Synthesis of the 1,2-seco fusicoccane diterpene skeleton by Stille coupling reaction between the highly functionalized A and C ring segments of cotylenin A

Article abstract of DOI:10.1016/j.tet.2017.08.056

1-Hydroxy-14-isopropyl-3β-methoxymethyl-7β,11β-dimethyl-3α-[((2-trimethylsilyl)ethoxy)methoxy]-1,2-secofusicocca-8,10(14)-dien-2-one, a highly functionalized 1,2-seco fusicoccane diterpene skeleton related to cotylenin A was synthesized in a convergent manner. The A ring segment, i. e., (1′R,2S, 2′E,5S)-2-methoxymethyl-5-[1′-methyl-3’-(trimethylstannyl)prop-2-enyl]-2-[((2″-trimethylsilyl)ethoxy)methoxy]cyclopentanone, was synthesized in 20.1% yield over 18 steps from known (S)-5-isopropenyl-2-methylcyclopent-1-enecarbaldehyde. This was coupled with the C ring segment, i. e., (R)-5-hydroxymethyl-2-isopropyl-5-methylcyclopent-1-en-1-yl trifluoromethylsulfonate, which was prepared according to our previous report. The Stille coupling reaction between alkenylstannane and sterically hindered triflate proceeded successfully in the presence of PEPPSI-SIPr (85%), and the total yield of the target molecule was 17.1% over the longest linear sequences (19 steps) from (S)-5-isopropenyl-2-methylcyclopent-1-enecarbaldehyde.

Full text of DOI:10.1016/j.tet.2017.08.056

Accepted Manuscript
Synthesis of the 1,2-seco fusicoccane diterpene skeleton by Stille coupling reaction
between the highly functionalized A and C ring segments of cotylenin A
Kazuaki Kuwata, Kengo Hanaya, Shuhei Higashibayashi, Takeshi Sugai, Mitsuru
Shoji
PII:
S0040-4020(17)30903-1
10.1016/j.tet.2017.08.056
TET 28950
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 August 2017
Revised Date: 28 August 2017
Accepted Date: 31 August 2017
Please cite this article as: Kuwata K, Hanaya K, Higashibayashi S, Sugai T, Shoji M, Synthesis of the
1,2-seco fusicoccane diterpene skeleton by Stille coupling reaction between the highly functionalized A
and C ring segments of cotylenin A, Tetrahedron (2017), doi: 10.1016/j.tet.2017.08.056.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Synthesis of the 1,2-seco fusicoccane diterpene skeleton by Stille coupling reaction between the
highly functionalized A and C ring segments of cotylenin A
Kazuaki Kuwata,a Kengo Hanaya, a Shuhei Higashibayashi, a Takeshi Sugai*, a Mitsuru Shoji* a,b
a Department of Pharmaceutical Sciences, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen,
Minato-ku, Tokyo 105-8512, Japan
b Present address: Faculty of Pharmacy, Yokohama University of Pharmacy, 601 Matano-cho,
Totsuka-ku, Yokohama 245-0066, Japan
*Corresponding authors. Tel & fax +81 3 5400 2665; e-mail: sugai-tk@pha.keio.ac.jp (T. Sugai);
mitsu.shoji@hamayaku.ac.jp (M. Shoji)
Abstract
1-Hydroxy-14-isopropyl-3β-methoxymethyl-7β,11β-dimethyl-3α-[((2-
trimethylsilyl)ethoxy)methoxy]-1,2-secofusicocca-8,10(14)-dien-2-one, a highly functionalized 1,2-
seco fusicoccane diterpene skeleton related to cotylenin A was synthesized in a convergent manner.
The A ring segment, i. e., (1’R,2S, 2’E,5S)-2-methoxymethyl-5-[1’-methyl-3’-
(trimethylstannyl)prop-2-enyl]-2-[((2”-trimethylsilyl)ethoxy)methoxy]cyclopentanone, was
synthesized in 20.1% yield over 18 steps from known (S)-5-isopropenyl-2-methylcyclopent-1-
enecarbaldehyde. This was coupled with the C ring segment, i. e., (R)-5-hydroxymethyl-2-
isopropyl-5-methylcyclopent-1-en-1-yl trifluoromethylsulfonate, which was prepared according to
our previous report. The Stille coupling reaction between alkenylstannane and sterically hindered
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triflate proceeded successfully in the presence of PEPPSI-SIPr (85%), and the total yield of the
target molecule was 17.1% over the longest linear sequences (19 steps) from (S)-5-isopropenyl-2-
methylcyclopent-1-enecarbaldehyde.
1. Introduction
Cotylenin A (1, Figure 1) was first isolated from Cladosporium sp. as a plant growth regulator
and its structure was later determined by Sassa and co-workers.1,2 Because of its biological effects
such as induction of differentiation in murine and human myeloid leukemia cells,3 and apoptosis in
the cooperation with interferon (INF)-α,4 this compound has been suggested to act as anticancer
agent.
In in vivo animal studies, the combined use of 1 and INF-α shows high therapeutic
efficacy in tumor-bearing mice, inoculated with human lung adenocarcinoma cells4 and human
ovarian carcinoma cells.5
Figure 1. Structure of cotylenin A (1) and the numbering of the fusicoccane diterpene skeleton.
However, the original fungal strain lost its ability to proliferate with consequent of lack of
production of cotylenin A (1).6 This prompted synthetic chemists to develop new methodologies
for the construction of carbon skeleton with proper oxygen functionalities. Convergent
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approaches were reported in pioneering and intensive works by Kato, Takeshita and co-workers.7-9
For example, the A ring and the C ring segment (2 and 3, respectively) were coupled between C-1
and C-11 (in fusicoccane numbering) to form 8,9-seco derivatives as in 4 and 5 (Scheme 1).9
In the present work, we designed an alternative convergent approach involving the coupling of
A and C ring segments (6 and 710) between C-9 and C-10 to construct highly functionalized 1,2-
seco derivative 8 with correct stereochemistreis at C-3, C-6, C-7, and C-11. Herein, we describe
the elaboration of coupling conditions between 7 and A ring segment 6 toward 8. The synthesis of
alkenylstannane 6 was envisaged via known aldehyde 911 starting from commercially available
(4R)-limonene oxide (10).
