Enantioselective Total Synthesis of (+)-EBC-23, a Potent Anticancer Agent from the Australian Rainforest

Article abstract of DOI:10.1021/acs.joc.1c00172

We describe here an enantioselective synthesis of (+)-EBC-23, a potent anticancer agent from the Australian rainforest. Our convergent synthesis features a [3+2] dipolar cycloaddition of an olefin-bearing 1,3-syn diol unit and an oxime segment containing

Full text of DOI:10.1021/acs.joc.1c00172

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Enantioselective Total Synthesis of (+)-EBC-23, a Potent Anticancer
Agent from the Australian Rainforest
Arun K. Ghosh* and Che-Sheng Hsu
Cite This: J. Org. Chem. 2021, 86, 6351−6360
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ABSTRACT: We describe here an enantioselective synthesis of (+)-EBC-23, a potent anticancer agent from the Australian
rainforest. Our convergent synthesis features a [3+2] dipolar cycloaddition of an olefin-bearing 1,3-syn diol unit and an oxime
segment containing 1,2-syn diol functionality as the key step. The segments were synthesized in a highly enantioselective manner
using Noyori asymmetric hydrogenation of a β-keto ester and Sharpless asymmetric dihydroxylation of an α,β-unsaturated ester.
Cycloaddition provided isoxazoline derivative which upon hydrogenolysis furnished the β-hydroxy ketone expediently. A one-pot,
acid-catalyzed reaction removed the isopropylidene group, promoted spirocyclization, constructed the complex spiroketal lactone
core, and furnished EBC-23 and its C11 epimer. The C11 epimer was also converted to EBC-23 by chemoselective oxidation and
reduction sequence. The present synthesis provides convenient access to this family of natural products in an efficient manner.
EBC-23 possesses a unique spiroketal with a fused α,β-
unsaturated δ-lactone structural feature and six asymmetric
centers. The initial structural assignment was carried out by
extensive spectroscopic studies and comparison with a natural
product, osumundalactone. Subsequently, Williams and co-
workers confirmed the structure of EBC-23 and its absolute
configuration through enantioselective total synthesis using
efficient linchpin strategies.5−7 The EBC-family of natural
products generated much interest in synthesis due to their
interesting structural features and potent anticancer activity.
Yamamoto and co-workers reported an efficient synthesis of
EBC-23 utilizing a supersilyl-aldol reaction as the key step.8
Yadav and co-workers recently reported the synthesis of EBC-
23 utilizing gold-catalyzed spiroketalization of alkylnol as one
of the key steps.9 As part of our interests in exploration of
chemistry and biology of EBC-family of natural products, we
sought to develop a practical and convergent synthesis of EBC-
23 in an effort to facilitate the synthesis of structural variants.
Herein, we report an enantioselective synthesis of EBC-23 in a
convergent manner employing a [3+2] dipolar cycloaddition as
INTRODUCTION
■
Bioactive natural products are an important source of
structurally diverse molecules for drug discovery and develop-
ment.1,2 Australia is the home to some of the most magnificent
rainforests in the world. The great land size, ecosystem, and
climate range of this continent have produced a unique and
highly diverse flora and fauna. In 2007, as a part of a screening
program in search of novel anticancer agents from the
Australian tropical rainforests, Reddell and Gordon reported
the isolation of an intriguing family of natural products, EBC-
23 (1a, Figure 1), diacetate of 23 (1b), 24 (1c), 25 (1d), 72
(1e), 73 (1f), 75 (1g), and 76 (1h) with spiroketal and fused
α,β-unsaturated δ-lactone structural cores from the fruit of
Cinnamonum laubatii (family Lauraceae).3,4 These natural
products exhibited potent anticancer activity against a number
of representative human cancer cell lines. In particular, EBC-23
showed inhibition of cell growth against MM96L (melanoma),
MCF7 (breast cancer), and DV145 (prostate cancer) with IC50
values of 0.2, 0.45, and 0.48 μg/mL, respectively. In
comparison, normal cells are less susceptible to EBC, showing
an IC50 value of 1.8 μg/mL against NFF (normal fibroblasts)
cell lines.3,4 Furthermore, EBC-23 was evaluated in mouse
xenograft models with human prostate tumor cell line, DV-145.
EBC-23 inhibited tumor growth with no observable side effects
compared to solvent-only controls. This result indicated that
EBC-23 and its structural variants have the potential for the
treatment of refractory solid tumors in adults.3,4
Received: January 22, 2021
Published: April 19, 2021
https://doi.org/10.1021/acs.joc.1c00172
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 6351−6360
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Scheme 1. Retrosynthesis of EBC-23 (1a)
Figure 1. Structures of EBC-23 (1a) and related family of natural
products.
one of the key reactions. The spiroketal bearing fused α,β-
unsaturated δ-lactone structural core was constructed in a one-
pot reaction from the isoxazoline-derived polyhydroxy ketone
intermediate. The route is potentially amenable toward the
synthesis of structural variants of the EBC-family of natural
products for medicinal chemistry optimization.
RESULTS AND DISCUSSION
■
The EBC-23 family of natural products has shown significant
potential for medicinal application. One of our main objectives
in the total synthesis is to develop an efficient and practical
asymmetric synthesis of (+)-EBC-23 (1a) that can be
amenable to the synthesis of other members of the EBC-
family as well as to the synthesis of structural variants for the
structure−activity relationship studies and medicinal chemistry
development. Our retrosynthetic analysis is shown in Scheme
1. As depicted, we envisioned that EBC-23 (1a) would be
obtained from an appropriately protected polyhydroxy ketone
intermediate 2. Presumably, the removal of the protection
would affect spiroketal formation as the construction of the
α,β-unsaturated δ-lactone functionality leading to EBC-23
concommitantly. The polyhydroxy ketone intermediate is
masked in the isoxazoline derivative 3, where reductive
cleavage of the isoxazoline ring would provide the planned
β-hydroxy ketone functionality. The isoxazoline heterocycle
would be synthesized conveniently by a [3+2] nitrile oxide
cycloaddition reaction involving functionalized alkene deriva-
tive 4 and aldoxime 5. The cycloaddition reaction will install
the C-11 hydroxyl group necessary for EBC-23 synthesis.
While the nitrile oxide cycloaddition of alkene containing
allylic stereocenter has been shown to proceed with high
diastereoselectivity, the stereocontrol with a homoallylic
substrate is likely to be limited.10−13 However, the formation
of a mixture of diastereomers can provide ready access to the
C11 epimer of EBC-23. Also, the C11 epimer can be readily
converted to EBC-23 by inversion of configuration. Function-
alized alkene 4 can be derived from β-keto ester 6 by Noyori
asymmetric hydrogenation followed by syn-selective reduction
of a β-hydroxy ketone intermediate. Also, the 1,2-syn-hydroxy
stereochemistry of oxide 5 can be constructed by Sharpless
asymmetric dihydroxylation of an appropriately protected α,β-
unsaturated ester 7. All stereocenters of the functionalized
alkene and oxime segments will be set by asymmetric synthesis.
