Formal total synthesis of (?)-hamigeran B from a chemo-enzymatically prepared building block with quaternary chiral center

Article abstract of DOI:10.1016/j.tet.2017.12.054

A formal total synthesis of (?)-hamigeran B was achieved in 17 steps from commercially available ethyl 2-oxocyclopentanecarboxylate. Carbonyl reductase-catalyzed asymmetric reduction and the subsequent chemical transformations furnished an enantiomerically pure synthetic intermediate, (R)-5-formyl-2-isopropyl-5-methylcyclopent-1-en-1-yl trifluoromethylsulfonate. Suzuki-Miyaura coupling with Gao's arylboronate [2-(2-formyl-3-methoxy-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane], under PdCl₂(dppf)?CH₂Cl₂ catalysis, and the subsequent cyclization by way of intramolecular reductive SmI₂-mediated 1,2-diol formation provided a tricyclic skeleton with a tetrasubstituted double bond between C-1 and C-9b. Upon hydrogenation of this double bond, the proper stereochemistry of the remaining chiral centers was established. Exclusive addition of the hydrogen atom from the β-face occurred, owing to the shielding of the α-face with a bulky TBS protective group on the C-4 alcohol. The hydrogenation products were transformed into Clive's synthetic precursor for (?)-hamigeran B.

Full text of DOI:10.1016/j.tet.2017.12.054

Accepted Manuscript
Formal total synthesis of (–)-hamigeran B from a chemo-enzymatically prepared
building block with quaternary chiral center
Kazuaki Kuwata, Rie Fujita, Kengo Hanaya, Shuhei Higashibayashi, Takeshi Sugai
PII:
S0040-4020(17)31338-8
10.1016/j.tet.2017.12.054
TET 29210
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 30 November 2017
Revised Date: 25 December 2017
Accepted Date: 27 December 2017
Please cite this article as: Kuwata K, Fujita R, Hanaya K, Higashibayashi S, Sugai T, Formal total
synthesis of (–)-hamigeran B from a chemo-enzymatically prepared building block with quaternary chiral
center, Tetrahedron (2018), doi: 10.1016/j.tet.2017.12.054.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Formal total synthesis of (–)-hamigeran B from a chemo-enzymatically prepared building block
with quaternary chiral center
Kazuaki Kuwata, Rie Fujita, Kengo Hanaya, Shuhei Higashibayashi, Takeshi Sugai*
Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen,
Minato-ku, Tokyo 105-8512, Japan
*Corresponding author. e-mail: sugai-tk@pha.keio.ac.jp
Abstract
A formal total synthesis of (–)-hamigeran B was achieved in 17 steps from commercially
available ethyl 2-oxocyclopentanecarboxylate. Carbonyl reductase-catalyzed asymmetric
reduction and the subsequent chemical transformations furnished an enantiomerically pure synthetic
intermediate, (R)-5-formyl-2-isopropyl-5-methylcyclopent-1-en-1-yl trifluoromethylsulfonate.
Suzuki-Miyaura coupling with Gao’s arylboronate [2-(2-formyl-3-methoxy-5-methylphenyl)-
4
,4,5,5-tetramethyl-1,3,2-dioxaborolane], under PdCl (dppf)•CH Cl catalysis, and the subsequent
2 2 2
cyclization by way of intramolecular reductive SmI -mediated 1,2-diol formation provided a
2
tricyclic skeleton with a tetrasubstituted double bond between C-1 and C-9b. Upon hydrogenation
of this double bond, the proper stereochemistry of the remaining chiral centers was established.
Exclusive addition of the hydrogen atom from the β-face occurred, owing to the shielding of the α-
face with a bulky TBS protective group on the C-4 alcohol. The hydrogenation products were
transformed into Clive’s synthetic precursor for (–)-hamigeran B.
1

ACCEPTED MANUSCRIPT
1. Introduction
In 2000, (–)-hamigeran B (1) was isolated from marine sponge, Hamigera tarangaensis, and
1
found to show antiviral activity. Since then, many efforts have been devoted to its chemistry and
2
-16
many total and formal total syntheses have been achieved.
We envisaged that Clive’s diketone
5
(
1R,3aR,9bR)-2, a synthetic precursor for 1, could be synthesized by stepwise transformation
1
7
involving: 1) Suzuki-Miyaura coupling between Gao’s arylboronate 3 and (R)-4 with the proper
1
6
branched side chain and quaternary chiral center; and 2) SmI -mediated ring closure as the key
2
steps (Scheme 1). The cyclopentenoid (R)-4 would be available from (S)-5, and its alkenyl triflate
moiety was expected to aid in the palladium-catalyzed C-C bond formation.
Scheme 1. Synthetic plan for (–)-hamigeran B (1) and the precursor (1R,3aR,9bR)-2, by the
coupling between aromatic segment 3 and cyclopentenoid segment (R)-4 and subsequent ring
closure.
2. Results and discussion
1
8
To this end, in the same manner as the synthesis of its antipode (R)-5, (S)-5 was synthesized
from 6 by enzyme-catalyzed asymmetric reduction and 8 additional chemical transformations of the
resulting stereochemically pure (1R,2S)-7. 1-Methyl-2-azaadamantane N-oxyl (1-Me-AZADO)-
catalyzed oxidation of the primary alcohol furnished (R)-4 in 84% yield (Scheme 2). Its
2

