Synthesis of decaline analogues of isovelleral

Article abstract of DOI:10.1515/znb-2005-0913

Decaline analogues of the bioactive fungal sesquiterpene (+)-isovelleral (1a), retaining the bicyclo[4,1,0]hept-2-en-1,2-dicarbaldehyde system, were prepared, and their cytotoxic and antimicrobial activities were compared with those of the natural product. While the two isomers (±)-2 and (±)-3 were as active as isovelleral (1a), the isomer (±)-4 was approximately 10 times less potent.

Full text of DOI:10.1515/znb-2005-0913

Synthesis of Decaline Analogues of Isovelleral
a
a
a
b
a
M. Johansson , I. Aujard , D. R o¨ me , H. Anke , and O. Sterner
a
Department of Organic Chemistry, Lund University, P. O. Box 124, S-221 00 Lund, Sweden
IBWF, Erwin-Schr o¨ dinger-Straße 56, D-67663 Kaiserslautern, Germany
b
Reprint requests to Prof. O. Sterner. E-mail: Olov.Sterner@organic.lu.se
Z. Naturforsch. 60b, 984 – 989 (2005); received May 19, 2005
Decaline analogues of the bioactive fungal sesquiterpene (+)-isovelleral (1a), retaining the
bicyclo[4,1,0]hept-2-en-1,2-dicarbaldehyde system, were prepared, and their cytotoxic and antimi-
crobial activities were compared with those of the natural product. While the two isomers (± )-2 and
(± )-3 were as active as isovelleral (1a), the isomer (± )-4 was approximately 10 times less potent.
Key words: Bioactive Sesquiterpenoids, Unsaturated 1,4-Dialdehydes, Isovelleral
Introduction
Isovelleral (1a), an extremely pungent sesquiterpene
isolated from the fruit bodies of Lactarius vellereus,
possesses several potent biological activities [1]. It is
formed enzymatically from an inactive precursor in
seconds as a response to injury to the fruit body, appar-
ently to protect it from parasites [2]. The unsaturated
1
,4-dialdehyde moiety, which also is present in a num-
ber of other terpenoids claimed to be part of natural de-
fence systems, is thought to be responsible for the bio-
logical activities of 1a [3]. However, the cyclopropane
ring of 1a may also be involved in the biological ac-
tivity. When 1a was allowed to react with a primary
amine in ethanol the dialdehyde was transformed to a
pyrrol ring and the cyclopropane was opened by the
solvent as it is slightly activated towards nucleophilic
attack [4]. When the activities of the two previously
prepared bicyclic analogues 5 and 6 were compared,
Fig. 1. Analogues of isovelleral.
cal activity. It has been shown for other terpenoid un-
saturated dialdehydes that the dihedral angle between
the two aldehyde groups in the unsaturated dialde-
hyde moiety is correlated with the antimicrobial activ-
ity [6]. The cyclopentane ring of 1a would certainly
affect the positioning of the aldehyde groups in space
by altering the conformation of the six-membered ring,
however, it is not evident that the best effect is ac-
complished with a cyclopentane ring. The purpose
of this study was therefore to prepare and assay de-
calin analogues of isovelleral (e. g. 2), with a cyclohex-
ane ring instead of a cyclopentane and lacking methyl
groups.
5
, with the methyl group attached to the cyclopropane
ring, was approximately 10 times less potent than 6,
lacking this methyl [4]. The structures are shown in
Fig. 1.
This would be expected if a nucleophilic attack on
the methylated cyclopropane carbon (C3) is part of the
molecular mechanism by which isovelleral (1a) ex-
erts its activity. The isovelleral analogue lacking the
methyl groups, tridemethylisovelleral (1b) was conse-
quently prepared and found to be approximately 10
times as cytotoxic towards common tumour cell lines
Results and Discussion
The decalin analogues 2, 3, and 4 were syn-
as isovelleral itself [5]. In addition, as 1a is consid- thesized according to the procedure described in
erably more potent that 5, the cyclopentane ring of Scheme 1, starting from commercially available hy-
isovelleral also appears to contribute to the biologi- droxytetralin 7.