Cl
H
CrCl3 - LiAlH4
THF - DMF
H
H
O
+
O
O
OMe
OH
OH
OMe
OMe
2
3
4
5
Stille
coupling
SnMe3
H
TfO
HO
H
O
O
OH
OMe
OMe
SEMO
SEMO
A-ring
segment (6)
C-ring
segment (7)
8
Lit.11
H
O
O
10
9
Scheme 1. Previous strategy based on bond formation between C-1 and C-11 in Kato and
Takeshita’s work (top), and our strategy toward 8 based on Stille cross-coupling between 6 and 7 to
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form 8 (bottom).
2. Results and discussion
First, the conditions of the Stille reaction of 7 were investigated using styrylstannane (11), as
the model substatrate. As 11 was poorly soluble in DMSO, toluene was added as a co-solvent to
ensure the homogeneity of the reaction mixture.
Due to the severe steric hindrance around
triflate, we supposed that low reactivity of 7 would be caused by poor efficiency of oxidative
addition. At first, the widely used Pd2(dba)3-CHCl3 was tested (entries 1-3). In the absence of
ligands, the formation of undesired dimer 13 competed with the desired cross-coupling reaction
(entry 1). Addition of Ph3As suppressed the reactivity of 7, resulting in the predominant formation
of 13 (entry 2). In the presence of more electron-donating XPhos,12 the conversion of 7 increased;
however, undesired 13 was still the major product (entry 3). On the basis of these results, we
envisioned that a more electron-rich palladium catalyst would promote the coupling. As expected,
in the presence of PEPPSI-IPr,13 a palladium complex containing an N-heterocyclic carbene ligand,
7 was cleanly converted into the desired 12 (entry 4). In all entries, 11 was completely consumed
in the reaction mixture, judged by 1H NMR analysis of the crude products.
We thought that
PEPPSI-IPr not only accelerated the oxidative addition to 7, but also suppressed the undesired
dimerization to incline 11 to the cross-coupling with 7.
Table 1. Optimization of the Stille coupling reaction conditions between 7 and 11.
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entry
Pd cat (mol%)
additive (mol%)
None
Ph3As (33)
XPhos (15)
None
time (h)
ratio (7: 12:13)a
1:1:1
1
2
3
4
Pd2(dba)3-CHCl3 (5)
Pd2(dba)3-CHCl3 (3)
Pd2(dba)3-CHCl3 (7)
PEPPSI-IPr (5)
4
3
7
4
5:1:3
2:2:3
0:1:0
a: determined by 1H NMR spectra. For details, see section 4.2.
Encouraged by these results, we next prepared 6, for the use as the coupling partner of 7
(Scheme 2). First, aldehyde 911 was reduced with sodium borohydride in methanol, and the
resulting primary alcohol was protected as tert-butyldimethylsilyl (TBS) ether, forming 14 in 83%
yield over two steps. The following hydroboration-oxidation sequence proceeded regio- and
stereoselectively to give 15a as a single diastereomer, as confirmed after transformation to 15b.
Comparison of the 1H NMR spectrum with those of the diastereomers of 15b14 showed no
contamination of the C-1’ epimer (see Experimental, section 4.4).
To avoid the interference of
coordinating oxygen atoms, the unhindered =CH2 group was chosen as a temporary protecting
group for the terminal hydroxyl moiety, as in compound 16.
Dess-Martin oxidation followed by one carbon homologation with a Wittig reagent yielded 16a.
Removal of the TBS group and subsequent epoxidation with m-chloroperoxybenzoic acid
proceeded site- and stereoselectively to give 17 as a single product. The free hydroxy group in
16b was beneficial to achieve high site-selectivity, improving the discrimination between internal
and terminal olefins. Next, Lewis acid-mediated isomerization of the epoxide and acetylation of
the resulting diol at the less hindered position afforded 18 in 97% yield over two steps. The
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second stereoselective epoxidation-regioselective ring opening sequences were carried out with
tert-butylhydroperoxide using vanadyl acetylacetonate as a catalyst, followed by the treatment with
sodium methoxide in methanol to obtain methyl ether 19a with a properly installed methoxy group
in 92% yield. The three hydroxy groups were differentially protected; the less hindered glycol
moiety reacted with triphosgene, and the remaining tertiary alcohol was protected by a 2-
(trimethylsilyl)ethoxymethyl (SEM) group to give 19b in 75% yield over two steps. In 20, the
correct stereochemistry with cis relationship between the side chains at C-6 and C-9 was confirmed
by nuclear Overhauser effect (Scheme 2).
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Scheme 2. Stereoselective synthesis of A ring segment intermediate 20 from 9.
Treatment of 20 with (iodomethyl)triphenylphosphonium iodide15 led to the successful
introduction of a cis-iodovinyl group to form 21 (Scheme 3). Methanolysis of the cyclic carbonate
protective group followed by the oxidative degradation of the unnecessary carbon atom under mild
conditions furnished a cyclopentanone intermediate in 91% yield over two steps. Treatment of the
alkenyl iodide with hexamethylditin in the presence of bis(triphenylphosphine)palladium dichloride
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provided 6, the desired A ring segment, as a single stereoisomer in 64% yield. The results
summarized in Table 1 prompted us to examine PEPPSI-type catalysts, for the subsequent Stille
coupling reaction, and PEPPSI-SIPr successfully gave the desired product 8 in 85% yield.
Scheme 3. Formation of Stille coupling precursor 6 and the successful construction of the 1,2-
seco fusicoccane skeleton in 8.
3. Conclusion
En route to the synthesis of highly functionalized 1,2-seco fusicoccane skeleton of 8, the A ring
segment 6 was prepared in 20.1% yield over 18 steps from (S)-9. The choice of functionalities and
their size were important to achieve the correct stereochemical disposition of substituents on the
congested cyclopentene ring, as shown in 16b. The conditions for the Stille coupling reaction
were optimized between triflate 7, the C ring segment, and model alkenylstannane 11 were
optimized, and PEPPSI-type catalysts were found to be most effective. The key cross-coupling
reaction between 6 and 7 proceeded in 85% yield, and the desired 8 was obtained in 17.1% total
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yield over 19 steps from (S)-9, which was easily accessible from commercially available (4R)-
limonene oxide.
