Synthesis of the Epimeric Secosteroids Strophasterols A and B

Article abstract of DOI:10.1002/anie.201706086

Two epimeric rearranged ergostanes, strophasterols A and B, with an unprecedented carbon skeleton were synthesized from ergosterol, both in 17 steps via a common secosteroidal intermediate. The conversion of ergosterol into the pivotal intermediate involved an efficient acid-catalyzed double-bond migration from ring B to ring D, oxidative cleavage of the double bond, and a completely diastereoselective acyl radical cyclization to form an isolated cyclopentanone ring unique to this recently discovered family of steroidal compounds produced by mushrooms. The intermediate was transformed stereodivergently into two epimeric cyclopentane derivatives through hydrogenation using two types of catalysts. One epimer was elaborated into strophasterol B by utilizing peracid oxidation of an iodide to provide an epoxide directly, and the other epimer was elaborated into strophasterol A, which is known to be a suppressor of endoplasmic reticulum stress.

Full text of DOI:10.1002/anie.201706086

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Accepted Article
Title: Synthesis of Two Epimeric Secosteroids, Strophasterols A and B
Authors: Shuntaro Sato, Yuki Fukuda, Yusuke Ogura, Eunsang Kwon,
and Shigefumi Kuwahara
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201706086
Angew. Chem. 10.1002/ange.201706086
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10.1002/anie.201706086
Angewandte Chemie International Edition
COMMUNICATION
Synthesis of Two Epimeric Secosteroids, Strophasterols A and B
Shuntaro Sato, Yuki Fukuda, Yusuke Ogura, Eunsang Kwon, and Shigefumi Kuwahara*
Abstract: Two epimeric rearranged ergostanes, strophasterols A and B,
with an unprecedented carbon skeleton have been synthesized from
ergosterol, both in 17 steps via a common secosteroidal intermediate. The
20
22
conversion of ergosterol into the pivotal intermediate involved an efficient
D'
15
acid-catalyzed double bond migration from ring B to ring D, oxidative
H
H
O
cleavage of the double bond, and a completely diastereoselective acyl
O
radical cyclization to form an isolated cyclopentanone ring unique to this
recently-discovered family of steroidal compounds produced by
mushrooms. The intermediate was transformed stereodivergently into two
epimeric cyclopentane derivatives via hydrogenation using two types of
catalysts. One of the epimer was elaborated into strophasterol B by utilizing
peracid oxidation of an iodide to provide an epoxide directly, and the other
epimer into strophasterol A known as a suppressor of endoplasmic
reticulum stress.
HO
OH
HO
OH
O
O
1
2
strophastereol A
strophasterol B
O
HO
23
H
H
O
O
In the course of screening for ER (endoplasmic reticulum) stress-
suppressing and anti-methicillin resistant Staphylococcus aureus
(MRSA) substances of mushroom origin, Kawagishi and co-workers
discovered four novel steroidal compounds in the extract of the fruiting
body of Stropharia rugosoannulata, an edible mushroom, and named
them strophasterols A, B, C, and D.[1] The structures of strophasterols
A and B, including their absolute configurations, were determined to
be 1 and 2, respectively, by X-ray crystallographic analysis of the
HO
OH
O
HO
OH
O
3
4
strophastereols C and D
glaucoposterol A
22
H
H
D
cyclization
15
HO
H
H
corresponding
bis-p-bromobenzoates
(Figure
1),[1,2]
while
cleavage
HO
HO
OH
5
O
strophasterols C and D were only given a planar structure represented
by 3 that bears an additional keto functionality at the C23 position.[3]
Quite recently, Aung and co-workers also isolated strophasterol C from
the fruiting body of Cortinarius glaucopus along with some novel
steroids including glaucoposterol A (4) with the same carbon skeleton
as the strophasterols, and revealed the absolute configuration of
strophasterol C to be the same as that of strophasterol A based mainly
on its NOESY spectrum and biosynthetic considerations.[4] The totally
unprecedented carbon framework found in strophasterols A–D and
ergosterol
6
Figure 1. Structures of strophasterols
products.
