Formal Semisynthesis of Demethylgorgosterol Utilizing a Stereoselective Intermolecular Cyclopropanation Reaction

Article abstract of DOI:10.1002/ejoc.202100035

In this study, we report a convenient and high yielding formal semisynthesis of demethylgorgosterol, a marine steroid with an intriguing sidechain containing a cyclopropane unit. This was achieved through the synthesis of an advanced ketone intermediate.

Full text of DOI:10.1002/ejoc.202100035

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doi.org/10.1002/ejoc.202100035
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Formal Semisynthesis of Demethylgorgosterol Utilizing a
Stereoselective Intermolecular Cyclopropanation Reaction
[a]
[a]
[a, e]
[b]
[c]
Nicolai Rosenbaum, Lisa Schmidt, Florian Mohr, Olaf Fuhr, Martin Nieger, and
[a, d]
Stefan Bräse*
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In this study, we report a convenient and high yielding formal
semisynthesis of demethylgorgosterol, a marine steroid with an
intriguing sidechain containing a cyclopropane unit. This was
achieved through the synthesis of an advanced ketone
intermediate. The synthetic route features a total of ten steps,
starting from commercially available stigmasterol, with an
overall yield of 27%. The key step was a stereoselective
intermolecular cyclopropanation reaction. This reaction pro-
ceeded in 82% yield, the resulting cyclopropane carboxylic
ester shows a trans/cis ratio of 89:11, with a diastereomeric
ratio for the trans-diastereomers of >99:1. A reduction/
oxidation sequence afforded the corresponding aldehyde,
which was used in a Grignard reaction. A final oxidation step
then yielded the desired ketone. This novel route presents a
platform to further investigate the medicinal applications of
gorgosterol-type steroids and to fully understand their role in
coral symbiosis.
Introduction
One of these many natural products, gorgosterol (1a), was
first isolated by Bergmann et al. in 1943 from the soft coral
[7]
Corals and coral reefs, despite only covering about 1% of the
ocean floor, are the most diverse aquatic ecosystems. They are
associated with an estimated 25% of all marine species and
rivaled in biodiversity only by rain forests. Their ecological, as
well as economic impact, is of global scale, and they are a
source of countless natural products. Yet, they are endangered
by climate change in multiple ways, as well as by environ-
mental pollution, amongst others.
Plexaura flexuosa. Gorgosterol is also found in various other
[1]
[8]
animals and their symbionts. It had chemists puzzled due to
[
7,9]
its unusual properties,
until its structure was elucidated
[2]
[10]
unambiguously, and its first derivative demethylgorgosterol
(1b) was discovered. Nowadays, a plethora of derivatives are
[3]
[11]
[
4]
known, e.g. 2–5 (Figure 1), showing a multitude of biological
[
5]
[12]
activities. These include cytotoxicity against various cancer
[5a]
[6]
[12c,13]
[14]
cell lines,
reversal of multidrug resistance in cancer cells,
[15]
[16]
antitubercular activity , and antifungal activity. A common
feature of these steroids is their distinctive sidechain, containing
[a] N. Rosenbaum, L. Schmidt, Dr. F. Mohr, Prof. Dr. S. Bräse
Institute of Organic Chemistry (IOC)
Karlsruhe Institute of Technology (KIT)
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
E-mail: braese@kit.edu
http://www.ioc.kit.edu/braese/index.php
b] Dr. O. Fuhr
[
Institute for Nanotechnology (INT) and Karlsruhe Nano Micro Facility
(
KNMF)
Karlsruhe Institute of Technology (KIT)
Hermann-von-Helmholtz Platz 1, 76344 Eggenstein-Leopoldshafen
[c] Dr. M. Nieger
Department of Chemistry
University of Helsinki
P. O. Box 55, 00014 Helsinki, Finland
[d] Prof. Dr. S. Bräse
Institute of Biological and Chemical Systems – Functional Molecular
Systems (IBCS-FMS)
Karlsruhe Institute of Technology (KIT)
Hermann-von-Helmholtz Platz 1, 76344 Eggenstein-Leopoldshafen
https://fms.ibcs.kit.edu
[
e] Dr. F. Mohr
New address: Pharmazeutisches Institut
Eberhard-Karls-Universität Tübingen
Auf der Morgenstelle 8, 72076 Tübingen
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100035
©
2021 The Authors. European Journal of Organic Chemistry published by
Wiley-VCH GmbH. This is an open access article under the terms of the
Creative Commons Attribution Non-Commercial License, which permits use,
distribution and reproduction in any medium, provided the original work is
properly cited and is not used for commercial purposes.
Figure 1. Structures of Gorgosterol (1a), Demethylgorgosterol (1b), and
selected derivatives 2–5.
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doi.org/10.1002/ejoc.202100035
a C22/C23 cyclopropane ring and additional methyl groups at
C23 and C24.
The exact mechanism of the biosynthesis of the gorgosterol
family has not been fully elucidated yet. Several plausible routes
have been proposed and discussed, with no final conclusion.
However, biosynthesis is believed to be part of the complex
symbiotic relationship between corals and algae. Recently, it
then cyclized to yield the known aldehyde 12 (Scheme 1c).
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These routes, despite involving more steps, produced the
[18]
intermediary ketone 8 in a higher yield. Ikekawa et al. also
presented a stereoselective semisynthesis of gorgosterol (1b)
[19]
[24]
using a similar 3-exo-tet cyclization.
was shown that corals depend on sterols provided by their Results and Discussion
symbionts and that their sterol composition varies substantially
[20]
to symbiont species and even cell line.