0
932–0776 / 05 / 0900–0984 $ 06.00 ꢀc 2005 Verlag der Zeitschrift f u¨ r Naturforschung, T u¨ bingen · http://znaturforsch.com
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M. Johansson et al. · Synthesis of Decaline Analogues of Isovelleral
985
◦
◦
Scheme 1. Reaction conditions: (a) i) MeI, K CO , DMF, 55 C; ii) Li, NH , EtOH, THF, −78 C; iii) 10% HCl, MeOH,
2
3
3
◦
6
6% (3 steps); (b) DIPA, n-BuLi, MeO CCN, THF, −78 C, 69%; (c) HCO NH , 10% Pd/C, MeOH, reflux; (d) i) PhSeCl,
2
2
4
◦
pyridine, 30% H O , CH Cl ; ii) Me SOCH , THF, 20 C, 54%; (e) DIPA, n-BuLi, PhNTf , THF, 77%; (f) Pd(OAc) , PPh ,
2
2
2
2
2
2
2
2
3
◦
◦
CO, MeOH, Et N, DMF, 20 C, 90%; (g) DIBAL-H, THF, 75%; (h) oxalyl chloride, DMSO, Et N, CH Cl , −78 C, 78%.
3
3
2
2
Fig. 2. Lowest energy con-
formers of the two epimers
of 9.
Birch reduction of the methyl ether and acidic hy- compound was to some degree transformed to the ther-
drolysis afforded the bicyclic enone 8 [7, 8], which was modynamically more stable trans compound (∆E =
∗
transformed into an epimeric mixture of the ester 9 6 kJ/mol) . However, this was not considered a prob-
after treatment with LDA followed by reaction with lem as we desired several stereoisomers of the final
methylcyanoformate [9]. Hydrogenation of 9 resulted products for determining structure-activity relations.
in a cis/trans mixture of the saturated β-keto ester from By not isolating the α,β-unsaturated β-keto ester, but
which the major cis isomers (10) could be obtained instead treating it immediately with the cyclopropa-
in 48% yield after chromatography on silica gel. The nation reagent [12], the epimerisation gave approxi-
lack of selectivity, which is in contrast to the hydro- mately a 1:1 mixture of cis and trans decalines, and
genation of indanes, can be explained by the reversed while the cyclopropanation of the cis compound was
facial discrimination of the two epimers, and the low- stereoselective, as expected, adding from the least hin-
est energy conformers of both epimers are shown in
Fig. 2.
∗
The lowest energy conformer of each compound was deter-
mined by a conformational search. Calculations were performed us-
The oxidation of 10 to the α,β-unsaturated β-keto
ester with PhSeCl and hydrogen peroxide, preceding
the cyclopropanation, also generated isomeric mix-
tures [10, 11], as the allyllic bridgehead proton was
prone to epimerisation and the initially desired cis
ing MacroModel v8.6 (Force field: MMFFs; Solvent: Octanol (us-
ing the analytical Gereralized Born/Surface-Area (GB/SA) model);
Minimization method: TNCG; Conformational search: MonteCarlo
(MCMM); Steps: 2000). The energy was then determined by equi-
librium geometry ab initio calculation (6-31G**) using MacSpartan-
Pro.
