Construction of cis-fused hydrindane skeleton with a lactone tether utilizing intramolecular diels-Alder reaction

Article abstract of DOI:10.3987/COM-15-S(T)34

Synthetically important, cis-fused hydrindane skeleton having quaternary angular stereogenic centers was selectively furnished by intramolecular Diels-Alder reaction of ester-Tethered precursor via endo transition state. The reaction was applicable for a construction of the steroidal BCD ring system with cis-hydrindane framework.

Full text of DOI:10.3987/COM-15-S(T)34

HETEROCYCLES, Vol. 93, No. 1, 2016, pp. -. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 31st August, 2015, Accepted, 17th September, 2015, Published online, 29th September, 2015
DOI: 10.3987/COM-15-S(T)34
CONSTRUCTION OF cis-FUSED HYDRINDANE SKELETON WITH A
LACTONE TETHER UTILIZING INTRAMOLECULAR DIELS-ALDER
REACTION
Shuqiang Yin,a Kenji Takai,a Daishiro Minato,a Kenji Sugimoto,a Hideki
Ohtsu,b Kiyoshi Tsuge,b and Yuji Matsuyaa,*
aGraduate School of Medicine and Pharmaceutical Sciences, University of
b
Toyama, 2630 Sugitani, Toyama 930-0194, Japan, Graduate School of Science
and Engineering, University of Toyama, 3190 Gofuku, Toyama 930-8555, Japan.
E-mail: matsuya@pha.u-toyama.ac.jp
Abstract – Synthetically important, cis-fused hydrindane skeleton having
quaternary angular stereogenic centers was selectively furnished by
intramolecular Diels-Alder reaction of ester-tethered precursor via endo transition
state. The reaction was applicable for a construction of the steroidal BCD ring
system with cis-hydrindane framework.
Hydrindane skeletons, a 6/5-fused bicyclic system, have been widely found in biologically active
compounds, representatively such as a steroidal CD ring.1 Many of the naturally occurring steroidal
compounds have a trans stereochemistry on the CD ring juncture, and consequently, considerable efforts
have been devoted for development of efficient construction methods of trans-hydrindane skeletons.2
Among them, an intramolecular Diels-Alder approach has been explored for the predominant formation
of the trans-hydrindanes (Scheme 1-a).3 In general, this approach preferentially gave the trans-hydrindane
skeleton, and only minor cases have been reported for providing the cis-fused hydrindanes.4 On the other
hand, the intermolecular Diels-Alder reaction between cyclopentenes and dienes are a promising and
reliable approach for the formation of cis-hydrindanes due to the inherent stereospecificity of Diels-Alder
reactions (Scheme 1-b).5,6
R
R
R
Diels-Alder
Diels-Alder
R'
(a)
(b)
+
R
R'
R'
trans-hydrindane
R'
cis-hydrindane
Scheme 1. Reaction modes of Diels-Alder reaction
This paper is dedicated to Professor Lutz F. Tietze on the occasion of his 75th birthday.

