon to a solution of 0.288 g (1.2 mmol) of
NiCl2·6H2O in 3.0 mL of ethanol. A black–green solu-
tion was formed, and 0.2 g (0.48 mmol) of sulfonate
IV or 0.48 mmol of III was added. When the reaction
was complete (TLC), the mixture was filtered through
a Schott filter. The filtrate was treated with water and
extracted with methylene chloride (3×10 mL), the ex-
tract was dried over MgSO4 and concentrated, and the
residue was purified by chromatography. Yield 0.1 g
(80%), colorless crystals, mp 122°C, Rf 0.4 (EtOAc),
[α]D20 = –190.8° (c = 1.0, CHCl3). IR spectrum, ν, cm–1:
1
1359, 1078, 835. H NMR spectrum, δ, ppm: 1.08 s
(6H, CH3), 2.21 d.d (1H, 12-H, J = 12.7, 1.9 Hz),
2.24 s (2H, 11-H), 2.40 s (2H, 9-H) 2.66 d.d (1H,
12-H, J = 3.5, 12.7 Hz), 3.15 m (1H, 7-H), 3.16 s (3H,
SO2CH3), 3.91 d.d (1H, 5-exo-H, J = 7.6, 4.4 Hz),
4.17 d (1H, 5-endo-H, J = 7.6 Hz), 4.36 br.s (1H, 6-H),
13
5.36 d (1H, 3-H, J = 1.9 Hz). C NMR spectrum, δC,
ppm: 27.47 (C10), 27.67 (CH3), 28.54 (CH3), 31.43
(C7), 32.73 (C12), 41.10 (C11), 41.32 (SO2CH3), 49.97
(C9), 68.92 (C5), 76.30 (C6), 102.20 (C3), 105.54 (C2),
113.64 (C7a), 174.99 (C11a), 195.40 (C8). Mass spec-
trum: m/z 345 [M + H]+. Found, %: C 52.33; H 5.78;
S 9.28. C15H20O7S. Calculated, %: C 52.31; H 5.85;
S 9.31. M 344.3811.
1
3000, 1726, 1666, 1465, 1400, 1114, 914. H NMR
spectrum, δ, ppm: 0.85 m (1H, 3′-H), 1.02 s (3H, CH3),
1.03 s (3H, CH3), 2.23 d (1H, 3′-H, J = 16.7 Hz),
2.30 m (1H, 3′-H, J = 4.1 Hz), 2.32 br.s (2H, 3-H),
2.93 d.d (1H, 3-H, J = 16.7, 8.6 Hz), 3.49 d (1H, 2-H,
J = 8.6 Hz), 4.00 d.d (1H, 7-exo-H, J = 7.7, 4.4 Hz),
4.12 d (1H, 7-endo-H, J = 7.7 Hz), 4.52 d (1H, 1-H,
J = 4.4 Hz), 5.08 s (1H, 5-H), 6.68 t (1H, 2′-H, J = 4.1,
4.1 Hz). 13C NMR spectrum, δC, ppm: 27.77 (CH3),
28.37 (CH3), 33.80 (C3′), 35.47 (C4′), 39.26 (C2), 40.10
(2R,3R,6S,7R)-3,6-Epoxy-10,10-dimethyl-8-oxo-
2,7-methano-2,3,5,6,7,9,10,11-octahydro-8H-1,4-
benzodioxonin-2-yl 4-methylbenzenesulfonate (IV).
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ELEUTHESIDES AND THEIR ANALOGS: V.
123
(C3), 51.80 (C5′), 68.14 (C7), 75.35 (C1), 100.69 (C5),
137.76 (C1′), 145.14 (C2′), 196.67 (C4), 200.86 (C6′).
Mass spectrum: m/z 251 [M + H]+. Found, %: C 68.18;
H 25.60. C14H18O4. Calculated, %: C 67.18; H 25.57.
M 250.2903.
(hereinafter, differing signals of the other diastereo-
isomer are given in brackets), δ, ppm: 1.06 s (6H,
CH3), 1.09 s (6H, CH3), 1.24 m (2H, CH2), 2.12–
1.50 m (4H, CH, CH2), 2.21 d and 2.36 d (2H each,
3-H, J = 16.8 Hz), 3.21 s [3.24] (3H, OCH3), 3.30 s
[3.35] (3H, OCH3), 4.02 m (2H, 6-H), 4.05 m (4H,
7″-H), 4.52 m (2H, 1′-H), 4.82 br.s (2H, 1″-H), 5.31 s
(2H, 5″-H). 13C NMR spectrum, δC, ppm: 24.75 (C4),
27.68 (CH3), 29.51 [30.93] (C3″), 33.51 (CH3), 37.33
(C5), 37.68 [38.20] (C2″), 44.73 [44.70] (C3), 48.05
[47.94] (OCH3), 48.82 [48.74] (OCH3), 68.55 [68.44]
(C7″), 73.38 [73.14] (C1″), 74.55 [74.33] (C6), 77.70
[78.32] (C1′), 96.73 [96.61] (OCH3), 99.52 (C5″),
171.38 [171.25] (C2). Found, %: C 58.90; H 7.93.