4. Experimental
4.1. General
IR spectra were measured as ATR on a Jeol FT-IR SPX60 spectrometer. 1H NMR spectra
were measured in CDCl3 at 400 MHz on a VARIAN 400-MR spectrometer or at 500 MHz on a
VARIAN 500-MR spectrometer and 13C NMR spectra were measured in CDCl3 at 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. (S)-3-Isopropyl-1-methyl-2-(2-phenylethenyl)cyclopent-2-enmethanol 12
To the mixture of Pd catalyst and additive were added the solutions of 7 (8 mg) in dimethyl
sulfoxide (DMSO, 300 µL) and 11 (10 mg) in toluene/DMSO (2:1, 300 µL) successively and stirred
at 60 °C. At the stage that the reaction no longer showed any progresss by TLC monitoring
(hexane/EtOAc = 8:1, Rf = 0.22 for 7, 0.26 for 12, 0.36 for 13, 0.69 for 11), the reaction was
quenched with H2O and organic materials were extracted with EtOAc. The ratio of the
components in crude mixture was estimated by 1H NMR spectra by the comparison with authentic
signals (CDCl3):
δ 3.32 (d, 1H, J = 12.2 Hz, for 7), 3.48 (d, 1H, J = 10.9 Hz, for 12), and 7.09 (d,
2H, J = 16.9 Hz, for 13).
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4.3. (S)-3-Isopropenyl-2-tert-butyldimethylsiloxymethyl-1-methylcyclopentene 14
To a solution of 9 (4.30 g, 28.6 mmol) in MeOH (50 mL) was added NaBH4 (875 mg, 23.1
mmol) and stirred at 0 °C for 1 h. The reaction was quenched with saturated NH4Cl aq. solution
and organic materials were extracted with EtOAc three times. The combined extract was
washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography with hexane/EtOAc (2:1) to give an
alcohol (3.92 g, 90%) as a colorless oil. 1H NMR spectrum was identical with that reported
previously.10c This was employed for the next step without further purification.
To a solution of the alcohol (7.13 mg, 7.42 mmol) in CH2Cl2 (20 mL) was added imidazole
(1.04 g, 15.3 mmol) and TBSCl (1.66 g, 11.0 mmol) at 0 °C and stirred for 29 h at room
temperature under argon atmosphere. The reaction was quenched with phosphate buffered
solution (pH 7.0, 0.2 M) and organic materials were extracted with EtOAc twice. The combined
extract was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel column chromatography with hexane/EtOAc
(1:0–20:1) to furnish 14 (1.82 g, 92%) as a colorless oil. [α]D20 +98.3 (c 1.14, CHCl3). 1H NMR
(500 MHz, CDCl3): δ 0.03 (3H, s), 0.04 (3H, s), 0.86 (9H, s), 1.59–1.71 (4H, m), 1.72 (3H, s), 2.03
(1H, m), 2.23 (1H, ddd, J = 15.5, 9.0, 3.5 Hz), 2.33–2.39 (1H, m), 3.45 (1H, dd, J = 9.0, 0.0 Hz),
3.93 (1H, d, J = 11.5 Hz), 4.23 (1H, d, J = 11.5 Hz), 4.65–4.68 (2H, m); 13C NMR (125 MHz,
CDCl3): δ –5.4, –5.3, 14.1, 18.5, 19.3, 26.0 (3C), 28.0, 37.9, 54.0, 58.2, 110.2, 135.6, 136.7, 148.1;
IR νmax 2953, 2927, 2895, 2856, 1471, 1438, 1371 cm–1.
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4.4. (1’S,2R)-2-(2’-tert-Butyldimethylsiloxymethyl-3’-methylcyclopent-2’-enyl)-2-
methylpropanol 15a
To a solution of 14 (1.82 g, 6.83 mmol) in tetrahydrofuran (THF, 27 mL) was added 9-BBN
dimer (1.76 g, 14.4 mmol) at 0 °C and stirred at room temperature for 2 h under argon atmosphere.
The reaction was treated with NaOH aq. solution (3 M, 30 mL) and H2O2 aq. solution (30%, 30
mL) and stirred for 1 h at room temperature. The organic materials were extracted with EtOAc
three times and the combined extract was washed with brine, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by silica gel column
chromatography with hexane/EtOAc (100:1–10:1) to furnish 15a (1.68 g, 86%) as a colorless oil.
[α]D21 +20.4 (c 1.22, CHCl3). 1H NMR (500 MHz, CDCl3): δ 0.08 (3H, s), 0.10 (3H, s), 0.85 (3H,
d, J = 7 Hz), 0.91 (9H, s), 1.61–1.66 (4H, m), 1.91 (1H, m), 2.11 (1H, m), 2.21 (1H, ddd, J = 14.5,
9.5, 4.5 Hz), 2.31–2.38 (1H, m), 2.97 (1H, m), 3.43 (1H, dd, J = 11.0, 6.0 Hz), 3.52 (1H, dd, J =
11.0, 8.0 Hz), 4.24 (2H, m); 13C NMR (100 MHz, CDCl3): δ –5.5, –5.3, 14.1, 15.1, 18.3, 24.1, 25.9
(3C), 37.9, 38.5, 49.2, 56.4, 66.1, 135.2, 136.1; IR νmax 3375, 2953, 2927, 2883, 2856, 1471, 1462,
1377, 1361, 1251 cm–1; HRMS (ESI) [M+Na]+ calculated for C16H32NaO2Si: 307.2069, found:
307.2014.
