Acidic isomerization of alantolactone derivatives

Article abstract of DOI:10.1007/s10600-006-0166-7

A series of derivatives of the natural sesquiterpene lactones alantolactone (1) and isoalantolactone (2) was prepared. The α-methylene-γ- lactone moiety was retained in the structures of these for further modifications using reactions that affected exclusively the nonconjugated double bonds of the decalin ring.

Full text of DOI:10.1007/s10600-006-0166-7

Chemistry of Natural Compounds, Vol. 42, No. 4, 2006
ACIDIC ISOMERIZATION OF ALANTOLACTONE DERIVATIVES
S. G. Klochkov, S. V. Afanas′eva, and A. N. Pushin
UDC 577.112
1
2
A series of derivatives of the natural sesquiterpene lactones alantolactone ( ) and isoalantolactone ( ) was
α
γ
prepared. The -methylene- -lactone moiety was retained in the structures of these for further modifications
using reactions that affected exclusively the nonconjugated double bonds of the decalin ring.
Key words: sesquiterpene lactones, alantolactone, isoalantolactone, acidic isomerization,
L.
Inula helenium
The great potential biological and pharmacological activities of natural sesquiterpene lactones are responsible for the
interest in developing this area of chemistry [1, 2]. The most promising direction is the chemical modification of compounds
isolated from natural sources in order to prepare substances with new properties. Certain natural sesquiterpene lactones have
been used as effective medicinal preparations (for example, the antitumor preparation Arglabin [3]).
The goal of the present work was to prepare a series of derivatives based on the natural sesquiterpene lactones
alantolactone (1) and isoalantolactone (2) in the structures of which the α-methylene-γ-lactone moiety was retained for further
modifications. This was achieved using reactions that affected exclusively the nonconjugated double bonds of the decalin ring.
14
H
H
H
O
O
O
12
1
9
O
O
O
5
7
3
11
13
H
H
H
15
2
3
1
A mixture of lactones 1 and 2 (~1:1 ratio) was isolated from roots of Inula helenium L. (Asteraceae) by a method
consisting of extraction of the ground raw material with CHCl and subsequent chromatography over a column of SiO .
3
2
Fractions containing this mixture were evaporated and crystallized (2-3 times) from aqueous CH OH(70%) toafford about 25%
3
(of the total content of the extract) of pure 2. The isomers were further separated over a column of SiO impregnated with
2
AgNO (5%) with gradient elution by benzene in light petroleum ether. The compounds isolated by chromatography over the
3
column impregnated with Ag contained an impurityof Ag (2-5% according to elemental analysis) that was removed bypassing
their benzene solution over a layer of neutral Al O (activity I). The resulting compounds were identical to those in the
2
3
literature [4].
It is well known that olefins can undergo acidic isomerization to form intermediates and transition-state carbonium
ions in which prototropic and skeletal rearrangements are observed. Therefore, we investigated the reactions of the
alantolactone derivatives with acids.
Alantolactone (1) is stable to acids (under drastic conditions the reaction mixture polymerizes) according to the
literature [5] and our data.
Shifts of the exocyclic double bond in the decalin ring of 2 that occur in the presence of acids have been reported [6].
Thisformed a mixture ofthe thermodynamicallymore favorableisomerictrisubstitutedolefinsthat contain an endocyclicdouble
bond between C-4 and C-5 (3) or C-3 and C-4. The ratio of products depends on the acid used (2:1 for methanesulfonic acid
in trifluoroethanol [5] and 1:3 in formic acid [7]). We found the conditions for selective isomerization of 2 into 3. The PMR
spectrum of 3 contained a singlet for the methyl on the double bond (1.60 ppm) instead of signals for the exomethylene protons
13
on C-15. The C NMR exhibited signals for C-15 at 26.6 ppm and showed shifts for C-4 and C-5 from 148.34 to 126.52 ppm
Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432, Moscow Region, Noginsk
District, Chernogolovka, Severnyi proezd, 1, fax 7-(495) 785 70 24, e-mail: klk@ipac.ac.ru. Translated from Khimiya
Prirodnykh Soedinenii, No. 4, pp. 325-330, July-August, 2006. Original article submitted March 27, 2006.
