Two approaches to 14,15-secoergostane intermediates for the synthesis of strophasterols

Article abstract of DOI:10.1080/09168451.2018.1452603

Two protected 14,15-secoergostane derivatives suitable as pivotal intermediates for the synthesis of strophasterols A and B, anti-MRSA and neuronal cell-protecting natural products bearing a recently discovered strophastane skeleton, have been synthesized by two different routes. The first approach employed an oxidative cleavage of an α-hydroxy ketone intermediate with the Jones reagent as the key step to reach the targeted secoergostane from ergosterol in ten steps. In the second approach, an unprecedented reaction cascade composed of four reactions enabled us to obtain the secoergostane more efficiently in six steps.

Full text of DOI:10.1080/09168451.2018.1452603

Bioscience, Biotechnology, and Biochemistry
ISSN: 0916-8451 (Print) 1347-6947 (Online) Journal homepage: http://www.tandfonline.com/loi/tbbb20
Two approaches to 14,15-secoergostane
intermediates for the synthesis of strophasterols
Yuki Fukuda, Shuntaro Sato, Yusuke Ogura & Shigefumi Kuwahara
To cite this article: Yuki Fukuda, Shuntaro Sato, Yusuke Ogura & Shigefumi Kuwahara (2018):
Two approaches to 14,15-secoergostane intermediates for the synthesis of strophasterols,
Bioscience, Biotechnology, and Biochemistry, DOI: 10.1080/09168451.2018.1452603
To link to this article: https://doi.org/10.1080/09168451.2018.1452603
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Bioscience, Biotechnology, and Biochemistry, 2018
https://doi.org/10.1080/09168451.2018.1452603
Two approaches to 14,15-secoergostane intermediates for the synthesis of
strophasterols
Yuki Fukuda, Shuntaro Sato, Yusuke Ogura and Shigefumi Kuwahara
laboratory of applied Bioorganic chemistry, graduate school of agricultural science, tohoku University, sendai, Japan
ABSTRACT
ARTICLE HISTORY
received 21 February 2018
accepted 6 march 2018
Two protected 14,15-secoergostane derivatives suitable as pivotal intermediates for the
synthesis of strophasterols A and B, anti-MRSA and neuronal cell-protecting natural products
bearing a recently discovered strophastane skeleton, have been synthesized by two different
routes. The first approach employed an oxidative cleavage of an α-hydroxy ketone intermediate
with the Jones reagent as the key step to reach the targeted secoergostane from ergosterol
in ten steps. In the second approach, an unprecedented reaction cascade composed of four
reactions enabled us to obtain the secoergostane more efficiently in six steps.
KEYWORDS
secosteroid; strophasterol;
oxidative cleavage; cascade
reaction
Strophasterol A (1) discovered by Kawagishi and
co-workers from the edible mushroom Stropharia
rugosoannulata is a rearranged ergostane with an
unprecedented carbon skeleton that exhibits anti-MRSA
and neuronal cell-protecting activities (Scheme 1) [1].
Recently, the new skeletal name “strophastane” was pro-
posed for the secosteroidal carbon framework [2], and
five strophastane-type natural products including 1 and
22-epi-1 (strophasterol B) have been isolated from two
species of mushrooms so far [1–3]. e totally unique
carbon skeleton as well as the interesting biological
profiles prompted synthetic studies on this small fam-
ily of natural products, which recently culminated in
the first synthesis of strophasterol A (1) from ergosterol
(4) by the Heretsch group as well as our stereodiver-
gent synthesis of strophasterols A and B from the same
starting material [4,5]. In our synthesis, ergosterol (4)
was converted into 3 by a three-step sequence involving
an acid-promoted double bond migration, and the Δ14
double bond of 3 was oxidatively cleaved in two steps to
afford 14,15-secoergostane derivative 2 (R = Ac), which
was elaborated in a stereodivergent manner to strophast-
erols A (1) and B via D’-ring formation (see structure 1
in Scheme 1) followed by B-ring functionalization [5].
Before establishing the synthetic pathway from 4 to 2
depicted in Scheme 1, we developed two alternative
approaches to the pivotal intermediate 2, which con-
tained some notable chemical transformations of steroi-
dal compounds. We describe herein our first successful
synthetic route from 4 to 2 [R = tert-butyldiphenylsilyl
(TBDPS)] as well as a more efficient second approach to
2 (R = Ac) which involves an unusual cascade reaction
of a γ-hydroxy-α,β-unsaturated ketone with zinc under
acidic conditions.
