Formal synthesis of (±)-hop ether, (±)-isoboonein, and (±)-iridomyrmecin

Article abstract of DOI:10.3987/COM-05-10612

A general synthesis of (±)-hop ether (5), (±)-isoboonein (6), and (±)-iridomyrmecin (7) from bicyclo[2.2.1]ketone (9) is described. Cyclopentenoid aldehyde (10) and bicyclo[3.2.1]lactone (11) are the key intermediates.

Full text of DOI:10.3987/COM-05-10612

HETEROCYCLES, Vol. 68, No. 2, 2006
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HETEROCYCLES, Vol. 68, No. 2, 2006, pp. 271 - 282. © The Japan Institute of Heterocyclic Chemistry
Received, 4th November, 2005, Accepted, 12th December, 2005, Published online, 13th December, 2005. COM-05-10612
FORMAL SYNTHESIS OF (±)-HOP ETHER, (±)-ISOBOONEIN,
AND (±)-IRIDOMYRMECIN
Meng-Yang Chang,*,a Ru-Ting Hsu,b Chun-Yu Lin,a Bor-Fong Chen,c
Shiang-Tsern Lin,d and Nein-Chen Chang*,c
aDepartment of Applied Chemistry, National University of Kaohsiung, Kaohsiung
b
811, Taiwan Department of Nursing, Shu-Zen College of Medicine and
c
Management, Kaohsiung 821, Taiwan Department of Chemistry, National Sun
d
Yat-Sen University, Kaohsiung 804, Taiwan Department of Nutrition, Chung-Ho
Memorial Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan
Abstract—A general synthesis of (±)-hop ether (5), (±)-isoboonein (6), and
(±)-iridomyrmecin (7) from bicyclo[2.2.1]ketone (9) is described. Cyclopentenoid
aldehyde (10) and bicyclo[3.2.1]lactone (11) are the key intermediates.
INTRODUCTION
The iridoids are a large class of naturally occurring compounds with over 300 members in the family.
They are characterized by a cyclopentane or cyclopentene ring cis-fused to a δ-lactone, dihydropyran or
dihydrofuran.1 Irido monoterpenoids with a cyclopentane ring are important because of their diverse and
interesting physiological and biological activities.2 The major challenge on the synthesis of iridoid
monoterpenoids was to provide the installation of contiguous stereogenic chiral centers on their molecular
system employing some various approaches and useful methodologies during three decades.
Figure 1.
X
HO
O
H
H
H
O
O
H
H
O
O
OH
H
HO
HO
boschnialactone (1)
iridolactone (2)
X=O, pedicularis-Lactone (3)
X=H2, ningpogenin (4)
H
H
O
H
O
HO
O
O
O
H
H
H
hop ether (5)
isoboonein (6)
iridomyrmecin (7)

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HETEROCYCLES, Vol. 68, No. 2, 2006
Previously, we have reported a facile and straightforward synthesis of (±)-boschnialactone (1),3a
(±)-iridolactone (2),3b (±)-pedicularis-lactone (3),3c and (±)-ningpogenin (4)3c via the key step of Norrish
type 1 photolytic cleavage as shown in Figure 1. To demonstrate the synthetic utility of the methodology
and continue our investigation on the application of this straightforward approach, the synthesis of
(±)-hop ether (5), (±)-isoboonein (6), and (±)-iridomyrmecin (7) was studied. Their related significant
features are described as follows. Hop ether (5) was first isolated and characterized from the volatile
constituents of Japanese hop “Shinshu-wase” by Naya and Kotake4 in 1967. Hop ether (5) is regarded as a
component which markedly affects the aroma and taste of beer5 and has attracted considerable interest
from synthetic chemists.6 Isoboonein (6)7a was an analog of boonein7b and it was isolated from Rauwolfia
grandiflora by Bianco and coworkers. To date, there are few reports for the synthesis of isoboonein (6)
citations8 and its related biological activities has not also been reported. Iridomyrmecin (7) exhibited
strong insecticide activities against preying insects from ants (Iridomyrmex humilis)9 and a lot of related
synthetic reports have been published.10
RESULTS AND DISCUSSION
Here we report that a general synthesis toward (±)-hop ether (5), (±)-isoboonein (6), and
(±)-iridomyrmecin (7) has been established by synthesizing aldehyde (10) and lactone (11) via Norrish
type 1 photolytic cleavage11 and Baeyer-Villiger ring-expanded lactonization of bicyclo[2.2.1]ketone
(9).12 Ketone (9) was yielded from anhydride (8) in overall 60% yield of four steps (Scheme 1).3c
Scheme 1.