C16H26O7. Calculated, %: C 58.17; H 7.93.
(2R,3R,6S,7R)-3,6-Epoxy-2-methoxy-10,10-di-
methyl-2,7-methano-2,3,5,6,7,9,10,11-octahydro-
8H-1,4-benzodioxonin-8-one (VI). A catalytic amount
of p-toluenesulfonic acid (5%) was added to a solution
of 1.0 g (3.76 mmol) of compound II in 15.0 mL of
methanol. When the reaction was complete (TLC), the
mixture was treated with a solution of sodium car-
bonate to pH 7, the remaining methanol was distilled
off, and the product was extracted into ethyl acetate
(3×10 mL). The combined extracts were dried over
MgSO4 and concentrated, and the residue was purified
by chromatography. Yield 1.0 g (95%), colorless crys-
tals, mp 97°C, [α]D20 = –69.3° (c = 0.35, CHCl3), Rf 0.5
(EtOAc). IR spectrum, ν, cm–1: 2900, 2800, 1641,
Cleavage of the 1,6-anhydro bridge in VI by the
action of HCl in methanol. A solution of 0.529 g
(1.9 mmol) of compound VI in 5.0 mL of methanol
was cooled to 0°C, 20.0 mL of a 18% solution of HCl
in methanol was added, and the mixture was stirred for
5 h at room temperature. When the reaction was com-
plete (TLC), the mixture was neutralized to pH 6 with
a saturated solution of sodium hydrogen carbonate and
extracted with ethyl acetate (3×20 mL). The combined
extracts were dried over MgSO4 and concentrated on
a rotary evaporator, and the residue was subjected to
chromatography on silica gel. We thus isolated 0.256 g
(44%) of ketal VIII and 0.091 g (16%) of diastereo-
isomer mixture IXa/IXb.
1
1612, 1463, 1390, 1118. H NMR spectrum, δ, ppm:
1.05 s (3H, CH3), 1.10 s (3H, CH3), 1.77 br.d (1H,
12-H, J = 12.4 Hz), 2.02 br.d (1H, 12-H, J = 6.1,
12.4 Hz), 2.22 br.s (2H, 11-H), 2.23 br.s and 2.36 br.s
(1H each, 9-H), 3.13 d.d (1H, 7-H, J = 3.0, 6.1 Hz),
3.36 s (3H, OCH3), 3.86 d.d (1H, 5-exo-H, J = 4.6,
7.6 Hz), 4.07 d (1H, 5-endo-H, J = 7.6 Hz), 4.33 br.s
(1H, 6-H), 5.12 d (1H, 3-H, J = 1.9 Hz). 13C NMR
spectrum, δC, ppm: 25.30 (C12), 27.99 (CH3), 28.50
(CH3), 30.99 (C7), 32.72 (C10), 41.68 (C11), 50.03 (C9),
50.03 (OCH3), 68.61 (C5), 76.96 (C6), 102.23 (C2),
103.05 (C3), 113.01 (C7a), 173.70 (C11a), 195.84 (C8).
Mass spectrum: m/z 279 [M + H]+. Found, %: C 64.30;
H 7.08. C15H20O5. Calculated, %: C 64.27; H 7.19.
M 280.3163.
(3S,4aS,10bR)-2,2,3-Trimethoxy-2,3,4a,5,7,8,-
9,10b-octahydropyrano[2,3-c]chromen-10(1H)-one
(VIII). Colorless crystals, mp. 149°C, [α]D20 = +209.3°
(c = 2.0, CHCl3), Rf = 0.5 (petroleum ether–EtOAc,
1:1). IR spectrum, ν, cm–1: 2955, 1608, 1385, 1062,
1
1005. H NMR spectrum, δ, ppm: 0.98 s (3H, CH3),
(6RS)-6-{(1R)-[(1S,2R,5R)-4,4-Dimethoxy-6,8-
dioxabicyclo[3.2.1]oct-2-yl](hydroxy)methyl}-4,4-
dimethyltetrahydro-2H-pyran-2-one (VIIa/VIIb).
An ozone–oxygen mixture was passed at –78°C
through a solution of 0.437 g (1.7 mmol) of methoxy
derivative VI in methanol. When the reaction was
complete (TLC), the mixture was purged with argon,
and 0.162 g (4.25 mmol) NaBH4 was added in small
portions at –40°C. When the reducing agent was con-
sumed completely, the mixture was allowed to warm
up to room temperature, the solvent was distilled off,
and the residue was subjected to chromatography to
isolate 0.366 g (68%) of a mixture of (6R) and (6S)
isomers VIIa and VIIb at a ratio of 1:1. Colorless oily
substance, Rf 0.46 (EtOH–EtOAc, 1:1), [α]D20 = –164°
(c = 0.5). IR spectrum, ν, cm–1: 3500, 2958, 1718,
1.18 s (3H, CH3), 1.22 d.d (1H, CH2, J = 12.6,
12.9 Hz), 2.08–2.22 m (5H, CH2), 2.55 d.d.d (1H,
10b-H, J = 1.6, 9.5, 9.6 Hz), 3.21 s and 3.28 s (3H
each, 2-OCH3), 3.44 s (3H, 3-OCH3), 3.75 d.d (1H,
5-H, J = 5.8, 6.9 Hz), 3.79 d (1H, 5-H, J = 6.9 Hz),
4.21 d (1H, 4a-H, J = 9.6 Hz), 4.58 d (1H, 3-H, J =
1.3 Hz). 13C NMR spectrum, δC, ppm: 26.86 (CH3),
28.60 (CH3), 29.14 (C1), 32.65 (C10b), 41.75 (C7),
41.75 (C8), 47.35 and 47.68 (2-OCH3), 50.68 (C9),
54.58 (3-OCH3), 66.21 (C4a), 67.89 (C5), 97.53 (C2),
99.46 (C3), 109.52 (C10a), 169.05 (C6a). Mass spec-
trum: m/z 311 [M – CH3]+. Found, %: C 62.16; H 8.02.