Results and discussion
Scheme 2 delineates our first approach to 2. To obtain
the 14,15-secosteroid 2, we initially aimed to prepare
intermediate 10 bearing a keto functionality at the C15
position on the D-ring, which would probably be con-
vertible into 2 via thermodynamically controlled for-
mation of a tetrasubstituted silyl enol ether derivative
and subsequent oxidative cleavage of its double bond.
Toward this relay compound 10, our synthetic efforts
commenced with double bond migration of ergosterol
(4) by its treatment with methanolic hydrogen chloride
in chloroform at 60 °C to give 5, which was, without
purification, acetylated to afford 6 in a satisfactory yield
of 90% for the two steps. is two-step conversion from
4 to 6 had previously been conducted by treating 4 with
hydrogen chloride in a mixture of acetic acid and chloro-
form at reflux and subsequently acetylating the resulting
product, providing 6 in a lower yield of 60% [6]. e
installation of a keto functionality at the C15 position
of 6 was effected by the Jones oxidation of 6 according
to the literature procedure [7], giving 7 in 44% yield in
a small-scale experiment (50 mg of 6); unfortunately,
this oxidation reaction, when conducted on gram scales,
resulted in lower yields of 7 (25–30%). Reduction of the
resulting γ-hydroxy-α,β-unsaturated ketone 7 with zinc
dust (12 equiv.) and sulfuric acid (5 equiv.) in MeOH/
CONTACT shigefumi Kuwahara
shigefumi.kuwahara.e1@tohoku.ac.jp
the supplemental data for this article can be accessed at https://doi.org/10.1080/09168451.2018.1452603
© 2018 Japan society for Bioscience, Biotechnology, and agrochemistry

2
Y. FUKUDA ET AL.
Scheme 1. outline of our previous synthesis of strophasterol a (1) from ergosterol (4) via 14,15-secoergostane intermediate 2.
Scheme 2. First approach to 14,15-secoergostane intermediate 2. reagents and conditions: (a) hcl/meoh, chcl3, 60 °c, 3 h; (b) accl,
Py, rt, 1 h, 90% from 4; (c) cro3, h2so4, aq. acetone, rt, 10 min, 44%; (d) Koh, ch2cl2, meoh, rt, 30 min, 85%; (e) li, liq. nh3, thF, –78 °c,
3 h, 80%; (f) tmscl, lii, (tms)2nh, ch2cl2, rt, 12 h; (g) m-cPBa, nahco3, ch2cl2, rt, 2 h, then 2 m hcl, rt, 3 h, 75% from 10; (h) tBdPscl,
imidazole, thF, dmF, rt, 3 h; (i) cro3, h2so4, aq. acetone, rt, 30 min, 79% from 12.
CH2Cl2 gave the corresponding deoxygenated enone 8
[8], which was then subjected to methanolysis under
basic conditions to afford enone 9 [9,10]. e Birch
reduction of 9 furnished 10 bearing a keto group on
the D-ring, the 1H and 13C NMR spectral data of which
showed good agreement with those of an authentic com-
pound prepared via a different route by Litvinovskaya
and co-workers [11]. Treatment of 10 with trimethylsilyl

BIOSCIENCE, BIOTECHNOLOGY, AND BIOCHEMISTRY
3
(TMS) chloride, LiI, and (TMS)2NH in CH2Cl2 at room
temperature brought about silyl enol etherification of
the C15 carbonyl and protection of the C3 hydroxyl
to afford 11 [12], which was immediately exposed to
the Rubottom oxidation conditions, giving α-hydroxy
ketone 12; the TMS protecting group of the C3 hydroxy
function was removed by aqueous HCl treatment during
the workup of the oxidation reaction. It is noteworthy
that compound 12 was obtained as a single stereoiso-
mer, although its stereochemistry was not determined.