ACCEPTED MANUSCRIPT
counterpart, arylboronate 3, was prepared from 3,5-dihydroxytoluene in 4 steps.
2
0
17,21,22
Scheme 2. Suzuki-Miyaura coupling between 3 and (R)-4 and the SmI -mediated ring closure.
2
3

ACCEPTED MANUSCRIPT
Suzuki-Miyaura coupling between 3 and (R)-4 was accomplished under Gao’s conditions with
PdCl (dppf)•CH Cl as the catalyst to furnish (R)-8 in 68% yield (Scheme 2). Switching the
2
2
2
palladium catalyst to PEPPSI-IPr or PEPPSI-SIPr, which had been reported to be effective for the
2
3
coupling of sterically hindered substrates, the yield of 8 decreased (ca. 40%). When the
coupling between 3 and another triflate (S)-5 was attempted, only an undesired borate ester on the
primary alcohol in 5 and a homo-coupling byproduct originating from 3 were observed. Moreover,
all attempts at Stille coupling, which was successful with a very similar cyclopentenyl triflate and
2
4
alkenylstannane failed with the corresponding aryltrimethylstananne instead of 3.
The coupling product (R)-8 was revealed to be a 56:44 mixture of two rotamers judging by its
1
H NMR spectrum as shown in section 4.3. The next step, the ring closure of 8, proceeded almost
quantitatively by treatment with SmI in tetrahydrofuran (THF) at –20 °C. In contrast to the
2
normal facial selectivity which prefers cis-1,2-diol formation, the preference for the trans-isomer in
an intramolecular fashion had been reported in a similar substrate with a rigid structure and bulky
1
6
neighboring substituents.
In our case, two diastereomers (3aR,4R,5R)-9a (51%) and
(3aR,4S,5S)-9a (49%) formed, which presumably originated from each rotamer in (R)-8, and were
separated by silica gel column chromatography.
The trans-stereochemistries of both diastereomers were assigned by the comparison of nuclear
1
Overhauser effect (nOe) and coupling constants in H NMR spectra as depicted in Figure 1. Upon
irradiation at methyl group at C-3a, nOe was observed at H-4 (4.0%) for (3aR,4R,5R)-9a, but at H-3
(2.0%) for (3aR,4S,5S)-9a. Coupling constants between H-4 and H-5 were agreeable for trans-
isomers; 0 Hz for (3aR,4R,5R)-9a and 7.4 Hz for (3aR,4S,5S)-9a as shown in Figure 1. It is also
4

ACCEPTED MANUSCRIPT
noted that both of H NMR spectra of (3aR,4R,5R)-9a and (3aR,4S,5S)-9a were different from that
1
1
7
of previously reported corresponding cis-9a.
Figure 1. Assignment of the stereochemistry by NMR analyses of SmI -mediated ring closure
2
products, (3aR,4R,5R)-9a and the diastereomeric (3aR,4S,5S)-9a.
The final task was the installation of the correct stereochemistry at C-1 and C-9b by
7
hydrogenation. Clive’s pioneering work revealed that a large substituent oriented over the α-face
at C-4 is necessary to control the stereochemistry at C-1 and C-9b to yield the desired (1R,9bR)-
stereochemistry upon hydrogenation of the double bond between C-1 and C-9b.
Thus, (3aR,4R,5R)-9a was submitted to the following sequence to form 2. As expected from
the 1,3-diaxial repulsion of bulky protective group on the C-5 hydroxy group and C-3a methyl
group, less sterically hindered alcohol at C-4 was protected with a tert-butyldimethylsilyl (TBS)
group (Scheme 2). The remaining pseudo-axially oriented secondary alcohol at C-5 was then
protected with a small acetyl group to minimize the blocking of the β-face upon hydrogenation.
5