C17H26O6. Calculated, %: C 62.56; H 8.03.
M 326.3847.
(2R,3RS,5S,6R)-5-Hydroxymethyl-2,3-dime-
thoxy-9,9-dimethyl-2,6-methano-2,3,6,8,9,10-hexa-
1
1373, 1246, 1112, 908, 600. H NMR spectrum
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KHALILOVA et al.
124
13
hydro-1,4-benzodioxocin-7(5H)-one (IXa/IXb,
a mixture of R and S isomers at a ratio of 3:1). Color-
less oily substance, Rf 0.08 (petroleum ether–EtOAc,
1:1). IR spectrum, ν, cm–1: 3000, 1618, 1458, 1375,
4.53 s (1H, 1-H). C NMR spectrum, δC, ppm: 20.53
(C4′), 23.67 (C5′), 25.99 (C3), 32.26 (C4), 38.38 (C3′),
47.48 (2-OCH3), 47.88 (2-OCH3), 48.91 (C1′), 54.74
(1-OCH3), 62.80 (C1″), 71.36 (C5), 97.37 (C2), 98.20
(C1), 218.00 (C2′). Found, %: C 58.30; H 8.40.
C14H24O6. Calculated, %: C 58.32; H 8.39.
1
1076, 721. H NMR spectrum (double number of pro-
tons is given for coinciding signals of diastereoiso-
mers), δ, ppm: 0.98 s (6H, CH3), 1.02 m (2H, CH2),
1.18 s (6H, CH3), 1.78–2.30 m (10H, CH, CH2),
3.38 m (2H, CH2), 3.51 s (6H, 3-OCH3), 3.43 (6H,
2-OCH3), 3.86–4.22 m (6H, CH, CH2), 3.98 [4.08] s
(1H, 3-H). 13C NMR spectrum, δC, ppm: 28.96 [28.12],
(CH3), 29.13 (CH3), 30.07 (C12), 32.16 [33.69] (C6),
34.07 [34.13] (C9), 37.75 [37.74] (C10), 51.16 [51.12]
(C8), 54.97 [54.98] (2-OCH3), 54.76 [54.14] (3-OCH3),
60.39 [61.16] (C11), 81.76 [81.38] (C5), 95.91 [96.85]
(C2), 106.25 [107.52] (C4), 116.90 [114.87] (C6a),
117.26 [177.02] (C10a), 194.67 [195.14] (C7). Found,
%: C 61.50; H 8.00. C16H24O6. Calculated, %: C 61.52;
H 7.74.
(3aS,5aS,7S,9aR,9bR)-3a,7,8,8-Tetramethoxy-
decahydro-1H-cyclopenta[b]pyrano[3,2-d]pyrane
(XIIb). Colorless oily substance, [α]D20 = +119° (c =
1.0, CHCl3), Rf 0.37 (petroleum ether–EtOAc, 3:1). IR
spectrum, ν, cm–1: 2957, 2924, 1063, 407. H NMR
1
spectrum, δ, ppm: 1.55–2.03 m (10H, CH, CH2), 3.22 s
(3H, 3a-OCH3), 3.23 s and 3.25 s (3H each, 8-OCH3),
3.43 s (3H, 7-OCH3), 3.50 d.d (1H, 5-H, J = 10.7,
5.0 Hz), 3.62 d.d (1H, 5-H, J = 5.6, 10.7 Hz),
13
3.78 d.d.d (1H, 5a-H, J = 4.7, 5.0, 5.6 Hz). C NMR
spectrum, δC, ppm: 20.22 (C2), 23.38 (C1), 29.41 (C9),
33.02 (C9a), 33.91 (C3), 46.60 (3a-OCH3), 47.47 and
47.78 (8-OCH3), 50.01 (C9b), 54.66 (7-OCH3), 62.96
(C5), 63.36 (C5a), 97.68 (C8), 98.75 (C7), 107.80 (C3a).
Found, %: C 59.60; H 8.60. C15H26O6. Calculated, %:
C 59.58; H 8.67.