CHO
hν, MeOH
(90%)
OBn
OBn
ref. 3c
10
O
OBn
OBn
O
O
O
MCPBA,
NaHCO3
(89%)
8
9
O
O
OBn
OBn
11
As shown in Scheme 2, sole aldehyde (10) was afforded in better yield via Norrish type 1 photolytic
cleavage (λ>310 nm) of ketone (9) in methanol. Treatment of aldehyde (10) with diethylamine and
dibromomethane under Hon’s condition13 gave a α-methylene aldehyde (12) which further reacted with
sodium borohydride in methanol to yield allylic alcohol (13). Compound (13) was transformed into diol
(14) by mesylation and Birch reduction under standard conditions. During the mesylation procedure, a
mixture of mesylate and chloride compounds was yielded in different ratio. Without further purification,

HETEROCYCLES, Vol. 68, No. 2, 2006
273
the resulting mixture was reacted directly with sodium and liquid ammonia to provide diol (14). In order
to provide sole compound and decrease the complexity of products during the mesylation procedure,
sodium iodide was added to the reaction mixture and the bicyclic skeleton (15) was isolated in only 31%
yield via a cyclization. This result was unexpected.
Scheme 2.
CH2Br2
NaBH4
(93%)
CHO
CHO
OH
OBn
Et2NH
(92%)
OBn
OBn
OBn
12
OBn
10
OBn
13
MsCl, pyr.
NaI (31%)
H
O
H
H
1) MsCl, pyr.
TsOH
(78%)
O
2) Na, NH3(l)
(two steps 47%)
H
OH
OH
OBn
OH
14
16
15
H
H
H
H
H
LDA
MsCl, pyr.
(80%)
TsNHNH2
NaOAc (75%)
O
O
O
(65%)
H
OMs
OMs
17
18
5
With diol (14) in hand, treatment of diol (14) with a catalytic amount of p-toluenesulfonic acid in
tetrahydrofuran gave a bicyclo[3.3.0]octane skeleton (16) by a cyclization. During the ring closure
process, the fused bicyco[3.2.1]octane framework was not observed. Reduction of olefinic group on
compound (16) with hydrogen in the presence of different transition metal catalyst was yielded complex
products. The desired saturated alcohol compound was only generated in trace yield (<5%). The possible
reaction mechanism has been proposed as follows. Presumably, once an allylic alcohol was formed under
double bond isomerization, the further allylic reduction proceeded in the catalytic hydrogenation reaction.
In order to increase the yield of desired product and reduce the opportunity of allylic reduction, the
diimide reduction was chosen as the next step.
Mesylation of olefin (16) with methanesulfonyl chloride and pyridine gave mesylate (17). Treatment of
mesylate (17) with 4-toluenesulfonylhydrazine and sodium acetate gave compound (18) in modest yield.
When the synthetic sequence of mesylation and reduction was exchanged, compound (18) was generated
in only 21% yield of two-step from compound (16). Attempts to form exo-olefin were unsuccessful under

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HETEROCYCLES, Vol. 68, No. 2, 2006
a variety of basic conditions. Finally, elimination of mesylate group by lithium diisopropylamide at reflux
temperature gave (±)-hop ether (5). A total synthesis of (±)-hop ether (5) was achieved.
For the synthetic study of (±)-isoboonein (6), compound (11) was chosen as starting material.
Baeyer-Villiger ring expansion of ketone (9) should be affected by the neighboring oxygen atom of
benzyl group under basic condition to produce sole lactone (11) with good regioselectivity. Another
ring-expanded lactone was not obtained in the reaction condition. As shown in Scheme 3, treatment of
lactone (11) with lithium aluminum hydride gave a diol (19). Jones oxidation of diol (19) gave keto acid
which further reacted with hydrogen and 10% palladium on activated carbon in methanol to yield single
1
13
product (21) via the formation of the proposed intermediate (20). The H and C NMR spectral data of
compound (21) was in accordance with the reported in the literature.8b Presumably, methyl group was
easy to epimerize into exo face during the acid-mediated allylic hydrogenation. The stereochemical
selectivity of methyl group at C-7 was well established. Here we provided a simple four-step synthetic
route toward synthesis of compound (21) from known ketone (9). Compound (21) was converted to
(±)-isoboonein (6) from a known two-step procedure.8b A formal synthesis of (±)-isoboonein (6) was
accomplished.
Scheme 3.
OH
LAH
1) Jones ox.