ACCEPTED MANUSCRIPT
In contrast, such desired approach of hydrogen atoms from the β-face cannot be expected for
(3aR,4S,5S)-9a which has both substituents at C-4 and C-5 in the pseudo-equatorial orientation, as
shown in Figure 1. Therefore, this diastereomer was recycled into the cyclization precursor (R)-8,
by C-C bond cleavage of the trans-1,2-diol moiety by oxidation with lead tetraacetate in 72% yield
(Scheme 2). The resulting (R)-8 became a mixture of rotamers again, as in almost same ratio as
1
the above-mentioned Suzuki-Miyaura coupling product, as indicated by the H NMR spectrum.
The hydrogenation of 9c catalyzed by Pd (5%) on charcoal was sluggish even under high
pressure of hydrogen gas. Desired (1R,3aR,4R,5R,9bR)-10a was obtained only in as low as 28%
yield with recovery of starting material (48%) (Scheme 3). To overcome the low efficiency, the
catalyst loading was increased from 5% to 10% under a higher concentration of the substrate in
ethanol. Under these conditions, deoxygenation at the benzylic C-5 position also occurred, and
(1R,3aR,4S,9bR)-11a was the major product with complete consumption of the starting material.
Hydrogenolysis at the benzylic position alleviated the steric hindrance, possibly promoting
hydrogenation of the tetrasubstituted double bond, although an intermediate for this pathway was
not detected in the crude products of the reaction. Pd(OH) brought about the same deoxygenation
2
at the benzylic C-5 position. Subsequent deprotection of the TBS ether in 11a furnished 11b in
82% yield from 9c.
6
-8
12
In contrast to the hydrogenation of conjugated tetrasubstituted bond (type A and type B ),
nobody has achieved the hydrogenation of an isolated double bond between C-1 and C-9b such as
in 9c. A possible intermediate, in which the double bond was isomerized to the disubstituted,
3
-5,9,10
sterically less hindered C-1 and C-2 positions (type C)
was not detected in our experiments.
6

ACCEPTED MANUSCRIPT
Scheme 3. Catalytic hydrogenation of tetrasubstituted double bond in 9c to 10a and 11a,
Alcohol 11b had been synthesized as an intermediate for (–)-hamigeran B by Taber and co-
1
0
workers. According to their procedure, 11b was submitted to tetra-n-propylammonium
perruthenate (TPAP)-catalyzed oxidation with N-methylmorpholine-N-oxide (NMO) as co-oxidant
to give Clives’ precursor 2 in 64% yield (Scheme 4). Physicochemical and spectral properties
2
1
were in good accordance with those of the previously reported sample [[α]D –228 (c 0.35,
8
CH Cl ); lit. [α] –187.1 (c 0.124, CH Cl )]. Then, transformation of 10a to 2 was also
2
2
D
2
2
attempted. Deprotection of the acetyl and TBS groups of the alcohols on C-4 and C-5 were
performed by sequential one-pot treatment with aqueous sodium hydroxide and tetra-n-
butylammonium fluoride (TBAF) solution in THF, to give (1R,3aR,4R,5R,9bR)-10b in 67% yield.
7

ACCEPTED MANUSCRIPT
Dess-Martin periodinane-mediated transformation of 10b preferred the oxidation at benzylic
position. The product was a 1:1.7 mixture of 2 and the corresponding hydroxyketone whose
hydroxy group at C-4 was intact. Instead, Swern oxidation proceeded on both secondary alcohols
at C-4 and C-5 to furnish 2, but the yield was as low as 38% (Scheme 4). The combined yield of 2
from 9c through 11b (52%) was much higher than that through 10a (7%).
OMe
H
OMe O
OH
O
TPAP, NMO
MS 4A
CH Cl
2
2
H
64%
11b
(1R,3aR,9bR)-2
OMe OAc
OMe OH
OTBS
OH
(
COCl)2
TBAF
NaOH aq.
DMSO, Et N
3
2
CH Cl
2
H
H
2
THF, 67%
–78 ~ 0 °C
38%
10a
(1R,3aR,4R,5R,9bR)-10b
Scheme 4. Transformation of 11b and 10a to (1R,3aR,9bR)-2, the intermediate of natural (–)-
hamigeran B via oxidation of the precursors.
3. Conclusion
The aldehyde (R)-4 with a cyclopentene skeleton and stereochemically pure chiral center was
effectively utilized in the formal total synthesis of (–)-hamigeran B. The tricyclic structure was
obtained by successive Suzuki-Miyaura coupling of two segments, and subsequent cyclization
mediated by the reductive coupling of two aldehydes with SmI . Upon hydrogenation, the
2
8

ACCEPTED MANUSCRIPT
stereochemistries of the remaining chiral centers at C-1 and C-9b were controlled with exclusive
selectivity, by the introduction of a bulky protective group at C-4. In this way, we achieved a
formal synthesis of (–)-hamigeran B in 17 steps from commercially available 6.
4
4
. Experimental
.1. General
Hydrogenation under high pressure was performed in a pressure vessel with inner vessel and
impeller, EYELA HIP-60. IR spectra were measured as ATR on a Jeol FT-IR SPX60 spectrometer.
1
H NMR spectra were measured in CDCl at 400 MHz on a VARIAN 400-MR spectrometer or at
3
1
3
5
00 MHz on a VARIAN 500-MR spectrometer and C NMR spectra were measured in CDCl at
3
100 MHz on a VARIAN 400-MR spectrometer or at 125 MHz on a VARIAN 500-MR spectrometer.
Merck silica gel 60 N (spherical, neutral, 63-210 µm, 37565-84) from Kanto Chemical Co. was
used for column chromatography, respectively. Optical rotation values were recorded on a Jasco
P-1010 polarimeter.
4.2. (R)-5-Formyl-2-isopropyl-5-methylcyclopent-1-ene-1-yl trifluoromethylsulfonate 4
To a solution of alcohol (S)-5 (71.8 mg, 0.238 mmol) in CH Cl (2.0 mL) were added 1-Me-
2
2
AZADO (1.1 mg, 0.006 mmol) and PhI(OAc) (81.0 mg, 0.251 mmol) at 0 °C and stirred for 4 h at
2
that temperature. The reaction was quenched with saturated Na S O aq. solution and organic
2
2
3
materials were extracted with EtOAc three times. The combined extract was washed with brine,
dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by
2
4
silica gel column chromatography with hexane/EtOAc (60:1–10:1) to give an aldehyde (R)-4 (60.2
9