To obtain the target molecule 2 (R = TBDPS), the α-hy-
droxy ketone 12 was protected as its TBDPS ether 13
and subjected to various conditions including NaIO4 in
acetone at 60 °C, Pb(OAc)4 in benzene at room tem-
perature, and Pb(OAc)4 in aq. AcOH at 50 °C. All the
conditions using NaIO4 or Pb(OAc)4 as the oxidizing
agent, however, resulted in the recovery of the starting
material 13. e only successful outcome was obtained
by treating 13 with the Jones reagent in acetone at room
temperature, furnishing 2 (R = TBDPS) in 79% yield
from 12 [13]; it is worth mentioning that the use of the
Jones reagent for this type of cleavage was rare in the
total synthesis of natural products [14,15]. Although the
transformation of ergosterol 4 into the D-ring cleaved
intermediate 2 suitable for the synthesis of strophasterols
was thus achieved, it required a considerably lengthy
10-step sequence (12% overall yield), which prompted
us to seek a more efficient synthetic route.
mixture by carefully inspecting minor products in the
deoxygenation step. We envisaged that if regioselective
epoxidation of the Δ14 double bond in the 14,22-diene
3 could be realized, the epoxide ring installed might
be oxidatively cleaved to give 2 . According to these
considerations, we scrutinized reaction conditions
capable of producing more amounts of 3 directly from
7, and found that the use of a large excess of zinc as
the reducing agent was effective to give 3 as the major
product (Scheme 3). e best result was obtained by
treating 7 with 60 equiv. of zinc dust and sulfuric acid
(10 equiv.) in MeOH/CH2Cl2, providing 3 in a much
improved yield of 62%. e direct formation of 3 from
7 might mean that the following four-reaction cascade
took place under the reductive conditions: (1) γ-deox-
ygenation of the γ-hydroxy-α,β-unsaturated ketone 7 to
enone 8; (2) 1,4-reduction of 8 to form saturated ketone
3-O-acetyl-10; (3) 1,2-reduction of 3-O-acetyl-10 to
alcohol 14; and (4) dehydration of 14 in the presence of
an excess amount of sulfuric acid to deliver trisubstituted
olefin 3. During this cascade reaction, the formation of
8 was clearly observed by TLC monitoring and it grad-
ually changed into 3, although we could not confirm
the formation of 3-O-acetyl-10 and 14. To the best of
our knowledge, this type consecutive transformations
in one pot have never been reported in the literature.
e regioselective epoxidation of 3 and the oxidative
cleavage of the resulting epoxide 15 were conducted, as
reported previously [5], with magnesium bis(monoper-
oxyphthalate) (MMPP) and chromic acid, respectively,
furnishing 2 (R = Ac) in 63% yield for the two steps;
During the efforts to convert 7 into 8 in our first
approach, we noticed that a trace amount of the dienic
product 3 (see Scheme 1) existed in the crude product
Scheme 3. second approach to 14,15-secoergostane intermediate 2.

4
Y. FUKUDA ET AL.
the conversion of 15 into 2 would probably involve
the epoxide ring opening of 15 to the corresponding
vicinal diol intermediate (14,15-diol) under the acidic
conditions and subsequent oxidation of its secondary
hydroxy group with chromic acid to afford 13 (R = Ac)
(see Scheme 1). By this second approach, we were able
to obtain 2 in a more efficient manner from ergosterol
4 (6 steps, 16% overall yield).
In summary, the 14,15-secoergostane 2, a key inter-
mediate in our synthesis of strophasterols, was synthe-
sized by two different approaches. In the first approach,
we could reach the target molecule 2 (R = TBDPS) from
ergosterol 4 via 15-keto steroidal intermediate 10 by a
ten-step sequence that involved oxidative cleavage of
the α-hydroxy ketone intermediate 13 with the Jones
reagent. In the second approach, we found an unusual
four-reaction cascade to convert the γ-hydroxy-α,β-un-
saturated ketone intermediate 7 into the olefinic inter-
mediate 3 with a large excess of zinc, which enabled us
to obtain 2 (R = Ac) more efficiently in a smaller number
of steps (6 steps).