To a solution of 15a (40.4 mg, 0.142 mmol) in THF (1.0 mL) was added tetra-n-
butylammonium fluoride (TBAF, 1 M solution in THF, 1 M, 300 µL) and stirred at room
temperature for 2 h. The reaction was quenched with saturated NH4Cl aq. solution and organic
materials were extracted with EtOAc four times. The combined extract was washed with brine,
dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the
residue was purified by silica gel column chromatography with hexane/EtOAc (10:1–1:1) to afford
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15b (17.7 mg, 73%). Diastereomeric ratio were estimated by 1H NMR spectra with the
comparison of authentic signals (CDCl3): δ 0.89 (d, 3H, J = 7 Hz, for 15b), 0.67 (d, 3H, J = 7 Hz,
for 1’-epi-15b).14
4.5. (1’S,3S)-3-(1’-methylprop-2’-enyl)-2-tert-butyldimethylsiloxymethyl-1-
methylcyclopentene 16a
To a solution of alcohol 15a (197 mg, 0.693 mmol) in CH2Cl2 (7.0 mL) was added NaHCO3
(312 mg, 3.72 mmol) and Dess-Martin periodinate (517 mg, 1.22 mmol) at 0 °C and stirred at room
temperature for 2 h. The reaction was quenched with a mixture of saturated NaHCO3 aq. solution
and saturated Na2S2O3 aq. solution, and the organic materials were extracted with EtOAc three
times. The combined extract was washed with brine and dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by silica gel column
chromatography with hexane/EtOAc (1:0–50:1) to furnish an aldehyde (185 mg, 95%) as a
colorless oil. [α]D21 –65.1 (c 1.14, CHCl3). 1H NMR (400 MHz, CDCl3): δ 0.05 (3H, s), 0.06
(3H, s), 0.89 (9H, s), 1.03 (3H, d, J = 6.8 Hz), 1.54 (1H, m), 1.66 (3H, s), 1.96–2.16 (1H, m), 2.17–
2.27 (2H, m), 2.75 (1H, dddd, J = 12.8, 6.8, 3.6, 1.2 Hz), 3.21 (1H, m), 4.15 (1H, d, J = 12.4 Hz),
4.28 (1H, d, J = 12.4 Hz), 9.71 (1H, d, J = 1.2 Hz); 13C NMR (100 MHz, CDCl3): δ –5.4 (2C), 11.2,
14.0 18.3, 25.0, 25. 9 (3C), 37.5, 48.4, 48.6, 58.3, 134.3, 136.8, 206.8; IR νmax 32953, 2030, 2895,
2885, 2857, 1722, 1471, 1462, 1251 cm–1; HRMS (ESI) [M+Na]+ calculated for C16H30NaO2Si:
305.1913, found: 305.1866.
To a solution of Ph3P+CH3I– (734 mg, 1.82 mmol) in THF (7 mL) was added n-BuLi solution in
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hexane (1.56 M, 1.20 mL) at 0 °C and stirred for 30 min. The mixture was cooled to –78 °C, added
a solution of the aldehyde (391 mg, 1.39 mmol) in THF (7 ml) and warmed to 0 °C in 1 h. The
reaction was quenched with saturated NH4Cl aq. solution and organic materials were extracted with
EtOAc three times. The combined extract was washed with brine, dried over Na2SO4 and filtered.
The filtrate was concentrated under reduced pressure and the residue was filtered through a short
pad of silica gel with hexane/EtOAc (100:1) to furnish a crude 16a. 1H NMR (400 MHz, CDCl3):
δ 0.05 (3H, s), 0.07 (3H, s), 0.90 (9H, s), 1.01 (3H, d, J = 6.8), 1.56 (1H, dddd, J = 13.6, 7.6, 5.6,
5.2 Hz), 1.65 (3H, s), 1.72–1.82 (1H, m), 2.14–2.21 (2H, m), 2.56–2.62 (1H, m), 2.86–2.94 (1H, m),
4.11 (1H, d, J = 12.0 Hz), 4.29 (1H, d, J = 12.0 Hz), 4.92–4.97 (2H, m), 5.75 (1H, m); 13C NMR
(125 MHz, CDCl3): δ –5.4, –5.3, 14.0, 17.7, 18.4, 22.6, 25.8 (3C), 37.6, 37.9, 51.4, 58.3, 113.5,
135.5, 135.8, 141.1; IR νmax 2956, 2927, 2885, 2856, 1471, 1462, 1371 cm–1. This was employed
for the next step without purification.
4.6. (1R,1’S,2R,5S)-1,2-epoxy-2-methyl-5-(1’-methylprop-2’-enyl)cyclopentanemethanol 17
To a solution of the above-mentioned crude 16a in THF (3.5 mL) was added TBAF solution in
THF (1 M, 2.50 mL) at 0 °C and stirred at room temperature for 2 days. The reaction was
quenched with phosphate buffered solution (pH 7.0, 0.2 M) and organic materials were extracted
with EtOAc four times. The combined extract was washed with brine, dried over Na2SO4 and
filtered. The filtrate was concentrated under reduced pressure and the residue was filtered through
short pad silica gel hexane/EtOAc (5:1) to furnish crude 16b. 1H NMR (500 MHz, CDCl3): δ 1.03
(3H, d, J = 7.0 Hz), 1.58 (1H, dddd, J = 14.0, 9.0, 5.5, 5.5 Hz), 1.80–1.88 (1H, m), 2.20–2.24 (2H,
m), 2.56–2.61 (1H, m), 2.92 (1H, m), 4.10 (1H, d, J = 12.0 Hz), 4.25 (1H, d, J = 12.0 Hz), 4.96–
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5.10 (2H, m), 5.77 (1H, ddd, J = 17.0, 10.5, 6.5 Hz); 13C NMR (100 MHz, CDCl3): δ 14.0, 17.5,
23.2, 37.7, 38.4, 51.5, 57.6, 114.0, 135.6, 138.4, 141.2; IR νmax 3310, 2958, 2914, 2870, 2841, 1637,
1456, 1436, 1413, 1379, 1371 cm–1.
To a solution of the above-mentioned crude 16b in CH2Cl2 (12 mL) was added NaHCO3 (230
mg, 2.74 mmol) and mCPBA (417 mg, 1.69 mmol) at –30 °C and stirred for 3 h. The reaction was
quenched with saturated Na2S2O3 aq. solution and organic materials were extracted with EtOAc
twice. The combined extract was washed with 2 M NaOH aq. solution and brine, dried over
Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was
purified by silica gel column chromatography with hexane/EtOAc (20:1–4:1) to furnish 17 (217 mg,
86% over three steps) as a colorless solid. Mp 71.3–71.9 °C (colorless fine needles from hexane).