A (1), B (2), and related natural
The strikingly unique carbon skeleton of the strophasterols
unveiled for the first time in the long history of steroid chemistry
coupled with the intriguing biological profiles of 1 prompted synthetic
studies on this class of natural products, which recently culminated in
the first synthesis of 1 from 5 by the Heretsch group that featured
unique base-promoted D-ring cleavage of a steroidal intermediate and
5-exo-trigonal radical cyclization of an iodo olefin to form the D’-ring
exclusively in a 20,22-trans fashion.[9] We were also attracted by the
unprecedented carbon framework of the strophasterols and, in addition,
took interest in their essential physiological roles in mushrooms per se,
which inspired our synthetic efforts to supply them in sufficient
amounts for detailed biological evaluation. We describe herein our
synthesis of 1 and 2 (22-epi form of 1) from 5 via a common synthetic
intermediate.
glaucoposterol
A was hypothesized to be biosynthesized from
ergosterol (5) via 6, a suppressor of osteoclast formation also isolated
from S. rugosoannulata,[5] through its D-ring cleavage followed by
bond formation between C15 and C22 to form a new five-membered
ring (ring D’, see structure 1) characteristic of this small family of
natural products.[1,6] From the viewpoint of biological activity,
strophasterol A was shown to exhibit moderate anti-MRSA effect as
well as suppress the ER stress-dependent apoptotic neuronal cell
death;[1,7] ER stress is considered to be
a major cause of
neurodegenerative disorders such as Alzheimer’s disease.[1,8] Detailed
biological evaluation of the strophasterols was, however, precluded due
to their limited availability from natural sources.
Scheme 1 outlines our retrosynthetic analysis of 1 and 2.
Compound 1 with 20,22-trans configuration would be derived from 7
by its B-ring functionalization using the 14-keto group as the foothold,
while 20,22-cis isomer 2 (22-epi-1) from 22-epi-7. As a common
precursor of
7 and 22-epi-7, we set 20,22-trans-substituted
[*]
S. Sato, Y. Fukuda, Dr. Y. Ogura, Prof. Dr. S. Kuwahara
Graduate School of Agricultural Science, Tohoku University
468-1 Aramaki-Aza-Aoba, Aoba-ku, Sendai 980-0845 (Japan)
E-mail: kuwahara.shigefumi.e1@tohoku.ac.jp
Prof. Dr. E. Kwon
Research and Analytical Center for Giant Molecules, Graduate
School of Science, Tohoku University, Sendai 980-8578 (Japan)
cyclopentanone 8 since its stereodivergent transformation into each of
the two epimers was considered to be possible by taking advantage of
the 15-keto function next to the C22-substituent. The intermediate 8
was then traced back to olefinic carboxylic acid 9 with the expectation
that 5-exo-trigonal cyclization of an acyl radical species generated
from 9 would lead to 8 in a diastereoselective manner due to its higher
thermodynamic stability compared to the corresponding 20,22-cis
cyclization product. Compound 9 would be prepared by Δ14-selective
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://
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10.1002/anie.201706086
Angewandte Chemie International Edition
COMMUNICATION
R2
oxidative cleavage of 10, which, in turn, would be accessible from 5
via double bond migration as the key step.
R2
H
R1
R1
22
D
H
a
c
5
14
8
Ref. [10]
H
H
H
20
22
D'
7
RO
AcO
H
H
H
H
O
11: R = H
12: R = Ac
10
b
H
O
14
H
R2
B
AcO
R2
H
HO
OH
7
O
e
d
f
H
1
H
R1
R1
15
CO2H
O
H
O
H
AcO
AcO
O
H
H
H
H
O
H
H
O
13
9
2
H
H
20
22
D'
AcO
AcO
H
H
H
O
22-epi-7
8
g
H
H
O
H
D'-ring formation
COSePh
O
H
H
22
AcO
AcO
5
H
H
14
8
H
H
H
H
H
CO2H
14
O
Scheme 2. Preparation of intermediate 8 with the D'-ring installed. Reagents
and conditions: a) Li, 2-methyl-2-butanol, THF, liq. NH3, –78 °C, 99%; b) AcCl,
pyridine, RT, 98%; c) HCl, CH2Cl2, –78 °C, 71% (85%, based on a single
separation/re-equilibration cycle); d) MMPP, EtOH/CH2Cl2, RT, 82%; e) CrO3,
H2SO4, acetone, RT, 77%; f) PhSeCl, nBu3P, Et3N, THF, RT, 94%; g)
15
H
oxidative
cleavage
AcO
AcO
H
H
10
9
nBu3SnH, AIBN, C6H6, 80 °C, 65%. MMPP
=
magnesium
Scheme 1. Retrosynthetic analysis of 1 and 2.