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9
86
M. Johansson et al. · Synthesis of Decaline Analogues of Isovelleral
Table 1. Dihedral angles and distances of relevant conform- those already reported for isovelleral (1a) [4], while
a,b
ers of 1a – 4
.
compound 4 was significantly less potent. The reason
for this difference is not clear, but it has been shown
that the dihedral angle between the aldehyde groups
is important for the antimicrobial activity of other ter-
penoid unsaturated 1,4-dialdehydes [6]. The dihedral
angles of the most stable conformers of compounds
Compound (conformer)
∆Ec
0
4.21
0
11.68
0
15.49
0
Dihedral angled
29.2
1
1
2
2
a(1)
a(2)
34.2
54.5
30.7
30.8
31.9
56.3
53.9
(1)
(2)
(1)
(2)
(1)
(2)
3
3
4
4
1a – 4 were calculated with MacroModel, and the re-
sults are shown in Table 1. Isovelleral (1a) has several
low energy conformers below 12 kJ/mol, compound 2
has two while compounds 3 and 4 have only one (ex-
23.93
a
Calculations were performed using MacroModel v8.6 (Force
field: MMFFs; Solvent: Water (using the analytical Gereralized
Born/Surface-Area (GB/SA) model); Minimization method: TNCG; cluding rotamers). The more active compounds 1a – 3
b
Conformational search: MonteCarlo (MCMM); Steps: 2000); the
all have at least one low energy conformer in which the
two lowest conformers, no rotamers, were taken into consideration;
dihedral angle between the two aldehyde groups is ap-
proximately 30 , while this angle is almost doubled in
c
d
energy is given in kJ/mol;
carbonyl carbons.
the dihedral angle between the two
◦
the less active compound (4).
dered side, the cyclopropanation of the trans com-
pound gave a 1:1 mixture of cyclopropane stereoiso-
mers. This resulted in a 2:1:1 mixture of cyclopropanes
Conclusion
Decaline analogues of the fungal sesquiterpene
isovelleral (1a) were synthesised and shown to be cy-
totoxic and antimicrobial agents, two of them as po-
tent as isovelleral itself. However, the removal of the
methyl group adjacent to the cyclopropane did not re-
sult in a 10-fold increase in the activity, as observed for
(
as determined by NMR), and the remaining steps were
carried out without separating the isomers. Introduc-
tion of the second ester group [13] and the oxida-
tion/reduction sequence to transform the ester groups
to aldehyde groups [14, 15] followed essentially a pre-
viously described procedure developed for the total
synthesis of (± )-isovelleral (1a) [16], affording a mix-
ture of the three decalin-type dialdehydes 2, 3 and 4 as
racemates. Final purification with HPLC gave the pure
compounds for characterisation and biological assays.
The structure and relative stereochemistry of each di-
aldehyde was determined by NMR spectroscopy.
6
compared to 5 and 1b compared to 1a. Obviously, the
six-six-three fused system of the compounds investi-
gated here is less suitable for isovelleraloids with high
activity, compared to the natural five-six-three fused
variant.
Experimental Section
The cytotoxic and antimicrobial activity of the new
dialdehydes 2, 3 and 4 were compared with those of
Materials were obtained from commercial suppli-
1
a. Previously, it has been shown that the antimicro- ers and were used without further purification un-
bial and cytotoxic activities of the two enantiomers of less otherwise noted. THF was dried by refluxing over
isovelleral (1) are comparable [17], and it is reasonable sodium/benzophenone ketyl immediately prior to use.
to compare the potency of the racemic compounds 2, CH2Cl2 and triethylamine were distilled from calcium hy-
dride prior to use. DMF and DMSO were distilled under
3
and 4 with the natural product (+)-isovelleral (1a).