The biological
The starting point for our semisynthesis was the commercially
available stigmasterol (6). The latter phytosterol was trans-
formed into the alkene 19, which was needed for the enantio-
and diastereoselective intermolecular cyclopropanation, accord-
ing to known procedures in five steps (Scheme 2). The first two
steps were necessary to protect the steroidal A- and B-rings in
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function of gorgosterol is unknown, but it exhibits activity as a
[21]
growth inhibitor of human colon tumor cell lines. Addition-
ally, it was identified as a new chemotype of farnesoid-X-
[
12d]
receptor (FXR) antagonist,
making it a potential target for
[22]
the treatment of cholestasis.
[25]
In the past, several semisyntheses of demethylgorgosterol
the form of the i-steroid methyl ether 16. This was followed
[
26]
(1b) and its stereoisomers, as well as one of gorgosterol (1a),
by the cleavage of the side chain by ozonolysis,
subsequent transformation of the resulting aldehyde 17.
and
A
[
23]
were achieved by the groups of Djerassi and Ikekawa. The first
attempts to methylenate a suitable precursor using either a
Simmons-Smith reaction or a Corey-Chaykovsky reaction did
Julia-like, two-step alkene synthesis was employed, rather than
one step procedures like the Wittig reaction, since this resulted
[23]
[27]
not yield the desired configuration.
All of the following
in higher yields. Alkene 19 was obtained from stigmasterol
syntheses used an intramolecular 3-exo-tet ring-closure strategy
to form the cyclopropane moiety in the desired configuration
(6) in up to 52% yield on a multi-gram scale.
Since rhodium-based catalysts often show poor selectivity
[
28]
(Scheme 1). The shortest route, developed by Djerassi et al.,
and yields for the cyclopropanation of aliphatic alkenes, and
asymmetric Corey-Chaykovsky- and Simmons-Smith-type reac-
tions were chemically not applicable to alkene 19, we opted for
consists of a total of 15 steps. The key step was a domino
cyclization/alkylation-reaction of 7 to 8 (Scheme 1a). However,
the overall yield of the above-mentioned semisynthesis was
[29]
Iwasa’s ruthenium-based procedure. From their model for the
chiral induction in this Ru-pheox catalyzed cyclopropanation we
deduced that the (R)-configured catalyst would produce the
desired stereochemistry. The ligand 21 and catalyst 22 were
synthesized according to literature from (R)-2-phenylglycinol
[17]
very low. Ikekawa et al. developed three different routes, all
leading to ketone 8 eventually and converging into Djerassi’s
route. Starting from steroid 9, which was transformed into
aldehyde 11 and then cyclized yielding 12. The cyclized
aldehyde 12 was then transformed into the known ketone 8
[
30]
(20) in yields of 73% and 88% respectively (Scheme 3).
[18a]
(Scheme 1b).
Alternatively, starting material 13 could either
Scheme 4 shows the cyclopropanation carried out under
optimized reaction conditions. A yield of 82% was achieved,
be transformed into 10 to join route (b) or into 14, which was
[17]
[18]
Scheme 1. Previous semisyntheses of demethylgorgosterol (1b). Routes developed by (a) Djerassi et al. and (b), (c) Ikekawa et al.
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Scheme 2. Synthesis of the alkene 19 starting from commercially available stigmasterol (6). Reaction conditions: a) TsCl, pyridine, rt, 16 h, quant. b) MeOH,
pyridine, reflux, 4 h, 78%. c) i) O
e) Dimethyl sulfone, nBuLi, THF, 0
3
, DCM, MeOH, À 78 C, 45 min; ii) Zn, HOAc, rt, 1 h, 80%. d) TsNHNH
°
2
, MS 3 Å, ethanol, rt, 30 min, 50 C, 30 min, 95%.
°
°
C to rt, 16 h, 88%.
Scheme 3. Synthesis of (R)-Ru-pheox 22 from (R)-2-phenylglycinol (20).
Reaction conditions: a) i) benzoyl chloride, Et
3
N, DCM, 0°C to rt, 16 h.
ii) SOCl
2
, CHCl
3
, 0°C to rt, 24 h. iii) 2.5 m NaOH, 1,4-dioxan, 0°C to rt, 4 h,
73%. b) benzeneruthenium(II) chloride dimer, 1 m NaOH, KPF , MeCN, 80°C,
6
4
8 h, 88%.
Figure 2. ORTEP-style representation of ester 23. Thermal ellipsoids are
shown at a 50% probability level. The absolute configuration was
determined crystallographically.
Scheme 4. Cyclopropanation of 19 using optimized reaction conditions.
factoring in recovered starting material it rose to a nearly
quantitative yield of 99%. Key optimization steps from Iwasa’s
procedure were a prolonged addition time and an increased
alkene concentration. Detailed information on the optimization
of the cyclopropanation procedure can be found in chapter 3 of
the supporting information.
Single-crystal x-ray analysis revealed that the main diaster-
eomer had the desired (1S,2R) configuration at the newly
constructed cyclopropane unit (Figure 2). The stereoselectivity
of the reaction was further investigated using GC/MS. The
trans/cis ratio was found to be 89:11 with a diastereomeric
ratio for the two trans-diastereomers of >99:1. Only one of the
two possible cis-diastereomers was detected, for which we
deduced a (1S,2S) configuration in agreement with the chiral
induction model for the catalyst system. Separation of the
minor diastereomers is possible but quite tedious. Therefore,
we decided to do so at a later stage.
Scheme 5. Transformation of ester 23 into the known ketone 8 in four steps.