and extracted with CHCl3. e extract was successively
washed with water and brine, dried (MgSO4), and con-
centrated in vacuo. e residue was purified by silica
gel column chromatography (hexane/EtOAc = 20:1) to
give 6 (9.95 g, 90% from 4) as a white solid. Mp 145–
146 °C; [ꢀ]2D0 －54.6 (c 1.57, CHCl ); IR: νmax 3053 (w),
3
1730 (s), 1371 (m), 1265 (s); 1H NMR: δ 0.81–0.86 (9H,
m), 0.93 (3H, d, J = 6.8 Hz), 1.00 (3H, s), 1.04 (3H, d,
J = 6.6 Hz), 1.30 (1H, dt, J = 4.2, 13.6 Hz), 1.37–1.62 (8H,
m), 1.69–1.75 (1H, m), 1.83–1.93 (3H, m), 1.96–2.41
(11H, m), 4.71 (1H, tt, J = 5.4, 11.0 Hz), 5.20 (1H, dd,
J = 7.6, 15.2 Hz), 5.26 (1H, dd, J = 7.0, 15.2 Hz), 5.34
(1H, br s); 13C NMR: δ 15.8, 17.6, 18.2, 19.6, 19.9, 20.9,
21.4, 21.7, 25.1, 26.5, 27.6, 33.0, 34.1, 35.0, 36.5, 36.6,
36.8, 38.9, 40.7, 42.8, 44.7, 57.0, 73.3, 117.9, 123.2, 132.0,
135.5, 140.3, 150.7, 170.6; HRMS (EI): m/z calcd. for
C30H46O2, 438.3498; found, 438.3501 (M+).
(3S,5S,9S,10S,13R,17R)-17-((2R,5R,E)-5,6-
dimethylhept-3-en-2-yl)-9-hydroxy-10,13-dimethyl-
15-oxo-2,3,4,5,6,7,9,10,11,12,13,15,16,17-tetradecahy-
dro-1H-cyclopenta[a]phenanthren-3-yl acetate (7)
To a stirred solution of 6 (50 mg, 0.114 mmol) in
acetone (4 mL) was added dropwise the Jones reagent
(2.65 m, 84 μL, 0.228 mmol) at room temperature. Afer
10 min of stirring at the same temperature, the mixture
was quenched with 2-propanol, diluted with water, and
concentrated in vacuo to some extent. e residue was
extracted with ether and the extract was successively
washed with water and brine, dried (MgSO4), and con-
centrated in vacuo. e residue was purified by silica
gel column chromatography (hexane/EtOAc = 10:1) to
give 7 (23.7 mg, 50.3 μmol, 44%) as a white solid. Mp
197–198 °C;[ꢀ]D20 + 110.1 (c 1.38, CHCl ); IR: νmax 3471
(m), 1722 (s), 1687 (s), 1620 (m), 12523(s); 1H NMR: δ
0.80–0.85 (9H, m), 0.91 (3H, d, J = 6.8 Hz), 0.98 (3H,
s), 1.10 (3H, d, J = 6.7 Hz), 1.22–1.37 (2H, m), 1.39–
1.66 (8H, m), 1.72–2.08 (11H, m), 2.13–2.24 (2H, m),
2.29 (1H, dd, J = 8.0, 19.2 Hz), 3.92 (1H, ddd, J = 2.0,
4.5, 14.6 Hz), 4.72 (1H, tt, J = 5.4, 11.0 Hz), 5.16 (1H,
dd, J = 8.5, 15.3 Hz), 5.27 (1H, dd, J = 7.9, 15.3 Hz);
13C NMR: δ 15.5, 17.5, 17.7, 19.7, 20.0, 21.4 (2C), 22.6,
26.9, 27.8, 28.3, 29.4, 33.0, 33.5, 33.7, 35.1, 39.2, 41.3,
42.91, 42.93, 43.0, 50.5, 72.9, 74.3, 133.6, 134.0, 141.6,
148.0, 170.6, 208.4; HRMS (EI): m/z calcd. for C30H46O4,
470.3396; found, 470.3399 (M+).
Experimental
General procedure
IR spectra were recorded by a Jasco FT/IR-4100 spec-
trometer using an ATR (ZnSe) attachment. NMR spec-
tra were recorded with TMS as an internal standard in
CDCl3 by a Varian 400-MRTT spectrometer (400 MHz
1
for H and 100 MHz for 13C). Optical rotation values
were measured with a Jasco P-2200 polarimeter. Mass
spectra were obtained with JEOL JMS-700 spectrometer
operated in the EI mode. Melting points were determined
with a Yanaco MP-J3 apparatus and are uncorrected.
Kanto Kagaku silica gel 60 N (100–210 μm) was used
for column chromatography. Solvents for reactions were
distilled prior to use: THF from Na and benzophenone;
CH2Cl2 and DMF from CaH2; MeOH from Mg(OMe)2.
All air- or moisture-sensitive reactions were conducted
under a nitrogen atmosphere.