Hydrindanes having a cis stereochemistry have also been an important class of a substructure of bioactive
natural compounds. For example, pinguisone showing antifeedant activity is a natural sesquiterpene
possessing a furan-fused cis-hydrindane skeleton.7 Sarmentogenin and ouabagenin are aglycons of cardiac
glycosides rhodexin A8 and ouabain,9 respectively, having unusual cis-fused AB and CD rings on their
steroidal frameworks. Andrastins are meroterpenoids containing the cis-hydrindane substructure, and
reported to inhibit the activity of the ras protein farnesyltransferase, thus being a promising lead
compound for novel anticancer agents (Figure 1).10 All of these natural products commonly possess two
quaternary carbons on the ring juncture of the cis-hydrindane. Therefore, use of sterically hindered
tetra-substituted cyclopentenes as a dienophile is enforced in the forementioned intermolecular
Diels-Alder strategy for the construction of cis-hydrindanes of such natural products. This means that
dienes used in this strategy are often limited to sufficiently activated compounds such as Danishefsky’s
dienes, and this situation is really found in the past literatures.11 In this paper, we describe the Diels-Alder
reaction between highly electron-deficient tetra-substituted cyclopentene and unactivated dienes taking
advantage of the intramolecular fashion using ester-tethered substrates of dienes and dienophiles, leading
to a useful scaffold of natural compounds containing the cis-hydrindanes which have quaternary angular
carbons.
Me
O
Me
X
Me
HO
Me
Me
O
R1
R
H
Me
Me
R2
H
H
OH
O OMe
H
OH
X = β-butenolide
O
AcO
Me
Me
HO
Me
R3
Me
Sarmentogenin (R1 = R3 = H, R2 = Me)
Ouabagenin (R1 = R3 = OH, R2 = CH2OH)
Pinguisone
Andrastin A (R = CHO),
B (R = CH2OH), C (R = Me)
Figure 1. Natural compounds containing the cis-hydrindane substructure
Methyl 2-methylcyclopenten-3-one-1-carboxylate (2a)12 is considered as a highly activated dienophile for
Diels-Alder reaction. However, this compound has never used as a Diels-Alder dienophile with
unactivated dienes probably due to steric congestion, although several examples have been reported that
similar tetra-substituted cyclopentenone derivatives are conducted to intermolecular Diels-Alder reaction
with dienes activated by one or more alkoxy substituents. In regard to the cycloaddition reaction of the
compound 2a, photochemical [2+2] addition with allenes is only one example to the best of our
knowledge.13
In fact, the Diels-Alder reaction of 2a (R = Me) with the simple unactivated diene 1 did not proceed under
thermal conditions in an intermolecular fashion in our hands. We then decided to try the corresponding
intramolecular cycloaddition by using the ester-tethered substrate 3,14 which was prepared from the
carboxylic acid 2b (R = H) and 2,4-hexadien-1-ol under dehydrative condensation conditions.

Gratifyingly, the intramolecular Diels-Alder reaction of the substrate 3 cleanly proceeded at 180 °C
(sealed tube) to give the cis-hydrindane 4 in 91% yield. The reaction was endo selective (via endo-TS),
which was confirmed by the NOE observation experiments (Scheme 2).
Me
O
Me
toluene or xylene
+
no reaction
reflux
(2a: R = Me)
RO2C
NOE
O
2
Me
Me
1
H
Me
Me
OH
EDCI, DMAP, CH2Cl2
rt, 24 h, 84%
(2b: R = H)
O
O
4
Me
Me
O
91%
(endo : exo > 12 : 1)
Me
BHT, toluene
O
Me
O
sealed tube
180 °C, 24 h
O
O
O
3
endo-TS
Scheme 2. Successful Diels-Alder reaction for cis-hydrindane
Encouraged by the above results, we applied this strategy for the construction of the steroidal BCD ring
system with cis-hydrindane framework. The Diels-Alder substrate 9 was designed for this purpose, and
synthesized according to Scheme 3. Commercially available cyclohexanedione 5 was converted to the
iso-butyl enol ether 6 following the literature method,15 and the product 6 was allowed to react with
trans-propenyl Grignard reagent followed by acidic hydrolysis to afford the dienone 7 in good yield.
DIBAL reduction of 7 gave the alcohol 8, which was subjected to esterification with carboxylic acid 2
using EDCI and DMAP to furnish the Diels-Alder substrate 9 in an efficient manner.
Me
MgBr
O
O
Me
Me
Me
Me
Me
THF, 0 °C, 1.5 h
i-BuOH, TsOH
Me
Me
benzene, reflux
80%
then 10% HCl,
0 °C, 5 min, 66%
O
Oi-Bu
5
6
O
7
Me
Me
Me
O
2b, EDCI, DMAP
DIBAL, CH2Cl2
Me
Me
Me
CH2Cl2, rt, 0.5 h
99%
0 °C, 15 min
96%
Me
OH
O
O
8
9
Scheme 3. Preparation of a precursor for steroidal BCD ring system with cis-hydrindane framework