Reaction conditions: a) LiAlH , THF, reflux, 4 h, quant. b) IBX, DMSO, rt, 16 h,
4
9
2% c) iPrMgBr, THF, À 18 C, 2 h, 83%. d) PCC, DCM, 2 h, 84%.
°
The ester 23 was then transformed in four steps into the
[
17]
known ketone 8 (Scheme 5).
Ester 23 was reduced with
mixtures along with unreacted ester were obtained in every
case. Since very good yields were achieved with the two-step
procedure, this was not pursued further. As for the ester, it is
possible to separate the minor diastereomers on both stages,
but more easily for the alcohol. However, it is still tedious and
LiAlH , giving the alcohol 24 in a quantitative yield. The latter
4
one was then oxidized using 2-iodoxybenzoic acid (IBX) to
afford the aldehyde 25 in a yield of 92%. The direct reduction
of the ester 23 to the aldehyde 25 was also tested, but product
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they were only separated after the next step. The aldehyde 25
was very similar to the known aldehyde 12 used by Ikekawa
In total, our synthesis of the intermediary ketone 8 consists
of ten steps in a linear sequence starting from the commercially
available stigmasterol 6 (Table 1, entry 1). The key step, the
cyclopropanation of the alkene 19, proceeds with good stereo-
control and exceptional yield. For the complete sequence, a
yield of 27.4% and 33.1% based on recovered starting material
was achieved. In contrast, Djerassi’s route achieved the syn-
thesis of ketone 8 in just nine steps, again starting from 6
(Entry 2). However, the achieved yield was an order of
magnitude lower at only 3.7% and 5.1% yield, partly since the
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et al. in their semisynthesis, the only difference being the
[18b]
protecting group for the A/B-ring.
Therefore, the same
procedures were used to synthesize the ketone 8 from the
aldehyde 25.
The aldehyde 25 was first subjected to a Grignard reaction
with iPrMgBr. Due to the newly formed stereogenic center at
C24, this resulted in three pairs of epimers. Nevertheless,
separation of this mixture was easily achieved, yielding the
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[17]
alcohol 26 in 83%. The diastereomeric ratio determined by H-
stereodefining step proceeded with very low selectivity.
NMR was found to be 4.9:1, with the main epimer showing
Ikekawa et al. presented three different syntheses, with two
differing only in the first two steps. These two routes consist of
fourteen steps each. However, the route starting from 9
produces about twice as much of ketone 8 as the route starting
from 13, with a yield of 21.9% (Entries 3 and 4). The third
synthetic route again starts at 13 but reaches 8 in just ten steps
with a yield of 15.1% (Entry 5). The starting materials 13 and 9
used by Ikekawa et al. are not commercially available, and
potentially require a multi-step synthesis themselves, which was
(24S) configuration, as evidenced by single-crystal x-ray analysis.
The alcohol 26 was then oxidized with pyridinium chlorochro-
mate (PCC) providing the known ketone 8 in 84% yield. The
melting point of 104–106°C (Lit. 106–106.5°C) and optical
2
0
D
rotation value of [α] = +115.7° (Lit. +116.7°) match those
[17]
reported by Djerassi et al. Additionally, the desired config-
uration was again proven by single-crystal x-ray analysis (Fig-
ure 3) showing that no epimerization of the C23 stereogenic
center occurs under the chosen reaction conditions. We also
explored the possibility of the direct conversion of ester 23 to
ketone 8 by the addition of one equivalent of Grignard reagent,
[18]
not factored into the yields given in Table 1.
but no conversion was observed. The overall yield for the Conclusion
conversion of ester 23 to ketone 8 was 64% over four steps.
In conclusion, a short formal semisynthesis of demeth-
ylgorgosterol was achieved through the synthesis of the
advanced ketone intermediate 8, following a novel route and
using only easily available starting materials and reagents. The
key step of this novel route was the stereoselective cyclo-
propanation of steroidal alkene 19 in a high yield and stereo-
selectivity. Compared to previous syntheses, our work repre-
sents a new optimum in the number of steps and yield, with
1
0 steps and 33.1% yield for the synthesis of ketone 8.
Experimental Section
The starting materials, solvents, and reagents were purchased from
commercial sources and used without further purification. All
reactions containing air- and moisture-sensitive compounds were
performed under an argon atmosphere, using oven or flame dried
glassware applying standard Schlenk-techniques. All reactions were
monitored by thin-layer chromatography (TLC) using silica gel
coated aluminum plates (Merck, silica gel 60, F254). The detection
was performed with UV light (254 nm) or by staining with Seebach
Figure 3. ORTEP-style representation of one of the crystallographic inde-
pendent molecules of the ketone 8. Thermal ellipsoids are shown at a 50%
probability level. The absolute configuration was determined crystallo-
graphically.
[31]
solution. NMR spectra were recorded on a Bruker Avance 400 or a
Bruker Avance DRX 500 as solutions at room temperature. Chemical
shifts are expressed in parts per million (δ, ppm), downfield from
1
13
tetramethylsilane (TMS). References for H NMR and C NMR were
1
13
Table 1. Comparison of synthetic routes for the synthesis of the interme-
diary ketone 8.
the residual solvent peaks of chloroform-d ( H: δ=7.26 ppm, C:
1
1 13
δ=77.16 ppm), dichloromethane-d
( H: δ=5.32 ppm, C: δ=
2
13
1
5
3.84 ppm), or acetonitrile-d ( H: δ=1.94 ppm, C: δ=1.32 ppm).