monoperoxyphthalate, AIBN = 2,2’-azobis(isobutyronitrile).
The preparation of the common intermediate 8 began with the
acetylation of known sterol 11 obtained by the Birch reduction of 5
(Scheme 2).[10] Treatment of the resulting acetate 12 with hydrogen
chloride in CH2Cl2 at –78 °C brought about the migration of the Δ7
double bond, furnishing quantitatively a ca. 5:2 mixture of 10 (Δ14-
isomer) and its Δ8(14)-isomer, from which the two positional isomers
could be isolated in yields of 71% and 28%, respectively, by column
chromatography on SiO2/AgNO3. Re-exposure of the latter isomer to
the same reaction conditions effected re-equilibration of the Δ8(14)
double bond, furnishing an additional amount of 10 in 14% yield (total
yield: 85%).[11,12] The double bond positions in 10 and its Δ8(14)-isomer
were assigned by comparison of their 13C NMR data with those
reported for analogous steroids.[13] Compound 10 was then exposed to
magnesium monoperoxyphthalate to regioselectively give epoxide
13,[14] the oxidative cleavage of which under Jones’ oxidation
conditions afforded keto carboxylic acid 9.[15] Compound 9 was
converted into the corresponding selenoester 14,[16] the exposure of
which to Boger’s acyl radical cyclization conditions furnished the
pivotal intermediate 8 with 20,22-trans configuration as a single
diastereomer.[17] The stereochemical assignment of 8 was performed on
the basis of diagnostic NOE correlations observed among some protons
around the newly formed D’-ring (see the Supporting Information).
With the key intermediate
8 in hand, we set about its
stereodivergent transformation into 7 and 22-epi-7 (Scheme 3), which
have the same configuration in their D’-ring units as 1 and 2,
respectively. With the intention of obtaining 7 by desulfurization of
dithiane derivative 15, compound 8 was treated with 1,3-propanedithiol
and BF3·OEt2 in CH2Cl2 at room temperature for
2 h. The
dithioacetalization proceeded regioselectively at the keto function on
the D’-ring, but unexpectedly, the product obtained quantitatively was
a ca. 2:1 mixture of 15 and its C22-epimer (22-epi-15). Fortunately,
SiO2 column chromatography enabled the separation of the two
epimers, providing 15 and 22-epi-15 in isolated yields of 60% and 31%,
respectively. Each epimer was subjected to Raney nickel
desulfurization to afford 7 (66% yield) and 22-epi-7 (65% yield); the
relative configuration of 7 was determined by X-ray crystallographic
analysis.[18] The generation of 22-epi-15 would be explainable by the
intervention of a thioenol ether intermediate prior to the dithiane ring
formation (cf. structure 16). Interestingly, this epimerization was
suppressed when the reaction was conducted at –40 to –20 °C,
affording 15 as virtually a single isomer in 94% yield and thereby
establishing a diasteroselective two-step route from 8 to 7 in 62%
overall yield. Although 22-epi-7, which we set as a precursor to 2,
could also be secured (20% yield through 2 steps from 8) by
conducting the dithioacetalization at room temperature, we sought a
better way to give 22-epi-7 preferentially and examined
stereoselectivity in the hydrogenation of trisubstituted cyclopentene 17
prepared from
experimentation, we found that exposure of 17 to hydrogen in the
8
via thioenol ether 16.[19] After considerable
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10.1002/anie.201706086
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COMMUNICATION
presence of palladium on carbon in hexane gave 7 exclusively (95%
isolated yield),[20] while hydrogenation with Crabtree’s catalyst in
CH2Cl2 afforded a separable 1.7:1 mixture of 22-epi-7 and 7, favoring
the former isomer.[21] Chromatographic separation of the mixture
provided 22-epi-7 in 58% yield (and 7 in 34%), thus realizing the
preferential formation of 22-epi-7 from the common intermediate 8.