0009-3130/06/4204-0400 ©2006 Springer Science+Business Media, Inc.
400

and from 45.55 to 130.56 ppm, respectively. The spectral data as a whole defined the compound as alloalantolactone, which
was isolated previously from another plant of this genus, I. racemosa [8].
Isoalantolactone (2) also isomerized if trifluoroacetic acid (in CHCl ) or H SO (in acetic acid) were used at room
3
2
4
temperature. The yield was highest (81%) for the reaction with a 5-fold excess of trifluoroacetic acid. The product was purified
by chromatography. In contrast with 1 and 2, it turned out to be quite labile and gradually polymerized upon storage under
normal conditions.
Lactones 1-3 were epoxidized by peracid at the nonconjugated double bond using the literature method [9]. The
conversion occurred at room temperature during 1-7 days depending on the structure of the starting compound (1 was the most
reactive). In all instances, the epoxy derivatives 4-6 were obtained in quantitative yields.
H
H
H
O
O
O
O
O
O
O
O
H
H
O
H
4
5
6a, b
The epoxidation of 1 and 2 by peracetic acid was reported to be stereospecific, i.e., one structural isomer formed in
which the epoxide oxygen had the α-orientation according to an x-ray crystal structure (XCS) [9]. This was confirmed by our
investigations. Tables 1 and 2 give the NMR spectra of the starting compounds and the resulting products.
The PMR spectrum of epoxyalantolactone 4 lacked a signal for a C-6 olefinic proton. Instead, a doublet appeared at
2.89 ppm that corresponded to the proton on the epoxide C atom (signals for C-5 and C-6 appeared at 66.77 and 60.43 ppm,
13
respectively, in the C NMR spectrum). The PMR spectrum of epoxyisoalantolactone 5 also had signals for protons of the
oxirane ring at 2.63 (dd, 1H) and 2.50 ppm (d, 1H) instead of a signal for the exomethylene protons. Corresponding changes
13
were observed also in the C NMR spectrum (Table 2). Signals for the epoxide C atoms shifted to strong field (from 106.02
to 50.23 ppm for C-15 and from 148.34 to 57.99 ppm for C-4). Our spectral results agreed with those in the literature [9] and
confirmed the structures of 4 and 5 and the orientation of the epoxide O atom.
13
Epoxidation of 3 produced a mixture of isomers in a 3:2 ratio. The PMR and C NMR spectra of 6a and 6b were very
similar (Tables 1 and 2). Epoxidation of the lactone telekin, which has a similar structure, is known to form the α-epoxide as
the main product and the β-epoxide as the minor one [10]. The chemical shift (CS) of the angular methyl on C-10 of the major
component of 6 was 1.03 ppm whereas that of the minor one shifted to weaker field to 1.16 ppm. This is comparable with data
for α- and β-epoxyisotelekin [10]. Thus, the major component was assumed to have the α-orientation of the oxirane O atom;
the minor, the β-orientation, based on the literature data and the NMR spectra. Pure epimers 6a and 6b were obtained by
repeated recrystallization from CH OH.
3
Attempts were made to open the epoxide ring in 4-6. Lactones containing an epoxide are known to convert usually
into diols under acid-catalysis conditions [11]. However, we showed that 4 formed alcohol 7 as the main product under various
acidic conditions (boiling in aqueous oxalic acid; stirring at room temperature in aqueous acetone with trifluoroacetic, sulfuric,
or perchloric acids). The ester (formate) of this alcohol was prepared by treating 4 with formic acid in acetone [12]. This
reaction is an example of the transformation of the eudesmane lactone skeleton into that of eremophilane.
The best yield (~50%) of 7 was obtained after boiling for 5 h in a 3-fold excess of oxalic acid. Work up of the reaction
mixture isolated 7 as large transparent crystals (from benzene with hexane). Column chromatography over Silpearl (benzene
eluent) detected a side product of this reaction (13% yield), conjugated diene lactone 8. The formation of 7 and 8 can be
explained by the following sequence of transformations (Scheme 1).