˚
reduced pressure and kept over 4 A MS. MeOH was dried
The in vitro cytotoxicity towards the two cell lines
L1210 (lymphocytic leukaemia mouse) and Colo 320
by distilling from magnesium/iodine. All moisture and air-
sensitive reactions were carried out under an atmosphere
of dry nitrogen using oven-dried glassware. ESIMS spec-
(human colon adenocarcinoma) showed that the cis
isomer 2 and the trans isomer 3 are as potent as the
natural product (IC -values 0.1 µg/ml towards L1210
and 1 µg/ml towards Colo 320), while the trans iso-
mer 5 was 10 times less potent. The antimicrobial ac-
tivity towards the bacteria Bacillus subtilis, B. brevis,
Micrococcus luteus and Enterobacter dissolvens, and
the fungi Mucor miehi, Paecilomyces varioti, Penicil-
tra (H PO for calibration and as internal standard) were
3
4
5
0
recorded with a Micromass Q-Tof Micro spectrometer, while
EIMS (direct inlet, 70 eV) and CI spectra (direct inlet,
methane) were recorded with a JEOL SX102 spectrome-
ter. The NMR spectra (in CDCl ) were recorded with a
3
1
Bruker DRX 400 spectrometer at 400 MHz ( H) and at
00 MHz ( C) and with a Bruker DRX 500 spectrome-
1
3
1
1
13
lium notatum and Nematospora coryli was compara- ter at 500 MHz ( H) and at 125 MHz ( C), in CDCl or
3
ble for compounds 1a, 2 and 3, and in agreement with
C D . Chemical shifts are given in ppm relative to TMS us-
6 6
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M. Johansson et al. · Synthesis of Decaline Analogues of Isovelleral
987
ing the residual CHCl peak in CDCl solution as internal δ = 25.90, 27.30, 29.53, 34.80, 35.90, 36.87, 38.23, 124.61,
3
3
+
standard (7.26 and 77.00 ppm, respectively relative to TMS) 167.74, 200.36. – MS (EI, 70 eV): m/z (%) = 150 (61) [M] ,
or using the residual C HD peak in C D solution (7.16 122 (100), 79 (34), 77 (13). – HRMS (EI): C H O calcd.
6
5
6
6
10 14
+
and 128.06 ppm, respectively). Organic extracts were dried 150.1045 [M] , found 150.1047.
over MgSO . All flash chromatography was performed on
4
3-Oxo-1,2,3,5,6,7,8,8a-octahydronaphthalene-2-carb-
oxylic acid methyl ester (9). To a solution of 10.8 ml
(76.2 mmol) of diisopropylamine in 55 ml of THF, cooled
˚
6
0 A 35 – 70 µm Matrex silica gel (Grace Amicon). TLC
analyses were made on Silica Gel 60 F254 (Merck) plates
and visualised with anisaldehyde/sulphuric acid and heating.
HPLC separations were performed using a Dynamax SD-
◦
to −78 C, was added drop wise 7.8 ml (73.1 mmol, 9.4 M
in hexanes) of n-BuLi. After 20 min a solution of 9.30 g
2
1
00 solvent delivery pump system with a Varian Microsorb
00 Si (particle size, 5 µm) column and a Dynamax UV-1
(
61.9 mmol) of the enone 8 in 40 ml of THF was added
◦
slowly. The solution was warmed to 0 C after 20 min
and stirred for 1 h at 0 C. The solution was cooled to
detector (254 nm) with hexane/isopropanol 99:1 to 90:10
gradient with a flow of 4 ml/min. The biological assays
for antimicrobial and cytotoxic activities were carried out
as described previously [3, 18, 19]. Calculations were per-
formed using MacroModel v8.6 (Force field: MMFFs; Sol-
vent: Water (using the analytical Gereralized Born/Surface-
Area (GB/SA) model); Minimization method: TNCG; Con-
formational search: MonteCarlo (MCMM); Steps: 2000).
◦
◦
−
78 C and 7.95 ml (103.4 mmol) methylcyanoformate
was added quickly. The solution was allowed to warm to
room temperature and stirred for 40 min. 100 ml brine
and 100 ml of ether were added and the layers separated.