With the substrate compound 9 in hand, we investigated optimal conditions for the intramolecular
Diels-Alder reaction to establish the lactone-tethered tricyclic system formation (Table 1). Although the
reaction did not proceed under toluene reflux condition (entry 1), the desired cycloadducts were formed in
refluxing xylene in low yield (entry 2). Favorably the reaction was largely improved at 145 °C in a sealed
tube to realize 73% yield, whose endo/exo ratio was 53/20 (entry 3). The reaction was found to be highly
susceptible to the temperature, and the yield was decreased at 160 °C (entry 4) and considerable
decomposition was observed in short time at 180 °C in o-dichlorobenzene (entry 5). The stereostructure
of the product 10a was unambiguously determined by X-ray crystallography (Figure 2) to be an
endo-adduct, which was predominant product via the similar endo transition state in the case of Scheme
2.16 Thus, the best condition of the intramolecular Diels-Alder reaction of 9 was established, and efficient
approach for the tetracyclic framework 10 including the cis-hydrindane and the ester tether was
accomplished. These compounds would be versatile scaffolds for bioactive natural compounds containing
the cis-hydrindane substructure.
Table 1. Diels-Alder Reaction for steroidal BCD ring with cis-hydrindane framework
Me
Me
Me
Me
O
O
Me
Me
O
H
Me
Me
H
Me
Me
Me
Me
Conditions
+
O
O
O
O
O
O
H
H
9
10a (endo)
10b (exo)
solvent
temp
% yield (10a/10b)
entry
time (h)
toluene
xylene
xylene
xylene
reflux
reflux
no reaction
17 / 19
1
2
3
4
5
14
18
18
18
1.5
145 °C (sealed tube)
160 °C (sealed tube)
180 °C (sealed tube)
53 / 20
18 / 16
o-dichlorobenzene
complex mixture
Figure 2. ORTEP drawing of the endo-adduct 10a

In this paper, we have described the efficient intramolecular Diels-Alder strategy for the cis-hydrindane
skeleton construction, between highly congested tetra-substituted cyclopentenone and unactivated dienes
using ester-tethered substrates of dienes and dienophiles. These reactions would serve for providing
useful scaffolds of various compounds containing the cis-hydrindanes having quaternary angular carbons
such as illustrated in Figure 1. Further applications of these reactions for natural product syntheses are
now under investigation in our laboratory.
EXPERIMENTAL
All nonaqueous reactions were carried out under an Ar atmosphere. Reagents were purchased from
commercial suppliers and used as received. Anhydrous solvents were prepared by distillation over CaH2,
or purchased from commercial suppliers. 1H and 13C NMR spectra were measured on a JEOL ECX 400 or
1
13
a Varian GEMINI 300 instrument, using CHCl3 (7.26 ppm for H) and CDCl3 (77.0 ppm for C) as an
internal reference. The following abbreviations are used for spin multiplicity: s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, and br = broad. J values were in hertz. Mass spectra were measured on
a JEOL JMS-GCmate II or a JEOL JMS-AX 505 HAD mass spectrometer, and the ionization method was
electron impact (EI, 70 eV). IR spectra were recorded on a JASCO FT/IR-460Plus spectrometer. Column
chromatography was carried out by employing Cica Silica Gel 60N (spherical, neutral, 40-50 μm).
(2E,4E)-Hexadienyl 2-Methyl-3-oxo-cyclopent-1-ene-1-carboxylate (3). To a stirred solution of the
carboxylic acid 2b (440 mg, 3.14 mmol) in CH2Cl2 (15 mL) were added DMAP (192 mg, 1.57 mmol),
EDCI (900 mg, 4.70 mmol), and 2,4-hexadien-1-ol (463 mg, 4.70 mmol) at room temperature. After
stirred for 24 h at the same temperature, the mixture was concentrated in vacuo. The residue was purified
by flash column chromatography on silica gel (eluent: hexane/AcOEt = 20:1) to give the ester 3 (581 mg,
84%) as a colorless oil.
1H NMR (300 MHz, CDCl3) δ 6.35–6.27 (1H, m), 6.12–6.03 (1H, m), 5.84–5.63 (2H, m), 4.76 (2H, d, J =
6.9 Hz), 2.79–2.74 (2H, m), 2.48–2.45 (2H, m), 2.05 (3H, s), 1.77 (3H, d, J = 6.6 Hz); 13C NMR (75 MHz,
CDCl3) δ 209.3, 165.0, 154.1, 147.1, 135.4, 131.6, 130.1, 122.8, 65.5, 33.8, 26.4, 18.1, 9.9; IR (neat)
2929, 1700, 1447 cm–1; MS (EI) m/z 220 (M+); HRMS (EI) calcd for C13H16O3 (M+) 220.1100, found
220.1095.
6,6a-Dimethyl-3,3a,6,6a,8,9-hexahydro-1H,7H-indeno[3a,4-c]furan-1,7-dione (4). A stainless sealed
tube including a solution of the ester 3 (25.0 mg, 0.114 mmol) and BHT (2.5 mg, 0.0114 mmol) in
toluene (1.1 mL) was heated at 180 °C for 24 h. After removal of the solvent in vacuo, the residue was
purified by flash column chromatography on silica gel (eluent: hexane/AcOEt = 5:1) to give the lactone 4
(23.0 mg, 91%) as a white solid.