+
+
O
O
-H
~Me
O
O
OH
OH
+
O
H
B
7
O
4
+
OH
O
+
O
+
O
~H
-H
H
A
O
O
O
+
-H O
2
OH
OH
C
8
D
Scheme 1
401

TABLE 1. Chemical Shifts (δ, ppm) and Spin—Spin Coupling Constants (J/Hz) of Protons in PMR Spectra of Alantolactone
Derivatives (in CDCl3)
Signal of proton on C atoms
Compound
C-1
C-2
C-3
C-4
C-6
C-7
C-8
C-9
C-13
C-14
C-15
1
2
1.3-1.7
(6H)
2.43 m 5.12 d,
J = 4.1
3.56 m,
J1 = 1.8,
J2 = 3.3,
J3 = 4.1,
J4 = 10.9
4.79 m,
J1 = J2 =3.3,
J3 = 7.0
2.09 dd,
J1 = 3.3,
J2 = 14.9; 5.59 d,
1.52 dd,
J1 = 3.3,
J2 = 14.9
2.15 dd,
6.18 d, 1.17 s, 1.07 d,
J = 1.9; (3H)
J = 7.5
(3H)
J = 1.8
1.96-2.29 1.4-1.6 1.34-1.81
(2H) (2H) (2H)
-
-
1.68 ddd,
J1 = 2.7,
J2 = 7.0,
J3 = 14.1; J3 = 11.9
1.42 d
2.94 m,
J1 = 5.1,
J2 = 7.0,
4.46 dt,
J1 = J2 = 1.8, J1 = 1.4,
J3 = 4.9
6.08 d, 0.78 s
J = 0.8; (3H)
4.73 d,
J = 1.4;
4.39 d,
J = 1.2
J2 = 15.5; 5.56 d,
1.45 d,
J = 15.5
J = 0.7
J = 12.0
3
4
1.42 dd, 1.51-1.64 1.81-2.00
2.75 dd,
J1 = 7.6,
J2 = 13.5;
1.81-2.00
2.89 d,
3.01 m
4.45 dt,
1.69 d,
6.19 d, 1.03 s
1.60 s
(3H)
J1 = 4.3,
J2 = 7.2
(2H)
(2H)
(2H)
J1 = J2 = 7.24, J = 6.5 (2H) J = 2.7; (3H)
J3 = 6.5
5.57 d,
J = 2.4
1.3-2.0
(7H)
3.66 ddd,
4.66 ddd,
1.91 dd,
J1 = 4.3,
6.40 d, 1.10 s
1.03 d,
J = 2.54 J1 = J2 = 2.54, J1 = 1.4,
J = 2.8; (3H) J=7.63 (3H)
J3 = 8.8
J2 = 4.3,
J3 = 8.8
J2 = 15.2; 5.76 d,
1.55 dd,
J1 = 1.4,
J2 = 15.2
2.12 dd,
J1 = 1.5,
J = 2.54
5
0.8-1.9
(6H)
-
0.9 m;
2.86 m,
1.53 m J1 = J2 = 5.3,
J3 = 10.2
4.43 dt,
J1 = 1.5,
6.05 d, 0.92 s 2.63 dd,
J = 1.0; (3H) J1 = 1.96,
J2 = J3 = 4.8 J2 = 15.5; 5.50 d,
J2 = 4.4;
2.50 d,
J = 4.4
1.48 dd,
J1 = 4.8,
J2 = 15.5
1.1-1.9
(2H)
J= 0.8
6a
6b
1.1-1.9
(6H)
-
-
1.1-1.9
(2H)
3.22 m
3.22 m
6.29 d, 1.03 s
J = 2.9; (3H)
5.58 d,
1.35 s
(3H)
J = 2.5
1.1-1.9
(6H)
1.6 dd,
J1 = 7.4,
J2 = 14.5; J2 = 7.4,
1.8 dd,
J1 = 12.0,
J2 = 14.5
3.19 m
J1 = 5.2,
4.54 ddd,
J1 = 2.0,
J2 = 4.7,
J3 = 5.2
2.05 dd,
J1 = 2.0,
J2 = 15.5;
1.74 dd,
J1 = 4.7,
J2 = 15.5
2.62 dd,
6.11 d, 1.16 s
J = 1.2; (3H)
5.55 d,
1.27 s
(3H)
J3 = 12.0
3.24 m
J = 1.1
7
8
5.62 m
1.8-2.1
(2H)
1.3-1.5 1.8-2.1 3.98 d,
4.68 dt,
J1 = 7.2,
J2 = 8.0,
J3 = 9.6
6.32 d, 0.98 d,
J1 = 7.2, J = 3.13; J = 6.8
0.95 s
(3H)
(2H)
J = 5.67
J2 =14.1;
2.24 m,
J1 = 9.6,
J2 = 14.1
2.22 dd,
J1 = 2.3,
5.68 d, (3H)
J = 2.8
2.06
(2H)
1.37 m; 5.61 m
2.06
-
5.31 d,
J = 4.2
3.74 m
4.86 m
6.23 d, 1.01 s
J = 1.8; (3H)
1.75 s