[α]D21 –29.1 (c 1.08, CHCl3). 1H NMR (500 MHz, CDCl3): δ 1.04 (3H, d, J = 6.5 Hz), 1.36 (3H,
s), 1.44–1.47 (2H, m), 1.56–1.63 (1H, m), 1.85–1.89 (1H, m), 2.37–2.40 (1H, m), 2.53–2.61 (1H,
m), 3.64 (1H, d, J = 12.0 Hz), 4.15 (1H, d, J = 12.0 Hz), 4.99–5.06 (2H, m), 5.64 (1H, ddd, J = 17.5,
10.5, 7.5 Hz); 13C NMR (125 MHz, CDCl3): δ 15.5, 18.7, 20.4, 33.6 37.2, 46.3, 60.4, 70.2, 72.8,
114.5, 140.1; IR νmax 3296, 2958, 2939, 2927, 1639, 1460, 1425, 1379 cm–1; HRMS (ESI) [M+Na]+
calculated for C11H18NaO2: 205.1205, found: 205.1147.
4.7. (1S,1’S,5S)-1-hydroxy-2-methylene-5-(1’-methylprop-2’-enyl)cyclopentanemethyl acetate
18
To a solution of 17 (409 mg, 2.24 mmol) in toluene (13 mL) was added Ti(O-i-Pr)4 (670 µL,
2.26 mmol) at room temperature and stirred at 60 °C for 2 h under argon atmospher. The reaction
was quenched with 1 M HCl aq. solution and organic materials were extracted with EtOAc five
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times. The extract was dried over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography with hexane/EtOAc (6:1–2:1) to
furnish a diol (402 mg, 98%) as a colorless oil. [α]D21 –3.2 (c 1.08, CHCl3). 1H NMR (500 MHz,
CDCl3): δ 1.18 (3H, d, J = 6.8 Hz), 1.30–1.36 (1H, m), 1.72 (1H, dd, J = 8.3, 4.4 Hz), 1.76–1.87
(2H, m), 2.23 (1H, s), 3.28 (1H, ddd, J = 15.4, 15.4, 6.9 Hz), 2.38–2.42 (2H, m), 3.45 (1H, dd, J =
11.2, 4.4 Hz), 3.73 (1H, dd, J = 11.2, 8.3 Hz), 4.90 (1H, dd, J = 10.2, 1.7 Hz), 4.99 (1H, dd, J = 16.2,
1.7 Hz), 5.04–5.09 (2H, m), 5.68 (1H, ddd, J = 16.2, 10.2, 8.8 Hz); 13C NMR (125 MHz, CDCl3): δ
19.9, 25.5 27.5, 38.7, 53.2, 63.4, 82.1, 108.0, 113.1, 143.6, 155.4; IR νmax 3390, 3074, 2958, 2931,
2875, 1456, 1375 cm–1; HRMS (ESI) [M+Na]+ calculated for C11H18NaO2: 205.1205, found:
205.1206.
To a solution of the diol (402 mg, 2.21 mmol) in pyridine (2.2 mL) was added Ac2O (2.2 mL)
and stirred for 1 h at room temperature. The reaction was quenched with water and organic
materials were extracted with EtOAc four times. The combined extract was washed with 2 M HCl
aq. solution and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography with hexane/EtOAc (20:1–5:1) to furnish
18 (490 mg, 99%) as a colorless oil. [α]D21 –25.8 (c 1.11, CHCl3). 1H NMR (500 MHz, CDCl3):
1.20 (3H, d, J = 6.8 Hz), 1.36 (1H, dddd, J = 12.2, 12.2, 9.7, 9.7 Hz), 1.60–1.80 (1H, br–s), 1.74
(1H, ddd, J = 11.9, 9.7, 7.5 Hz), 1.80–1.87 (1H, m), 2.08 (3H, s), 2.22–2.28 (1H, m), 2.37–2.41 (2H,
m), 4.11(1H, d, J = 12.3 Hz), 4.24 (1H, d, J = 12.3 Hz), 4.90 (1H, dd, J = 10.1, 2.0 Hz), 4.96–5.00
(2H, m), 5.08 (1H, dd, J = 2.5, 2.5 Hz), 5.65 (1H, ddd, J = 18.6 10.1, 8.6); 13C NMR (125 MHz,
CDCl3): δ 19.8, 20.9, 25.8, 27.5, 39.1, 54.3, 65.5, 81.0, 108.1, 113.2, 143.3, 155.0, 171,2; IR νmax
3479, 2970, 1732, 1373, 1224 cm–1; HRMS (ESI) [M+Na]+ calculated for C13H20NaO3: 247.1310,
15

ACCEPTED MANUSCRIPT
found: 247.1301.
4.8. (1R,1’S,2S)-1-hydroxymethyl-2-methoxymethyl-5-(1’-methylprop-2’-enyl)cyclopentane-
1,2-diol 19a
To a solution of 18 (21.8 mg, 0.097 mmol) in toluene (1.5 mL) were added TBHP (solution in
toluene, 2 M, 53 µL) and VO(acac)2 (4.8 mg, 0.018 mmol) at 0 °C and stirred under argon
atmosphere. After 2 h, to the reaction was added NaOMe solution in MeOH (0.5 M, 1.9 mL, 0.95
mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction was
quenched with brine and organic materials were extracted with EtOAc eight times. The combined
extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography with hexane/EtOAc (5:1–2:1) to furnish 19a
(20.5 mg, 92%) as a colorless oil. [α]D21 –26.7 (c 1.20, CHCl3). 1H NMR (500 MHz, CDCl3): δ
1.12 (3H, d, J = 6.3 Hz), 1.16–1.20 (1H, m), 1.63–1.69 (1H, m), 1.78–1.87 (2H, m), 2.08–2.22 (2H,
m), 3.36 (1H, d, J = 10.0 Hz), 3.41 (3H, s), 3.46 (1H, d, J = 10.0 Hz), 3.64 (1H, d, J = 12.0 Hz),
3.71 (1H, d, J = 12.0 Hz), 4.86 (1H, dd, J = 10.0, 1.8 Hz), 4.96 (1H, ddd, J = 17.1, 1.8, 0.8 Hz),
5.62 (1H, ddd, J = 17.1, 10.0, 8.3 Hz); 13C NMR (125 MHz, CDCl3): δ 19.5, 24.4 29.7, 39.4, 48.5,
59.5, 61.1, 75.4, 81.1, 82.3, 112.8, 143.9; IR νmax 3432, 2952, 2896, 1637, 1456, 1375, 1338 cm–1;
HRMS (ESI) [M+Na]+ calculated for C12H22NaO4: 253.1416, found: 253.1395.