HO
O
OBn
O
OBn
OBn
(90%)
OBn
19
11
H
H
H
H
O
O
2) H2, Pd/C
CO2H
OBn
ref. 8b
HO
O
HO
7
O
O
(two steps
82% from 19)
H
H
OBn
20
21
6
We next turn our focus toward the formal synthesis of (±)-iridomyrmecin (7) via a mild two-step
reductive deoxygenation reactions from ketone (21) (Scheme 4): (i) protection of ketone (21) with
1,2-ethanedithiol and boron trifluoride etherate, (ii) deprotection of the resulting compound with Raney
nickel. Lactone (22) was converted to (±)-iridomyrmecin (7) and (±)-isoiridomyrmecin (23) using the
alkylation reaction.10d
Scheme 4.
R1
R2
O
H
H
H
O
O
O
1) (CH2SH)2
ref.10d
O
O
O
2) Raney Ni
(two steps 63%)
H
H
H
7, R1=Me, R2=H
23, R1=H, R2=Me
21
22

HETEROCYCLES, Vol. 68, No. 2, 2006
275
CONCLUSION
In summary, we have developed a straightforward approach to synthesis of (±)-hop ether (5),
(±)-isoboonein (6), and (±)-iridomyrmecin (7) based on Norrish photolytic cleavage and Baeyer-Villiger
lactonization of bicyclo[2.2.1]ketone (9) as the key step. We are currently studying the scope of this
process as well as additional applications of this approach to the synthesis of various potential biological
activities compounds using chiral bicyclo[2.2.1]ketone (9) as the starting material.
EXPERIMENTAL
General. Dichloromethane and tetrahydrofuran were distilled prior to use. All other reagents and solvents
were obtained from commercial sources and used without further purification. Reactions were routinely
carried out under an atmosphere of dry nitrogen with magnetic stirring. Products in organic solvents were
dried with anhydrous magnesium sulfate before concentration in vacuo. All reported melting temperatures
are uncorrected.
2-(4,5-Bisbenzyloxymethylcyclopentenyl)acetaldehyde (10).3c
Ketone (9) (1.0 g, 2.9 mmol) dissolved in methanol (200 mL) free of oxygen was irradiated under a
nitrogen atmosphere with a lamp (λ>310 nm), using a pyrex glass filter at rt for 15 h. The solvent was
evaporated under reduced pressure to afford crude product. Purification on silica gel (hexane/ethyl acetate
1
= 10/1) yielded aldehyde (10) (0.9 g, 90%) as a colorless oil: IR (neat) 3031, 2857, 2716, 1724 cm-1; H
NMR (CDCl3, 300 MHz) δ 9.67-9.66 (m, 1H), 7.36-7.25 (m, 10H), 5.83-5.80 (m, 1H), 5.75-5.73 (m, 1H),
4.45-4.31 (m, 4H), 3.61 (dd, J = 6.6, 9.3 Hz, 1H), 3.40 (t, J = 9.3 Hz, 1H), 3.37 (d, J = 5.4 Hz, 2H),
3.30-3.20 (m, 1H), 3.00-2.90 (m, 1H), 2.83-2.72 (m, 1H), 2.60 (ddd, J = 2.4, 6.9, 16.5 Hz, 1H), 2.35 (ddd,
13
J = 1.5, 7.8, 16.5 Hz, 1H); C NMR (CDCl3, 75 MHz) δ 202.12, 138.10, 134.71, 132.19, 128.32 (3x),
127.88 (3x), 127.79 (3x), 127.61 (2x), 73.20, 72.95, 70.53, 67.86, 46.98, 46.09, 41.75, 40.60; Anal. Calcd
for C23H26O3: C, 78.83; H, 7.48; Found: C, 78.83; H, 7.34.
2-(4,5-Bisbenzyloxymethylcyclopent-2-enyl)propenal (12).
A solution of aldehyde (10) (2.4 g, 6.86 mmol) in dichloromethane (20 mL) was added to the stirred
mixture of diethylamine (12.5 g, 171.23 mmol) and dibromomethane (23.8 g, 136.78 mmol). The reaction
mixture was heated to 55 °C for 16 h and concentrated under reduced pressure. The residue was diluted
with water (10 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were
washed with brine, dried, filtered and evaporated under reduced pressure to afford crude product.