(3H)
J2 = 15.3; 5.67 d,
1.58 dd,
J = 15.3
J = 1.4
402

TABLE 1. (continued)
Signal of proton on C atoms
Compound
C-1
C-2
C-3
C-4
-
C-6
C-7
C-8
C-9
C-13
C-14
C-15
9
1.24-1.42 1.24-1.42; 2.47 dt,
2.94 dd,
J1 = 11.2,
J2 = 12.5;
2.33 dd,
J1 = 4.7,
J2 = 11.2
1.70 m
3.25 m
4.7 dt,
J1 = 6.8,
J2 = J3 = 8.8
2.01 m
(2H)
6.31 d,
J = 2.9;
5.65 d,
J = 2.7
1.00 s
(3H)
1.14 s
(3H)
(2H)
1.50-1.72 J1 = J2 = 7.0,
J3 = 13.0;
1.50-1.72
10a
1.1-1.9
(6H)
-
3.24 m,
4.51 dt,
2.00 dd, 6.09 d,
1.09 s
(3H)
1.21 s
(3H)
J1 = 9.0, J1 = 6.0, J1 = J2 = 5.1, J1 = 5.1, J = 1.2;
J2 = 15.0; J2 = 9.0, J3 = 6.0 J2 = 15.5; 5.52 d,
1.85 m J3 = 11.0 1.68 m J = 1.0
__________
aMethoxy proton signals observed at 3.07 ppm (s, 3H).
It can be assumed that protonation of 4 opens the oxirane ring to form cation A, which can rearrange by two pathways.
In the first, the methyl migratesfrom the10-position tothe 5-position bythe known Wagner—Meerwein rearrangement. Cation
B is stabilized byloss of a proton from the 1-position and forms a double bond between C-1 and C-10 (7). Loss of a proton from
the 9-position does not occur apparently because of the presence of the C-8 oxygen and the increased CH acidity of the 9-CH
2
group due to this. The structure of 7 was established using NMR spectra.
The PMR spectrum exhibited signals for the exomethylene of the lactone ring (doublets at 6.32 and 5.68 ppm), the
olefinic proton (multiplet at 5.62 ppm), lactone protons H-8 (doublet of triplets at 4.68 ppm), and H-7 (multiplet at 3.24 ppm).
The SSCC of these protons corresponded with cis-fusion of the lactone ring. A doublet at 3.98 ppm was assigned to proton H-6,
13
which is conjugated to the hydroxyl. The C NMR spectrum contained signals for C atoms of the double bond C-1
(127.70 ppm) and C-10 (quaternary signal at 136.28 ppm), C-6 with the hydroxyl (73.79 ppm), and methyls shifted to weak
field owing to the effect of the OH oxygen. The structure of 7 was confirmed by an XCS (performed by V. A. Tofienko at the
Chemistry Department of Moscow State University, to be reported separately).
A hydride ion can also migrate from C-4 in cation A to give cation C (Scheme 1). Deprotonation of cation C forms
intermediate alcohol D (identified in the reaction mixture using PMR spectroscopy) that then dehydrates to conjugated
diene 8.