Our synthesis of functionalized alkene derivative 4 is shown
in Scheme 2. The preparation of β-keto ester 9 was
accomplished from the commercially available 1-tetradecanal
8, as reported in the literature.14,15 Noyori asymmetric
hydrogenation16,17 of β-keto ester 9 using RuCl2 [(S,S)-
BINAP] catalyst (0.5 mol %) in ethanol under 400 psi
hydrogen pressure at 50 °C for 3 h provided β-hydroxy ester
10 enantioselectively in 87% yield. To determine optical purity,
ethyl ester 10 was subject to saponification using aqueous
NaOH in tetrahydrofuran (THF) at 23 °C for 8 h. The
resulting carboxylic acid was esterified with benzyl bromide
and K2CO3 in dimethylformamide (DMF) at 70 °C for 2 h to
provide benzyl ester 11 in 90% yield over two steps. The
enantiomeric excess of 11 was determined to be 95% ee by
chiral high-performance liquid chromatography (HPLC)
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Scheme 2. Synthesis of Functionalized Alkene 13
Scheme 3. Synthesis of Functionalized Aldoxime 18
chromatography. The desired Z-isomer 17 was obtained in
81% yield from diol 15.
analysis using chiralpak OD-H column. Ester 10 was converted
to the corresponding Weinreb amide,18,19 by exposure to
AlMe3 and MeNHOMe·HCl in THF at −10 to 23 °C for 2 h.
The resulting Weinreb amide was reacted with allyl magnesium
bromide in THF at 0 °C for 2 h to furnish allyl ketone 12 in
78% yield over two steps. The hydroxyl group directed
stereoselective reduction of β-hydroxy ketone using the
protocol developed by Narasaka and co-workers,20,21 with
NaBH4 in the presence of Et2BOMe in a mixture (4:1) of THF
and methanol at −78 °C to 0 °C for 3 h resulted in the
corresponding syn-1,3-diol derivative. The resulting diol was
protected as an isopropylidene derivative by reaction with
dimethoxypropane in the presence of PPTS in CH2Cl2 at 23
°C for 4 h to afford the functionalized alkene 13 in only five
steps from keto ester 9. The reaction sequence proved highly
efficient, delivering multigram quantities of alkene 13.
Our synthetic route to functionalized aldoxime segment 5 is
shown in Scheme 3. The α,β-unsaturated ester 14 was
prepared as described previously.22 Sharpless asymmetric
dihydroxylation23,24 of 14 using AD-mix-α in the presence of
MeSO2NH2 and NaHCO3 in aqueous t-BuOH at 0 °C for 48 h
furnished syn-1,2-diol 15 in 90% yield. The optical purity of
diol 15 was over 95% ee as determined by chiral HPLC
analysis using chiralpak OD-H column. The resulting diol was
protected as its isopropylidene derivative using dimethox-
ypropane and PPTS in acetone at 23 °C for 4 h to provide
ester 16. LAH reduction of the ester at 0 °C in THF for 2 h
followed by (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO)
oxidation,25,26 of the resulting alcohol in the presence of
diacetoxyiodobenzene (DIB) at 23 °C for 6 h provided the
corresponding aldehyde which was subjected to Z-selective27,28
Wittig olefination with ethoxycarbonyl triphenylphosphorene
in MeOH at 23 °C for 12 h to provide a mixture (1:5 ratio by
1H nuclear magnetic resonance (NMR) analysis) of E/Z-α,β-
unsaturated esters, which were separated by silica gel
Ester 17 was converted to oxime 18 in a three-step sequence
involving: (1) exposure of 17 to DDQ in aqueous CH2Cl2 at
0−23 °C for 2 h to remove the PMB group, (2) TEMPO
oxidation,25,26 of the resulting alcohol to give aldehyde, and
(3) reaction of aldehyde with hydroxylamine at 23 °C for 2 h
to furnish functionalized oxime 18 in 81% yield over three
steps. The overall route to oxime was very efficient and all
steps leading to α,β-unsaturated ester 18 were carried out on
multigram scale.
With the synthesis of the requisite alkene and oxime
partners, our focus now shifted to the union of the alkene and
oxime segments via intermolecular [3+2] nitrile oxide
cycloaddition, as shown in Scheme 4. There are a number of
reported methods for the generation of nitrile oxide and the
formation of isoxazoline heterocyles under mild condi-
tions.29,30 However, our initial attempts to merge alkene 13
and aldoxime 18 under various conditions gave unsatisfactory
low yields of the target along with unidentified products. As
shown in Table 1, known conditions with t-BuOCl, NaOCl, or
NCS hardly provided any desired cycloadduct 19.31,32 The
possible reason is that the oxidation of aldoxime 18 forms the
linear aliphatic nitrile oxide, which is chemically very reactive
and readily undergoes dimerization in an organic solvent or
mixed solvent system. We have then examined the generation
of nitrile oxide using an environmentally benign condition
using oxone.33−35 As shown, we found that nitrile oxide
generated using oxone at 23 °C for 5 h provided cycloadduct
19 in 11% yield as an inseparable mixture (1:1) of
diastereomers by 1H NMR analysis (entry 6). Further
optimization using oxone in combination with potassium
chloride (1:1 mixture) and addition of aldoxime 19 in portions
for 4 h in water at 23 °C improved the result, affording
isoxazolines 19 as an inseparable mixture (1:1) of diaster-
eomers in 45% yield (entry 9).35 Reductive cleavage of the
isoxazoline ring was carried out under mild conditions using
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Scheme 4. Convergent Synthesis of EBC-23 (1a)
Table 1. Cycloaddition of Alkene 13 and Aldoxime 18
Under Various Conditions
a
temperature
yield
(%)
entry
1
conditions (equiv)
solvent
CH2Cl2
(time)
13 (1) + 18 (1) Et3N,
0 °C (12 h)
<5
tBuOCl (1.1)
2
13 (1) + 18 (1) Et3N,
CH2Cl2
0 °C (12 h)
<5
tBuOCl (slow addition)
t
3
4
5
13 (1) + BuOCl (1:1) Et3N, CH2Cl2
18 (1) slow addition
0 °C (12 h)
0 °C (12 h)
23 °C (24 h)
<5
13 (1) + 18 (1) Et3N, NaOCl CH2Cl2
(10)
13 (1) + 18 (1) Na2CO3
(1.5), oxone (3)
NR
NR
CH3CN-
H2O
(20:1)
6
13 (1) + 18 (1) KCl (1),
oxone (2)
MeOH
H2O
(1:3)
23 °C (3 h)
11
7
8
13 (1.1) + 18 (1) KCl (1),
H2O
23 °C (3 h)
23 °C (3 h)
28
34
oxone (2)
13 (1.1) + oxone (2); KCl
(1); 18 (1), added in five
portions, 1 h
H2O
9
13 (4), oxone (2), KCl (1); H2O
18 (1) added in four
23 °C (3 h)
40 °C (1 h)
45
<5
portions, 15 min
10
18 (1) and NCS (1.2); 13
DMF/
CH2Cl2
(1.1)
23 °C (12 h)
a
1
The diastereomeric ratio of the cycloaddduct was 1:1 by H NMR
iron catalyst.36−38 Treatment of isoxazoline 19 with Fe powder
in a mixture of EtOH and water at 23 °C for 6 h resulted in
reductive cleavage of the isoxazoline ring and provided β-
hydroxyl ketone diasetereomers 20 and 21 in nearly 1:1 ratio
with a combined yield of 66%. Both diastereomers were readily
separated by column chromatography over silica gel. The
configuration of the carbinol carbon in compounds 20 and 21
was assigned after transformation to their respective cyclization
products. The (3+2) cycloaddition reaction installed the C11
stereocenter as a 1:1 mixture, thus providing an option to
synthesize EBC-23 as well as its C11 epimer. With the
polyketide backbone in place, we investigated a sequential
deprotection, spirocyclization, and esterification in a one-pot
manner to provide the target EBC-23. To this end, as
summarized in Table 2, a variety of typical acid conditions led
to low yields of the target along with a lot of complex and
unidentified products.39 Fortunately, montmorillonite K10 clay
which provides a mild proton source offered encouraging
results (entries 8−10). Exposure of diastereomeric β-hydroxy
ketone 21 to montmorillonite K10 clay in dichliroethane
(DCE) at 15 °C for 72 h removed the isopropylidene group,
formed spiroketal and δ-lactone concommitatly, and furnished
analysis.