1H NMR (400 MHz, CDCl3) δ 5.89–5.86 (1H, m), 5.77–5.74 (1H, m), 4.51–4.48 (1H, m), 4.15–4.10 (1H,
m), 3.11–3.05 (1H, m), 2.39–2.31 (1H, m), 2.16–2.01 (3H, m), 1.87–1.82 (1H, m), 1.21 (3H, s), 0.99 (3H,
13
d, J = 7.8 Hz); C NMR (100 MHz, CDCl3) δ 217.0, 176.5, 136.5, 123.1, 67.6, 54.2, 52.3, 40.3, 39.9,
34.3, 23.1, 17.8, 17.1; IR (neat) 2978, 1757, 1734 cm–1; MS (EI) m/z 220 (M+); HRMS (EI) calcd for
C13H16O3 (M+) 220.1100, found 220.1092; Mp 141–143 °C.
3-Isobutyl-6,6-dimethylcyclohex-2-en-1-one
(6).
To
a
stirred
solution
of
4,4-dimethylcyclohexane-1,3-dione (5.00 g, 35.6 mmol) in benzene (100 mL) were added p-TsOH (355
mg, 1.86 mmol) and i-BuOH (6.7 mL, 72.5 mmol) at room temperature. After reflux with Dean-Stark
apparatus for 15 h, the reaction mixture was diluted with Et2O and the reaction was quenched with
saturated aqueous NaHCO3. The water phase was extracted with Et2O and the combined organic extracts
were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified
by flash column chromatography on silica gel (eluent: hexane/AcOEt = 3:1) to give the vinylogous ester 6
(5.57 g, 80%) as a pale yellow oil.
1H NMR (300 MHz, CDCl3) δ 5.23 (1H, s), 3.58 (2H, d, J = 6.6 Hz), 2.43 (2H, t, J = 5.8 Hz), 2.17–2.15
13
(1H, m), 1.80 (2H, t, J = 6.3 Hz), 1.15 (6H, s), 0.98 (6H, d, J = 6.6 Hz); C NMR (75 MHz, CDCl3) δ
204.2, 175.8, 100.8, 74.4, 39.9, 34.8, 27.5, 26.0, 24.4, 18.9; IR (neat) 1655, 1611 cm–1; HRMS (EI) calcd
for C12H20O2 (M+) 196.1463, found 196.1463.
(E)-4,4-Dimethyl-3-(prop-1-en-1-yl)cyclohex-2-en-1-one (7). To a stirred suspension of Mg (604 mg,
24.9 mmol) in THF (48 mL) was added trans-propenyl bromide (2.1 mL, 24 mmol) at room temperature
and heated at reflux for 1.5 h. To a solution of the vinylogous ester 6 (201 mg, 1.02 mmol) in THF was
added the above Grignard reagent (0.5 M in THF, 6.2 mL, 3.06 mmol) at 0 °C. After stirred for 80 min at
room temperature, 10% aqueous HCl was added to the mixture at 0 °C. After stirred for 5 min at the same
temperature, the water phase was extracted with Et2O. The combined organic phases were washed with
brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (eluent: hexane/AcOEt = 5:1) to give the dienone 7 (112 mg, 66%) as a pale
yellow oil.
1H NMR (300 MHz, CDCl3) δ 6.26–6.08 (2H, m), 5.97 (1H, s), 2.43–2.38 (2H, m), 1.85–1.81 (5H, m),
1.16 (6H, s) ; 13C NMR (75 MHz, CDCl3) δ 199.4, 166.3, 132.6, 127.8, 121.5, 37.5, 34.6, 34.3, 26.8, 19.0;
IR (neat) 1665 cm–1; MS (EI) m/z 164 (M+); HRMS (EI) calcd for C11H16O (M+) 164.1201, found
164.1203.
(E)-4,4-Dimethyl-3-(prop-1-en-1-yl)cyclohex-2-en-1-ol (8). To a stirred solution of the dienone 7 (51.7
mg, 0.314 mmol) in CH2Cl2 (2.0 mL) was added DIBAL (1.0 M in toluene, 0.9 mL, 0.9 mmol) at 0 °C.
After stirred for 15 min at the same temperature, the reaction was quenched with saturated aqueous
NH4Cl at 0 °C. The filtrate was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo.