Purification on silica gel (hexane/ethyl acetate = 4/1) yielded α,β-unsaturated aldehyde (12) (2.28 g, 92%)
as a viscous oil: IR (CHCl3) 1690, 1635, 1097 cm-1; EI-MS (30 eV) C24H26O3 m/z (%) = 91 (100), 363
(M++1, 1); 1H NMR (500 MHz, CDCl3) δ 9.46 (s, 1H), 7.33-7.20 (m, 10H), 6.08 (s, 1H), 5.98 (dt, J = 2.5,

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HETEROCYCLES, Vol. 68, No. 2, 2006
6.0 Hz, 1H), 5.93 (s, 1H), 5.60 (dt, J = 2.5, 6.0 Hz, 1H), 4.45 (d, J = 12.0 Hz, 1H), 4.39 (d, J = 12.0 Hz,
1H), 4.28 (d, J = 11.5 Hz, 1H), 4.23 (dd, J = 11.5 Hz, 1H), 3.98 (d, J = 8.5 Hz, 1H), 3.53 (dd, J = 6.0, 9.0
13
Hz, 1H), 3.37 (dd, J = 7.5, 9.5 Hz, 1H), 3.32-3.24 (m, 2H), 3.12-3.09 (m, 1H), 2.99-2.92 (m, 1H); C
NMR (125 MHz, CDCl3) δ 194.21, 150.13, 138.32, 138.15, 134.69, 134.35, 131.63, 128.30 (2x), 128.25
(2x), 127.79 (2x), 127.70 (2x), 127.56, 127.45, 73.06, 72.82, 70.58, 68.00, 47.48, 44.09, 42.54; Anal.
Calcd for C24H26O3: C, 79.53; H, 7.23; Found: C, 79.82; H, 7.61.
2-(4,5-Bisbenzyloxymethylcyclopent-2-enyl)prop-2-en-1-ol (13).
Sodium borohydride (310 mg, 8.38 mmol) was added to a stirred solution of α,β-unsaturated aldehyde
(12) (2.0 g, 5.52 mmol) in methanol (100 mL) at ice bath. The mixture was stirred for 3 h at this
temperature. Saturated aqueous sodium bicarbonate solution (2 mL) was added to the mixture and then
the whole was concentrated under reduced pressure. The residue was diluted with water (10 mL) and
extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried,
filtered and evaporated under reduced pressure to afford crude product. Purification on silica gel
(hexane/ethyl acetate = 4/1) yielded product (13) (1.87 g, 93%) as a viscous oil: IR (CHCl3) 3466, 1792,
1599, 1473 cm-1; EI-MS (70 eV) C24H29O3 m/z (%) = 105 (100), 365 (M++1, 1); HRMS (ESI, M++1)
1
calcd for C24H29O3 365.2117, found 365.2119; H NMR (500 MHz, CDCl3) δ 7.35-7.25 (m, 10H), 5.78
(dt, J = 2.5, 5.5 Hz, 1H), 5.64 (dt, J = 2.5, 5.5 Hz, 1H), 5.08 (s, 1H), 4.80 (s, 1H), 4.45 (s, 2H), 4.34 (dd, J
= 11.5, 16.0 Hz, 2H), 4.08 (br s, 2H), 3.57 (dd, J = 4.0, 9.5 Hz, 2H), 3.42 (dd, J = 9.5, 11.0 Hz, 2H), 3.36
(t, J = 9.5 Hz, 1H), 3.15-3.10 (m, 2H), 2.94-2.88 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 149.65, 138.20,
137.44, 134.00, 132.04, 128.44 (2x), 128.35 (2x), 128.10 (2x), 127.89, 127.73 (2x), 127.60, 111.74, 73.14,
73.10, 70.38, 67.87, 67.76, 49.84, 48.01, 43.90; Anal. Calcd for C24H28O3: C, 79.09; H, 7.74; Found: C,
79.22; H, 8.05.
(2-Hydroxymethyl-5-isopropenylcyclopent-3-enyl)methanol (14).
A solution of methanesulfonyl chloride (615 mg, 5.37 mmol) in dichloromethane (1 mL) was added to a
stirred solution of compound (13) (1.3 g, 3.57 mmol) in pyridine (10 mL) at rt. The reaction mixture was
reflux for 2 h. The resulting mixture was washed with brine, cooled to ice bath, poured into aqueous
hydrogen chloride solution (2 N, 10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined
organic layers were dried, filtered and evaporated under reduced pressure to afford crude product.