(3S, 5S, 10S, 13R , 17R)-17-((2R , 5R , E)-5, 6-
d i m e t hy l h e p t - 3 - e n - 2 - y l ) - 1 0 , 1 3 - d i m e t hy l -
2,3,4,5,6,7,10,11,12,13,16,17-dodecahydro-1H-cyclopen-
ta[a]phenanthren-3-yl acetate (6)
To a stirred solution of 4 (10.0 g, 25.2 mmol) in CHCl3
(133 mL) was added 1.25 m HCl in MeOH (26.2 mL,
27.2 mmol) at room temperature and the mixture was
stirred at 60 °C for 3 h. e mixture was quenched
with satd aq NaHCO3 and extracted with CHCl3. e
extract was successively washed with water and brine,
dried (MgSO4), and concentrated in vacuo to give
crude 5 (10.2 g) as a yellow solid which was used in
the next step without further purification. To a stirred
solution of crude 5 (10.2 g) in pyridine (64 mL) was
added AcCl (3.0 mL, 42.8 mmol) at room temperature.
Afer 1 h of stirring, the mixture was diluted with water
(3S,5S,9R,10S,13R,17R)-17-((2R,5R,E)-5,6-
dimethylhept-3-en-2-yl)-10,13-dimethyl-15-
oxo-2,3,4,5,6,7,9,10,11,12,13,15,16,17-tetradecahy-
dro-1H-cyclopenta[a]phenanthren-3-yl acetate (8)
To a stirred solution of 7 (1.63 g, 3.47 mmol) in a
mixed solvent of MeOH (181 mL) and CH2Cl2 (44 mL)
was added at room temperature a solution of concen-
trated H2SO4 (0.92 mL, 17 mmol) in MeOH (17.1 mL) by
using a syringe pump over a period of 1 h, during which
activated zinc powder (1.36 g, 20.8 mmol) was also
added portionwise. Afer 15 min, additional activated

BIOSCIENCE, BIOTECHNOLOGY, AND BIOCHEMISTRY
5
zinc powder (1.36 g, 20.8 mmol) was added, and the
stirring was continued for another 15 min. e mixture
was quenched with solid NaHCO3 and filtered through
a pad of Celite. e filtrate was concentrated in vacuo to
remove MeOH and extracted with CH2Cl2. e extract
was successively washed with water and brine, dried
(MgSO4), and concentrated in vacuo. e residue was
purified by silica gel column chromatography (hexane/
EtOAc = 15:1) to give 8 (1.19 g 75%) as a white solid.
Mp 160 °C; [ꢀ]D20 + 65.7 (c 1.08, CHCl3); IR: νmax 1739
(s), 1698 (s), 1623 (m), 1264 (s); 1H NMR: δ 0.73 (3H,
s), 0.82 (3H, d, J = 6.9 Hz), 0.84 (3H, d, J = 7.0 Hz), 0.91
(3H, d, J = 6.8 Hz), 0.99 (3H, s), 1.09 (3H, d, J = 6.6 Hz),
1.20–1.78 (14H, m), 1.80–1.91 (3H, m), 1.98–2.28 (7H,
m), 4.12 (1H, ddd, J = 1.9, 4.1, 14.2 Hz), 4.73 (1H, tt,
J = 5.4, 11.0 Hz), 5.16 (1H, dd, J = 8.5, 15.3 Hz), 5.26 (1H,
dd, J = 7.8, 15.3 Hz); 13C NMR: δ 12.7, 17.6, 18.8, 19.4,
19.5, 19.9, 21.26, 21.34, 27.1, 27.3, 28.9, 32.9, 33.5, 36.1,
36.7, 38.5, 39.2, 42.2, 42.77, 42.79, 43.8, 50.6, 50.7, 73.0,
133.1, 134.2, 140.2, 149.9, 170.4, 207.7; HRMS (EI): m/z
calcd. for C30H46O3, 454.3447; found, 454.3444 (M+).