The water layer was extracted with 100 ml ether and the
combined ether layers were washed with 250 ml brine,
dried and concentrated. The oil was purified with flash
4
,4a,5,6,7,8-Hexahydronaphthalen-2(3H)-one (8). To a chromatography (H/E 10:1) to give 8.90 g (42.7 mmol, 69%)
1
solution of 20.1 g (0.14 mol) of 5,6,7,8-tetrahydro-naphtol of a 3:1 epimeric mixture of the ester 9: H NMR (400 MHz,
(
7) in 140 ml DMF was added 12.7 ml (0.20 mol) of CDCl , major isomer): δ = 1.20 (m, 1H), 1.44 (m, 2H), 1.91
3
methyliodide and 29.9 g (0.22 mol) of anhydrous K CO . (m, 3H), 2.20 (m, 2H), 2.43 (m, 2H), 3.37 (m, 1H), 3.76
2
3
◦
13
1
The solution was stirred at 55 C for 22 h. 200 ml water and (s, 3H), 5.84 (s, 1H). – C{ H} NMR (100 MHz, CDCl ,
3
1
60 ml ether were added and the phases were separated and major isomer): δ = 25.73, 26.91, 32.50, 34.91, 35.51, 37.62,
the aqueous phases extracted with two portions (200 ml) of 52.57, 53.49, 167.78, 171.46, 194.50. – MS (EI, 70 eV): m/z
ether. The combined organic layers were washed with 200 ml (%) = 208 (55) [M] , 177 (18), 148 (42), 122 (100), 94 (26),
5
+
+
% NaOH and 200 ml brine, dried and concentrated to give 91 (23). – HRMS (EI): C12H O calcd. 208.1099 [M] ,
16
3
1
8.8 g as a pale brown oil.
found 208.1102.
The crude product was dissolved in 600 ml liquid ammo-
3
-Oxodecahydronaphthalene-2-carboxylic acid methyl
◦
nia with 100 ml of THF and 100 ml of EtOH at −78 C under
nitrogen. 3.46 g (0.50 mol) of lithium was carefully added in
small pieces to the solution that turned dark blue upon addi-
tion. After 1 h the dark blue colour had disappeared and the
ammonia was allowed to evaporate over night. 400 ml water
was added to the remainder and extracted with three 400 ml
portions of ether. The combined ether layers were washed
with 400 ml 5% aqueous NaOH and 400 ml brine, dried and
concentrated to give 17.0 g as a pale yellow oil.
ester (10). 6.3 g (30.3 mmol) of the methyl ester 9 was
dissolved in 580 ml of MeOH with 315 mg of 10% palla-
dium on carbon. 9.55 g (151.5 mmol) of ammonium formate
was added and the reaction mixture was refluxed under N2
for 30 min and then allowed to cool to room temperature.
The reaction mixture was filtered through a bed of celite
which was washed with MeOH. The solvent was removed
under reduced pressure and the remains were dissolved in
5
00 ml ether and 500 ml water. The layers were separated
1
7.0 g of the pale yellow oil was dissolved in 455 ml and the aqueous layer was extracted with 500 ml of ether. The
MeOH and 137 ml 10% aqueous HCl was carefully added combined organic layers were dried and concentrated. Re-
and the solution was stirred at room temperature for 2 h. crystallisation from heptane gave 3.08 g (14.5 mmol, 44%)