EBC-23 (1a) in 42% yield. The H NMR and 13C NMR
spectra of synthetic (+)-EBC-23 (1a) {[α]D + 15.5 (c, 0.75,
1
20
CHCl3)} are in complete agreement with reported spectra for
synthetic and natural (+)-EBC-23 (1a).5−7
We have converted epimeric β-hydroxy ketone 20 into its
C11-epimeric EBC-23 derivative and also transformed it into
EBC-23 (1a) by an oxidation and reduction sequence. As
shown in Scheme 5, montmorillonite K10 clay-promoted
spirocyclization and lactonization of hydroxy ketone 20
resulted in C11-epimeric EBC-23 (22) in 58% yield. The
yield of spirocyclization improved possibly due to the
formation of a more stable spiroketal with equatorial C11
hydroxyl group in 22. Selective epimerization of the C11
alcohol stereocenter in 22 turned out to be a significant
problem. When diol 22 was subjected to Mitsunobu
conditions, only starting material was recovered. We then
planned selective oxidation of the cyclic alcohol over the C15
acyclic alcohol followed by selective reduction to obtain axial
alcohol. Swern oxidation or Dess−Martin periodinane
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Table 2. Reaction Conditions for Spirocyclization and
Lactonization
Scheme 5. Synthesis of EBC-23 Epimer (22) and
Epimerization of C11 Stereochemistry
temperature
a
entry
1
acid conditions
PTSA
solvent
MeOH
(time)
result
b
23 °C
(24 h)
complex
b
2
PPTS
MeOH
MeOH
23 °C
complex
(24 h)
3
Amberlyst-15
(25% w/w)
AcOH-H2O (1:1)
23 °C
(48 h)
23 °C
(12 h)
23 °C
(24 h)
23 °C
(24 h)
<5% yield
b
4
complex
b
5
PTSA
THF-H2O (10:1)
complex
synthesis is the K-10-mediated formation of spiroketal and
osumundalactone core of EBC-23 from the polyketide
intermediate that removes protecting group and leads to
spiroketalization and lactonization in a one-pot operation. This
synthetic route provides EBC-23 in 3.8% overall yield for 11
longest linear steps. The scalable synthesis of isoxazoline as the
β-hydroxyl ketone precursor uses environmentally friendly
conditions. The synthesis provides access to C11-(R)-epimer
of EBC-23 and a route to the conversion of the epimer to
EBC-23. The present convergent asymmetric synthesis is
practical and will provide rapid access to the synthesis of
important structural variants for medicinal chemistry opti-
mization.
b
6
CSA
MeOH/THF-H2O
(10:5:1)
THF-H2O (10:1)
complex
b
7
1 M HCl
23 °C
(48 h)
complex
8
K10 (500% w/w) CH2Cl2
K10 (500% w/w) DCE
K10 (500% w/w) DCE
23 °C
20% yield
26% yield
42% yield
(48 h)
9
23 °C
(48 h)
15 °C
(72 h)
10
a
b
Yield after silica gel chromatography. Unidentified complex mixture
of products.
conditions resulted in the oxidation of both alcohols. However,
TEMPO oxidation25,26 turned out to be selective for the cyclic
C11 alcohol. Thus, exposure of 22 to TEMPO in the presence
of DIB yielded the desired ketone 23 in 72% yield. Selective
reduction of 23 using metal hydrides was unsatisfactory due to
the presence of the sensitive α,β-unsaturated-δ-lacone
functionality.40 Noyori asymmetric reduction41,42 of 23 with
a catalytic amount (0.5 mol %) of RuCl(p-cymene)[(S,S)-Ts-
DPEN] in the presence of HCO2H and Et3N in CH2Cl2 at 23
°C for 20 h afforded a diastereomeric 3.8:1 mixture of alcohols
in 83% combined yield. The major isomer EBC-23 (1a) was
separated by silica gel chromatography in 66% yield.
EXPERIMENTAL SECTION
■
All reactions were performed in oven-dried round-bottom flasks
followed by flame drying in the case of moisture-sensitive reactions.
The flasks were fitted with rubber septa and kept under a positive
pressure of argon. Cannula was used in the transfer of moisture-
sensitive liquids. Heated reactions were allowed to run using an oil
bath on a hot plate equipped with a temperature probe. Thin-layer
chromatography (TLC) analysis was conducted using glass-backed
thin-layer silica gel chromatography plates (60 Å, 250 μm thickness,
F-254 indicator). Flash chromatography was done using a 230−400
mesh, a 60 Å pore diameter silica gel. Organic solutions were
1
concentrated at 30−35 °C on a rotary evaporator. H NMR spectra
were recorded on a 400 MHz spectrometer. 13C{1H} NMR spectra
were recorded at 100 MHz NMR. Chemical shifts are reported in
parts per million and referenced to the deuterated residual solvent
peak (CDCl3, 7.26 ppm for 1H and 77.0 ppm for 13C). NMR data are
reported as δ value (chemical shift), J-value (Hz), and integration,
where s = singlet, bs = broad singlet, d = doublet, t = triplet, q =
quartet, p = quintet, m = multiplet, dd = doublet doublets, and so on.
Optical rotations were recorded on a digital polarimeter. Low-
resolution mass spectra (LRMS) spectra were recorded using a
quadrupole LCMS under positive electrospray ionization (ESI+).
High-resolution mass spectrometry (HRMS) spectra were recorded at
CONCLUSIONS
■
An enantioselective synthesis of EBC-23 has been accom-
plished. EBC-23 and members of this family of natural
products from the Australian rainforest show potent anticancer
activity with potential for clinical application. The synthesis
involves asymmetric assembly of EBC-23 using highly
enantioselective sharpless dihydroxylation and Noyori hydro-
genation reactions. One of the key features of the current
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the Purdue University Department of Chemistry Mass Spectrometry
Center. These experiments were performed under ESI+ and positive
atmospheric pressure chemical ionization (APCI+) conditions using
an Orbitrap XL Instrument.
1.47 (m, 1H), 1.47−1.35 (m, 2H), 1.35−1.15 (m, 21H), and 0.89−
0.80 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.9, 67.8, 61.2,
38.1, 36.5, 31.8, 31.7, 29.6, 29.5, 29.3, 25.5, 22.6, and 14.0; [α]D
20
+26.3 (c 3.76 CHCl3); IR (neat): vmax 3459, 2924, 2853, 1650, and
Ethyl (S)-3-hydroxyhexadecanoate (10). A suspension of
[RuCl2(C6H6)]2 complex (84 mg, 0.17 mmol) and (S)-BINAP
(210 mg, 0.34 mmol) in dry DMF (5.7 mL) was heated at 100 °C for
10 min, until complete dissolution, and then cooled down to room
temperature. The dark red mixture was then added via cannula to a
previously degased solution of α-keto ester 9 (10.0 g, 33.5 mmol) in
dry ethanol (19 mL). The resulting solution was placed under a 400
psi hydrogen atmosphere and stirred at 50 °C for 3 h. After
evaporation of the solvents, the crude product was purified by flash
chromatography on silica using ethyl acetate/hexane mixtures of
increasing polarity (5−20 (v/v%)) as eluent to afford the desired
alcohol 10 (8.75 g, 87%). 1H NMR (400 MHz, CDCl3) δ 4.15 (q, J =
7.1 Hz, 2H), 3.98 (d, J = 3.0 Hz, 1H), 2.97 (br. s., 1H), 2.48 (d, J =
16.0 Hz, 1H), 2.38 (dd, J = 16.4, 9.3 Hz, 1H), 1.50 (d, J = 8.9 Hz,
1H), 1.41 (d, J = 8.2 Hz, 2H), 1.37−1.18 (m, 24H), and 0.86 (t, J =
7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.1, 68.0, 60.6,
41.3, 36.5, 31.9, 29.6 (4C), 29.5, (3C), 29.3, 25.4, 22.7, 14.1, and
14.0; [α]D20 +11.3 (c 6.00 CHCl3); IR (neat): vmax 3355, 2970, 2855,
1720,1378, 1302, 1160, 1129, 952, 817, and 757 cm−1; HRMS (ESI)
m/z: [M+Na]+ calcd for C18H36O3Na 323.2565; found 323.2574.