ACCEPTED MANUSCRIPT
2
4
1
mg, 84%) as a colorless oil. [α]D +125.5 (c 1.14, CHCl3). H NMR (500 MHz, CDCl ): δ
3
1
.07 (3H, d, J = 6.9 Hz), 1.08 (3H, d, J = 6.9 Hz), 1.29 (3H, s), 1.80 (1H, ddd, J = 13.4, 8.0, 4.4 Hz),
.31 (1H, ddd, J = 13.5, 8.0, 4.4 Hz), 2.38–2.48 (2H, m), 2.92 (1H, qq, J = 6.9, 6.9 Hz), 9.56 (1H,
2
1
3
s); C NMR (125 MHz, CDCl ): δ 17.2, 20.2, 20.5, 24.4, 26.1, 31.0, 58.0, 117.1, 118.3 (q, J =
3
–
1
3
19.6 Hz), 139.3, 144.5, 199.2; IR νmax 2970, 2937, 1732, 1410, 1212 cm . HRMS (DART)
+
[
M+H] calculated for C H F O S : 301.1721, found: 301.0719.
11
16
3
4 1
4.3. (R)-5-(5’-Formyl-2’-isopropyl-5’-methylcyclopent-1’-enyl)-6-methoxy-4-
methylbenzaldehyde 8
To a mixture of PdCl (dppf)•CH Cl (10.5 mg, 0.013 mmol) and K CO was added a solution
2
2
2
2
3
of boronate 3 (81.5 mg, 0.295 mmol) and triflate (R)-4 (80.5 mg, 0.268 mmol) in DMSO (4.0 mL)
and stirred for 12 h at 80 °C under argon atmosphere. The reaction was quenched with H O and
2
organic materials were extracted with EtOAc twice. The combined extract was washed with brine,
dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by
2
4
silica gel column chromatography with hexane/EtOAc (1:0–20:1) to furnish a 56:44 rotamer
1
mixture of 8 (55.1 mg, 68%,) as a pale-yellow oil. H NMR (500 MHz, CDCl ): δ 0.87 (1.32H, d,
3
J = 8.7 Hz), 0.89 (1.32H, d, J = 6.9 Hz), 0.91 (1.68H, d, J = 6.9 Hz), 0.93 (1.68H, d, J = 6.9 Hz),
1
2
3
9
1
.04 (1.68H, s), 1.10 (1.32H, s), 1.77–1.81(0.44H, m), 1.88 (0.56H, ddd, J = 13.2, 9.3, 9.3 Hz),
.17–2.20 (0.56H, m), 2.28–2.38 (1H, m), 2.34 (1.68H, s), 2.38 (1.32H, s), 2.47–2.60 (2.56H, m),
.88 (1.32H, s), 3.91 (1.68H, s), 6.25 (0.56H, s), 6.40 (0.44H, s), 6.72 (0.56H, s), 6.73 (0.44 H, s),
1
3
.53 (0.44H, s), 9.61 (0.56H, s), 10.25 (0.56H, s), 10.31 (0.44H, s); C NMR (125 MHz, CDCl ): δ
3
7.5, 19.8, 19.9, 20.4, 21.1, 21.7, 22.3, 22.3, 28.2, 28.5, 28.7, 28.9, 32.7, 33.2, 55.7, 55.8, 63.7, 64.1,
1
0