The solution was concentrated and 350 ml water and 350 ml of the trans isomers. The cis isomers were purified with
CH Cl was added. The layers were separated and the wa- flash chromatography to give 2.80 g (13.3 mmol, 40%):
2
2
1
ter layer was extracted with 350 ml CH Cl . The combined
H NMR (400 MHz, CDCl , major cis isomer): δ = 0.94
2
2
3
extracts were washed with saturated aqueous NaHCO and (m, 1H), 0.99 (m, 1H), 1.14 (m, 1H), 1.27 (m, 2H), 1.27
3
brine, dried and concentrated. The crude product was puri- (m, 1H), 1.73 (m, 2H), 1.76 (m, 2H), 1.78 (m, 1H), 2.00
fied by vacuum distillation to give 13.5 g (89.6 mmol, 66% (dd, J = 16.9, 11.2 Hz, 1H), 2.09 (dd, J = 17.0, 5.1 Hz,
◦
from 7) of 8 (75 – 77 C, 0.15 mm Hg) as a colourless oil: 1H), 2.41 (dd, J = 17.0, 5.3 Hz, 1H), 3.68 (s, 3H), 12.1 (s,
1
13
1
H NMR (400 MHz, CDCl ): δ = 1.12 (dq, J = 12.9, 3.6 Hz, 1H). – C{ H} NMR (100 MHz, CDCl , major cis isomer):
3
3
1
(
5
H), 1.25 – 1.45 (m, 2H), 1.48 – 1.59 (m, 1H), 1.70 – 1.91 δ = 26.03, 26.22, 31.62, 33.37, 33.41, 37.50, 38.33, 38.86,
1
m, 3H), 2.00 (dq, J = 13.5, 5.0 Hz, 1H), 2.05 – 2.40 (m, 50.41, 91.59, 156.23, 170.52. H NMR (400 MHz, CDCl ,
3
H), 5.71 (s, 1H). – 13C{ H} NMR (100 MHz, CDCl ): major trans isomer): δ = 0.99 (m, 1H), 1.15 (m, 1H), 1.27
1
3
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9
88
M. Johansson et al. · Synthesis of Decaline Analogues of Isovelleral
(
2
1
m, 3H), 1.76 (m, 3H), 2.02 (ddd, J = 17.0, 11.1, 1.2 Hz, 1H), 221 (52), 189 (100), 161 (48), 145 (22), 91 (38), 79 (22). –
+
.11 (dd, J = 17.0, 5.3 Hz, 1H), 2.42 (dd, J = 15.7, 5.3 Hz, HRMS (EI): C14H F O S calcd. 354.0749 [M] , found
17
3
5
H), 3.68 (s, 3H), 12.1 (s, 1H). – 13C{ H} NMR (100 MHz, 354.0758.
1
CDCl , major trans isomer): δ = 26.56, 26.70, 32.03, 33.88,
3
HRMS (ESI): C12H O calcd. 211.1334 [M+H] , found (0.94 mmol) of 12, 272 µl (1.96 mmol) of triethylamine,
2
1,3a,4,5,6,7,7a,7b-Octahydro-1aH-cyclopropa[a]naph-
3
3.81, 37.94, 38.78, 39.23, 50.99, 91.95, 156.75, 171.07. – thalene-1a,2-dicarboxylic acid dimethyl ester (13). 348 mg
+
19
3
11.1331.
1.59 ml (39.2 mmol) MeOH, 6.6 mg (0.03 mmol) of
palladium acetate and 15.4 mg (0.06 mmol) of triph-
2
-Oxodecahydro-1aH-cyclopropa[a]naphthalene-1a-
carboxylic acid methyl ester (11). 1.60 g (8.32 mmol) of enylphosphine were dissolved in 4 ml of DMF. CO was
PhSeCl was dissolved in 80 ml of CH Cl under N2 and bubbled through the solution and the reaction mixture was
2
2
◦
cooled to 0 C. To the cooled solution was added 732 µl stirred for 2 h under a CO atmosphere at room temperature.
9.07 mmol) of pyridine and after 20 min of stirring 1.55 g The mixture was diluted with 40 ml of ether, washed with
(
(
7.56 mmol) of 10 in 16 ml of CH Cl2 was added drop 40 ml of water and 40 ml brine, dried and concentrated.