Benzyl (S)-3-hydroxyhexadecanoate (11). To a solution of
ester 10 (170 mg, 0.57 mmol) in THF (3.4 mL) were added 2M
NaOH (3.4 mL, 6.8 mmol). The solution was stirred at ambient
temperature for 8 h. The reaction was quenched by 4M HCl until pH
< 7 and extracted with ethyl acetate. The organic layer was then dried
over MgSO4, filtered, and concentrated in vacuo. The residue was
without purification to further step.
1387 cm−1; LRMS (ESI) m/z: 316.3 (M + H)+.
To the above amide dissolved in anhydrous tetrahydrofuran (40
mL) under an argon atmosphere was added allyl magnesium bromide
(1 M in ethyl ether, 42.2 mL, 42.2 mmol) at 0 °C. The mixture was
stirred for 2 h at 0 °C. The reaction was then quenched by an addition
of a saturated NH4Cl aqueous solution followed by addition of ethyl
acetate. The resulting mixture was stirred overnight, then the phases
were separated and the aqueous phase was extracted twice by ethyl
acetate. Combined organic phases were dried over anhydrous
Na2SO4, filtered, and evaporated. The crude product was purified
by flash chromatography on silica using ethyl acetate/hexane mixtures
of increasing polarity (20 (v/v%)) as eluent to afford desired
1
compound 12 (4.89 g, 80%). H NMR (400 MHz, CDCl3) δ 5.98−
5.84 (m, 1H), 5.31−5.10 (m, 2H), 4.05 (d, J = 2.7 Hz, 1H), 3.21 (d, J
= 7.2 Hz, 2H), 2.94 (d, J = 2.4 Hz, 1H), 2.70−2.60 (m, 1H), 2.60−
2.50 (m, 1H), 1.58−1.18 (m, 24H), and 0.89 (t, J = 6.8 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 209.9, 130.0, 119.3, 67.6, 48.7,
48.4, 36.5, 31.9, 29.69, 29.67, 29.59, 29.55, 29.37, 25.5, 22.7, and 14.1;
[α]D20 + 22.4 (c 8.87 CHCl3); IR (neat): vmax 3380, 2969, 2925, 2855,
1710,1379, 1129, 952, 817, and 757 cm−1; HRMS (ESI) m/z: [M
+Na]+ calcd for C19H36O2Na 319.2617; found: 319.2625.
(4R,6S)-4-Allyl-2,2-dimethyl-6-tridecyl-1,3-dioxane (13). To
a solution of hydroxy ketone 12 (4.40 g, 14.9 mmol) in anhydrous
tetrahydrofuran (102 mL) and anhydrous methanol (27 mL) at −78
°C under argon was added dropwise diethylmethoxyborane (2.3 mL,
16.2 mmol), and the resulting mixture was stirred for 15 min. Then,
sodium borohydride (603 mg, 16.2 mmol) was added. The resulting
mixture was stirred at 0 °C for 3 h. MeOH (70 mL), aq. NaOH (2 M;
21 mL), and aq. H2O2 (30%; 20 mL) were added. The resulting
mixture was stirred at ambient temperature for 15 h. The mixture was
concentrated. The residue was dissolved in a mixture of CH2Cl2 (50
mL) and brine (50 mL). The layers were separated, and the aq. layer
was extracted with CH2Cl2 (5 × 30 mL). The combined organic
extracts were washed with satd. aq. Na2SO3 (30 mL), dried with
Na2SO4, and concentrated under reduced pressure. The crude
product was used without purification.
To a solution of residue in DMF (1.1 mL) was added K2CO3 (87
mg, 0.63 mmol), followed by benzyl bromide. The mixture was stirred
at 70 °C for 2 h. The reaction was added water and extracted with
ethyl acetate. The organic layer was then dried over MgSO4, filtered
and concentrated in vacuo. The crude product was purified by flash
chromatography on silica using ethyl acetate/hexane mixtures of
increasing polarity (5−20 (v/v%)) as eluent to afford desired
compound 11 (0.18 mg, 90%); 1H NMR (400 MHz, CDCl3) δ
7.44−7.31 (m, 5H), 5.18 (s, 2H), 4.05 (d, J = 3.8 Hz, 1H), 2.94 (d, J
= 4.1 Hz, 1H), 2.63−2.54 (m, 1H), 2.54−2.42 (m, 1H), 1.58−1.49
(m, 1H), 1.45 (d, J = 5.1 Hz, 2H), 1.40−1.20 (m, 23H), and 0.91 (t, J
= 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.9, 135.6,
128.6, 128.4, 128.3, 68.1, 66.5, 41.4, 36.5, 32.0, 29.7, 29.7, 29.6, 29.6,
To the above diol dissolved in anhydrous dichloromethane (90
mL) under an argon atmosphere were added pyridium p-
toluenesulfonate (190 mg, 0.7 mmol) and dimethoxypropane (7.3
mL, 59.4 mmol). The mixture was then stirred for 4 h at room
temperature. The filtrate was washed with NaHCO3 solution (30 mL,
5%) and brine (30 mL), dried over Na2SO4, and concentrated in
vacuo. The crude product was purified by flash chromatography on
silica using ethyl acetate/hexane mixtures of increasing polarity (4 (v/
v%)) as eluent to afford desired compound 13 [4.79 g, 95% (two
20
29.4, 25.5, 22.7, and 14.2; [α]D +12.4 (c 6.02 CHCl3); IR (neat):
v
max 3360, 2970, 2855, 1724,1379, 1216, 1128, 951, 816, 755, and 697
cm−1; HRMS (APCI-Orbitrap) m/z: [M + H]+ calcd for C23H39O3
363.2894; found 363.2898. Enantiomeric excess of 11 was determined
to be 95% ee of the S-enantiomer (tR = 18.03 min) by normal phase
chiral HPLC analysis (column: Chiralcel OD-H 4.6 × 250 mm2,
eluent A: hexane; eluent B: i-PrOH; 95% A/5% B, flow rate: 0.5 mL/
min, detection: UV 220 nm).