ACCEPTED MANUSCRIPT
111.5, 111.5, 121.2, 121.9, 123.2, 124.9, 131.9, 134.9, 139.0, 141.3, 145.4, 146.0, 147.9, 152.4,
161.1, 162.3, 190.2, 190.9, 201.9, 203.7; IR νmax 2958, 2927, 1718, 1688, 1599, 1568, 1449, 1401,
–
1
+
1
289 cm ; HRMS (ESI) [M+Na] calculated for C H NaO : 323.1623, found: 323.1650.
19 24 3
4.4. (3aR,4R,5R)-1-Isopropyl-6-methoxy-3a,8-dimethyl-2,3,4,5-tetrahydro-3aH-
cyclopenta[a]naphthalene-4,5-diol 9a and (3aR,4S,5S)-9a
To a solution of SmI (0.1 M in THF, 1.9 mL) was added a solution of aldehyde 8 (5.8 mg,
2
0.019 mmol) at –20 °C and stirred at that temperature for 5 h under argon atmosphere. The
reaction was quenched with saturated sodium/potassium tartrate aq. solution and the organic
materials were extracted with EtOAc three times. The combined extract was washed with brine,
dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by
2
4
silica gel column chromatography with hexane/EtOAc (1:0–1:1) to furnish (3aR,4R,5R)-9a (3.0 mg,
1%) and (3aR,4S,5S)-9a (2.9 mg, 49%) as colorless oil.
3aR,4R,5R)-9a: R = 0.50 (hexane:EtOAc = 2:1). [α] –154 (c 0.50, CHCl3). H NMR
5
2
D
5
1
(
f
(
500 MHz, CDCl ): δ 1.05 (3H, d, J = 6.6 Hz), 1.15 (3H, s), 1.22 (3H, d, J = 6.8 Hz), 1.25 (1H, d, J
3
=10.0 Hz), 1.63 (1H, ddd, J = 13.2, 9.8, 4.9 Hz), 2.22 (1H, ddd, J = 13.2, 10.0, 6.8 Hz), 2.35 (3H, s),
2.46–2.60 (2H, m), 3.16 (1H, s), 3.24 (1H, qq, J = 6.8, 6.6 Hz), 3.76 (1H, d, J = 10.0 Hz), 3.89 (3H,
1
3
s), 4.83 (1H, s), 6.67 (1H, s), 6.88 (1H, s); C NMR of (3aR,4R,5R)-9a (125 MHz, CDCl ): δ 21.5,
3
21.9, 22.0, 23.4, 27.4, 29.8, 31.8, 51.4, 55.4, 70.3, 76.8, 110.1, 120.4, 121.6, 130.5, 132.5, 138.2,
–
1
+
1
48.5, 158.4; IR νmax 3427, 2956, 1607, 1572, 1455, 1343 cm ; HRMS (ESI) [M+Na] calculated
for C H NaO : 325.1779, found: 325.1773.
1
9
26
3
2
2
1
(
3aR,4S,5S)-9a: R = 0.20 (hexane:EtOAc = 2:1). [α] –158 (c 0.64, CHCl3). H NMR
f
D
11

ACCEPTED MANUSCRIPT
(
500 MHz, CDCl ): δ 0.95 (3H, s), 1.01 (3H, d, J = 6.6 Hz), 1.18 (3H, d, J = 6.8 Hz), 1.72 (1H, ddd,
3
J = 13.2, 8.8, 4.4 Hz), 1.99 (1H, ddd, J = 13.2, 9.5, 8.1 Hz), 2.35 (3H, s), 2.40–2.43 (1H, br-s) 2.49–
2
4
2
1
.59 (2H, m), 3.20 (1H, qq, J = 6.8, 6.6 Hz), 3.76 (1H, d, J = 7.4 Hz), 3.89 (3H, s), 4.03 (1H, s),
1
3
.84 (1H, d, J = 7.4 Hz), 6.60 (1H, s,), 6.85 (1H, s); C NMR (125 MHz, CDCl ): δ 17.2, 21.2,
3
1.5, 21.9, 27.4, 29.7, 33.8, 53.2, 55.4, 73.0, 81.0, 109.6, 120.7, 122.6, 133.3, 134.7, 138.3, 145.0,
–
1
+
57.9; IR νmax 3437, 2958, 1607, 1573, 1456, 1342 cm ; HRMS (ESI) [M+Na] calculated for
C H NaO : 325.1779, found: 325.1787.
19
26
3
4.5. (3aR,4R,5R)-4-tert-Butyldimethylsilyloxy-1-isopropyl-6-methoxy-3a,8-dimethyl-2,3,4,5-
tetrahydro-3aH-cyclopenta[a]naphthalene-5-yl acetate 9c
To a solution of (3aR,4R,5R)-9a (9.2 mg, 0.030 mmol) in CH Cl (0.7 mL) was added 2,6-
2
2
lutidine (21 µL, 0.179 mmol) and TBSOTf (17 µL, 0.074 mmol) at 0 °C, and the mixture was
stirred for 30 min at that temperature. The reaction was quenched with phosphate buffer solution
(pH 7.0, 0.1 M), and the organic materials were extracted with EtOAc twice. The combined
extract was washed with brine and dried over Na SO , filtered, and concentrated under reduced
2
4
pressure to furnish crude TBS ether (3aR,4R,5R)-9b. To this was added pyridine (0.4 mL), Ac O
2
(0.4 mL) and 4-dimethylaminopyridine (DMAP, 4.6 mg, 0.038 mmol), and the mixture was stirred
for 16 h at room temperature. The reaction was quenched with H O and the organic materials
2
were extracted with EtOAc twice. The combined extract was washed with brine, dried over
Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel
2
4
column chromatography with hexane/EtOAc (1:0–20:1) to furnish (3aR,4R,5R)-9c (8.4 mg, 60%) as
2
2
1
a colorless amorphous powder. [α]D –129 (c 0.32, CHCl3). H NMR (500 MHz, CDCl ): δ
3
1
2