The residue was purified by flash column chromatography on silica gel (eluent: hexane/AcOEt = 2:1) to
give the alcohol 8 (50.2 mg, 96%) as a colorless oil.
1H NMR (300 MHz, CDCl3) δ 5.96 (1H, d, J = 15.3 Hz), 5.89–5.80 (1H, m), 5.65 (1H, d, J = 3.3 Hz),
4.18 (1H, br s), 1.92–1.84 (1H, m), 1.74 (3H, d, J = 6.3 Hz), 1.60–1.38 (4H, m), 1.06 (3H, s), 1.00 (3H,
13
s); C NMR (75 MHz, CDCl3) δ 147.0, 129.4, 126.1, 123.1, 66.7, 35.6, 33.7, 29.0, 28.0, 27.8, 18.5; IR
(neat) 3329 cm–1; MS (EI) m/z 166 (M+); HRMS (EI) calcd for C11H18O (M+) 166.1358, found 166.1380.
(E)-4,4-Dimethyl-3-(prop-1-en-1-yl)cyclohex-2-en-1-yl-2-methyl-3-oxo-cyclopent-1-ene-1-carboxyl-
ate (9). To a solution of carboxylic acid 2b (108 mg, 0.774 mmol) and alcohol (82.7 mg, 0.497 mmol) in
CH2Cl2 (5.0 mL) were added EDCI (195 mg, 1.02 mmol) and HOBt·H2O (30.4 mg, 0.249 mmol) at room
temperature. After stirred for 35 min, the mixture was diluted with CH2Cl2 and the organic phase was
washed with saturated aqueous NaHCO3 and 10% aqueous citric acid, dried over MgSO4, filtered, and
concentrated in vacuo. The residue was used for the next reaction without further purification because of
instability against column chromatography on silica gel.
1H NMR (300 MHz, CDCl3) δ 5.96 (1H, d, J = 16.5 Hz), 5.93–5.82 (1H, m), 5.69 (1H, d, J = 3.8 Hz),
5.42 (1H, q, J = 4.7 Hz), 2.79–2.73 (2H, m), 2.47–2.44 (2H, m), 2.03 (3H, s), 2.00–1.92 (1H, m), 1.83–
1.78 (1H, m), 1.75 (3H, d, J = 6.1 Hz), 1.71–1.63 (1H, m), 1.58–1.46 (1H, m), 1.10 (3H, s), 1.03 (3H, s);
13C NMR (75 MHz, CDCl3) δ 209.7, 165.1, 154.9, 149.7, 128.8, 127.1, 117.6, 70.3, 35.1, 33.8, 33.5, 27.9,
27.3, 26.4, 25.1, 18.4, 9.9; IR (neat) 1713, 1645, 1570 cm–1; MS (EI) m/z 288 (M+); HRMS (EI) calcd for
C18H24O3 (M+) 288.1726, found 288.1753.