22 and 22’ in isolated yields of 48% and 9.7%, respectively, for the
two steps. Exposure of the iodide 22 to m-chloroperbenzoic acid in
CH2Cl2 in the presence of NaHCO3 at room temperature elicited three
consecutive reactions: (1) oxidation of 22 to iodoso compound 24; (2)
syn-elimination of 24 to form an olefinic intermediate bearing a Δ5-
double bond; and (3) epoxidation of the double bond by excess
mCPBA from its less hindered α face to produce 23 in 78% yield.[26]
Finally, removal of the two protecting groups at the C3 and C7
positions in one pot completed the synthesis of 1, which showed good
agreement with natural strophasterol A in NMR, melting point, and
specific rotation. Application of essentially the same 7-step sequence
of reactions to 22-epi-7 afforded 2 (see the Supporting Information),
the physical data of which were also identical with those reported for
natural strophasterol B.
R1
R1
22
S
a
b
22
D'
22-epi-15
+
R3
S
R3
O
c
15
H
H
O
22-epi-7
H
15
AcO
8
H
c
R1
d
R1
R1
22
22
f
H
H
O
SEt
R3
H
a
b
H
H
O
H
O
16
17
9
AcO
7
8
H
e
H
AcO
AcO
R1
H
H
7
18
R1
R1
R3
H
H
O
g
+
7
H
d
c
C
H
O
H
O
AcO
22-epi-7
H
B
3
7
AcO
AcO
Br
H
H
Scheme 3. Stereodivergent transformation of 8 into 7 and 22-epi-7. Reagents
and conditions: a) HS(CH2)3SH, BF3·OEt2, CH2Cl2, RT, 15: 60%, 22-epi-15:
31%; b) HS(CH2)3SH, BF3·OEt2, CH2Cl2, –40 to –20 °C, 94%; c) H2, Raney Ni,
THF, EtOH, RT, 66% for 7, 65% for 22-epi-7; d) EtSH, TMSCl, CH2Cl2, RT,
88%; e) H2, Raney Ni, EtOH, 60 °C, 83%; f) H2, Pd/C, hexane, RT, 95%; g) H2,
Crabtree’s catalyst, CH2Cl2, RT, 22-epi-7: 58%, 7: 34%. TMSCl = trimethylsilyl
chloride.