4.9. (1’S,5R,6S,9S)-6-Methoxymethyl-9-(1’-methylprop-2’-enyl)-6-[(2”-
trimethylsilylethoxy)methoxy]-1,3-dioxabicyclo[4.4]nonan-2-one 19b
To a solution of 19a (33.1 mg, 0.144 mmol) in CH2Cl2 (1.0 mL) was added pyridine (115 µL,
16

ACCEPTED MANUSCRIPT
1.42 mmol) and triphosgene (24.7 mg, 0.0832 mmol) at 0 °C and stirred for 1 h under argon
atmosphere. The reaction was quenched with saturated NH4Cl aq. solution and organic materials
were extracted with EtOAc four times. The combined extract was washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel
column chromatography with hexane/EtOAc (10:1–3:1) to furnish a carbonate (30.2 mg, 82%) as a
colorless oil. [α]D22 –55.6 (c 1.14, CHCl3). 1H NMR (500 MHz, CDCl3): δ 1.09 (3H, d, J = 6.6
Hz), 1.10–1.16 (1H, m), 1.47 (1H, ddd, J = 14.9, 11.5, 4.9 Hz), 1.72 (1H, ddd, J = 14.9, 10.3, 5.9
Hz), 1.99 (1H, dddd, J = 10.3, 10.3, 5.1, 4.9 Hz), 2.13–2.19 (1H, m), 2.67 (1H, m), 3.15–3.20 (1H,
br–s), 3.36 (3H, s), 3.44 (1H, d, J = 10.2 Hz), 3.53 (1H, d, J =10.2 Hz), 4.43 (1H, d, J = 9.5 Hz),
4.45 (1H, d, J = 9.5 Hz), 4.95 (1H, dd, J = 10.1, 1.5 Hz), 5.01 (1H, ddd, J = 16.9, 1.5, 0.8 Hz), 5.65
(1H, ddd, J = 16.9, 10.1, 8.6 Hz); 13C NMR (125 MHz, CDCl3): δ 19.2, 23.6, 28.4, 39.5, 45.0, 59.3,
66.0, 74.8, 80.4, 92.3, 114.2, 142.2, 154.3; IR νmax 3500, 2969, 2933, 1877, 1793, 1735, 1637, 1456,
1375, 1241 cm–1; HRMS (ESI) [M+Na]+ calculated for C13H20NaO5: 279.1208, found: 279.1173.
To the solution of carbonate (391 mg, 1.53 mmol) in THF (4.0 mL) was added N,N-
diisopropylethylamine (1.40 mL, 8.02 mmol), SEMCl (800 µL, 4.56 mmol) and TBAI (178 mg,
0.477 mmol) and stirred for 14 h at 80 °C under argon atmosphere. The reaction was quenched
with saturated NaHCO3 aq. solution and organic materials were extracted with EtOAc three times.
The combined extract was washed with 1 M HCl aq. solution, 1 M NaOH aq. solution and brine,
dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by
silica gel column chromatography with hexane/EtOAc (30:1–3:1) to furnish 19b (543 mg, 92%) as
a colorless solid. Mp 85.3–86.0 °C (colorless fine needles from hexane). [α]D22 –29 (c 0.75,
CHCl3). 1H NMR (500 MHz, CDCl3): δ 0.02 (9H, s), 0.87–0.97 (2H, m), 1.08 (3H, d, J = 6.8 Hz),
17

ACCEPTED MANUSCRIPT
1.19–1.27 (1H, m), 1.55–1.62 (1H, m), 1.89–2.05 (2H, m), 2.21 (1H, ddq, J = 8.6, 8.6, 6.8 Hz), 2.58
(1H, ddd, J = 8.6, 8.6, 8.6 Hz), 3.33 (3H, s), 3.46 (1H, d, J = 11.2 Hz), 3.64 (1H, ddd, J =10.2, 10.2,
6.4 Hz), 3.67 (1H, d, J = 11.2 Hz), 3.73 (1H, ddd, J = 10.2, 10.2, 6.4 Hz), 4.38 (1H, d, J = 9.3 Hz),
4.47 (1H, d, J = 9.3 Hz), 4.83 (1H, d, J = 7.8 Hz), 4.95–5.04 (3H, m), 5.65 (1H, ddd, J = 18.6, 10.3,
8.6 Hz); 13C NMR (125 MHz, CDCl3): δ –1.43 (3C), 18.3, 19.4, 23.4, 26.5, 39.2, 46.2, 59.2, 65.8,
65.9, 72.6, 85.5, 90.6, 92.6, 114.4, 141.8, 154.5; IR νmax 2953, 2925, 2893, 1789, 1248, 1181 cm–1;
HRMS (ESI) [M+Na]+ calculated for C19H34NaO6Si: 409.2022, found: 409..2024.