Without further purification, the resulting compound was reacted in the next following step. A three-neck
round-bottomed flask (100 mL), equipped with a stirrer, a dropping funnel and a reflux condenser, was
filled with liquid ammonia (20 mL), tetrahydrofuran (10 mL) and sodium (530 mg, 23.04 mmol). The
resulting residue in tetrahydrofuran (3 mL) was added at -78 °C. The reaction mixture was stirred for 1 h
at that temperature. Saturated aqueous sodium bicarbonate solution (2 mL) was added to the mixture and

HETEROCYCLES, Vol. 68, No. 2, 2006
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then the whole was concentrated under reduced pressure. The residue was diluted with water (10 mL) and
extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine, dried,
filtered and evaporated under reduced pressure to afford crude product. Purification on silica gel
(hexane/ethyl acetate = 1/1) yielded product (14) (282 mg, 47%, two-steps from compound 13) as a
viscous oil: IR (CHCl3) 3544, 1421, 1265 cm-1; HRMS (ESI, M++1) calcd for C10H17O2 169.1229, found
1
169.1231; H NMR (500 MHz, CDCl3) δ 5.71 (br s, 2H), 4.90 (s, 1H), 4.75 (s, 1H), 3.79-3.67 (m, 4H),
3.36 (d, J = 8.5 Hz, 1H), 3.13-3.09 (m, 1H), 3.00 (br s, 1H), 2.85 (br s, 1H), 2.84-2.78 (m, 1H), 1.76 (s,
13
3H); C NMR (125 MHz, CDCl3) δ 145.35, 134.03, 131.49, 112.58, 62.66, 61.04, 53.78, 50.62, 44.88,
23.69; Anal. Calcd for C10H16O2: C, 71.39; H, 9.59; Found: C, 71.80; H, 9.88.
7-Benzyloxymethyl-4-methylene-1,3,4,4a,7,7a-hexahydrocyclopenta[c]pyran (15).
A solution of methanesulfonyl chloride (103 mg, 0.90 mmol) in dichloromethane (1 mL) was added to a
stirred solution of compound (13) (300 mg, 0.82 mmol) and sodium iodide (150 mg, 1.00 mmol) in
pyridine (5 mL) at rt. The reaction mixture was reflux for 2 h. The resulting mixture was cooled to ice
bath, poured into aqueous hydrogen chloride solution (2 N, 10 mL) and extracted with ethyl acetate (3 x
20 mL). The combined organic layers were washed with brine, dried, filtered and evaporated under
reduced pressure to afford crude product. Purification on silica gel (hexane/ethyl acetate = 4/1) yielded
product (15) (65 mg, 31%) as a viscous oil: IR (CHCl3) 1630, 1165 cm-1; 1H NMR (500 MHz, CDCl3) δ
7.36-7.26 (m, 5H), 5.80-5.78 (m, 2H), 4.86 (s, 2H), 4.45 (br s, 2H), 4.05 (d, J = 12.5 Hz, 1H), 3.97 (d, J =
12.5 Hz, 1H), 3.78 (dd, J = 8.5, 12.0 Hz, 1H), 3.61 (dd, J = 8.5, 11.5 Hz, 1H), 3.48 (d, J = 7.5 Hz, 2H),
3.45-3.42 (m, 1H), 3.08-3.04 (m, 1H), 2.69-2.63 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 144.89, 138.27,
133.83, 133.08, 128.37 (2x), 127.70 (2x), 127.60, 110.42, 73.23, 70.91, 69.67, 65.51, 49.01, 48.01, 41.13.
4-Hydroxymethyl-1,1-dimethyl-3,3a,4,6a-tetrahydrocyclopenta[c]furan (16).
p-Toluenesulfonic acid monohydrate (10 mg, 0.05 mmol) was added to a solution of compound (14) (100
mg, 0.60 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred for 12 h at rt. Saturated
aqueous sodium bicarbonate solution (5 mL) was added to the resulting mixture and then the whole was
concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with
ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried, filtered and
evaporated under reduced pressure to afford crude product. Purification on silica gel (hexane/ethyl acetate
= 1/1) yielded product (16) (78 mg, 78%) as a viscous oil: IR (CHCl3) 3548, 1595, 1495, 1352 cm-1;
EI-MS (30 eV) C10H16O2 m/z (%) = 79 (100), 168 (M+, 2); HRMS (ESI, M++1) calcd for C10H17O2
169.1229, found 169.1230; 1H NMR (500 MHz, CDCl3) δ 5.69 (br s, 2H), 3.92 (dd, J = 3.0, 10.0 Hz, 1H),
3.86-2.82 (m, 2H), 3.72-3.68 (m, 2H), 3.12-3.06 (m, 2H), 3.01-2.98 (m, 1H), 1.24 (s, 3H), 1.21 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 132.81, 131.35, 82.38, 65.83, 62.76, 60.59, 50.29, 44.13, 27.31, 24.24.