20
19
R1
R1
f
g
H
O
H
1
2
O
B
I
OR4
AcO
AcO
OTMS
H
O
23
21: R2 = H
The B-ring functionalization of 7 and 22-epi-7 leading to the target
molecules 1 and 2, respectively, is shown in Scheme 4. Installation of a
double bond at the C8/C9-position of 7 was effected in one pot by α-
bromination of the ketone followed by in-situ dehydrobromination to
afford 18.[22] Allylic bromination of 18 with N-bromosuccinimide and
2,2’-azobis(4-methoxy-2,4-dimethylvaleronitrile) gave 7α-bromo
derivative 19 in 50% yield together with a small amount of a 7,11-
dibrominated product.[23,24] The structure of 19 was assigned on the
basis of a 1H coupling sequence from H3 to H7 observed in its TOCSY
spectrum as well as small coupling constants between H7 and the two
adjacent protons at the C6 position.[25] Dehydrobromination of 19 to
diene 20 was first attempted by its treatment with DBU in THF, but the
e
22: R2 = TMS
7 steps
9.7%
22-epi-7
C
B
I
B
O
B
OR4
OTMS
H
H
O
I
H
20'
21': R4 = H
24
22': R4 = TMS
Scheme 4. Completion of the synthesis of 1 and 2. Reagents and conditions:
a) PhNMe3·Br3, THF, 50 °C, then DBU, 50 °C, 89%; b) NBS, V-70, CCl4, 40 °C,
50%; c) PhSeSePh, NaBH4, THF, RT, then 30% H2O2, RT, 74%; d) NIS, H2O,
acetone, RT; e) TMSOTf, 2,6-lutidine, RT, 48% (2 steps) (21’: 9.7%); f)
mCPBA, NaHCO3, CH2Cl2, RT, 78%; g) KOH, MeOH, RT, 80%. DBU = 1,8-
product obtained was a ca. 1:4 mixture of 20 and undesired Δ7,9(11)
-
diene 20’. This problem could be circumvented by prior conversion of
19 into a selenide intermediate and subsequent oxidative elimination in
one pot, furnishing 20 in 74% yield, which set the stage for the
installation of the epoxy alcohol unit on the B-ring. This challenging
task was accomplished by a four-step sequence beginning with regio-
and disasterselective iodohydroxylation of 20 with NIS in aq THF,
which delivered a ca. 5.5:1 mixture of 21 and its diastereomer 21’. The
inseparable mixture was treated with TMSOTf in 2,6-lutidine to give
diazabicyclo[5.4.0]-7-undecene; NBS
azobis(4-methoxy-2,4-dimethylvaleronitrile),
TMSOTf trimethylsilyl trifluoromethanesulfonate, mCPBA
chloroperbenzoic aicd.
=
N-bromosuccinimide, V-70
NIS N-iodosuccinimide,
meta-
= 2,2’-
=
=
=
In conclusion, strophesterol A (1) has been synthesized in 1.8%
overall yield from ergosterol (5) by a 17-step sequence via 17 (or in
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10.1002/anie.201706086
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COMMUNICATION
[9]
a) R. C. Heinze, D. Lentz, P. Heretsch, Angew. Chem. Int. Ed. 2016, 55,
11656–11659; Angew. Chem. 2016, 128, 11828–11831; b) R. C. Heinze, P.
Heretsch, Synlett 2017, 28, 1127–1133.
1.6% overall yield via 15 through 16 steps). The new synthesis
featured: (1) efficient HCl-mediated double bond migration from ring
B to ring D (12 → 10); (2) acyl radical cyclization to form exclusively
the D’-ring with 20,22-trans configuration (14 → 8); (3) completely
selective palladium-catalyzed hydrogenation to establish the 20,22-
trans-relationship (17 → 7); and (4) mCPBA oxidation of protected
iodohydrin 22 to deliver epoxide 23 in one pot. The first synthesis of
strophasterol B (2) has also been achieved from 5 in 17 steps (1.1%
overall yield) involving 20,22-cis-selective iridium-catalyzed
hydrogenation as the pivotal transformation (17 → 22-epi-7).
[10] S. Giroux, E. J. Corey, Org. Lett. 2008, 10, 801–802.
[11] For analogous double bond migrations, see: a) E. Caspi, W. L. Duax, J. F.
Griffin, J. P. Moreau, T. A. Wittstruck, J. Org. Chem. 1975, 40, 2005–2006; b)
T. M. Peakman, J. R. Maxwell, J. Chem. Soc. Perkin Trans. 1 1988, 1065–
1070.
[12] Exposure of 12 to p-toluenesulfonic acid monohydrate in toluene at 80 °C for 3
h gave the Δ8(14) isomer almost exclusively in 89% yield.
[13] W. K. Wilson, R. M. Sumpter, J. J. Warren, P. S. Rogers, B. Ruan, G. J.
Schroepfer, Jr., J. Lipid Res. 1996, 37, 1529–1555. See also the Supporting
Information.
[14] Literature precedents strongly support that the epoxide 13 is α-configured. See
for examples: a) M. Morisaki, T. Igata, S. Yamamoto, Chem. Pharm. Bull.