(2S,4aR,6RS,12aS)-6-Hydroxy-2,3,3-trimethoxy-
8,8-dimethyldecahydropyrano[3,2-c]oxecine-5,10-
dione (Xa/Xb) was synthesized as described above for
VIIa/VIIb from 0.233 g (0.7 mmol) of VIII. Yield
0.051 g (25%), colorless oily substance, Rf 0.45 (petro-
leum ether–EtOAc, 1:1). IR spectrum, ν, cm–1: 1736,
1151, 1057. 1H NMR spectrum (double number of pro-
tons is given for coinciding signals of diastereoiso-
mers), δ, ppm: 1.04 s (6H, CH3), 1.12 s (6H, CH3),
1.70–2.03 m (4H, CH2), 2.32–2.82 m (6H, CH, CH2),
2.68 d and 2.81 d (2H each, 9-H, J = 17.2 Hz), 3.18 m
(4H, 12-H), 3.24 [3.20] s (3H, 3-OCH3), 3.38 [3.40] s
(6H, 2-OCH3, 3-OCH3, 3.68 [3.60] m (1H, 6-H),
3.72 m (2H, 12a-H), 4.50 [4.52] s (1H, 2-H). 13C NMR
spectrum, δC, ppm: 28.36 (CH3), 32.83 (C4), 36.41
(CH3), 38.63 (C8), 44.14 (C9), 47.83 (3-OCH3), 47.07
(C7), 48.23 (3-OCH3), 51.32 (C4a), 54.91 (2-OCH3),
62.70 (C12), 69.37 (C6), 79.67 (C12a), 97.60 (C3), 97.65
(C2), 172.85 (C10), 211.35 (C5). Mass spectrum: m/z
360 [M + H]+. Found, %: C 56.60; H 7.76. C17H28O8.
Calculated, %: C 56.65; H 7.83. M 360.3994.
Following the procedure described above for the
synthesis of VIII, from 0.4 g (1.8 mmol) of
XIIIa/XIIIb we obtained 0.155 g (50%) of XIVa and
0.144 g (27%) of XIVb.
[(2R,3S,5S,6R,6aR,10aR)-2,3,10a-Trimethoxy-
decahydro-2,6-methano-1,4-benzodioxocin-5-yl]-
methanol (XIVa). Colorless crystals, mp 130°C,
[α]D20 = +86° (c = 1.0, CHCl3), Rf 0.3 (petroleum ether–
EtOAc, 3:1). IR spectrum, ν, cm–1: 3425, 2920, 2852,
1
1450, 1056, 974. H NMR spectrum, δ, ppm: 1.22 m
(6H, CH2), 1.50–1.8 m (6H, CH, CH2), 3.22 s (3H,
10a-OCH3), 3.25 s (3H, 2-OCH3), 3.47 s (3H,
3-OCH3), 3.54 d.d (1H, 11-H, J = 5.1, 10.4 Hz),
3.68 d.d (1H, 11-H, J = 5.2, 10.4 Hz), 3.92 m (1H,
13
5-H), 4.56 s (1H, 3-H). C NMR spectrum, δC, ppm:
20.78 (C7), 24.28 (C9), 25.14 (C8), 28.18 (C10), 32.71
(C6), 38.14 (C12), 45.89 (C6a), 47.30 (10a-OCH3), 47.73
(2-OCH3), 54.49 (3-OCH3), 62.61 (C11), 68.19 (C5),
95.74 (C2), 97.56 (C10a), 98.06 (C3). Found, %: C 59.61;
H 8.48. C15H26O6. Calculated, %: C 59.58; H 8.67.
As described above for the synthesis of VIII, from
0.5 g (2.4 mmol) of XIa/XIb we obtained 0.149 g
(22%) of XIIa and 0.294 g (41%) of XIIb.
Methyl (1′R,1S,2S,4R)-3,4-dideoxy-2-methoxy-
2-O-methyl-4-(2-oxocyclopentyl)-erythro-hexopyra-
noside (XIIa). Colorless oily substance, [α]D20 = +95°
(c = 1.0, CHCl3), Rf 0.14 (petroleum ether–EtOAc,
3:1). IR spectrum, ν, cm–1: 2976, 2866, 1381, 1122.
1H NMR spectrum, δ, ppm: 1.43–2.38 m (10H, CH,
CH2), 3.45–3.80 m (3H, CH, CH2), 3.19 s (3H,
2-OCH3), 3.21 s (3H, 2-OCH3), 3.40 s (3H, 1-OCH3),
(3S,4aS,6aS,10aR,10bR)-2,2,3,6a-Tetramethoxy-
dodecahydropyrano[2,3-c]chromene (XIVb). Color-
less crystals, mp 118°C, [α]D20 = +117° (c = 1.0,
CHCl3), Rf 0.6 (petroleum ether–EtOAc, 3:1). IR spec-
trum, ν, cm–1: 2900, 1735, 1458, 1151, 1064, 1049,
979. H NMR spectrum, δ, ppm: 1.17–1.40 m (8H,
CH2), 1.56–1.90 m (4H, CH, CH2), 3.17 s (3H,
6a-OCH3), 3.22 s and 3.25 s (3H each, 2-OCH3), 3.46 s
1
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ELEUTHESIDES AND THEIR ANALOGS: V.