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4-Methanesulfonylmethyl-1,1-dimethyl-3,3a,4,6a-tetrahydrocyclopenta[c]furan (17).
A solution of methanesulfonyl chloride (120 mg, 1.05 mmol) in dichloromethane (1 mL) was added to a
stirred solution of alcohol (16) (70 mg, 0.42 mmol) and pyridine (3 mL) at rt. The reaction mixture was
stirred for 2 h at rt. The resulting mixture was cooled to ice bath, poured into aqueous hydrogen chloride
solution (2 N, 10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were
dried, filtered and evaporated under reduced pressure to afford crude product. Purification on silica gel
(hexane/ethyl acetate = 1/1) yielded product (17) (82 mg, 80%) as a viscous oil: IR (CHCl3) 1590, 1174
cm-1; HRMS (ESI, M++1) calcd for C11H19O4S 247.1004, found 247.1006; 1H NMR (500 MHz, CDCl3) δ
5.77-5.75 (m, 1H), 5.61-5.60 (m, 1H), 4.30 (dd, J = 6.5, 9.5 Hz, 1H), 4.22 (dd, J = 9.5, 9.5 Hz, 1H), 3.84
(dd, J = 7.0, 10.0 Hz, 1H), 3.75 (dd, J = 5.0, 10.0 Hz, 1H), 3.26-3.21 (m, 1H), 3.17-3.10 (m, 2H), 3.03 (s,
3H), 1.25 (s, 3H), 1.20 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 133.14, 129.97, 81.69, 69.76, 65.51, 61.05,
47.12, 43.76, 37.35, 27.60, 24.32.
4-Methanesulfonylmethyl-1,1-dimethyl-3,3a,4,5,6,6a-hexahydrocyclopenta[c]furan (18).
A solution of olefin (17) (70 mg, 0.28 mmol) in dioxane (2 mL) was added to a solution of
4-toluenesulfonylhydrazine (200 mg, 1.08 mmol) and sodium acetate (100 mg, 1.22 mmol) in the
co-solvent of water (5 mL) and l,4-dioxane (5 mL). The reaction mixture was reflux for 4 h. The mixture
was cooled to rt, poured into water (5 mL) and extracted with dichloromethane (3 x 30 mL). The
combined organic layers were dried, filtered and evaporated under reduced pressure to afford crude
product. Purification on silica gel (hexane/ethyl acetate = 1/1) yielded product (18) (53 mg, 75%) as a
viscous oil: IR (CHCl3) 1632 cm-1; EI-MS C11H20O4S m/z (%) = 79 (100), 248 (M+, 1); HRMS (ESI,
1
M++1) calcd for C11H21O4S 249.1161, found 249.1162; H NMR (500 MHz, CDCl3) δ 4.30 (dd, J = 7.0,
10.0 Hz, 1H), 4.20 (t, J = 10.0 Hz, 1H), 3.79 (dd, J = 8.0, 10.0 Hz, 1H), 3.65 (dd, J = 5.0, 10.0 Hz, 1H),
3.01 (s, 3H), 2.99-2.94 (m, 1H), 2.44-2.17 (m, 2H), 1.84-1.78 (m, 1H), 1.77-1.71 (m, 1H), 1.62-1.54 (m,
13
1H), 1.39-1.31 (m, 1H), 1.23 (s, 3H), 1.19 (s, 3H); C NMR (125 MHz, CDCl3) δ 82.48, 70.92, 65.07,
52.66, 46.01, 42.46, 37.33, 28.67, 28.17, 26.93, 23.65.
1,1-Dimethyl-4-methylene-3,3a,4,5,6,6a-hexahydrocyclopenta[c]furan (Hop ether) (5).6c
A solution of lithium diisopropylamide (1.0 M in tetrahydrofuran, 1.0 mL, 1.0 mmol) was added to a
stirred solution of mesylate (18) (20 mg, 0.08 mmol) in tetrahydrofuran (10 mL) at -78 oC. The reaction
mixture was stirred at reflux for three days. The reaction was quenched with aqueous ammonium chloride
solution (15%, 10 mL) and the mixture was extracted with ethyl acetate (3 x 20 mL). The combined
organic layers were washed with brine, dried, filtered and evaporated under reduced pressure to afford
crude product. Purification on silica gel (hexane/ethyl acetate = 8/1) afforded hop ether (5) (8 mg, 65%)
1
as a colorless oil: HRMS (EI, M++1) calcd for C10H17O 153.1280, found 153.1282; H NMR (300 MHz,

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279
CDCl3) δ 4.82 (br s, 1H), 4.67 (br s, 1H), 4.07 (dd, J = 4.8, 9.0 Hz, 1H), 3.63 (dd, J = 4.8, 9.0 Hz, 1H),
3.33-3.25 (m, 1H), 2.39-2.25 (m, 3H), 1.75-1.64 (m, 2H), 1.25 (s, 3H), 1.21 (s, 3H).