1
steps)] as a white solid. H NMR (400 MHz, CDCl3) δ 5.89−5.70
(m, J = 7.2 Hz, 1H), 5.16−4.95 (m, 2H), 3.91−3.82 (m, 1H), 3.82−
3.72 (m, 1H), 2.37−2.23 (m, 1H), 2.14 (td, J = 14.1, 7.1 Hz, 1H),
1.50 (td, J = 12.7, 2.3 Hz, 2H), 1.45−1.40 (m, 3H), 1.39 (s, 4H),
1.33−1.19 (m, 23H), 1.16−1.04 (q, J = 12.6 Hz, 1H), and 0.87 (t, J =
6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 134.2, 116.9, 98.3,
68.9, 68.6, 40.8, 36.4, 36.3, 31.8, 30.2, 29.6, 29.57, 29.52, 29.28, 24.9,
(S)-6-Hydroxynonadec-1-en-4-one (12). MeONHMe·HCl
(4.54 g, 46.5 mmol) was dissolved in THF (20.0 mL) at −10 °C
and a solution of AlMe3 (2 M solution, 23.3 mL, 46.5 mmol) was
added via syringe over a 30 min period. The reaction mixture was
stirred at room temperature for 45 min and then a THF solution
(20.0 mL) of ester 10 (6.35 g, 21.2 mmol) was added and the
resulting mixture was stirred at room temperature for 2 h. The
reaction was then quenched by a careful addition of a saturated
NH4Cl aqueous solution followed by an addition of ethyl acetate and
by an aqueous saturated solution of Rochelle salt. The resulting
mixture was stirred overnight, then the phases were separated and the
aqueous phase was extracted twice by ethyl acetate. The combined
organic phases were dried over anhydrous Na2SO4, filtered, and
evaporated. The crude product was purified by flash chromatography
on silica using ethyl acetate/hexane mixtures of increasing polarity
(40−50 (v/v%)) as eluent to afford desired compound 10′ (6.55 g,
20
22.6, 19.7, and 14.0; [α]D +1.8 (c 1.81 CHCl3); IR (neat): vmax
2924, 2854, 1464, 1379, 1199, 1172, and 954 cm−1; HRMS (APCI-
Orbitrap) m/z: [M + H]+ calcd for C22H43O2; 339.3258; found:
339.3260.
Ethyl (2R,3S)-2,3-dihydroxy-5-((4-methoxybenzyl)oxy)-
pentanoate (15). A solution of AD-mix-α (33.0 g), NaHCO3
(5.70 g, 67.9 mmol), and MeSO2NH2 (2.20 g, 23.1 mmol) in t-
BuOH/H2O 1:1 (230 mL) was stirred at r.t. until both phases were
clear and then cooled to 0 °C. Ethyl(E)-5-((4-methoxybenzyl)oxy)-
pent-2-enoate 14 (6.00 g, 22.7 mmol) was added and the slurry was
stirred at 0 °C for 48 h. Solid Na2S2O5 (1 g) was added at 0 °C, and
the resulting mixture was warmed to r.t. and stirred for 1 h. Extraction
with ethyl acetate and evaporation of the washed (2 N NaOH) org.
soln. gave a solid crude residue. The crude product was purified by
1
98%); H NMR (400 MHz, CDCl3) δ 3.98 (br. s., 1H), 3.76 (br. s.,
1H), 3.66 (s, 3H), 3.16 (s, 3H), 2.62 (m, 1H), 2.43 (m, 1H), 1.59−
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Article
flash chromatography on silica using ethyl acetate/hexane mixtures
(40 (v/v%)) as eluent to afford desired compound 15 (6.10 g, 90%
yield, 95% ee). H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.3 Hz,
876, and 820 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C20H29O6
365.1959; found 365.1963.
1
Ethyl (2Z)-3-((4S,5S)-5-(2-(hydroxyimino)ethyl)-2,2-dimeth-
yl-1,3-dioxolan-4-yl)acrylate (18). To a solution of the alkene 17
(7.00 g, 19.2 mmol) in a mixture of CH2Cl2/H2O (17/1, 100 mL),
DDQ (6.50 g, 28.6 mmol) was added at 0 °C. After 30 min, the
reaction mixture was warmed to room temperature and further stirred
for 2 h before it was diluted with CH2Cl2 and quenched with sat. aq.
NaHCO3. The organic phase was separated, washed with sat. aq.
NaHCO3, dried with Na2SO4, and concentrated. The crude product
was purified by flash chromatography on silica using ethyl acetate/
hexane mixtures of increasing polarity (30−40 (v/v%)) as eluent to
2H), 6.87 (d, J = 8.3 Hz, 2H), 4.50−4.41 (m, 2H), 4.32−4.21 (m,
2H), 4.18−4.12 (m, 1H), 4.06 (d, J = 1.6 Hz, 1H), 3.79 (s, 3H),
3.72−3.58 (m, 2H), 2.04−1.94 (m, 1H), 1.84 (m, 1H), and 1.30 (t, J
= 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.1, 159.2,
129.9, 129.3, 113.8, 73.5, 72.9, 71.4, 67.6, 61.8, 55.2, 33.2, and 14.1;
[α]D28 −2.7 (c 3.22 CHCl3); IR (neat): vmax 3471, 2962, 2855, 1734,
1613, 1368, 1247, 1130, 1032, and 821 cm−1; HRMS (ESI) m/z: [M
+ Na]+ calcd for C15H22O6Na; 321.1309; found 321.1312.
Enantiomeric excess of 15 was determined to be 95% ee of the S-
enantiomer (tR = 15.08 min) by normal phase chiral HPLC analysis
(column: Chiralcel OD-H 4.6 × 250 mm2, eluent A: hexane; eluent B:
i-PrOH; 80% A/20% B, flow rate: 0.5 mL/min, detection: UV 220
nm).
1
afford desired compound 17′ (4.13 g, 88%). H NMR (400 MHz,
CDCl3) δ 6.19−6.06 (m, 1H), 5.93 (d, J = 11.6 Hz, 1H), 5.33 (t, J =
8.4 Hz, 1H), 4.15 (q, J = 6.7 Hz, 2H), 3.87 (dt, J = 7.9, 3.4 Hz, 1H),
3.83−3.68 (m, 2H), 2.27 (br. s., 1H), 2.01−1.84 (m, 2H), 1.53−1.32
(m, 7H), and 1.32−1.18 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 165.4, 145.2, 123.2, 109.7, 79.6, 76.1, 60.5, 60.4, 34.0, 27.2, 27.0,
Ethyl (4R,5S)-5-(2-((4-methoxybenzyl)oxy)ethyl)-2,2-di-
methyl-1,3-dioxolane-4-carboxylate (16). To the above diol 15
(6.10 g, 20.5 mmol) dissolved in acetone (73 mL) were added p-
toluenesulfonic acid (28.2 mg, 0.16 mmol) and dimethoxypropane
(2.60 g, 24.6 mmol). The mixture was then stirred for 4 h at room
temperature. The filtrate was washed with NaHCO3 solution (3 mL,
5%) and brine (3 mL), dried over Na2SO4, and concentrated in
vacuo. The crude product was purified by flash chromatography on
silica using ethyl acetate/hexanes mixtures (10 (v/v%)) as eluent to
afford desired compound 16 (6.6 g, 98%). 1H NMR (400 MHz,
CDCl3) δ 7.24 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 4.42 (s,
2H), 4.33−4.13 (m, 4H), 3.79 (s, 3H), 3.67−3.51 (m, 2H), 2.17−
2.02 (m, 1H), 2.01−1.89 (m, 1H), 1.45 (s, 3H), 1.43 (s, 3H), 1.26 (t,
J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.6, 159.1,
130.3, 129.1, 113.7, 110.6, 79.1, 76.4, 72.6, 66.2, 61.2, 55.2, 33.5, 27.1,
20
and 14.1; [α]D +46.3 (c 6.86 CHCl3); IR (neat): vmax 3421, 2986,
2850, 1720, 1658, 1418, 1371, 1162, 1067, 1031, 873, 825, and 508
cm−1; HRMS (ESI) m/z: [M + Na]+ calcd for C12H20O5Na 267.1203;
found 267.1205.