Entry Route
No. of steps Starting material Yield of 8 [%]
3
All coupling constants are absolute values and expressed in Hertz
J, Hz). The spectra were analyzed according to first-order and the
[a]
1
2
3
4
5
This work
Djerassi et al.
Ikekawa et al.
Ikekawa et al.
Ikekawa et al.
10
9
14+
14+
9+
6
6
13
9
13
27.4/33.1
3.7/5.1
11.0
21.9
15.2
(
[
17]
[a]
descriptions of signals include: s=singlet, d=doublet, dd=doublet
of doublets, t=triplet, q=quartet, m=multiplet. The C signal
[
18]
18]
[b]
[b]
13
[
[18a]
[b]
structure was analyzed by multiplicity-edited HSQC (heteronuclear
single quantum correlation) and is described as follows: + =primary
or tertiary C-atom (positive signal), À =secondary C-atom (negative
[
a] Based on the recovered starting material. [b] Starting material not
commercially available.
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signal), and C .=quaternary C-atom (no signal). Assignments were
made based upon the IUPAC numbering system for steroids. EI-MS
and FAB (3-NBA) were performed by using a Finnigan MAT 90
(70 eV). The molecular fragments are reported as mass-to-charge-
ratio (m/z). GC-MS measurements were performed on an Agilent
Technologies 6890 N (electron impact ionization), equipped with an
Agilent HP-5MS column and a 5975B VL MSD detector.
CHHOH), 3.32 (s, 3H, OCH ), 3.25 (dd, J=11.2, 7.8 Hz, 1H, CHHOH),
2.77 (t, J=2.9 Hz, 1H, 6-CH), 2.00–1.86 (m, 3H), 1.80–1.58 (m, 4H),
1.55–1.46 (m, 3H), 1.44–1.36 (m, 2H), 1.26 (q, J=9.7 Hz, 1H, CH),
q
3
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1.19–0.97 (m, 11H, contains 1.01 (s, 3H, 19-CH ), 0.99 (d, J=6.7 Hz,
3
3H, 21-CH
)), 0.92–0.71 (m, 4H), 0.69–0.62 (m, 4H, contains 0.66 (s,
3
1
3H, 18-CH )), 0.46–0.36 (m, 2H), 0.29 (dt, J=8.9, 4.7 Hz, 1H, 22 -
3
1
13
CHH), 0.23 (dt, J=8.2, 5.0 Hz, 1H, 22 -CHH). C NMR (126 MHz,
CDCl ): δ [ppm]=82.5 (+, CH-6), 67.3 (À , CH OH), 58.3 (+, CH), 56.7
3
2
Ethyl (1S,2R)-2-(6β-Methoxy-3α,5-cyclopregnan-20R-yl)cyclopro-
panecarboxylate (23): Alkene 19 (631 mg, 1.84 mmol, 1.00 equiv.)
and Ru-catalyst 22 (70.0 mg, 111 μmol, 6 mol%) were weight in an
oven-dried vial, evacuated and backfilled with argon three times.
Dry DCM (2.4 mL) was added and the solution was cooled to 0°C.
Ethyl diazoacetate (2.60 g, 2.40 mL, 19.4 mmol, 10.5 equiv.) was
added over a period of 8 h by syringe pump, while the reaction was
(
+, OCH ), 56.3 (+, CH), 48.2 (+, CH), 43.5 (C ), 43.1 (C ), 40.3 (À ,
3
q
q
CH ), 40.1 (+, CH), 35.4 (C , C-5), 35.2 (À , CH ), 33.5 (À , CH ), 30.7
2
q
2
2
(+, CH), 28.2 (À , CH
), 25.14 (À , CH
), 25.10 (+, CH), 24.4 (À , CH
2
),
2
2
2
3.2 (+, CH), 22.9 (À , CH ), 21.6 (+, CH), 20.1 (+, CH -21), 19.4 (+,
3
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2
CH -19), 13.2 (À , CH -4), 12.4 (+, CH -18), 7.9 (À , CH -22 ). MS (FAB,
3
2
3
2
+
+
3
-NBA): m/z (%)=386 (28) [M] , 385 (37) [MÀ H] , 371 (16)
+
+
+
[MÀ CH ] , 355 (100) [MÀ OCH ] , 338 (24) [MÀ OCH À OH] , 337 (86)
3
3
+ + +
3
kept at 0
°
C. After complete addition, the reaction was stirred over
[
MÀ OCH À H O] , 255 (24) [C H ] , 253 (28) [C H ] , 213 (22)
3
+
2
19 27
19 25
night at room temperature. DCM was removed under reduced
pressure and the crude product was purified by silica gel flash
+
[C H ] . HRMS (FAB, 3-NBA, m/z): calcd. for C H O , [M] :
1
6
21
26 42
2
À 1
386.3185; found: 386.3186. IR (ATR): ~v [cm ]=3425 (w), 3058 (vw),
931 (vs), 2863 (vs), 1453 (m), 1383 (m), 1329 (w), 1268 (w), 1201
w), 1054 (vs), 1030 (vs), 970 (m), 857 (m), 612 (m). EA (C H O ,
column chromatography (pentane/Et O 10:1). Volatile dimerization
2
2
(
products were removed under high vacuum to yield a yellowish
solid which was recrystallized from acetone/water to yield the pure
ester 23 as a colorless crystalline solid (649 mg, 1.51 mmol, 82%,
26
42
2
386.6): calcd.: C 80.77, H 10.95; found: C 80.80, H 11.03.