125
(3H, 3-OCH3), 3.60 m (2H, 5-H), 3.58 m (1H, 4a-H),
28.17 (C4), 34.10 (C9), 40.00 (C6), 47.85 and 48.24
(3-OCH3), 51.72 (C4a), 55.30 (2-OCH3), 64.81 (C12),
67.70 (C12a), 96.54 (C3), 97.35 (C2), 172.58 (C10),
208.11 (C5). Mass spectrum: m/z 316 [M + H]+. Found,
%: C 56.98; H 7.66. C15H24O7. Calculated, %: C 56.95;
H 7.65. M 316.3469.
13
4.56 s (1H, 3-H). C NMR spectrum, δC, ppm: 22.20
(C8), 24.23 (C10), 25.23 (C9), 28.38 (C1), 31.31 (C7),
34.33 (C10b), 46.88 (C10a), 46.47 (6a-OCH3), 47.47 and
47.91 (2-OCH3), 54.66 (3-OCH3), 62.48 (C5), 68.20
(C4a), 97.73 (C2), 98.05 (C6a), 98.31 (C3). Found, %:
C 60.74; H 8.90. C16H28O6. Calculated, %: C 60.74;
H 8.92.
1,6-Anhydro-3,4-dideoxy-4-[(1RS)-2-oxocyclo-
hept-1-yl]-β-D-erythro-hex-2-ulose (XIXa/XIXb).
4-(Cyclohept-1-en-1-yl)morpholine (XVII), 0.348 g
(1.9 mmol), was added to a solution of 0.200 g
(1.6 mmol) of levoglucosenone (I) in 10.0 mL of ben-
zene, and the mixture was heated for 2 h under reflux.
When the reaction was complete (TLC), the mixture
was treated with water and was heated for 1 h more
under reflux. The mixture was cooled to room tem-
perature and extracted with ethyl acetate (4×10 mL),
and the combined extracts were dried over MgSO4 and
evaporated. Yield 0.184 g (48%, a mixture of R and S
isomers at a ratio of 2:1), colorless oily substance,
[α]D20 = +0.2° (c = 1.0, CHCl3), Rf 0.2 (petroleum
ether–EtOAc, 3:1). IR spectrum, ν, cm–1: 2927, 1735,
1701, 1115, 429. 1H NMR spectrum (double number of
protons is given for coinciding signals), δ, ppm: 1.11 m
(4H, CH2), 1.58 m (6H, CH2), 2.00 m (4H, CH2), 2.21–
2.40 m (8H, CH, CH2), 2.38 m (2H, 4-H), 2.51 m and
2.67 m (2H each, 3′-H), 2.70 m (2H, 3-H), 2.85 m (2H,
1′-H), 3.87 m (2H, 6-exo-H), 3.95 m (2H, 6-endo-H),
4.52 d (1H, 5-H, J = 4.7 Hz) [4.68 d (1H, 5-H, J =
3.7 Hz)], 5.00 [5.02] s (1H). 13C NMR spectrum, δC,
ppm: 23.09 [23.32 (C4′), 27.93 [27.85] (C6′), 27.97
[28.41] (C7′), 28.48 [29.31] (C5′), 33.95 [36.08] (C3),
41.26 [42.00] (C4), 43.73 [44.04] (C3′), 51.72 [51.85]
(C1′), 68.10 [68.17] (C6), 73.73 [74.96] (C5), 101.19
[101.15] (C1), 200.12 [200.18] (C2), 215.13 [214.40]
(C2′). Found, %: C 65.54; H 7.61. C13H18O4. Calculat-
ed, %: C 65.53; H 7.61.
(2S,4aS,11aS)-2,3,3-Trimethoxyhexahydro-2H-
pyrano[2,3-c]oxonane-5,9(3H,6H)-dione (XV). Pyri-
dinium chlorochromate, 0.215 g (1.0 mmol), was
added in small portions under thorough stirring to
a solution of 0.157 g (0.5 mmol) of compound XIIb in
5.0 mL of methylene chloride. After 48 h (TLC), the
mixture was diluted with 5.0 mL of diethyl ether, the
precipitate was filtered off through a layer of silica gel
on a Schott filter, the filtrate was evaporated, and the
residue was subjected to chromatography on silica gel.
Yield 0.071 g (45%), colorless oily substance, [α]D20
=
+45° (c = 1.0, CHCl3), Rf 0.18 (petroleum ether–
EtOAc, 3:1). IR spectrum, ν, cm–1: 2976, 2864, 1383,
1
1122. H NMR spectrum, δ, ppm: 1.90–2.00 m (3H,
CH, CH2), 2.55 d.d.d (1H, 6-H, J = 2.0, 10.3, 14.3 Hz),
2.90 d.d (1H, 6-H, J = 6.7, 10.3 Hz), 3.18 s and 3.22 s
(3H each, 3-OCH3), 3.43 s (3H, 2-OCH3), 4.01 d.d
(1H, 11-H, J = 9.3, 10.7 Hz), 4.29 d.d.d (1H, 11a-H,
J = 6.3, 9.3, 9.6 Hz), 4.49 d.d (1H, 11-H, J = 6.3,
10.7 Hz), 4.52 s (1H, 2-H). 13C NMR spectrum, δC,
ppm: 21.99 (C7), 28.09 (C4), 33.32 (C8), 41.19 (C6),
47.81 and 48.17 (3-OCH3), 55.24 (2-OCH3), 50.89
(C4a), 63.58 (C11), 69.20 (C11a), 96.27 (C3), 97.23 (C2),
171.62 (C9), 210.52 (C5). Mass spectrum: m/z 301
[M + H]+. Found, %: C 55.62; H 7.34. C14H22O7. Cal-
culated, %: C 55.62; H 7.33. M 302.3203.