ACCEPTED MANUSCRIPT
0.12 (3H, s), 0.20 (3H, s), 0.78 (9H, s), 0.97 (3H, d, J = 6.8 Hz), 1.05 (3H, s), 1.19 (3H, d, J = 7.0
Hz), 1.44 (1H, ddd, J = 12.7, 9.0, 3.9 Hz), 2.00 (3H, s), 2.12 (1H, ddd, J = 12.7, 10.0, 7.5 Hz), 2.37
(3H, s), 2.40–2.51 (2H, m), 3.26 (1H, qq, J = 7.0, 6.8 Hz), 3.69 (1H, d, J = 1.7 Hz), 3.78 (3H, s),
1
3
5
2
1
.88 (1H, d, J = 1.7 Hz), 6.60 (1H, s), 6.91 (1H, s); C NMR (125 MHz, CDCl ): δ –5.2, –4.0, 18.0,
3
1.1, 21.5, 22.1, 23.4, 25.9 (3C), 27.5, 29.6, 31.7, 51.4, 55.4, 70.0, 75.7, 109.6, 117.6, 120.1, 131.2,
–
1
34.8, 138.3, 145.9, 158.8, 170.0; IR νmax 2955, 2928, 1732, 1607, 1574, 1462, 1235 cm ; HRMS
+
(
ESI) [M+Na] calculated for C H NaO Si: 481.2750, found: 481.2718.
2
7
42
4
4.6. C-C bond cleavage of (3aR,4S,5S)-9a
To a solution of (3aR,4S,5S)-9a (7.8 mg, 0.026 mmol) in THF (600 µL) was added pyridine (50
µL, 0.619 mmol) and Pb(OAc) (41 mg, 0.092 mmol) at 0 °C, and the mixture was gradually
4
warmed to room temperature with stirring for 2 h. The reaction was quenched with saturated
Na S O aq. solution and organic materials were extracted with EtOAc three times. The combined
2
2
3
extract was washed with brine, dried over Na SO , filtered, and concentrated under reduced
2
4
pressure. The residue was purified by silica gel column chromatography with hexane/EtOAc
1
(
20:1–10:1) to furnish 8 (5.6 mg, 72%) as a pale-yellow oil. The H NMR spectrum was identical
to that of 8 in section 4.3.
4
.7. (1R,3aR,4R,5R,9bR)-4-tert-Butyldimethylsilyloxy-1-isopropyl-6-methoxy-3a,8-dimethyl-
,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-5-yl acetate 10a
2
To a solution of 9c (6.4 mg, 0.014 mmol) in EtOH (2.0 mL) was added Pd/C (5% on carbon,
0.2 mg) in a pressure vessel as shown in section 4.1. The mixture was stirred under H2
1
1
3

ACCEPTED MANUSCRIPT
atmosphere (8 atm) for 39 h. Then the mixture was then filtered through a pad of Celite, and the
combined filtrate and washings were concentrated under reduced pressure. The residue was
purified by silica gel column chromatography with hexane/EtOAc (1:0–40:1) to furnish
(1R,3aR,4R,5R,9bR)-10a (1.8 mg, 28%) as a colorless oil and (3aR,4R,5R)-9c (3.1 mg, 48%
1
recovery). (1R,3aR,4R,5R,9bR)-10a: H NMR (500 MHz, CDCl ): δ 0.06 (6H, s), 0.59 (3H, d, J =
3
6
.6 Hz), 0.89 (9H, s), 0.97 (3H, d, J = 6.4 Hz), 0.97–1.54 (3H, m), 1.23 (3H, s), 1.34–1.42 (1H, m),
.85–1.91 (1H, m), 2.07 (3H, s), 2.29 (3H, s), 2.29–2.34 (1H, m), 3.02 (1H, d, J = 6.8 Hz), 3.65 (1H,
1
1
3
d, J = 7.8 Hz), 3.74 (3H, s), 6.13 (1H, d, J = 7.8 Hz), 6.52 (1H, s), 6.61 (1H, s); C NMR (125
MHz, CDCl ): δ –3.8, –3.7, 18.3, 21.5, 21.6, 21.9, 23.8, 26.0 (3C), 26.4, 28.4, 30.8, 33.1, 43.8, 53.9,
3
5
1
4
3.2, 55.3, 70.4, 77.8, 109.4, 121.4, 122.8, 137.0, 138.2, 157.2, 170.9; IR νmax 2954, 2928, 1745,
–
1
+
610, 1579, 1235 cm ; HRMS (ESI) [M+Na] calculated for C H NaO Si: 483.2907, found:
2
7
44
4
83.2906.
4.8. (1R,3aR,4S,9bR)-1-Isopropyl-6-methoxy-3a,8-dimethyl-2,3,3a,4,5,9b-hexahydro-1H-
cyclopenta[a]naphthalen-4-ol 11b
In a similar manner as described in the section 4.7, a mixture of 9c (22.0 mg, 0.048 mmol) and
Pd/C (10% on carbon, 21.0 mg) in EtOH (3.0 mL) was stirred under H atmosphere (8 atm) for 20 h.
2
The mixture was filtered through a pad of Celite, and the combined filtrate and washings were
concentrated under reduced pressure. The residue was dissolved in a mixture of hexane/EtOAc
1
(
40:1), and the solution was filtered through short pad of silica gel to furnish 11a. H NMR (500
MHz, CDCl ): δ 0.00 (3H, s), 0.07 (3H, s), 0.63 (1H, d, J = 6.7 Hz), 0.91 (9H, s), 0.97–1.03 (1H,
3
m), 1.07 (1H, d, J = 6.2 Hz), 1.19 (3H, s), 1.39–1.43 (1H, m), 1.79–1.88 (1H, m), 2.21–2.27 (1H,
1
4