9
9%brsm). Compound 23 was obtained with a 89.0:10.7:0.3
(1S,2R)-2-(6β-Methoxy-3α,5-cyclopregnan-20R-yl)cyclopropane-
diastereomeric ratio as determined by GC-MS using a HP-5MS
carboxaldehyde (25): Alcohol 24 (459 mg, 1.19 mmol, 1.00 equiv.)
and 2-iodoxybenzoic acid (IBX) (1.66 g, 5.94 mmol, 5.00 equiv.) were
dissolved in 10 mL of DMSO and stirred overnight at room
temperature. 50 mL of water was added to the reaction mixture
and the resulting precipitate was filtered and washed thoroughly
with diethyl ether. The aqueous phase was extracted with diethyl
ether (3×50 mL). The combined organic layers were dried over
Na SO and the solvent was removed under reduced pressure. The
column; 120°C, 3 min, 20°C/min, 270°C, 30 min; τ
=20.8 min,
1S,2R)
=21.6 min. Recrystallization from acetone/
(
τ
=21.1 min, τ
(
1S,2S)
(1R,2S)
H O afforded crystals suitable for X-ray crystallographic analysis
2
2
0
(CCDC 2040692). R =0.28 (pentane/Et O 10:1). [α] = +68.4° (c=
f
2
D
1
0.56, CHCl
). Mp: 99–100°C. H NMR (500 MHz, CD
Cl ): δ [ppm]=
2 2
3
4
1
1
.13–4.03 (m, 2H, OCH CH ), 3.28 (s, 3H, OCH ), 2.74 (t, J=2.9 Hz,
2
3
3
H, 6-CH), 1.96 (dt, J=12.5, 3.4 Hz, 1H, CHH), 1.90–1.60 (m, 5H),
.54–1.36 (m, 6H), 1.36–1.26 (m, 1H, CH), 1.22 (t, J=7.1 Hz, 3H,
2
4
crude product was purified by silica gel flash column chromatog-
raphy (pentane/EtOAc 10:1) to yield the desired aldehyde 25 as a
OCH CH ), 1.20–0.96 (m, 12H, contains 1.01 (d, J=6.7 Hz, 3H, 21-
2
3
CH ), 0.99 (s, 3H, 19-CH )), 0.92–0.80 (m, 4H), 0.67 (s, 3H, 18-CH ),
colorless glass (421 mg, 1.09 mmol, 92% yield). R =0.56 (pentane/
3
3
3
f
1
3
20
1
0.63–0.58 (m, 2H), 0.40 (dd, J=8.0, 5.0 Hz, 1H, 4-CHH). C NMR
(126 MHz, CD Cl ): δ [ppm]=174.4 (C , COOEt), 82.7 (+, CH-6), 60.5
À , OCH CH ), 58.2 (+, CH), 56.7 (+, OCH ), 56.5 (+, CH), 48.4 (+,
EtOAc 5:1). [α] = +50.7° (c=0.53, CHCl ). H NMR (500 MHz,
D
3
CD Cl ): δ [ppm]=8.89 (d, J=5.8 Hz, 1H, 24-CHO), 3.27 (s, 3H,
2 2
2
2
q
(
OCH ), 2.73 (t, J=2.9 Hz, 1H, 6-CH), 1.96 (dt, J=12.5, 3.4 Hz, 1H,
2
3
3
3
CH), 43.7 (C ), 43.2 (C ), 40.4 (À , CH ), 39.8 (+, CH ), 35.7 (C , C-5),
CHH), 1.90–1.59 (m, 6H), 1.54–1.22 (m, 7H), 1.22–1.03 (m, 8H,
q
q
2
2
q
3
5.4 (+, CH ), 33.7 (+, CH ), 31.0 (+, CH), 30.6 (+, CH), 28.1 (À ,
contains 1.05 (d, J=6.7 Hz, 3H, 21-CH )), 1.03–0.81 (m, 8H, contains
2
2
3
CH ), 25.3 (À , CH ), 24.6 (À , CH ), 23.1 (À , CH ), 22.6 (+, CH), 21.9
0.99 (s, 3H, 19-CH )), 0.68 (s, 3H, 18-CH ), 0.61 (dd, J=5.0, 3.7 Hz, 1H,
2
2
2
2
3
3
1
3
(
+, CH), 19.8 (+, CH -21), 19.5 (+, CH -19), 14.6 (+, OCH CH ), 13.3
4-CH ), 0.40 (dd, J=8.0, 5.0 Hz, 1H, 4-CH ). C NMR (126 MHz,
3
3
2
3
2
2
(À , CH
-4), 12.9 (À , CH
), 12.3 (+, CH
-18). MS (FAB, 3-NBA): m/z
CD
Cl
2
): δ [ppm]=201.0 (+, CHO-24), 82.7 (+, CH-6), 58.2 (+, CH),
2
2
2
3
+
+
+
(
[
[
%)=429 (13) [M+H] , 428 (21) [M] , 427 (31) [MÀ H] , 413 (11)
56.7 (+, OCH ), 56.4 (+, CH), 48.3 (+, CH), 43.7 (C ), 43.3 (C ), 40.5
3
q
q
+
+
+
MÀ CH ] , 397 (100) [MÀ OCH ] , 396 (18) [MÀ CH OH] , 255 (12)
(À , CH ), 39.5 (+, CH), 35.7 (C , C-5), 35.3 (À , CH ), 33.7 (À , CH ),
3
3
3
2
q
2
2
+
+
+
C H ] , 253 (17) [C H ] , 213 (10) [C H ] . HRMS (FAB, 3-NBA,
32.8 (+, CH), 30.9 (+, CH), 29.6 (+, CH), 28.3 (À , CH ), 25.3 (À , CH ),
1
9
27
19 25
16 21
2
2
+
m/z): calcd. for C H O , [M] : 428.3290; found: 428.3289. IR (ATR): ~v
24.6 (À , CH ), 23.1 (À , CH ), 21.9 (+, CH-3), 20.0 (+, CH -21), 19.5
28
44
3
2
2
3
À 1
1
[
cm ]=2942 (m), 2932 (m), 2870 (m), 1717 (vs), 1458 (w), 1333 (s),
1204 (m), 1170 (vs), 1098 (vs), 1038 (m), 1014 (m), 990 (w), 867 (m),
744 (w), 615 (w), 569 (vw). EA (C28 , 428.6): calcd.: C 78.46, H
0.35; found: C 78.46, H 10.06.