(2S,4aS,12aS)-2,3,3-Trimethoxydecahydropyra-
no[2,3-c]oxecine-5,10-dione (XVI) was synthesized in
a similar way from 0.268 g (0.9 mmol) of XIVa or
0.9 mmol of XIVb. Yield 0.164 g (59%, from XIVa)
or 0.117 g (42%, from XIVb), colorless crystals,
mp 74°C, [α]D20 = +56° (c = 1.0, CHCl3), Rf 0.16 (petro-
leum ether–EtOAc, 3:1). IR spectrum, ν, cm–1: 2853,
1,6-Anhydro-3,4-dideoxy-4-[(1RS)-2-oxocyclodo-
decyl]-β-D-erythro-hex-2-ulose (XXa/XXb) was syn-
thesized in a similar way from 0.500 g (8.0 mmol) of
levoglucosenone (I). Yield 0.285 g (24%, a mixture of
R and S isomers at a ratio of 2:1), colorless crystals,
mp 83°C, [α]D20 = –132° (c = 1.0, CHCl3), Rf 0.48
(petroleum ether–EtOAc, 6:1). IR spectrum, ν, cm–1:
2930, 1730, 1697, 1468, 1121, 914, 727, 430. 1H NMR
spectrum (double number of protons is given for coin-
ciding signals), δ, ppm: 1.05–1.18 m (4H, CH2), 1.20–
1.40 m (26H, CH2), 1.58–1.63 m (2H, CH2), 1.74–
1.82 m (2H, CH2), 1.90 m (2H, CH2), 2.07 m (2H,
CH2), 2.12–2.20 m (2H, CH2), 2.30 d (2H, CH2, J =
16.4 Hz), 2.60 m (2H, CH2), 2.75 [2.90] m (1H, CH),
3.0 m (2H, CH), 3.94 d.d (1H, 6-exo-H, J = 5.4,
1
1730, 1064, 968. H NMR spectrum, δ, ppm: 1.50 m
(1H, 8-H), 1.58 m and 1.75 m (1H each, 7-H), 1.87 m
(1H, 4-H), 1.90 m (1H, 8-H), 1.95 m (1H, 4-H), 2.22 m
(1H, 9-H), 2.32 m (1H, 6-H), 2.40 m (1H, 9-H), 2.48 m
(1H, 6-H), 2.62 d.d.d (1H, 4a-H, J = 4.0, 10.0,
12.6 Hz), 3.16 s and 3.18 s (3H each, 3-OCH3), 3.40 s
(3H, 2-OCH3), 4.05 d.d (1H, 12-H, J = 4.2, 10.5 Hz),
4.15 d.d.d (1H, 12a-H, J = 4.2, 10.0, 10.3 Hz), 4.30 d.d
(1H, 12-H, J = 10.3, 10.5 Hz), 4.50 s (1H, 2-H).
13C NMR spectrum, δC, ppm: 20.29 (C7), 22.50 (C8),
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KHALILOVA et al.
126
6.6 Hz), 4.01–4.09 m (1H, 6-endo-H) [4.01–4.09 m
(2H, 6-H)], 4.41 d (1H, 5-H, J = 5.4 Hz) [4.67 d (1H,
5-H, J = 3.9 Hz)], 5.03 [5.05] s (1H, 1-H). C NMR
Yield 0.055 g (30%), colorless oily substance, [α]D20
=
+27° (c = 1.0, CHCl3), Rf 0.38 (petroleum ether–
EtOAc, 3:1). IR spectrum, ν, cm–1: 2990, 1750, 1030,
13
spectrum, δC, ppm: 19.93 (C5′), 21.43 (C6′), 21.78 (C4′),
22.46 (C10′), 23.05 (C7′), 23.74 (C9′), 25.80 (C8′), 26.11
(C11′), 26.29 (C12′), 33.42 (C3′), 33.42 (C3), 39.41
[39.10] (C4), 52.27 [50.88] (C1′), 68.29 [67.87] (C6),
75.46 [73.91] (C5), 101.37 [109.98] (C1), 200.67
[200.67] (C2), 212.94 [211.98] (C2′). Found, %: C 70.25;
H 9.18. C18H28O4. Calculated, %: C 70.10; H 9.15.