6,7-Bisbenzyloxymethyl-2-oxabicyclo[3.2.1]octan-3-one (11).
A solution of ketone (9) (2.12 g, 6.06 mmol) in dichloromethane (30 mL) was added dropwise at rt to a
stirred solution of m-chloroperoxybenzoic acid (1.23 g, 70%, 7.13 mmol) and sodium bicarbonate (2.14 g,
25.48 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at rt for 18 h. The precipitate
was filtered through a short plug of Celite and the filtrate was washed with saturated sodium carbonate
solution (2 x 20 mL). The organic layer was washed with brine, dried, and evaporated under reduced
pressure to afford crude product. Purification on silica gel (hexane/ethyl acetate = 2/1) yielded lactone (11)
(1.97 g, 89%) as a viscous oil: IR (CHCl3) 1765, 1167 cm-1; HRMS (EI, M+) calcd for C23H26O4 366.1831,
1
found 366.1835; H NMR (300 MHz, CDCl3) δ 7.36-7.24 (m, 10H), 4.84 (br s, 1H), 4.52-4.29 (m, 4H),
3.72-3.39 (m, 4H), 2.72-2.52 (m, 5H), 2.00 (d, J = 12.9 Hz, 1H), 1.77 (d, J = 12.9 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 170.43, 137.88, 137.73, 128.29 (2x), 128.24 (2x), 127.63 (2x), 127.55 (2x), 127.51 (2x),
81.82, 73.36, 73.28, 67.46, 66.81, 45.55, 40.49, 35.18, 34.84, 34.65; Anal. Calcd for C23H26O4: C, 75.38;
H, 7.15; Found: C, 75.47; H, 6.88.
2,3-Bisbenzyloxymethyl-4-(2-hydroxyethyl)cyclopentan-1-ol (19).
Lithium aluminum hydride (350 mg, 9.21 mmol) was added to a stirred solution of lactone (11) (2.71 g,
7.40 mmol) in tetrahydrofuran (100 mL) at ice bath. The reaction mixture was further stirred for 3 h at rt.
The reaction was quenched with aqueous ammonium chloride solution (15%, 1 mL) and the mixture was
concentrated under reduced pressure. Water (10 mL) was added to the residue, and the mixture was
extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried,
filtered and evaporated under reduced pressure to afford crude product. Purification on silica gel
(hexane/ethyl acetate = 2/1) afforded pure diol (19) (2.46 g, 90%) as a viscous oil: IR (CHCl3) 3450, 1184
1
cm-1; HRMS (EI, M+) calcd for C23H30O4 370.2144, found 370.2145; H NMR (300 MHz, CDCl3) δ
13
7.35-7.26 (m, 10H), 4.52-4.31 (m, 4H), 4.18-4.14 (m, 1H), 3.73-3.45 (m, 6H), 2.45-1.10 (m, 9H); C
NMR (75 MHz, CDCl3) δ 138.41, 136.82, 128.62 (2x), 128.37 (2x), 128.23 (2x), 128.03 (2x), 127.97,
127.68, 73.80, 73.33, 72.30, 67.71, 66.79, 62.27, 47.96, 42.93, 42.45, 37.29, 34.28; Anal. Calcd for
C23H30O4: C, 74.56; H, 8.16; Found: C, 74.40; H, 7.98.