ACCEPTED MANUSCRIPT
m), 2.30 (3H, s), 2.34 (1H, dd, J = 15.6, 11.2 Hz), 2.90 (1H, dd, J = 15.6, 4.3 Hz), 2.95 (1H, d, J =
1
3
7
.0 Hz), 3.48 (1H, dd, J = 11.2, 4.3 Hz), 3.79 (3H, s), 6.50 (1H, s), 6.60 (1H, s); C NMR (125
MHz, CDCl ): δ –4.9, –3.9, 18.1, 21.5, 21.7, 23.9, 25.9 (3C), 26.5, 28.6, 29.8, 30.4, 32.6, 46.1, 53.7,
3
53.8, 55.4, 76.0, 108.2, 122.8, 123.1, 134.8, 138.5, 156.4. This was employed for the next step
without further purification.
To a solution of the above-mentioned 11a in THF (400 µL) was added TBAF (1.0 M in THF,
4
00 µL) and the mixture was stirred at 40 °C for 15 h. The reaction was quenched with H O and
2
organic materials were extracted with EtOAc three times. The combined extract was washed with
brine, dried over Na SO and filtered. The filtrate was concentrated under reduced pressure and
2
4
the residue was purified by silica gel column chromatography with hexane/EtOAc (20:1–5:1) to
2
1
furnish (1R,3aR,4S,9bR)-11b (11.3 mg, 82% from 9c) as a colorless solid. [α]D +70 (c 0.56,
1
CHCl3). H NMR (500 MHz, CDCl ): δ 0.66 (3H, d, J = 6.6 Hz), 0.96 (1H, m), 1.09 (3H, d, J =
3
6.1 Hz), 1.13 (1H, m), 1.30 (3H, s), 1.48 (1H, m), 1.61 (1H, m), 2.11 (1H, m), 2.30 (3H, s), 2.38
(1H, dd, J = 15.4, 11.5 Hz), 3.00 (1H, d, J = 6.4 Hz), 3.02 (1H, dd, J = 15.4, 4.4 Hz), 3.55 (1H, dd,
1
3
J = 11.5, 4.4 Hz), 3.79 (3H, s), 6.51 (1H, s), 6.60 (1H, s); C NMR (125 MHz, CDCl ): δ 21.5, 21.7,
3
23.9, 26.4, 28.3, 29.6, 29.7, 31.9, 45.7, 53.4, 53.9, 55.3, 75.7, 108.3, 122.5, 122.7, 135.0, 138.2,
–
1
+
1
56.3; IR νmax 2939, 2867, 1463, 1272 cm ; HRMS (ESI) [M+Na] calculated for C H NaO :
19 28 2
311.1987, found: 311.1962. Its NMR and IR spectra were identical with those reported
11
previously.
4.9. (1R,3aR,9bR)-1-Isopropyl-6-methoxy-3a,8-dimethyl-2,3,3a,9b-tetrahydro-1H-
cyclopenta[a]naphthalene-4,5-dione 2
1
5