500. H NMR spectrum, δ, ppm: 1.15–1.35 m (8H,
1
CH2), 1.41–1.82 m (4H, CH2), 2.40 m (3H, CH2),
3.0 m (1H, CH), 3.20–3.40 m (2H, CH2), 4.11–4.20 m
(3H, CH, CH2), 3.22 s and 3.28 s (3H each, 3-OCH3),
3.43 s (3H, 2-OCH3), 4.57 s (1H, 2-H). 13C NMR spec-
trum, δC, ppm: 21.66 (C8), 24.01 (C14), 25.21 (C7),
25.71 (C10), 25.80 (C11), 26.11 (C13), 26.68 (C9), 29.09
(C4), 40.87 (C6), 46.32 (C4a), 47.90 and 48.30
(3-OCH3), 55.12 (2-OCH3), 64.30 (C18), 66.96 (C18a),
96.41 (C3), 97.60 (C2), 173.63 (C16), 210.56 (C5). Mass
spectrum: m/z 400 [M + H]+. Found, %: C 62.99;
H 9.11. C21H36O7. Calculated, %: C 62.98; H 9.06.
M 400.5063.
(2S,4aS,13aS)-2,3,3-Trimethoxyoctahydro-2H-
pyrano[2,3-c]oxacycloundecine-5,11(3H,6H)-dione
(XXI). A solution of 0.184 g (0.8 mmol) of diastereo-
isomer mixture XIXa/XIXb in 2.0 mL of methanol
was cooled to 0°C, 10.0 mL of a 18% solution of HCl
in methanol was added, and the mixture was stirred for
3 days at room temperature. When the reaction was
complete (TLC), the mixture was neutralized to pH 7
with a saturated solution of sodium hydrogen car-
bonate and extracted with ethyl acetate (3×8 mL), the
extracts were combined, dried over MgSO4, and con-
centrated on a rotary evaporator, the residue was
dissolved in 5.0 mL of methylene chloride, and 0.215 g
(1.0 mmol) of PCC was added in small portions under
thorough stirring. After 48 h (TLC), the mixture was
diluted with 5.0 mL of diethyl ether and filtered
through a layer of silica gel on a Schott filter, the
filtrate was evaporated, and the residue was subjected
to chromatography on silica gel to isolate 0.071 g
(28%) of compound XXI as colorless crystals with
mp 54°C, [α]D20 = +19° (c = 1.0, CHCl3), Rf 0.27 (petro-
leum ether–EtOAc, 3:1). IR spectrum, ν, cm–1: 2930,
Ethyl (6S)-6-hydroxy-6-[(2S,3R,6S)-2-hydroxy-
methyl-5,5,6-trimethoxytetrahydro-2H-pyran-3-yl]-
hexanoate (XXIII) and {(2S,3R,6S)-3-[(1S)-6-
ethoxy-1-hydroxy-6-oxohexyl]-5,5,6-trimethoxy-
tetrahydro-2H-pyran-2-yl}methyl (2E)-3-(1-methyl-
1H-imidazol-4-yl)prop-2-enoate (XXV). Sodium
tetrahydridoborate, 0.032 g (0.8 mmol), was added to
a solution of 0.220 g (0.7 mmol) of lactone XIV in
5.0 mL of ethanol, the mixture was stirred until the
reaction was complete (TLC), 1.0 mL of acetone was
added, the mixture was concentrated on a rotary evap-
orator, and the residue was subjected to chromatog-
raphy on silica gel to isolate 0.090 g (41%) of alcohol
XXIII (major product). Compound XXIII, 0.090 g
(0.3 mmol), was dissolved in 10.0 mL of chloroform,
0.137 g (0.9 mmol) of N-methylurocanic acid (XXIV),
0.247 g (1.2 mmol) of N,N′-dicyclohexylcarbodiimide,
and 0.183 g (1.5 mmol) of 4-dimethylaminopyridine
were added, and the mixture was heated under reflux
until the reaction was complete (TLC). The mixture
was then treated with a saturated solution of ammoni-
um chloride and extracted with chloroform (3×5 mL),
the combined extracts were dried over MgSO4 and
concentrated on a rotary evaporator, and the residue
was purified by chromatography on silica gel. Yield of
XXV 0.077 g (60%).
1
1740, 1050. H NMR spectrum, δ, ppm: 1.14 m (1H,
CH2), 1.52 m (2H, CH2), 1.72 m (2H, CH2), 1.83 m
(1H, CH2), 2.00 m (2H, CH2), 2.28 m (1H, CH2),
2.44 m (1H, CH2), 2.69 m (1H, CH2), 3.07 d.d.d (1H,
4a-H, J = 3.2, 3.5, 10.0 Hz), 3.22 s and 3.32 s (3H
each, 3-OCH3), 3.51 s (3H, 2-OCH3), 3.82 d.d (1H,
8-H, J = 5.7, 11.4 Hz), 4.28 d.d (1H, 8-H, J = 4.2,
11.4 Hz), 4.56 s (1H, 2-H). 13C NMR spectrum, δC,
ppm: 21.73 (C9), 22.33 (C8), 25.49 (C7), 29.01 (C4),
33.78 (C10), 40.98 (C6), 47.75 (C4a), 47.76 and 48.22
(3-OCH3), 55.08 (2-OCH3), 65.09 (C13), 67.16 (C13a),
96.39 (C3), 97.67 (C2), 172.92 (C11), 210.63 (C5). Mass
spectrum: m/z 330 [M + H]+. Found, %: C 58.17;
H 7.96. C16H26O7. Calculated, %: C 58.17; H 7.93.
M 330.3734.