The alcohol (4.15 g, 17.0 mmol) dissolved in CH2Cl2 (80 mL)
were added 2,2,6,6-tetramethyl-1-piperidinyloxy (530 mg, 3.39 mmol)
and (diacetoxyiodo)benzene (8.20 g, 25.5 mmol). The mixture was
stirred for 6 h at room temperature. The reaction was quenched by a
saturated Na2S2O3 aqueous solution followed by an addition of
CH2Cl2, then the phases were separated and the aqueous phase was
extracted twice by CH2Cl2. Combined organic phases were dried over
anhydrous Na2SO4, filtered, and evaporated. The crude was used
without purification.
28
25.7, and 14.1; [α]D −18.2 (c 3.81 CHCl3); IR (neat): vmax 2988,
To the above aldehyde dissolved in the mixture of EtOH/H2O 1/1
(52 mL) were added NH2OH·HCl (1.30 g, 18.7 mmol) and Na2CO3
(900 mg, 8.50 mmol). The reaction was stirred at room temperature
for 2 h. The reaction was then quenched with water followed by an
addition of ethyl acetate. The reaction was extracted with ethyl
acetate. The organic layer was then dried over Na2SO4, filtered, and
concentrated in vacuo. The crude product was purified by flash
chromatography on silica using ethyl acetate/hexane mixtures of
increasing polarity (5−20 (v/v%)) as eluent to afford desired
2936, 2855, 1756,1613, 1464, 1212, 1171, 1034, and 820 cm−1;
HRMS (ESI) m/z: [M + Na]+ calcd for C18H27O6Na; 361.1622;
found: 361.1624.
Ethyl (Z)-3-((4S,5S)-5-(2-((4-methoxybenzyl)oxy)ethyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)acrylate (17). The ester 16 (5.00 g,
14.8 mmol) dissolved in THF (50 mL) at 0 °C. LiAlH4 (1.12 g, 29.5
mmol) was slowly added to the reaction at 0 °C and stirred for 2 h.
The reaction was then quenched by a careful addition of a saturated
NH4Cl aqueous solution followed by an addition of ethyl acetate and
an aqueous saturated solution of Rochelle salt. The resulting mixture
was stirred until clear, then the phases were separated and the
aqueous phase was extracted twice by ethyl acetate. Combined
organic phases were dried over anhydrous Na2SO4, filtered, and
evaporated. The crude was used without purification.
To the above alcohol dissolved in CH2Cl2 (60 mL) were added
2,2,6,6-tetramethyl-1-piperidinyloxy (463 mg, 2.96 mmol) and
(diacetoxyiodo)benzene (7.10 g, 22.2 mmol). The mixture was
stirred for 6 h at room temperature. The reaction was quenched by a
saturated Na2S2O3 aqueous solution followed by an addition of
CH2Cl2, then the phases were separated and the aqueous phase was
extracted twice by CH2Cl2. Combined organic phases were dried over
anhydrous Na2SO4, filtered, and evaporated. The crude was used
without purification.
1
diastereomeric mixture of oxime 18 (3.99 g, 92%). H NMR (400
MHz, CDCl3) δ 7.49 (t, J = 5.8 Hz, 1H), 6.95−6.81 (m, 1H), 6.23−
6.05 (m, 2H), 5.95 (d, J = 11.6 Hz, 2H), 5.33 (t, J = 8.2 Hz, 2H),
4.26−4.07 (m, 4H), 3.89 (dtd, J = 15.5, 7.9, 3.9 Hz, 2H), 2.92−2.79
(m, 1H), 2.75−2.43 (m, 3H), 1.49−1.34 (m, 12H), and 1.34−1.20
(m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.4 (minor isomer),
165.3, 148.6, 145.0 (minor isomer), 144.6, 123.5, 123.4 (minor
isomer), 109.9 (minor isomer), 109.8, 78.3, 77.7, 76.1, 76.0 (minor
20
isomer), 60.6, 32.3, 27.0 (minor isomer), 26.9, and 14.1; [α]D
+
21.2 (c 4.66 CHCl3); IR (neat): vmax 3339, 2972, 2854, 1722,1381,
1196, 1162, 1129, 951, 817, and 757 cm−1; HRMS (ESI) m/z: [M +
H]+ calcd for C12H20NO5 258.1336; found: 258.1335.
Ethyl (Z)-3-((4S,5S)-5-((5-(((4S,6S)-2,2-dimethyl-6-tridecyl-
1,3-dioxan-4-yl)methyl)-4,5-dihydroisoxazol-3-yl)methyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)acrylate (19). To a solution of alkene
13 (5.28 g, 15.6 mmol) and a solution of potassium chloride (0.46 g,
6.22 mmol) and oxone (1.90 g, 12.5 mmol) in H2O (56 mL) was
added aldoxime 18 (1.60 g, 6.22 mmol) in four portions in 1 h
intervals. After the last addition, the solution was stirred at room
temperature for additional 3 h until the completion of reaction,
monitored by TLC and NMR. The reaction mixture was diluted with
ethyl acetate (50 mL), washed with brine (2 mL), dried over Na2SO4,
and concentrated in vacuo to give the crude product. The crude
product was purified by flash chromatography on silica using ethyl
acetate/hexane mixtures of increasing polarity (10−20 (v/v%)) as
eluent to provide the corresponding isoxazoline 19, diasterisomers
To an ice-cooled solution of aldehyde in MeOH (75 mL) was
added ethoxycarbonyl triphenylphosphorane (5.67 g, 16.3 mmol) in
small portions and the mixture was stirred at room temperature
overnight. After the solvent was evaporated in vacuo, The crude
product was purified by flash chromatography on silica using ethyl
acetate/hexane mixtures (10 (v/v%)) as eluent to afford Z-selectivity
1
olefin 17 (4.47 g, 83%). H NMR (400 MHz, CDCl3) δ 7.26−7.20
(m, 2H), 6.86 (d, J = 8.5 Hz, 2H), 6.11 (dd, J = 11.6, 8.9 Hz, 1H),
5.94−5.87 (m, 1H), 5.29 (t, J = 8.5 Hz, 1H), 4.42 (d, J = 1.4 Hz, 2H),
4.15 (q, J = 7.1 Hz, 2H), 3.93−3.82 (m, 1H), 3.82−3.75 (m, 3H),
3.60−3.51 (m, 2H), 2.04−1.84 (m, 2H), 1.42 (s, 6H), and 1.27 (t, J =
7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.4, 159.1,
145.2, 130.5, 129.2, 123.1, 113.7, 109.3, 77.8, 76.1, 72.6, 66.7, 60.4,
1
ratio: 1:1 (1.56 g, 45%). H NMR (400 MHz, CDCl3) δ 6.21−6.12
(m, 2H), 5.96 (d, J = 11.6 Hz, 2H), 5.35 (d, J = 3.1 Hz, 2H), 4.78−
4.61 (m, 2H), 4.17 (q, J = 7.2 Hz, 4H), 4.10−3.99 (m, 2H), 3.95 (d, J
= 2.0 Hz, 2H), 3.85−3.73 (m, 2H), 3.18−2.98 (m, 2H), 2.87−2.76
20
55.2, 32.4, 27.3, 27.0, and 14.2; [α]D +41.0 (c 6.04 CHCl3); IR
(neat): vmax 2983, 2852, 1718,1656, 1587, 1418, 1302, 1165, 1034,
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Article
(m, 3H), 2.63 (d, J = 7.9 Hz, 3H), 1.98−1.88 (m, 1H), 1.78−1.53 (m,
9H), 1.51−1.46 (m, 4H), 1.46−1.38 (m, 18H), 1.38−1.33 (m, 8H),
1.33−1.05 (m, 46H), and 0.88 (t, J = 6.8 Hz, 6H); 13C{1H} NMR
(100 MHz, CDCl3) δ 165.4, 156.8, 145.2 (minor isomer), 145.1,
123.3, 110.0 (minor isomer), 109.9, 98.4, 98.2, 78.4, 77.7, 77.5, 76.4,
68.9, 66.1, 66.0 (minor isomer), 60.5, 43.5, 42.9, 42.5, 41.1, 37.4, 36.5
(minor isomer), 36.4, 31.9, 31.1 (minor isomer), 31.0, 30.2, 29.6,
29.5, 29.3, 29.2, 27.3, 27.0, 24.9, 22.6, 19.9, 19.7, 14.1, and 14.0
HRMS (ESI) m/z: [M + Na]+ calcd for C26H44O6Na; 475.3048;
found 475.3055.