2
wise. After 30 min the reaction mixture was extracted with Flash chromatography (H/E 4:1, 1% EtOH) gave 282 mg
+
2
× 40 ml of 10% aqueous HCl and cooled in an ice-bath. (quant) of 13. – MS (EI, 70 eV): m/z (%) = 264 (73) [M] ,
A solution of 30% aqueous H O was added in 515 µl 232 (100), 200 (36), 173 (37), 145 (60), 91 (19), 83 (22). –
2
2
+
portions with 10 min intervals. 10 min after the last H O
HRMS (EI): C15H20O4 calcd. 264.1362 [M] , found
2
2
addition 40 ml of water was added and the phases were 264.1351.
separated. The organic phase was washed with saturated
(2-Hydroxymethyl-1,3a,4,5,6,7,7a,7b-octahydro-1aH-
aqueous NaHCO , dried and concentrated giving 1.71 g of cyclopropa[a]naphthalen-1a-yl)-methanol (14). 100 mg
3
crude product, which was used without further purification (0.38 mmol) of 13 was dissolved in 1 ml of THF under a
◦
in the next step.
nitrogen atmosphere and cooled to −78 C and 3.0 ml (1.0 M
To 100 mg of the crude product was added 800 µl in hexane) of DIBAL-H was added dropwise. The solution
0.04 mmol, 0.5 M in THF) of dimethylsulfoxonium was stirred at room temperature for 30 min and then cooled
(
◦
methylide. The cloudy white-yellowish solution was stirred to 0 C. 510 mg (12.16 mmol) of NaF followed by 3 ml
at room temperature under nitrogen atmosphere for 40 min. of water were added to the cooled solution. The reaction
The solution was diluted with both ether and water and the mixture was diluted with 30 ml of water and extracted twice
phases were separated. The aqueous phase was extracted with 30 ml of ethyl acetate. The combined organic extracts
with ether and the combined etheral phases were washed were dried and concentrated. Flash chromatography (H/E
with brine, dried and concentrated. The crude product was 1:1, 0.1% MeOH) afforded 59 mg (75%) of 14. – MS (EI,
+
purified by flash chromatography (H/E 4:1) to give 43 mg 70 eV): m/z (%) = 208 (18) [M] , 159 (100), 105 (100),
(
0.19 mmol, 43% from 10) of an isomeric mixture of 11. – 91 (100), 79 (62). – HRMS (EI): for C13H20O2 calcd.
MS (EI, 70 eV): m/z (%) = 222 (87) [M] , 190 (64), 208.1463 [M] , found 208.1470.
+
+
1
2
34 (100), 95 (66), 79 (50). – HRMS (EI): C H O calcd.
22.1256 [M] , found 222.1255.
1,3a,4,5,6,7,7a,7b-Octahydro-1aH-cyclopropa[a]naph-
13
18
3
+
thalene-1a-2-dicarbaldehyde (2, 3 and 4). To a solution of
◦
2
-Trifluorometanesulfonyloxy-1,3a,4,5,6,7,7a,7b-octa-
54 µl (0.76 mmol) of DMSO in 1 ml of CH2Cl2 at −78 C
hydro-1aH-cyclopropa[a]naphthalene-1a-carboxylic acid was added 26 µl (0.30 mmol) of oxalyl chloride. The
methyl ester (12). To an ice-cold solution of 237 µl solution was stirred for 15 min when 15.8 mg (0.08 mmol)
(
1.68 mmol) of diisopropylamine in 1.25 ml of THF was of 14 in 1 ml of CH2Cl2 was added. After 30 min stirring
◦
added drop wise 800 µl (1.9 M in cyclohexane) of n-BuLi at −78 C, 254 µl (1.82 mmol) of triethylamine was added.
under a nitrogen atmosphere. After 10 min the solution was The stirring was continued for an additional 30 min before
◦
cooled to −78 C and 308 mg (1.39 mmol) of 11 dissolved in the reaction mixture was allowed to reach room temperature.
0
.63 ml of THF was added drop wise. The reaction mixture After 20 min stirring at room temperature the mixture was
◦
was stirred for 40 min at −78 C when 536 mg (1.50 mmol) diluted with 10 ml of water and 10 ml of ether. The phases
of N-phenyltrifluoromethanesulfonimide in 1.5 ml of THF were separated and the aqueous phase was extracted with
was added. The resulting solution was allowed to reach 10 ml of ether. The combined ether extracts were dried and
room temperature and stirred for 1 h. The reaction mixture concentrated. Flash chromatography (H/E 8:1) afforded
was then diluted with 10 ml saturated aqueous NaHCO3 12 mg (80%) of the isomeric mixture. The isomers were
and extracted with 10 ml of ether. The organic phase was separated on normal phase HPLC in the same system, to
washed with water, brine, dried and concentrated. The crude afford 5 mg of 2, 2.5 mg of 3 and 2.5 mg of 4.