( 3 S , 5 S , 9 R , 1 0 S , 1 3 R , 1 7 R ) - 1 7 - ( ( 2 R , 5 R , E ) -
5,6-dimethylhept-3-en-2-yl)-3-hydroxy-10,13-
dimethyl-1,2,3,4,5,6,7,9,10,11,12,13,16,17-tetradecahy-
dro-15H-cyclopenta[a]phenanthren-15-one (9)
To a stirred solution of 8 (1.04 g, 2.29 mmol) in
CH2Cl2 (20 mL) was added a solution of KOH (5% in
MeOH, 70 mL, 62 mol) at room temperature. Afer stir-
ring for 30 min, the reaction mixture was quenched with
satd aq NH4Cl and extracted with CH2Cl2. e extract
was successively washed with water and brine, dried
(MgSO4), and concentrated in vacuo. e residue was
purified by silica gel column chromatography (hexane/
EtOAc = 3:1) to give 9 (0.810 g, 85%) as a white solid. Mp
157–158 °C; [ꢀ]D20 + 81.7 (c 0.50, CHCl3); IR: νmax 3417
(br), 1704 (s), 1623 (s), 1455 (m); 1H NMR: δ 0.72 (3H,
s), 0.82 (3H, d, J = 7.0 Hz), 0.83 (3H, d, J = 7.0 Hz), 0.91
(3H, d, J = 6.9 Hz), 0.99 (3H, s), 1.09 (3H, d, J = 6.6 Hz),
1.15–1.76 (15H, m), 1.80–1.90 (3H, m), 1.99–2.28 (4H,
m), 3.65 (1H, tt, J = 5.2, 10.7 Hz), 4.09–4.16 (1H, m), 5.16
(1H, dd, J = 8.5, 15.4 Hz), 5.26 (1H, dd, J = 7.8, 15.4 Hz);
13C NMR: δ 12.8, 17.6, 18.9, 19.5, 19.6, 19.9, 21.4, 27.5,
29.1, 31.0, 32.9, 36.5, 36.8, 37.7, 38.7, 39.1, 42.3, 42.84,
42.85, 44.1, 50.8, 50.9, 70.7, 133.2, 134.2, 140.2, 150.5,
207.9; HRMS (EI): m/z calcd. for C28H44O2, 412.3341;
found, 412.3340 (M+).
extracted with EtOAc. e extract was washed with
brine, dried (MgSO4), and concentrated in vacuo. e
residue was purified by silica gel column chromatog-
raphy (hexane/EtOAc = 5:1) to give 10 (2.42 g, 80%)
as a white solid. Mp 183–184 °C; [ꢀ]2D0 + 11.1 (c 0.13,
CHCl3); IR: νmax 3419 (br), 1733 (s), 1457 (w); 1H NMR:
δ 0.60–0.68 (1H, m), 0.76 (3H, s), 0.79–0.85 (9H, m),
0.90 (3H, d, J = 6.8 Hz), 0.98 (1H, dt, J = 3.8, 13.4 Hz),
1.04–1.89 (22H, m), 2.06–2.17 (2H, m), 2.29 (1H, dd,
J = 8.7, 18.8 Hz), 2.65 (1H, dq, J = 13.1, 3.3 Hz), 3.59 (1H,
tt, J = 5.3, 10.8 Hz), 5.13 (1H, dd, J = 8.4, 15.4 Hz), 5.24
(1H, dd, J = 7.8, 15.3 Hz); 13C NMR: δ 12.2, 13.2, 17.7,
19.6, 20.0, 20.8, 21.3, 28.2, 29.7, 30.6, 31.4, 31.9, 33.0,
35.6, 36.9, 38.1, 39.8, 42.2, 42.3, 42.9, 44.8, 51.2, 54.0,
66.0, 71.2, 133.3, 134.3, 216.2; HRMS (EI): m/z calcd.
for C28H46O2, 414.3498; found, 414.3498 (M+).
(3R,4R,7R,E)-3-((2R,4aS,4bS,7S,8aS,10aR)-7-
acetoxy-2,4b-dimethyl-1-oxotetradecahydrophenanthren-
2-yl)-4,7,8-trimethylnon-5-enoic acid (12)
To a stirred solution of 10 (1.89 g, 4.56 mmol) and
(TMS)2NH (14.9 mL, 71.4 mmol) in CH2Cl2 (63 mL)
were successively added LiI (2.24 g, 16.7 mmol) and
TMSCl (6.08 mL, 47.6 mmol) at room temperature.