(2S,3aS,6′S,7aS)-6′-((S)-2-Hydroxypentadecyl)-3a,5′,6′,7a-
tetrahydrospiro[furo[3,2-b]pyran-2,2′-pyran]-4′,5(3H,3′H)-
dione (23). To a solution of diol 22 (23 mg, 0.051 mmol) dissolved
in dichloromethane (2.0 mL) were added 2,2,6,6-tetramethyl-1-
piperidinyloxy (1.6 mg, 0.010 mmol) and (diacetoxyiodo)benzene
(18 mg, 0.061 mmol) at 0 °C. The mixture was stirred for 8 h at room
temperature. The reaction was quenched with sat. aq. NaHCO3. The
organic phase was separated, washed with sat. aq. NaHCO3, dried
with Na2SO4, and concentrated. The crude product was purified by
flash chromatography on silica using ethyl acetate/hexane mixtures of
increasing polarity (30−40 (v/v%)) as eluent to afford desired
20
(minor isomer); [α]D +28.6 (c 1.68 CHCl3); IR (neat): vmax 2925,
2855, 1720, 1380, 1196, 1057, 1024, and 855 cm−1; HRMS (ESI) m/
z: [M + H]+ calcd for C34H60NO7 594.4364; found: 594.4355.
Ethyl (Z)-3-((4S,5S)-5-((R)-5-((4R,6S)-2,2-dimethyl-6-tridecyl-
1,3-dioxan-4-yl)-4-hydroxy-2-oxopentyl)-2,2-dimethyl-1,3-di-
oxolan-4-yl)acrylate (20) and ethyl (Z)-3-((4S,5S)-5-((S)-5-
((4R,6S)-2,2-dimethyl-6-tridecyl-1,3-dioxan-4-yl)-4-hydroxy-2-
oxopentyl)-2,2-dimethyl-1,3-dioxolan-4-yl)acrylate (21). To a
stirred degassed solution of 2-isoxazoline 19 (1.00 g, 1.69 mmol) and
NH4Cl (2.24 g, 42.3 mmol) in ethanol and water (1:1, 34 mL) was
added Fe powder (2.36 g, 42.3 mmol). The mixture was heated to 80
°C and was allowed to stir at this temperature for 6 h. The reaction
mixture was cooled to room temperature, diluted with ethyl acetate,
and filtered through a silica pad. The filtrate was washed with brine
and the organic layer was separated, dried over MgSO4, and
evaporated in vacuo. The residue was then purified by flash
chromatography on silica using ethyl acetate/hexane mixtures of
increasing polarity (10−20 (v/v%)) as eluent to give two isomers.
Hydroxy Ketone 20. (322 mg, 32%), 1H NMR (400 MHz, CDCl3)
δ 6.18 (dd, J = 11.6, 8.5 Hz, 1H), 5.95 (dd, J = 11.6, 1.0 Hz, 1H), 5.27
(t, J = 7.9 Hz, 1H), 4.39−4.27 (m, 1H), 4.24−4.07 (m, 4H), 3.87−
3.71 (m, 1H), 3.29 (d, J = 3.8 Hz, 1H), 2.95−2.76 (m, 2H), 2.62 (d, J
= 5.8 Hz, 2H), 1.64−1.45 (m, 7H), 1.45−1.39 (m, 10H), 1.39−1.33
(m, 6H), 1.33−1.16 (m, 20H), and 0.87 (t, J = 6.8 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 208.8, 165.6, 145.5, 123.0, 109.7, 98.5,
76.2, 76.0, 69.0, 66.2, 64.2, 60.5, 50.6, 46.0, 42.4, 36.9, 36.4, 31.9,
30.2, 29.6, 29.5, 29.3, 27.1, 26.9, 24.9, 22.6, 19.8, 14.1, and 14.0;
1
compound 23 (16.5 mg, 72%). H NMR (400 MHz, CDCl3) δ 6.85
(dd, J = 9.9, 5.1 Hz, 1H), 6.21 (d, J = 9.9 Hz, 1H), 5.12 (dt, J = 4.4,
2.2 Hz, 1H), 4.47 (t, J = 5.0 Hz, 1H), 4.35 (m, J = 4.1 Hz, 1H), 3.79
(br. s., 1H), 2.68−2.82 (m, 2H), 2.68−2.60 (m, 1H), 2.55−2.25 (m,
4H), 1.85−1.73 (m, 1H), 1.73−1.65 (m, 1H), 1.51−1.38 (m, 3H),
1.37−1.17 (m, 21H), and 0.88 (t, J = 6.8 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 202.7, 160.9, 138.6, 124.4, 107.3, 79.0, 70.8,
70.6, 68.6, 49.5, 47.1, 46.5, 42.6, 37.7, 31.9, 29.6, 29.5, 29.3, 25.4,
20
22.7, and 14.1; [α]D +50.2 (c 0.24 CHCl3); IR (neat): vmax 3552,
2919, 2851, 1742, 1716, 1468, 1334, 1279, 1104, 1068, and 817 cm−1;
HRMS (ESI) m/z: [M+H]+ calcd for C26H43O6 451.3054; found
451.3058.
(2R,3aS,4′S,6′S,7aS)-4′-Hydroxy-6′-((S)-2-hydroxypentadec-
yl)-3a,3′,4′,5′,6′,7a-hexahydrospiro[furo[3,2-b]pyran-2,2′-
pyran]-5(3H)-one (EBC-23, 1a). To a solution of ketone 23 (20 mg,
0.044 mmol) in CH2Cl2 (0.5 mL) were added RuCl(p-cymene)-
[(S,S)-Ts-DPEN] (0.14 mg, 0.5 mol %), HCO2H (16 μL, 0.44
mmol), and Et3N (60 μL, 0.44 mmol). The reaction mixture was
stirred at room temperature for 20 h. After being diluted with water (1
mL), the organic layer was collected, and the aqueous layer was
extracted with ethyl acetate (3 × 1 mL). The combined organic
fractions were washed with saturated aqueous NaHCO3 solution (0.5
mL) and brine (0.2 mL), dried over Na2SO4, and concentrated under
reduced pressure. The residue was then purified by flash
chromatography on silica using ethyl acetate/hexane mixtures of
increasing polarity (70−90 (v/v%)) as eluent to give the EBC-23 (1a)
(13.1 mg, 66% yield) and the 22 (3.4 mg, 17% yield) in 83% total
yield with a diastereomeric ratio of 3.8:1.