1
product was purified by flash chromatography (H/E 4:1, 1%
2: H NMR (500 MHz, CDCl ): δ = 1.09 (dd, J = 7.2,
3
EtOH) to give 379 mg (1.07 mmol, 77%) of 12. – MS (EI, 4.6 Hz, 1H), 1.24 (m, 1H), 1.34 (m, 1H), 1.59 (m, 3H), 1.67
0 eV): m/z (%) = 354 (35) [M] , 323 (19), 297 (8), 253 (6), (m, 3H), 1.79 (m, 2H), 2.08 (dd, J = 8.9, 4.6 Hz, 1H), 2.11
+
7
Unauthenticated
Download Date | 9/26/18 10:40 PM

M. Johansson et al. · Synthesis of Decaline Analogues of Isovelleral
989
1
(
m, 1H), 2.38 (m, 1H), 6.87 (d, J = 1.9 Hz, 1H), 9.58 (s,
4: H NMR (500 MHz, CDCl ): δ = 0.76 (dd, J = 5.9,
3 1
H), 9.80 (s, 1H). – 13C{ H} NMR (125 MHz, CDCl ): δ = 4.9 Hz, 1H), 1.02 (m, 1H), 1.16 (dt, J = 12.6, 2.9 Hz, 1H),
1
1
2
1
3
0.11, 23.34, 24.87, 26.12, 29.85, 30.12, 30.39, 33.45, 33.81, 1.24 (m, 1H), 1.35 (m, 1H), 1.37 (m, 1H), 1.50 (dt, J = 8.6,
42.04, 153.82, 192.48, 199.40. – HRMS (CI): C H17O2 6.1 Hz, 1H), 1.81, (m, 2H), 1.99 (dd, J = 8.3, 4.4 Hz, 1H),
13
+
[M+H] , calcd. 205.1229, found 205.1223.
2.02 (m, 1H), 2.07 (m, 1H), 2.12 (m, 1H), 6.87 (d, J = 2.2 Hz,
1
3
1
1
1
H), 9.09 (s, 1H), 9.57 (s, 1H). – C{ H} NMR (125 MHz,
3
: H NMR (500 MHz, C D ): δ = 0.53 (dd, J = 7.0,
6
6
CDCl ): δ = 26.03, 26.16, 27.62, 28.28, 30.84, 31.31, 33.11,
4
0
1
9
.4 Hz, 1H), 0.65 (m, 1H), 0.78 (m, 2H), 0.87 (m, 2H),
.94 (m, 1H), 0.99 (m, 1H), 1.33 (m, 2H), 1.50 (m, 2H),
.92 (dd, J = 8.8, 4.4 Hz, 1H), 6.50 (d, J = 2.0 Hz, 1H),
.56 (s, 1H), 9.96 (s, 1H). – 13C{ H} NMR (125 MHz,
3
4
0.76, 46.14, 139.52, 160.48, 191.96, 198.51. – HRMS (CI):
+
C H O [M+H] , calcd. 205.1229, found 205.1227.
13 17
2
1
Acknowledgement
C D ): δ = 18.28, 20.13, 26.41, 30.65, 31.73, 35.07, 36.11,
3
C H O [M+H] , calcd. 205.1229, found 205.1235.
6
6
7.95, 45.53, 139.92, 153.16, 192.69, 199.60. – HRMS (CI):
Financial support from the Swedish Natural Science
Council is gratefully acknowledged.
+
1
3 17 2
[
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(
Unauthenticated
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