ACCEPTED MANUSCRIPT
To a suspension of 11b (8.5 mg, 0.030 mmol) and powdered 4A molecular sieve (93.6 mg) in
CH Cl (1.0 mL) were added NMO (41.0 mg, 0.350 mmol) and TPAP (6.0 mg, 0.017 mmol), and
2
2
stirred under argon atmosphere for 4 h. The reaction mixture was directly purified by silica gel
column chromatography with hexane/EtOAc (10:1-2:1) to furnish a diketone 2 (5.7 mg, 64%) as a
2
1
1
pale-yellow oil. [α]D –228 (c 0.35, CH Cl ). H NMR (500 MHz, CDCl ): δ 0.44 (3H, d, J =
2
2
3
6.6 Hz), 0.57 (3H, d, J = 6.6 Hz), 1.14–1.23 (1H, m), 1.27 (3H, s), 1.48–1.59 (2H, m), 1.75–1.81
(1H, m), 2.20–2.28 (1H, m), 2.41 (3H, s), 2.47–2.52 (1H, m), 3.35 (1H, d, J = 9.5 Hz), 3.93 (3H, s),
1
3
6
5
1
.71 (1H, s), 6.77 (1H, s); C NMR (125 MHz, CDCl ): δ 20.4, 22.4, 23.1, 24.2, 28.0, 28.6, 35.4,
3
1.9, 55.1, 56.0 (2C), 110.9, 120.6, 124.4, 145.9, 147.2, 161.4, 180.8, 201.7; IR νmax 2955, 1721,
–
1
+
677, 1604 cm ; HRMS (ESI) [M+Na] calculated for C H NaO : 323.1623, found: 323.1634.
1
9
24
3
8
Its NMR, IR and MS spectra were identical with those reported previously.
4.10. (1R,3aR,4R,5R,9bR)-1-Isopropyl-6-methoxy-3a,8-dimethyl-2,3,3a,4,5,9b-hexahydro-1H-
cyclopenta[a]naphthalene-4,5-diol 10b
To (1R,3aR,4R,5R,9bR)-10a (1.8 mg, 3.9 µmol) were added TBAF (1.0 M in THF, 500 µL) and
NaOH (2.0 M in H O, 120 µL) and the mixture was stirred at 70 °C for 45 h. The reaction was
2
quenched with H O and organic materials were extracted with EtOAc three times. The combined
2
extract was washed with brine, dried over Na SO and filtered. The filtrate was concentrated
2
4
under reduced pressure and the residue was purified by silica gel column chromatography with
1
hexane/EtOAc (10:1–2:1) to furnish (1R,3aR,4S,9bR)-10b (0.8 mg, 67%) as a colorless oil.
H
NMR (500 MHz, CDCl ): δ 0.61 (3H, d, J = 6.6 Hz), 0.75–0.85 (1H, m), 1.07 (3H, d, J = 6.4 Hz),
3
1.18 (1H, ddd, J = 14.1, 12.0, 7.3 Hz), 1.31–1.39 (1H, m), 1.35 (3H, s), 1.54–1.60 (1H, m), 1.60–
1
6

ACCEPTED MANUSCRIPT
1.68 (1H, m), 2.19 (1H, m), 2.30 (3H, s), 3.01 (1H, d, J = 6.7 Hz), 3.46 (1H, d, J = 9.0 Hz), 3.87
1
3
(
3H, s), 4.73 (1H, d, J = 9.0 Hz), 6.58 (1H, s), 6.64 (1H, s); C NMR (125 MHz, CDCl ): δ 21.4,
3
2
1
1.6, 23.8, 26.3, 28.8, 29.6, 32.3, 43.0, 53.0, 53.1, 55.4, 69.5, 79.9, 109.4, 123.7, 124.4, 136.7,
–
1
+
37.5, 156.8; IR νmax 3493, 2952, 2866, 1612, 1577, 1462 cm ; HRMS (ESI) [M+Na] calculated
for C H NaO : 327.1936, found: 327.1955.
1
9
28
3
4.11. Synthesis of (1R,3aR,9bR)-2 by the oxidation of 10b
To a solution of (COCl) (5 µL, 0.058 mmol) in CH Cl (200 µL) was added a solution of
2
2
2
dimethyl sulfoxide (DMSO, 6 µL, 0.084 mmol) in CH Cl (200 µL) at –78 °C, and the mixture was
2
2
stirred under argon atmosphere at that temperature for 30 min. To the mixture was added a
solution of the diol (1R,3aR,4S,9bR)-11b (0.8 mg, 2.6 µmol) in CH Cl (200 µL) and the stirring
2
2
was continued at the same temperature. After 30 min, Et N (40 µL, 0.288 mmol) was added to the
3
mixture, and the temperature was gradually raised to 0 °C for over 2 h with stirring. The reaction
was quenched with saturated NH Cl aq. and the organic materials were extracted with EtOAc twice.
4
The combined extract was washed with brine, dried over Na SO , filtered, and concentrated under
2
4
reduced pressure. The residue was purified by silica gel column chromatography with
1
hexane/EtOAc (1:0–20:1) to furnish (1R,3aR,9bR)-2 (0.3 mg, 38%) as a pale-yellow oil. Its H
+
NMR spectrum was identical to that in section 4.9. HRMS (ESI) [M+Na] calculated for
C H NaO : 323.1623, found: 323.1639.
19
24
3
Acknowledgements
We express sincere thanks to Prof. Funitoshi Kakiuchi of Department of Chemistry, Keio
1
7

ACCEPTED MANUSCRIPT
University for the measurement of high resolution mass spectrum of (R)-5. This work was
supported by JSPS KAKENHI (16J01810 for K. K.) and acknowledged with thanks.
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