2000, 48, 1474–1479; b) M. E. Jung, T. W. Johnson, Tetrahedron 2001, 57,
1449–1481. MMPP was also employed by Heretsch and co-workers in their
first synthesis of 1 for Δ14-selective epoxidation of a more complex steroidal
intermediate. See Ref. [9a] for details.
Acknowledgements
This work was financially supported by MEXT KAKENHI (Grant No.
26102707). We thank Ms. Yuka Taguchi, Dr. Yuko Cho, Profs. Keiichi
Konoki, Itaru Nakamura, and Masahiro Terada (Tohoku University)
for their help in NMR and MS measurements.
[15] R. de A. Epifanio, W. Camargo, A. C. Pinto, Tetrahedron Lett. 1988, 29,
6403–6406.
[16] D. Batty, D. Crich, Synthesis 1990, 273–275.
[17] D. L. Boger, R. J. Mathvink, J. Org. Chem. 1992, 57, 1429–1443.
[18] See the Supporting Information for the X-ray structure. CCDC 1540551
contains the supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic Data Centre.
[19] H. Mizuno, K. Domon, K. Masuya, K. Tanino, I. Kuwajima, J. Org. Chem.
1999, 64, 2648–2656.
Keywords: hydrogenation • radical reactions • steroids •
strophasterol • total synthesis
[1]
[2]
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Hirai, H. Kawagishi, Angew. Chem. Int. Ed. 2012, 51, 10820–10822; Angew.
Chem. 2012, 124, 10978–10980.
[20] Hydrogenation of 17 using Pd/C in EtOAc (instead of hexane) afforded a
mixture of 7 and 22-epi-7 in a ratio of 21:1.
J. Wu, H. Kobori, M. Kawaide, T. Suzuki, J.-H. Choi, N. Yasuda, K. Noguchi,
T. Matsumoto, H. Hirai, H. Kawagishi, Biosci. Biotechnol. Biochem. 2013, 77,
1779–1781.
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[22] T. G. Back, N.-X. Hu, Tetrahedron Lett. 1992, 33, 5685–5688.
[23] Y. Kita, A. Sano, T. Yamaguchi, M. Oka, K. Gotanda, M. Matsugi,
Tetrahedron Lett. 1997, 38, 3549–3552.
[3]
[4]
The numbering of carbons follows that in Ref. [4].
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2017, 14, e1600421.
[24] For an analogous allylic bromination, see: T. Tokoroyama, H. Koike, K.
Hirotsu, Tetrahedron 1982, 38, 2559–2568.
[5]
[6]
[7]
[8]
J. Wu, K. Fushimi, S. Tokuyama, M. Ohno, T. Miwa, T. Koyama, K. Yazawa,
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[25] H7 was observed at δ 5.46 ppm as a broad singlet with a W1/2 value of 6.8 Hz.
[26] a) T. L. Macdonald, N. Narasimhan, L. T. Burka, J. Am. Chem. Soc. 1980, 102,
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In Ref. [4], Aung et al. proposed the new skeletal name “strophastane” as well
as
a numbering system for the carbon skeleton of strophasterol-type
compounds.
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887–894.
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COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Two from one: Two epimeric
secosteroids of mushroom origin,
D-ring cleavage &
strophasterols A and B, have been
D’-ring formation
Shuntaro Sato, Yuki Fukuda, Yusuke
Ogura, Eunsang Kwon, Shigefumi
Kuwahara*
ergosterol
synthesized from ergosterol in a
Page No. – Page No.
stereodivergent manner by using two
types of hydrogenation. An isolated
cyclopentane ring unit unique to the
strophastane family of natural
products was installed via an acyl
radical cyclization and the B-ring
functionalization was achieved
through peracid oxidation of an iodide
to deliver an epoxide directly.
H
H
O
B-ring
functionalization
H
Synthesis of Two Epimeric
Secosteroids, Strophasterols A and B
AcO
H
22
D’
hydrogenation
(Pd or Ir)
H
O
strophasterol B
(22-epi form)
HO
OH
O
strophasterol A
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