Diene 8 is more conveniently prepared in preparative amounts from another epoxy derivative. It is the main product
(56% yield) from opening of the epoxide ring in 6 under analogous conditions. Apparently the epoxide is hydrolyzed and a
double dehydration of the resulting diol occurs during the transformation. Like for 4, the reaction is not selective. Epoxide 6
isomerized in parallel to ketone 9 (24% yield). The formation of 9 is explained by migration of methyl into the 5-position from
intermediate carbonium ion E with loss of a proton from the protonated O atom of the carbonyl (Scheme 2).
+
O
O
H
O
O
-2H O
2
OH
OH
+
O
H
8
O
6
+
O
H
+
O
O
O
-H
~Me
O
O
O
+
+
+
H
MeOH
O
OH
O
HO
9
E
HO
O
OH
10
Scheme 2
403

TABLE 2. 13C NMR Spectra (δ, ppm) of Alantolactone Derivatives (in CDCl3)
C atom
Compound
C-1
C-2
C-3
C-4
C-5
C-6
C-7
C-8
C-9
C-10 C-11 C-12 C-13 C-14 C-15
1
2
41.15 16.23 32.14 37.01 139.28 118.19 38.92 75.88 42.05 32.04 148.58 169.99 121.14 28.05 22.05
41.57 22.14 36.24 148.34 45.55 26.91 39.91 76.22 40.75 33.68 141.56 170.05 119.49 17.11 106.02
42.29 18.35 31.63 126.52 130.56 27.61 40.93 75.94 36.77 33.28 139.69 170.20 121.03 19.06 26.60
38.78 15.71 28.78 36.30 66.77 60.43 36.63 74.43 36.93 31.81 135.93 168.94 123.09 23.23 17.34
41.26 19.84 34.75 57.99 43.63 22.58 39.87 75.96 40.84 33.75 141.28 170.01 120.15 18.04 50.23
33.99 15.23 37.81 69.44 65.26 26.75 38.25 76.18 28.65 31.66 142.63 172.63 121.97 22.78 20.90
31.87 16.30 43.44 66.41 63.84 29.86 37.41 74.65 34.81 31.59 140.44 171.50 125.27 22.99 19.86
127.70 25.38 27.15 32.25 42.60 73.79 46.16 75.68 36.10 136.28 134.78 172.55 123.40 19.28 17.20
39.70 36.93 126.93 140.77 142.72 119.77 39.49 76.18 22.04 30.54 130.21 172.78 122.93 36.23 22.04
37.86 31.77 38.72 212.80 61.57 34.72 38.17 76.57 19.51 44.05 140.82 171.31 125.24 25.72 18.47
35.88 16.63 29.81 75.16 78.41 28.75 36.97 76.32 39.22 34.89 143.06 171.24 121.09 18.47 24.12
3
4
5
6a
6b
7
8
9
10a
______
*Methoxy signals appeared at 48.91 ppm.
TABLE 3. Mass and IR Spectral Data of Alantolactone Derivatives 6-10
Compound
Diagnostic ion, m/z (Irel, %)
248 (M+, 17), 233 (7), 230 (8), 217 (3), 215 (7), 205 (38), 190 (65), 178 (100), 163 (20), 145 (34), 1758, 1232, 1127,
137 (45), 119 (33), 109 (51), 95 (56), 78 (77), 71 (45), 55 (49), 43 (27) 1028, 990
248 (M+, 10), 233 (4), 230 (8), 217 (3), 215 (7), 205 (35), 190 (47), 178 (100), 163 (24), 145 (37), 1758, 1261, 1138,
137 (40), 119 (34), 109 (52), 95 (51), 78 (100), 71 (44), 55 (78), 43 (30) 1000, 937
248 (M+, 14), 230 (100), 219 (14), 215 (48), 201 (47), 188 (28), 173 (20), 163 (22), 152 (21), 145 3453, 1753, 1293,
(41), 134 (44), 123 (70), 107 (77), 91 (69), 80 (54), 69 (77), 55 (63), 34 (27) 1106, 1000, 973
230 (M+, 54), 215 (11), 197 (12), 187 (6), 169 (23), 143 (25), 128 (27), 121 (100), 105 (33), 91 1720, 1640, 1267, 1147,
(48), 76 (28), 65 (24), 55 (29), 43 (28) 1120, 1000, 960, 894
248 (M+, 6), 233 (3), 230 (16), 207 (54), 179 (11), 139 (16), 121 (23), 111 (24), 95 (100), 80 (57), 1753, 1691, 1278,
55 (51), 43 (34) 1152, 998, 944
280 (M+, 20), 265 (23), 248 (64), 237 (27), 230 (15), 205 (17), 187 (15), 180 (47), 161 (24), 133 3545, 1748, 1266,