8,8,10,10a-Tetramethyl-2,3,5a,6,7,8,10,10a-octahydro-4H-cyclopenta[7,8]naphtha-[1,8-bc]furan-1,4(
3a1H)-dione (10a and 10b). A stainless sealed tube including a solution of the ester 9 (30.2 mg, 0.104
mmol) in xylene (0.9 mL) was heated at 145 °C for 18 h. After removal of the solvent in vacuo, the
residue was purified by flash column chromatography on silica gel (eluent: hexane/AcOEt = 4:1) to give
the lactones 10a (16.0 mg, colorless prism, 53%) and 10b (5.9 mg, pale yellow prism, 20%).
10a: 1H NMR (300 MHz, CDCl3) δ 5.43 (1H, t, J = 2.5 Hz), 4.70–4.62 (1H, m), 3.14 (1H, d, J = 8.5 Hz),
2.48–2.34 (1H, m), 2.15–1.99 (1H, m), 1.96–1.88 (4H, m), 1.64–1.52 (3H, m), 1.20 (6H, s), 1.15 (3H, s),
1.01 (3H, d, J = 7.6 Hz); 13C NMR (75 MHz, CDCl3) δ 217.4, 176.6, 146.9, 128.2, 77.0, 56.4, 53.2, 43.0,
42.4, 36.4, 34.9, 33.6, 32.5, 29.5, 29.4, 26.0, 18.0, 16.5; IR (neat) 1761, 1734 cm–1; MS (EI) m/z 288
(M+); HMRS (EI) calcd for C18H24O3 (M+) 288.1726, found 288.1758; Mp 175–177 °C.
10b: 1H NMR (300 MHz, CDCl3) δ 5.47 (1H, t, J = 3.0 Hz), 4.72–4.65 (1H, m), 2.77–2.64 (2H, m),
2.49–2.27 (3H, m), 2.19–2.11 (1H, m), 2.08–2.01 (1H, m), 1.63–1.48 (2H, m), 1.35–1.29 (1H, m), 1.12
(6H, s), 1.01 (3H, s), 0.98 (3H, d, J = 7.1 Hz); 13C NMR (75 MHz, CDCl3) δ 216.0, 178.8, 138.8, 126.3,
76.7, 53.2, 52.6, 41.6, 34.6, 34.5, 33.2, 31.4, 29.8, 28.8, 25.7, 16.6, 14.1; IR (neat) 1750 cm–1; MS (EI)
m/z 288 (M+); HRMS (EI) calcd for C18H24O3 (M+) 288.1726, found 288.1699; Mp 156–158 °C.

Deposition number CCDC-1421053 for compound 10a. Free copies of the data can be obtained via
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge, CB2 1EZ, UK; Fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
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16. CCDC 1421053 includes the crystallographic data for this manuscript.