Compound XXIII. Colorless oily substance, Rf 0.9
1
(petroleum ether–EtOAc, 1:1). H NMR spectrum, δ,
ppm: 1.23 t (3H, CH3, J = 7.2 Hz), 1.30–1.60 m (6H,
CH, CH2), 1.79–2.00 m (3H, CH, CH2), 2.30 m (2H,
CH2), 3.20 s (6H, 5-OCH3), 3.40 s (3H, 6-OCH3),
3.51 br.s (1H, 2-H), 3.53 br.s (1H, 1″-H), 3.70 d.d
(1H, 1′-H, J = 11.5, 3.8 Hz), 3.75 d.d (1H, 1′-H, J =
11.5 Hz), 4.08 q (2H, 8′′′-H, J = 7.1 Hz), 4.50 s (1H,
6-H). 13C NMR spectrum, δC, ppm: 14.19 (CH3), 24.61
(2S,4aS,18aS)-2,3,3-Trimethoxyhexadecahydro-
pyrano[2,3-c]oxacyclohexadecine-5,16-dione (XXII)
was synthesized in a similar way from 0.138 g
(0.4 mmol) of diastereoisomer mixture XXa/XXb.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 1 2014

ELEUTHESIDES AND THEIR ANALOGS: V.
127
(C4″), 25.24 (C3″), 26.66 (C4), 32.44 (C5″), 34.11 (C2″),
40.40 (C3), 47.63 and 48.13 (5-OCH3), 54.88
(6-OCH3), 60.34 (CH2O), 63.89 (C1′), 70.66 (C1″),
71.97 (C3), 97.48 (C5), 97.77 (C6), 173.81 (C6″).
3. Lindel, T., Angew. Chem., Int. Ed., 1998, vol. 37, p. 774.
4. Chen, X.-T., Gutteridge, C.E., Bhattacharya, S.K.,
Zhou, B., Pettus, T.R.R., Hascall, T., and Danishef-
sky, S.J., Angew. Chem., Int. Ed., 1998, vol. 37, p. 185.
5. Drager, G., Kirschning, A., Thiericke, R., and
Zerlin, M., Nat. Prod. Rep., 1996, p. 365.
6. Hanaki, N., Ishihara, K., Kaino, M., Naruse, Y., and
Compound XXV. Colorless oily substance, [α]D20
=
+48.6° (c = 1.05, CHCl3), Rf 0.9 (EtOAc). IR spec-
1
trum, ν, cm–1: 1713, 1271, 1169, 1057. H NMR spec-
Yamamoto, H., Tetrahedron, 1996, vol. 52, p. 7297.
trum, δ, ppm: 1.25 t (3H, CH3, J = 7.2 Hz), 1.34–
1.42 m (3H, 2′′′-H, 2′′′-H), 1.53 d.d (1H, 3-H, J = 13.2,
13.2 Hz), 1.55–1.68 m (3H, 3′′′-H, 4′′′-H), 1.96 m (1H,
3-H), 2.08 d.d (1H, 4-H, J = 13.2, 2.6 Hz), 2.30 m (2H,
5′′′-H), 3.22 s and 3.23 s (3H each, 5-OCH3), 3.44 s
(3H, 6-OCH3), 3.68 m (1H, 1′′′-H), 3.71 s (3H, NCH3),
3.81 d.d.d (1H, 2-H, J = 9.2, 6.4, 2.3 Hz), 4.12 q (2H,
8-H, J = 7.2 Hz), 4.23 d.d (1H, 7-H, J = 12.0, 6.4 Hz),
4.52 d.d (1H, 7-H, J = 12.0, 2.3 Hz), 4.59 s (1H, 6-H),
6.59 d (1H, 4′-H, J = 15.6 Hz), 7.10 s (1H, 5″-H),
7.48 s (1H, 7″-H), 7.57 d (1H, 5′-H, J = 15.6 Hz).
13C NMR spectrum, δC, ppm: 14.24 (C9′′′), 24.71 (C3′′′),
25.51 (C4′′′), 26.49 (C4), 32.23 (C2′′′), 33.63 (NCH3),
34.19 (C5′′′), 40.62 (C3), 47.77 and 48.13 (5-OCH3),
54.90 (6-OCH3), 60.29 (C8′′′), 65.28 (C7′′′), 69.26 (C2),
70.90 (C1′′′), 97.34 (C5), 97.49 (C6), 115.52 (C4′),
122.76 (C5″), 136.58 (C5′), 138.38 (C4″), 139.25 (C2″),
167.71 (C3′), 173.74 (C6′′′). Mass spectrum: m/z 498
[M + H]+. Found, %: C 57.79; H 7.70; N 5.62.
C24H38N2O9. Calculated, %: C 57.82; H 7.68; N 5.62.
M 498.5666.
7. Borowitz, I.J. and Rapp, R., J. Org. Chem., 1969,
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and Degl’Innocenti, A., J. Am. Chem. Soc., 1988,
vol. 110, p. 4754.
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khin, L.V., Salikhov, Sh.M., and Valeev, F.A., Russ. J.
Org. Chem., 2014, vol. 50, p. 110.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
nos. 11-03-97024-r_povolzh’e_a, 13-00-14056).
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