(18), 125 (64), 98 (79), 84 (100), 72 (84), 59 (78), 55 (72), 43 (28) 1165, 1081, 968
IR spectrum (ν, cm-1)
6a
6b
7
8
9
10
Compound8wasassignedthestructure5,8a-dimethyl-3-methylene-3a,7,8,8a,9,9a-hexahydro-3 -naphtho[2,3- ]furan-
H
b
2-one based on NMR spectra. The PMR spectrum contained signals for protons of the lactone exomethylene (doublets at 6.23
and 5.67 ppm), olefinic H-3 protons (multiplet at 5.61 ppm), and H-6 (doublet at 5.31 ppm) in addition to a signal for the C-15
13
methyl protons shifted to weak field at 1.75 ppm. The C NMR spectrum confirmed the proposed structure (Table 2). Signals
were observed for C atoms of the double bonds C-3 (126.93 ppm) and C-4 (140.77 ppm, quaternary) and C-5 (142.72 ppm,
quaternary) and C-6 (119.77 ppm). The CS of C-5 and C-6 were close to those for 1 (Table 2).
Thestructure4a,8a-dimethyl-3-methylenedecahydronaphtho[2,3- ]furan-2,5-dionewasproposedfor9based on spectral
b
data. Thus, the PMR of 9 contained signals for protons of the lactone exomethylene (doublets at 6.31 and 5.65 ppm) and one
13
of the H-3 protons (doublet of triplets at 2.47 ppm). The presence of the carbonyl was confirmed by a signal in the C NMR
spectrum for quaternary C-4 at 212.80 ppm.
Epoxyisoalantolactone 5 formed immediatelya complicated mixture ofcompounds in thepresenceofacids(even under
mild conditions). Derivatives with an aldehyde (according to PMR spectra) and polymers dominated the products.
We demonstrated the capabilityfor acid-catalyzed nucleophilic opening ofthe oxirane ring byaliphatic alcohols (using
CH OH as an example) using the mixture of 6a and 6b as an example. The structure of the product 10 was established using
3
404

NMR spectroscopy. Thus, the PMR spectrum contained signals for the exomethylene protons as doublets at 6.09 and 5.52 ppm
13
and a well resolved signal for the methoxy as a singlet at 3.07 ppm. The C NMR spectrum exhibited signals for C atoms
conjugated to O for quaternary C-4 (75.16 ppm) and C-5 (78.41 ppm) that were shifted to weak field compared with 6, for
methoxy (48.91 ppm), and for methyls on C-14 (18.47 ppm) and C-15 (24.12 ppm).
Thus, acid-catalyzed transformations of 1-3 and their epoxide derivatives 4-6 occur with retention of the lactone ring.
The products contain an exomethylene conjugated to the lactone carbonyl and make it possible to prepared from these
compounds a large set of lactones substituted with various functionalities that possess higher biological activity, are water
soluble, and can be transported.
EXPERIMENTAL
NMR spectra were recorded on a Bruker DPX-200 spectrometer at working frequency 200 MHz (data given in Tables
1 and 2). Mass spectra were recorded in a Finnigan 4021 GC—MS at 70 eV ionization energy. IR spectra (KBr disks) were
obtained on a Bruker ZFS-113v instrument (Table 3).
The course of reactions and purity of products were monitored using TLC on Silufol plates using benzene:ethylacetate
(3:2) and GC (Chrom-5 chromatograph, 3.6 m × 3 mm column packed with Inerton Super 0.125-0.160 mm with 5% XE-60,
flame-ionization detector, detector and vaporizer temperature 250°C, thermostat 75°C). Elemental analyses of all initially
prepared compounds agreed with those calculated.