(2R,3aS,4′S,6′S,7aS)-4′-Hydroxy-6′-((S)-2-hydroxypentadec-
yl)-3a,3′,4′,5′,6′,7a-hexahydrospiro[furo[3,2-b]pyran-2,2′-
pyran]-5(3H)-one (EBC-23, 1a). To a solution of ketone 21 (100
mg, 0.17 mmol) dissolved in 1,2-dichloroethane was added
montmorillionite K10 (500 mg, 500 w/w%). The mixture was stirred
for 2 days at 15°. The reaction mixture was filtered through a Celite to
remove the K10 clay. The Celite was washed with MeOH (3 × 5 mL)
and the solvent removed from the combined filtrates under reduced
pressure to give a yellow residue. The residue was then purified by
flash chromatography on silica using ethyl acetate/hexane mixtures of
increasing polarity (70−90 (v/v%)) as eluent to give the EBC-23 (1a)
(32.3 mg, 42%). 1H NMR (400 MHz, CDCl3) δ 6.90 (dd, J = 9.9, 5.1
Hz, 1H), 6.22 (d, J = 9.9 Hz, 1H), 5.05 (ddd, J = 7.0, 4.6, 2.5 Hz,
1H), 4.52 (t, J = 5.0 Hz, 1H), 4.43−4.33 (m, 1H), 4.12 (br. s., 1H),
3.80 (d, J = 3.4 Hz, 1H), 2.55 (dd, J = 15.0, 6.8 Hz, 1H), 2.31 (dd, J =
14.9, 2.2 Hz, 1H), 2.08−1.97 (m, 2H), 1.79 (d, J = 14.0 Hz, 1H),
1.68−1.56 (m, 3H), 1.56−1.36 (m, 5H), 1.36−1.17 (m, 21H), and
0.87 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.0,
138.6, 124.6, 106.6, 78.8, 71.8, 68.9, 67.7, 64.2, 47.7, 42.2, 38.7, 37.7,
31.9, 29.7, 29.3, 25.4, 22.7, and 14.1; [α]D20 +15.5 (c 0.75 CHCl3); IR
(neat): vmax 3448, 2924, 2854, 1729,1396, 1260, 1100, 1024, and 800
cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C26H45O6 453.3211;
found 453.3208.
20
[α]D +21.1 (c 4.78 CHCl3); IR (neat): vmax 3403, 2925, 2855,
1718,1381, 1198, 1100, 1048, and 860 cm−1; HRMS (ESI) m/z: [M +
H]+ calcd for C34H61O8 597.4361; found: 597.4350.
Hydroxy Ketone 21. (343 mg, 34%), 1H NMR (400 MHz, CDCl3)
δ 6.18 (dd, J = 11.8, 8.4 Hz, 1H), 5.94 (dd, J = 11.6, 1.0 Hz, 1H), 5.25
(t, J = 7.9 Hz, 1H), 4.29−4.06 (m, 5H), 3.86−3.75 (m, 1H), 3.56 (d,
J = 1.4 Hz, 1H), 2.95−2.79 (m, 2H), 2.75−2.52 (m, 2H), 1.68−1.44
(m, 10H), 1.42 (br. s., 3H), 1.41 (br. s., 3H), 1.37 (s, 3H), 1.31−1.22
(m, 22H), 1.21−1.09 (m, 2H), and 0.87 (t, J = 6.8 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 207.9, 165.6, 145.5, 123.0, 109.7, 98.5,
76.2, 75.9, 69.0, 68.8, 66.7, 60.5, 50.2, 46.1, 42.5, 36.9, 36.3, 31.9,
30.2, 29.7, 29.6, 29.5, 29.5, 29.3, 27.2, 26.9, 24.9, 22.6, 19.9, 14.1, and
14.0; [α]D20 +25.9 (c 4.36 CHCl3); IR (neat): vmax 3403, 2927, 2854,
1718,1396, 1260, 1196, and 862 cm−1; HRMS (ESI) m/z: [M + Na]+
calcd for C34H60O8Na 619.4180; found 619.4172.
(2R,3aS,4′R,6′S,7aS)-4′-Hydroxy-6′-((S)-2-hydroxypentadec-
yl)-3a,3′,4′,5′,6′,7a-hexahydrospiro [furo[3,2-b]pyran-2,2′-
pyran]-5(3H)-one (22). To a solution of ketone 20 (100 mg,
0.168 mmol) dissolved in 1,2-dichloroethane was added montmor-
illionite K10 (500 mg, 500 w/w%). The mixture was stirred for 3 days
at room temperature. The reaction mixture was filtered through a
Celite to remove the K10. The Celite was washed with MeOH (3 ×
20 mL) and the solvent removed from the combined filtrates under
reduced pressure to give a yellow residue. The residue was then
purified by flash chromatography on silica gel to give the 22 (44.0 mg,
58% yield). 1H NMR (400 MHz, CDCl3) δ 6.88 (dd, J = 9.9, 5.1 Hz,
1H), 6.20 (d, J = 9.9 Hz, 1H), 5.04 (td, J = 4.4, 2.2 Hz, 1H), 4.41 (t, J
= 4.8 Hz, 1H), 4.06 (dd, J = 10.9, 4.4 Hz, 2H), 3.83−3.70 (m, 1H),
2.55 (dd, J = 15.0, 6.8 Hz, 1H), 2.33 (dd, J = 14.9, 1.9 Hz, 1H), 2.23−
2.13 (m, 1H), 2.02−1.91 (m, 1H), 1.73−1.56 (m, 5H), 1.46−1.36
(m, 4H), 1.36−1.19 (m, 21H), and 0.87 (t, J = 6.8 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 161.3, 139.0, 124.3, 106.7, 79.3, 71.7,
71.1, 68.2, 64.4, 47.2, 42.8, 42.3, 40.2, 37.7, 31.9, 29.7, 29.6, 29.5,
ASSOCIATED CONTENT
■
sı
* Supporting Information
20
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00172.
29.3, 25.4, 22.7, and 14.1; [α]D +11.5 (c 0.75 CHCl3); IR (neat):
vmax 3462, 2920, 2850, 1749,1387, 1254, 1120, 1041, and 863 cm−1;
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pubs.acs.org/joc
Article
1H and 13C NMR spectra for all new compounds; chiral
HPLC data; and comparison of 1H NMR data for EBC-
23 (PDF)
tives from 4-vinyl-1,3-dioxolanes and nitroacetaldehyde acetals.
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AUTHOR INFORMATION
■
Corresponding Author
Arun K. Ghosh − Department of Chemistry and Department
of Medicinal Chemistry, Purdue University, West Lafayette,
Indiana 47907, United States; orcid.org/0000-0003-
2472-1841; Email: akghosh@purdue.edu
Author
Che-Sheng Hsu − Department of Chemistry and Department
of Medicinal Chemistry, Purdue University, West Lafayette,
Indiana 47907, United States
(15) Ganeshapillai, D.; Woo, L. W. L.; Thomas, M. P.; Purohit, A.;
Potter, B. V. L. C-3- and C-4-Substituted Bicyclic Coumarin
Sulfamates as Potent Steroid Sulfatase Inhibitors. ACS Omega 2018,
3, 10748−10772.
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H.; Akutagawa, S.; Ohta, T.; Takaya, H.; Noyori, R. Homogeneous
asymmetric hydrogenation of functionalized ketones. J. Am. Chem.
Soc. 1988, 110, 629−631.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00172
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Financial support of this work was provided by the National
Institutes of Health (GM122279). The authors would like to
thank Anando Ghosh (graphic designer) for his help with
cover art design. They would also like to acknowledge H.
Nicholson for the original photograph of the plant, Cinnamon
laubatii, on the cover art. NMR and mass spectrometry were all
performed using shared resources that are partially supported
by the Purdue Center for Cancer Research through NIH grant
(P30CA023168).
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