Afer 12 h of stirring at same temperature, the mix-
ture was quenched with satd aq NaHCO3 and Et3N,
and extracted with ether. e extract was successively
washed with water and brine, dried (MgSO4), and con-
centrated in vacuo to give crude 11 as a white solid. To
a stirred mixture of crude 11 (2.56 g, 4.58 mmol) and
NaHCO3 (0.60 g, 7.1 mmol) in CH2Cl2 (35 mL) was
added m-CPBA (1.17 g, 4.76 mmol) at 0 °C. Afer 2 h of
stirring at room temperature, the mixture was quenched
with satd aq Na2S2O3 and extracted with CH2Cl2. e
CH2Cl2 solution was mixed with 2 m HCl and stirred
for 3 h at room temperature. e resulting mixture was
extracted with CH2Cl2 and the extract was successively
washed with water and brine, dried (MgSO4), and con-
centrated in vacuo. e residue was purified by silica
gel column chromatography (hexane/EtOAc = 10:1) to
give 12 (1.47 g, 75%) as a white solid. Mp 241–242 °C;
[ꢀ]2D0 + 7.7 (c 0.65, CHCl3); IR: νmax 3750 (br), 1733 (s),
1457 (w); 1H NMR: δ 0.78–0.85 (12H, m), 0.90 (3H, d,
J = 6.9 Hz), 0.94–2.21 (26H, m), 2.45 (1H, dq J = 12.5,
3.4 Hz), 2.53 (1H, dd, J = 9.0, 19.3 Hz), 3.59 (1H, tt,
J = 5.3, 10.7 Hz), 5.14 (1H, dd, J = 8.4, 15.3 Hz), 5.24
(1H, dd, J = 7.7 15.3 Hz); 13C NMR: δ 12.1, 14.2, 17.6,
19.6, 19.9, 20.0, 21.3, 25.8, 28.2, 30.3, 31.4, 33.0, 34.6,
35.8, 37.0, 38.0, 39.8, 40.7, 42.8, 44.3, 44.6, 45.8, 46.8,
71.1, 82.6, 133.1, 134.7, 214.6; HRMS (EI): m/z calcd.
for C28H46O3, 430.3447; found, 430.3446 (M+).
(3S,5S,8R,9S,10S,13R,14S,17R)-17-((2R,5R,E)-
5,6-dimethylhept-3-en-2-yl)-3-hydroxy-10,13-
dimethylhexadecahydro-15H-c yclopenta[a]
phenanthren-15-one (10)
To a stirred solution of Li (1.11 g, 160 mmol) in
liq. NH3 (300 mL) was added a solution of 9 (3.00 g,
7.27 mmol) in THF (80 mL) at –78 °C. Afer 3 h of stir-
ring at the same temperature, the mixture was quenched
with solid NH4Cl and stirred at ambient temperature to
remove NH3. e mixture was diluted with water and
(3R,4R,7R,E)-3-((2R,4aS,4bS,7S,8aS,10aR)-7-((tert-
butyldiphenylsilyl)oxy)-2,4b-dimethyl-1-oxotetradec-
ahydrophenanthren-2-yl)-4,7,8-trimethylnon-5-enoic
acid (2: R = TBDPS)
To a stirred solution of 12 (1.52 g, 3.65 mmol) in a
mixed solvent of DMF (10 mL) and THF (4 mL) were

6
Y. FUKUDA ET AL.
successively added imidazole (0.745 g, 11.0 mmol) and
TBDPSCl (1.42 mL, 5.48 mmol) at room temperature.
Afer 3 h of stirring at the same temperature, the mix-
ture was quenched with satd aq NH4Cl and extracted
with ether. e extract was successively washed with
water and brine, dried (MgSO4), and concentrated in
vacuo to give crude 13 (2.35 g) as a white solid, which
was taken up in acetone (100 mL). To the solution was
added dropwise the Jones reagent (2.65 m, 7.97 mL,
21.1 mmol) while stirring at room temperature. Afer
30 min, the mixture was quenched with 2-propanol,
diluted with water, and concentrated in vacuo to some
extent. e residue was extracted with ether and the
extract was successively washed with water and brine,
dried (MgSO4), and concentrated in vacuo. e resi-
due was purified by silica gel column chromatography
(hexane/EtOAc = 5:1) to give 2 (R = TBDPS) (1.98 g,
79% from 12) as an amorphous solid. [ꢀ]20 + 6.6 (c
1.00, CHCl3); IR: νmax 3070 (br), 1737 (m)D, 1704 (s),
Acknowledgments
We thank Ms. Yuka Taguchi (Tohoku University) for NMR
and MS measurements and Prof. Hirokazu Kawagishi
(Shizuoka University) for valuable discussion.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
is work was supported by MEXT KAKENHI [grant num-
ber 26102707].
ORCID
Shigefumi Kuwahara
6875
http://orcid.org/0000-0002-5839-
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