7-Methyl-1,3,4,4a,5,6,7,7a-octahydrocyclopenta[c]pyran-3,6-dione (21).8b
Excess Jones reagent (10 mL) was added to a solution of diol (19) (1.53 g, 4.14 mmol) in acetone (50 mL)
at rt. The mixture was stirred for 20 min and treated with 2-propanol (4 mL) to destroy the unreacted
oxidation reagent. After the solvent was removed, the residue was diluted with water (10 mL) and

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extracted with ether (4 x 50 mL). The combined organic layers were washed with brine, dried, filtered
and evaporated under reduced pressure to afford crude product. Without further purification, 10%
palladium on activated carbon (50 mg) and one drop of 37% hydrogen chloride solution were added to a
stirred solution of resulting compound in methanol (20 mL). Hydrogen was bubbled into the mixture for
10 min, and the reaction mixture was continued to stir for 10 h at rt. The catalyst was filtered through a
short plug of Celite and washed with methanol (2 x 20 mL). The combined organic layers were
evaporated under reduced pressure to afford crude product. Purification on silica gel (hexane/ethyl acetate
= 1/1) produced lactone (21) (570 mg, 82%, two steps from compound (19)) as a solid: mp 86-88 oC; IR
1
(CHCl3) 1733, 1245 cm-1; HRMS (EI, M+) calcd for C9H12O3 168.0786, found 168.0784; H NMR (300
MHz, CDCl3) δ 3.87 (dd, J = 3.9, 11.7 Hz, 1H), 4.26 (dd, J = 4.5, 11.7 Hz, 1H), 2.98-2.76 (m, 2H), 2.61
(dd, J = 9.3, 19.2 Hz, 1H), 2.45 (dd, J = 6.0, 15.3 Hz, 1H), 2.35-2.27 (m, 2H), 2.20 (dd, J = 5.4, 19.2 Hz,
1H), 1.14 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 215.88, 171.69, 68.75, 43.77, 43.29, 40.68,
34.81, 28.04, 13.24; Anal. Calcd for C9H12O3: C, 64.27; H, 7.19; Found: C, 64.51; H, 7.32.
7-Methyl-1,3,4,4a,5,6,7,7a-octahydrocyclopenta[c]pyran-3-one (22).10j
1,2-Ethanedithiol (32 mg, 0.34 mmol) was added to ketone (21) (50 mg, 0.30 mmol) in dichloromethane
(10 mL), and boron trifluoride etherate (0.02 mL) was added to the reaction mixture. The mixture was
stirred for 24 h at rt. Saturated aqueous sodium bicarbonate solution (5 mL) was added to the resulting
mixture and then the whole was concentrated under reduced pressure. The residue was diluted with water
(5 mL) and extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with
brine, dried, filtered and evaporated under reduced pressure to afford crude compound. Purification on
silica gel (hexane/ethyl acetate = 4/1) produced dithiane compound (69 mg, 95%) as a solid: mp 120-122
oC; HRMS (EI, M+) calcd for C11H16O2S2 244.0592, found 244.0587; 1H NMR (300 MHz, CDCl3) δ 4.29
(dd, J = 3.9, 11.4 Hz, 1H), 4.15 (dd, J = 3.9, 11.4 Hz, 1H), 3.35-3.22 (m, 4H), 2.80-2.38 (m, 4H),
13
2.25-2.14 (m, 1H), 2.12-2.00 (m, 1H), 1.96-1.84 (m, 1H), 1.16 (d, J = 6.6 Hz, 3H); C NMR (75 MHz,
CDCl3) δ 172.76, 74.36, 68.08, 51.49, 46.25, 42.98, 39.60, 39.49, 33.87, 32.26, 13.26; Anal. Calcd for
C11H16O2S: C, 54.06; H, 6.60; Found: C, 54.15; H, 6.49.
Raney nickel (100 mg) was added to a stirred solution of dithiane compound (50 mg, 0.2 mmol) in
methanol (10 mL) at rt. The reaction mixture was reflux for 24 h. Raney nickel was filtered through a
short plug of Celite and washed with methanol (2 x 20 mL). The combined organic layers were
evaporated under reduced pressure to afford crude product. Purification on silica gel (hexane/ethyl acetate
o
= 4/1) produced lactone (22) (21 mg, 67%) as a solid: mp 56-57 C; HRMS (EI, M+) calcd for C9H14O2
154.0994, found 154.0993; 1H NMR (300 MHz, CDCl3) δ 4.27 (dd, J = 4.2, 11.4 Hz, 1H), 4.15 (dd, J =
4.2, 11.4 Hz, 1H), 2.65-2.55 (m, 2H), 2.39-2.21 (m, 1H), 2.08-1.95 (m, 1H), 1.94-1.68 (m, 3H), 1.33-1.07

HETEROCYCLES, Vol. 68, No. 2, 2006
281
(m, 2H), 1.06 (d, J = 6.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 172.65, 68.87, 44.85, 37.42, 34.90, 34.86,
34.62, 33.45, 18.73.
ACKNOWLEDGEMENTS
The authors would like to thank the National Science Council (NSC 94-2113-M-390-001) of the Republic
of China for financial support.
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