Alloalantolactone (5,8a-dimethyl-3-methylene-3a,4,6,7,8,8a,9,9a-octahydro-3H-naphtho[2,3-b]furan-2-one, 3).
A solution of 1 (1.16 g, 5 mmol) in CHCl (20 mL) was stirred, treated with trifluoroacetic acid (4.5 mL), and left at room
3
temperature. After the starting lactone disappeared (course of reaction monitored using PMR spectroscopy), the mixture was
poured into water, neutralized with saturated Na CO solution, and extracted with CHCl (3 × 20 mL). The extracts were
2
3
3
washed and dried. Solvent was evaporated. The solid was passed over a layer of SiO (benzene eluent) to afford a colorless
2
oil (0.94 g, 81%).
Epoxyalloalantolactones 6a and 6b were prepared by cooling (ice) a solution of peracetic acid (acetic anhydride,
5 mL; H O , 1.1 mL, 30%; H SO , one drop) and adding solid sodium acetate until the pH was ~5-6 and a solution of
2
2
2
4
alloalantolactone (3, 2.32 g, 10 mmol) in CH Cl (5 mL). The mixture was left at room temperature. The formation of products
2
2
was monitored using TLC. After the starting lactone disappeared (1-2 d), the mixture was poured into water, neutralized with
NaHCO solution, and extracted with CHCl (3 × 10 mL). Solvent was evaporated. The solid was passed over a column of
3
3
neutral Al O in benzene to remove traces of acetic anhydride and afforded 6a and 6b (2.1 g, 85%). Repeated crystallization
2
3
from CH OH (PMR monitoring) isolated pure 6a (mp 103-104°C) and 6b (mp 136-139°C).
3
4-Hydroxy-4a,5-dimethyl-3-methylene-3a,4,4a,5,6,7,9,9a-octahydro-3H-naphtho[2,3-b]furan-2-one (7)and5,8a-
dimethyl-3-methylene-3a,7,8,8a,9,9a-hexahydro-3H-naphtho[2,3-b]furan-2-one (8). Epoxyalantolactone (4, 2.48 g,
10 mmol) in aqueous oxalic acid (5 g in 50 mL water) was boiled for 5 h, cooled, neutralized with NaHCO solution (5%), and
3
extracted with CHCl (3 × 30 mL). Solvent was evaporated to afford a yellowoil, crystallization of which from benzene:hexane
3
(3:1) afforded 7 (1.2 g, 48%). The mother liquor was evaporated and passed over a column of SiO (Silpearl) with elution by
2
benzene to afford 8 (0.3 g, 13%), mp 93-95°C (hexane). Addition to the eluent of ethylacetate (5%) isolated 7 (0.28 g), mp 101-
102°C. Overall yield of 7, 61%.
4a,8a-Dimethyl-3-methylenedecahydronaphtho[2,3-b]furan-2,5-dione (9). A mixture of 6a and 6b (2.48 g,
10 mmol) in aqueous oxalic acid (4 g in 50 mL water) was boiled for 3 h, neutralized with NaHCO (6 g in 100 mL water), and
3
extracted with CHCl (3 × 30 mL). The solid left after evaporation of solvent was passed over a column of SiO (Silpearl) with
3
2
elution by benzene to isolate two compounds 8 (1.3 g, 56%) and 9 (0.6 g, 24%), mp 170-171°C (CH OH).
3
4a-Hydroxy-5-methoxy-5,8a-dimethyl-3-methylenedecahydronaphtho[2,3-b]furan-2-one (10).
Epoxyalloalantolactones 6a and 6b (1.24 g, 5 mmol) in CH OH (100 mL) were treated with KU-2 ion-exchanger in the H-form
3
(1 g) and stirred at room temperature until the starting material disappeared. The resin was filtered off. CH OH was
3
evaporated. The solid was passed over a column of SiO (Silpearl) with elution by benzene. A fraction with R 0.5 was
f
2
collected. Recrystallization from benzene:hexane afforded 10 (0.7 g, 51%), mp 115-116°C.
405

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