(+, CH -19), 13.2 (À , CH -4), 12.3 (+, CH -18), 12.0 (À , CH -22 ). MS
3
2
3
+ +
2
(FAB, 3-NBA): m/z (%)=384 (21) [M] , 383 (36) [MÀ H] , 369 (15)
+
+
+
H
O
[MÀ CH
] , 354 (28) [MÀ CH
O] , 353 (100) [MÀ OCH
] , 352 (23)
44
3
3
2
3
+
+
+
1
[MÀ CH OH] , 255 (23) [C H ] , 253 (25) [C H ] , 213 (14)
3
+
19 27
19 25
+
[
3
2
8
C H ] . HRMS (FAB, 3-NBA, m/z): calcd. for C H O , [M] :
16 21 26 40 2
(
1S,2R)-2-(6β-Methoxy-3α,5-cyclopregnan-20R-yl)cyclopropane-
À 1
84.3028; found: 384.3029. IR (ATR): ~v [cm ]=3058 (vw), 2931 (s),
867 (s), 2721 (vw), 1704 (vs), 1455 (m), 1381 (w), 1095 (vs), 1016 (s),
63 (m), 613 (w). EA (C H O , 384.6): calcd.: C 81.20, H 10.48; found:
methanol (24): A flame-dried round bottom flask was charged with
ester 23 (1.00 g, 2.33 mmol, 1.00 equiv.) and LiAlH4 (354 mg,
2
6
40
2
9
.33 mmol, 4.00 equiv.). 28 mL of abs. THF were added and the
C 81.38, H 10.39.
mixture was refluxed for 4 h under argon atmosphere. After cooling
to room temperature, excess LiAlH was quenched by slow addition
6β-Methoxy-3α,5-cyclo-22R,23S-methylene-5α-cholestan-24ξ-ol
(26): A mixture of aldehyde 25 (60.0 mg, 156 μmol, 1.00 equiv.) and
iPrMgBr (2 m, 156 μL, 312 μmol, 2.00 equiv.) in 1 mL of dry THF was
stirred at À 18°C for 2 h under argon atmosphere and then
4
of KOH (50%). The organic phase was separated and the aqueous
phase was extracted with diethyl ether (3×25 mL). The combined
organic layers were dried over Na SO and the solvent was removed
2 4
under reduced pressure. The crude product was purified by silica
gel flash column chromatography (pentane/EtOAc 5:1 to 3:1) to
yield the alcohol 24 as a colorless solid (902 mg, 2.33 mmol, quant.).
quenched with sat. NH Cl. The layers were separated and the
4
aqueous layer was washed with EtOAc. The combined organic
layers were washed with brine, dried over Na SO , and the solvent
2
4
Recrystallization from acetone/H O afforded crystals suitable for X-
was removed under reduced pressure. The residue was purified by
silica gel flash column chromatography (pentane/EtOAc 15:1) to
give a diastereomeric mixture of the alcohol as an off-white solid
(55.7 mg, 130 μmol, 83% yield). Compound (24S)-26 was obtained
2
ray crystallographic analysis (CCDC 2041206). R =0.23 (pentane/
f
2
0
1
EtOAc 4:1). [α] = +44.0° (c=0.50, CHCl ). Mp: 150–155°C.
H
D
3
NMR (500 MHz, CDCl
): δ [ppm]=3.64 (dd, J=11.1, 6.0 Hz, 1H,
3
Eur. J. Org. Chem. 2021, 1568–1574
www.eurjoc.org
1572
© 2021 The Authors. European Journal of Organic Chemistry published
by Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100035
1
with a 4.9:1 diastereomeric ratio as determined by H NMR
Deposition Numbers 2047122 (for 8), 2041205 (for 15), 2041206 (for
24), 2041207 (for 26), 2040691 (for 18), and 2040692 (for 23)
contain the supplementary crystallographic data for this paper.
These data are provided free of charge by the joint Cambridge
Crystallographic Data Centre and Fachinformationszentrum Karls-
ruhe Access Structures service www.ccdc.cam.ac.uk/structures.
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
spectroscopy. Recrystallization from isopropanol/H O afforded
crystals suitable for X-ray crystallographic analysis (CCDC 2041207).