4.10. (1’R,5R,6S,9S)-6-Methoxymethyl-9-(1’-methyl-1’-oxo-ethyl)-6-[((2”-
trimethylsilyl)ethoxy)methoxy]-1,3-dioxabicyclo[4.4]nonan-2-one 20
To a solution of 19b (297 mg, 0.767 mmol) in THF (1.4 mL) and H2O (0.7 mL) was added
K2OsO2(OH)4 (17.6 mg, 0.0478 mmol), 2,6-lutidine (225 µL, 1.91 mmol) and NaIO4 (420 mg, 1.96
mmol) and stirred for 3 h at room temperature. The reaction was quenched with saturated
Na2S2O3 aq. solution and organic materials were extracted with EtOAc three times. The combined
extract was washed with brine and dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel column chromatography with hexane/EtOAc
(20:1–3:2) to give 20 (261 mg, 88%) as a colorless solid. Mp 81.8–83.1 °C (colorless fine needles
from hexane). [α]D24 +1.12 (c 1.08, CHCl3). 1H NMR (500 MHz, CDCl3): δ 0.03 (9H, s), 0.92–
0.96 (2H, m), 1.23 (3H, d, J = 7.1 Hz), 1.24–1.27 (1H, m), 1.64 (1H, ddd, J = 14.4, 10.5, 5.6 Hz),
2.50 (1H, ddd, J = 14.4, 9.7, 4.6 Hz), 2.10–2.18 (1H, m), 2.40–1.48 (1H, m), 2.95 (1H, ddd, J =
10.0, 9.8, 9.8 Hz), 3.34 (3H, s), 3.52 (1H, d, J =11.2 Hz), 3.65 (1H, ddd, J = 9.8, 9.8, 7.1 Hz), 3.72–
3.77 (2H, m), 4.24 (1H, d, J = 9.5 Hz), 4.52 (1H, d, J = 9.5 Hz), 4.84 (1H, d, J = 8.1 Hz), 4.99 (1H,
18

ACCEPTED MANUSCRIPT
d, J = 8.1 Hz); 13C NMR (125 MHz, CDCl3): δ –1.4 (3C), 12.6, 18.3, 23.1, 26.7, 42.1, 47.4, 59.3,
65.9, 66.6, 72.5, 84.9, 90.6, 92.3, 154.1, 202.1; IR νmax 2951, 2892, 1800, 1724, 1457, 1393, 1248,
1179 cm–1; HRMS (ESI) [M+Na]+ calculated for C18H32NaO7Si: 411.1815, found: 411..1797.
4.11. (1’R,3E,5R,6S,9S)-6-Methoxymethyl-9-(3’-iodo-1’-methylprop-2’-enyl)-6-[((2”-
trimethylsilyl)ethoxy)methoxy]-1,3-dioxabicyclo[4.4]nonan-2-one 21
To a suspension of Ph3PCH2I·I (206 mg, 0.388 mmol) in THF (1.5 mL) was added sodium
bis(trimethylsilyl)amide (NaHMDS, solution in THF, 1.0 M, 385 µL) and stirred at room
temperature under argon atmosphere. After 1 h, the red solution was cooled to –78 °C and added a
solution of hexamethylphosphoric triamide (HMPA, 24 µL, 0.138 mmol) in THF (400 µL) and a
solution of 20 (75.3 mg, 0.194 mmol) in THF (800 µL) successively. The reaction mixture was
warmed to –10 °C over 2 h and quenched with saturated NH4Cl aq. solution and organic materials
were extracted with EtOAc three times. The combined extract was washed with brine and dried
over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica
gel column chromatography with hexane/EtOAc (30:1–4:1) to furnish 21 (104 mg, quant.) as a
colorless oil. [α]D22 –19.2 (c 1.53, CHCl3). 1H NMR (500 MHz, CDCl3): δ 0.02 (9H, s), 0.86–
0.96 (2H, m), 1.21–1.30 (1H, m), 1.61 (1H, ddd, J = 14.4, 10.7, 5.4 Hz), 1.87–1.93 (1H, m), 1.98
(1H, ddd, J = 14.4, 9.5, 5.1 Hz), 2.65–2.76 (2H, m), 3.34 (3H, s), 3.49 (1H, d, J = 11.2 Hz), 3.64
(1H, ddd, J = 9.6, 9.6, 6.1 Hz), 3.69–3.74 (2H, m), 4.42 (1H, d, J = 9.5 Hz), 4.49 (1H, d, J = 9.5 Hz),
4.84 (1H, d, J = 7.9 Hz), 4.97 (1H, d, J = 7.9 Hz), 5.96 (1H, dd, J = 9.1, 7.4 Hz), 6.21 (1H, d, J =
7.4 Hz); 13C NMR (125 MHz, CDCl3): δ –1.4 (3C), 18.2, 18.3, 23.3, 26.7, 40.2, 45.9, 59.3, 65.7,
66.1, 72.8, 81.7, 85.4, 90.6, 92.4, 144.1, 154.3; IR νmax 2953, 2888, 1806, 1246, 1075 cm–1; HRMS
19

ACCEPTED MANUSCRIPT
(ESI) [M+Na]+ calculated for C19H33NaO6Si: 535.0989, found: 535.0964.
4.12. (1’R,2S, 2’E,5S)-2-Methoxymethyl-5-[1’-methyl-3’-(trimethylstannyl)prop-2-enyl]-2-
[((2”-trimethylsilyl)ethoxy)methoxy]cyclopentanone 6
To a solution of 20 (64.0 mg, 0.125 mmol) in MeOH (1.5 mL) was added K2CO3 (97.4 mg,
0.705 mmol) and stirred for 13 h at room temperature. The mixture was diluted with H2O and
organic materials were extracted with EtOAc three times. The combined extract was washed with
brine and dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude diol.
This was employed for the next reaction without further purification.