2
2
0
R =0.66 (pentane/EtOAc 4:1). [α] = +61.9° (c=0.52, CHCl ). Mp:
f
D
3
1
91–94
°
C. H NMR (500 MHz, CDCl ): δ [ppm]=3.32 (s, 3H, OCH ),
3
3
2
.95 (dd, J=6.7, 4.8 Hz, 1H, 24-CHOH), 2.77 (t, J=2.9 Hz, 1H, 6-
CHOCH ), 2.00–1.87 (m, 3H), 1.83–1.67 (m, 3H), 1.67–1.58 (m, 1H),
3
1
.55–1.46 (m, 2H), 1.46–1.33 (m, 3H), 1.27–1.00 (m, 9H, contains 1.02
(
s, 3H, 19-CH )), 0.97 (d, J=6.9 Hz, 6H, 26-CH and 27-CH ), 0.92–
3
3
3
0.77 (m, 7H, contains 0.87 (d, J=6.7 Hz, 3H, 21-CH )), 0.69 (s, 3H, 18-
3
Acknowledgements
CH
), 0.65 (dd, J=5.0, 3.7 Hz, 1H, 4-CHH), 0.62–0.55 (m, 1H, CH), 0.43
3
1
(dd, J=8.0, 5.0 Hz, 1H, 4-CHH), 0.33 (dt, J=9.0, 4.7 Hz, 1H, 22 -CHH),
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
1
We gratefully thank the Jürgen Manchot Stiftung for supporting
this research with a Ph.D. scholarship. Open access funding
enabled and organized by Projekt DEAL.
0
.19 (ddd, J=8.5, 5.5, 4.5 Hz, 1H, 22 -CHH). Missing Signal (1H, OH)
13
due to H/D exchange. C NMR (126 MHz, CDCl ): δ [ppm]=82.6 (+,
CH-6), 79.1 (+, CH-24), 57.8 (+, CH), 56.7 (+, OCH ), 56.4 (+, CH),
3
3
4
8.2 (+, CH), 43.5 (C ), 43.0 (C ), 40.3 (À , CH ), 38.3 (+, CH), 35.4 (C ,
q
q
2
q
C-5), 35.2 (À , CH ), 34.0 (+, CH), 33.5 (À , CH ), 30.7 (+, CH), 28.3 (À ,
2
2
CH
), 25.1 (À , CH
), 24.4 (À , CH
), 23.5 (+, CH), 23.0 (+, CH), 22.9 (À ,
2
2
2
Conflict of Interest
CH ), 21.6 (+, CH), 19.5 (+, CH -26 or CH -27), 19.4 (+, CH -19), 18.3
2
3
3
3
(
+, CH -21), 17.4 (+, CH -26 or CH -27), 13.2 (À , CH -4), 12.4 (+,
3
3
3
2
1
+
CH -18), 5.6 (À , CH -22 ). MS (FAB, 3-NBA): m/z (%)=428 (16) [M] ,
The authors declare no conflict of interest.
3
2
+
+
+
4
27 (37) [MÀ H] , 397 (19) [MÀ OCH ] , 379 (100) [MÀ OCH À H O] ,
3
+ + +
3
2
3
53 (14) [MÀ H À C H O] , 255 (26) [C H ] , 253 (45) [C H ] , 213
2
4
9
19 27
19 25
+
+
Keywords: Cyclopropanation
Stereoselective synthesis · Ruthenium
·
Gorgosterol
·
Steroids
·
(20) [C H ] . HRMS (FAB, 3-NBA, m/z): calcd. for C H O , [M] :
428.3649; found: 428.3651. IR (ATR):
2
16
21
29 48
2
À 1
~
v [cm ]=3493 (w), 3060 (vw),
932 (vs), 2866 (vs), 2846 (s), 1459 (s), 1380 (m), 1252 (w), 1198 (w),
152 (w), 1086 (vs), 1016 (s), 992 (m), 914 (m), 891 (w), 860 (m), 815
1
(w), 660 (w), 615 (w), 541 (w). EA (C H O , 428.7): calcd.: C 81.25, H
29 48 2
1
1.29; found: C 81.14, H 11.40.
[1] M. D. Spalding, A. M. Grenfell, Coral Reefs 1997, 16, 225–230.
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6
β-Methoxy-3α,5-cyclo-22R,23S-methylene-5α-cholestan-24-one
(
8): To a solution of alcohol 26 (211 mg, 492 μmol, 1.00 equiv.) in
5
mL of DCM was added 0.2 g of powdered molecular sieve 3 Å,
followed by pyridinium chlorochromate (PCC) (165 mg, 765 μmol,
1.56 equiv.). The mixture was stirred at room temperature for 2 h.
Diethyl ether was added (10 mL), and the mixture was filtered
through a short plug of Florisil. The solvent was removed under
reduced pressure to yield the crude ketone, which was purified by
silica gel flash column chromatography (pentane/EtOAc 20:1). The
ketone 8 was obtained as a colorless solid (176 mg, 413 μmol, 84%
yield). Spectroscopic properties were identical to those present in
[
4] A. R. Carroll, B. R. Copp, R. A. Davis, R. A. Keyzers, M. R. Prinsep, Nat.
Prod. Rep. 2020, 37, 175–223.
[
5] a) P. W. Glynn, Coral Reefs 1993, 12, 1–17; b) E. Rosenberg, L. Falkovitz,
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[17]
the literature.
Recrystallization from methanol/H O afforded
2
crystals suitable for X-ray crystallographic analysis (CCDC 2047122).
1
287; b) M. P. Rahelivao, T. Lubken, M. Gruner, O. Kataeva, R.
20
D
R =0.28 (pentane/EtOAc 20:1). [α] = +115.7° (c=0.555, CHCl ).
f
3
Ralambondrahety, H. Andriamanantoanina, M. P. Checinski, I. Bauer,
H. J. Knolker, Org. Biomol. Chem. 2017, 15, 2593–2608; c) R. G. Kerr, P. C.
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57, 317–323; e) T. Ando, A. Kanazawa, S. Teshima, H. Miyawaki, Mar. Biol.