To the solution of the above-mentioned crude diol in THF (1.5 mL) were added pyridine (100
µL, 1.24 mmol) and Pb(OAc)4 (95.4 mg, 0.215 mmol) at –20 °C and stirred for 1 h. The reaction
was quenched with a mixture of saturated NaHCO3 aq. solution and saturated Na2S2O3 aq. solution
and organic materials were extracted with EtOAc twice. The combined extract was washed with
brine and dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography with hexane/EtOAc (20:1–6:1) to give a ketone (51.8
mg, 91% over 2 steps) as a colorless oil. [α]D22 –1.07 (c 1.19, CHCl3). 1H NMR (500 MHz,
CDCl3): δ 0.01 (9H, s), 0.77–0.88 (2H, m), 1.10 (3H, d, J = 6.8 Hz), 1.64–1.72 (1H, m,), 2.02–2.18
(2H, m), 2.23 (1H, ddd, J = 13.6, 7.5, 4.1 Hz), 2.42 (1H, ddd, J = 9.3, 7.1, 7.1 Hz), 2.76–2.82 (1H,
m), 3.34 (3H, s), 3.43–3.47 (2H, m), 3.50 (1H, ddd, J =11.0, 9.5, 6.1 Hz), 3.61 (1H, ddd, J = 11.0,
9.5, 5.8 Hz), 4.65 (1H, d, J = 7.6 Hz), 4.87 (1H, d, J = 7.6 Hz), 6.14 (1H, dd, J = 9.1, 7.3 Hz), 6.19
(1H, d, J = 7.3 Hz); 13C NMR (125 MHz, CDCl3): δ –1.4 (3C),, 16.5 ,18.0, 22.7, 27.7, 39.6, 50.9,
59.6, 65.7, 74.3, 81.5, 82.0, 90.1, 144.1, 215.9; IR νmax 2952, 2891, 1743, 1456, 1249, 1111 cm–1;
20

ACCEPTED MANUSCRIPT
HRMS (ESI) [M+Na]+ calculated for C17H31INaO4Si: 477.0934, found: 477.0921.
To PdCl2(PPh3)2 (23.8 mg, 0.0339 mmol) was added a solution of the above-mentioned ketone
(317 mg, 0.697 mmol) and hexamethylditin (230 µL, 1.11 mmol) in THF (7 mL) and stirred 39 h at
room temperature under argon atmosphere. The reaction mixture was concentrated under reduced
pressure and the residue was purified by 10w/w% K2CO3 on silica gel column chromatography with
hexane/EtOAc (1:0–40:1) to give a crude alkenyl stannane 7 and the crude 7 was further purified by
silica gel column chromatography with hexane/EtOAc (1:0–40:1) to furnish 7 (220 mg, 64%).
23
[α]D –24.8 (c 1.32, CHCl3). 1H NMR (500 MHz, CDCl3): δ 0.01 (9H, s), 0.17 (9H, t, J = 26.4
Hz), 0.79–0.90 (2H, m), 1.12 (3H, d, J = 6.3 Hz), 1.60–1.67 (1H, m), 2.04–2.21 (3H, m), 2.28–2.32
(1H, m), 3.32 (3H, s), 3.38–3.40 (2H, m), 3.49 (1H, ddd, J = 10.9, 9.5, 6.1 Hz), 3.64 (1H, ddd, J =
10.9, 9.5, 5.9 Hz), 4.65 (1H, d, J = 7.8 Hz), 4.88 (1H, d, J = 7.8 Hz), 5.76 (1H, d, J = 12.5 Hz), 6.27
13
(1H, dd, J = 12.5, 9.5 Hz); C NMR (125 MHz, CDCl3): δ –8.4 (3C), –1.4 (3C), 18.0, 19.4, 22.5,
27.3, 41.0, 52.0, 59.5, 65.7, 73.8, 82.0, 90.1, 128.8, 151.3, 215.9; IR νmax 2954, 2893, 1743, 1598,
1250 cm–1; HRMS (ESI) [M+Na]+ calculated for C20H40NaO4SiSn: 515.1616, found: 516.1613.
4.13. 1-Hydroxy-14-isoprpyl-3β-methoxymethyl-7β,11β -dimethyl-3α-[((2-
trimethylsilyl)ethoxy)methoxy]-1,2-secofusicocca-8,10(14)-dien-2-one 8
To PEPPSI-SIPr (8.8 mg, 0.013 mmol) was added a solution of 7 (124 mg, 0.25 mmol) and 6
(114 mg, 0.376 mmol) in DMSO (5 mL) and stirred for 42 h at 60 °C under argon atmosphere.
The reaction was quenched with H2O and organic materials were extracted with EtOAc three times.
The combined extract was washed with brine and dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by silica gel column chromatography with
21

ACCEPTED MANUSCRIPT
hexane/EtOAc (40:1–3:1) to furnish 8 (103 mg, 85%) as a colorless oil. [α]D23 –53.2 (c 1.17,
CHCl3). 1H NMR (500 MHz, CDCl3): δ 0.01 (9H, s), 0.79–0.89 (2H, m), 0.94 (3H, d, J = 6.9 Hz),
0.96 (3H, s), 0.99 (3H, d, J = 6.8 Hz), 1.05 (3H, d, J = 6.6 Hz), 1.50–1.58 (1H, m), 1.64–1.73 (1H,
m), 1.80–1.84 (1H, m), 1.97 (1H, ddd, J = 12.7, 8.8, 6.4 Hz), 2.02–2.09 (1H, m), 2.10–2.22 (2H, m),
2.26–2.34 (2H, m), 2.39 (1H, ddd, J = 10.8, 9.3, 5.4 Hz), 2.60–2.68 (2H, m), 3.28–3.33 (4H, m),
3.37 (1H, dd, J = 10.7, 4.6 Hz), 3.40–3.43 (2H, m), 3.49 (1H, ddd, J = 11.0, 9.8, 6.3 Hz), 3.62 (1H,
ddd, J = 11.0, 9.5, 5.8 Hz), 4.65 (1H, d, J = 7.6 Hz), 4.87 (1H, d, J = 7.6 Hz), 5.58 (1H, ddd, J =
11.7, 2.5, 2.2 Hz), 5.64 (1H, dd, J = 11.7, 10.3 Hz); 13C NMR (125 MHz, CDCl3): δ –1.5 (3C), 17.9,
18.0, 20.9, 21.0, 21.8, 22.1, 27.5, 27.8, 28.0, 32.7, 33.2, 52.6, 53.4, 59.6, 65.7, 69.3, 73.8, 82.3, 90.2,
122.5, 134.1, 135.8, 146.3, 216.6; IR νmax 3460, 2953, 2893, 1740, 1455, 1249 cm–1; HRMS (ESI)
[M+Na]+ calculated for C27H48NaO5Si: 503.3169, found: 503.3170.
Acknowledgements
This work was supported by JSPS KAKENHI (Grant Number 17K01952 for M. S. and
16J01810 for K. K.) and acknowledged with thanks.
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23