1
Mp: 104–106°C. H NMR (500 MHz, CDCl ): δ [ppm]=3.32 (s, 3H,
3
OCH ), 2.77 (t, J=2.9 Hz, 1H, 6-CHOCH ), 2.72 (hept, J=6.9 Hz, 1H,
3
3
2
5-CH), 1.98–1.85 (m, 3H), 1.84–1.66 (m, 3H), 1.65–1.56 (m, 1H,
CHH), 1.55–1.47 (m, 2H), 1.47–1.32 (m, 3H), 1.31–1.21 (m, 2H), 1.19–
0.96 (m, 17H, contains 1.14 (d, J=7.0 Hz, 3H, 27-CH ), 1.11 (d, J=
.8 Hz, 3H, 26-CH ), 1.01 (s, 3H, 19-CH ), 1.00 (d, J=6.7 Hz, 3H, 21-
1
979, 50, 169–173.
3
[
9] a) D. H. Barton, J. Chem. Soc. 1945, 813–819; b) R. L. Hale, J. Leclercq, B.
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Scheuer, J. Am. Chem. Soc. 1970, 92, 2179–2180.
6
3
3
CH )), 0.93–0.78 (m, 4H), 0.70–0.61 (m, 5H, contains 0.67 (s, 3H, 18-
CH )), 0.43 (dd, J=8.1, 5.0 Hz, 1H, 4-CHH). C NMR (126 MHz,
CDCl ): δ [ppm]=214.1 (C , CO-24), 82.5 (+, CH-6), 57.8 (+, CH),
3
13
3
[10] N. C. Ling, R. L. Hale, C. Djerassi, J. Am. Chem. Soc. 1970, 92, 5281–5282.
[11] a) F. J. Schmitz, T. Pattabhiraman, J. Am. Chem. Soc. 1970, 92, 6073–
6074; b) E. L. Enwall, D. van der Helm, I. N. Hsu, T. Pattabhiraman, F. J.
Schmitz, R. L. Spraggins, A. J. Weinheimer, Chem. Commun. 1972, 215.
3
q
5
6.7 (+, OCH ), 56.3 (+, CH), 48.1 (+, CH), 43.5 (C ), 43.0 (C ), 41.5
3
q
q
(+, CH-25), 40.2 (À , CH ), 39.6 (+, CH), 35.3 (C , C-5), 35.2 (À , CH ),
2
q
2
[
12] a) Y. M. Sheikh, C. Djerassi, B. M. Tursch, Chem. Commun. 1971, 217;
b) Y. M. Sheikh, M. Kaisin, C. Djerassi, Steroids 1973, 22, 835–850; c) Y. Q.
He, S. Lee Caplan, P. Scesa, L. M. West, Steroids 2017, 125, 47–53;
d) M. Y. Putra, G. Bavestrello, C. Cerrano, B. Renga, C. D’Amore, S.
Fiorucci, E. Fattorusso, O. Taglialatela-Scafati, Steroids 2012, 77, 433–440;
e) Y. C. Shen, C. V. Prakash, Y. T. Chang, Steroids 2001, 66, 721–725.
33.5 (À , CH
), 32.6 (+, CH), 30.7 (+, CH), 28.9 (+, CH), 28.2 (À , CH
),
2
2
2
5.1 (À , CH ), 24.3 (À , CH ), 22.9 (À , CH ), 21.6 (+, CH), 19.7 (+,
2
2
2
CH -21), 19.4 (+, CH -19), 18.8 (+, CH -27), 18.0 (+, CH -26), 16.2
3
3
3
3
1
(
(
[
À , CH -22 ), 13.2 (À , CH -4), 12.4 (+, CH -18). MS (FAB, 3-NBA): m/z
2
2
3
+
+
+
%)=426 (38) [M] , 425 (50) [MÀ H] , 411 (12) [MÀ CH ] , 395 (100)
3
+
+
+
MÀ OCH ] , 371 (13), 297 (25) [C H ] , 255 (19) [C H ] , 253 (33)
[13] a) M. H. Uddin, N. Hanif, A. Trianto, Y. Agarie, T. Higa, J. Tanaka, Nat.
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L. P. van Ofwegen, J. Nat. Prod. 1998, 61, 538–541.
3
+
22 33
19 27
+
[C H ] , 213 (10) [C H ] . HRMS (FAB, 3-NBA, m/z): calcd. for
1
9
25
16 21
+
À 1
C H O , [M] : 426.3492; found: 426.3495. IR (ATR): ~v [cm ]=3060
29 46
2
[
14] J. Tanaka, A. Trianto, M. Musman, H. H. Issa, I. I. Ohtani, T. Ichiba, T. Higa,
(vw), 2956 (s), 2919 (vs), 2866 (s), 1687 (vs), 1459 (m), 1446 (m),
W. Y. Yoshida, P. J. Scheuer, Tetrahedron 2002, 58, 6259–6266.
1
9
381 (m), 1346 (m), 1181 (w), 1092 (vs), 1062 (vs), 1017 (s), 966 (m),
[15] X. Wei, A. D. Rodriguez, Y. Wang, S. G. Franzblau, Bioorg. Med. Chem.
Lett. 2008, 18, 5448–5450.
14 (m), 880 (w), 861 (m), 815 (w), 615 (w). EA (C H O , 426.7):
29
46
2
calcd.: C 81.63, H 10.87; found: C 81.35, H 10.72.
[
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Manuscript received: January 11, 2021
Revised manuscript received: January 16, 2021
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