Total Synthesis of the Cardiotonic Steroid (+)-Cannogenol

Article abstract of DOI:10.1021/acs.joc.0c02966

The total synthesis of (+)-cannogenol, an aglycon common to various biologically important cardiotonic glycosides, has been achieved. Synthesis of the versatile intermediate involves Mizoroki-Heck and intramolecular Diels-Alder reactions from the enantiomerically pure CD-ring segment, newly prepared in a multidecagram scale this time. Total synthesis by the site-selective transformations of the versatile intermediate demonstrated the applicability of our synthetic approach.

Full text of DOI:10.1021/acs.joc.0c02966

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Total Synthesis of the Cardiotonic Steroid (+)-Cannogenol
Shogo Watanabe, Toshio Nishikawa, and Atsuo Nakazaki*
Cite This: J. Org. Chem. 2021, 86, 3605−3614
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sı Supporting Information
ABSTRACT: The total synthesis of (+)-cannogenol, an aglycon common
to various biologically important cardiotonic glycosides, has been achieved.
Synthesis of the versatile intermediate involves Mizoroki−Heck and
intramolecular Diels−Alder reactions from the enantiomerically pure CD-
ring segment, newly prepared in a multidecagram scale this time. Total
synthesis by the site-selective transformations of the versatile intermediate
demonstrated the applicability of our synthetic approach.
INTRODUCTION
develop methods able to differentiate between the different
pendant groups on each steroidal ring, for example, the
characteristic bridged lactone moiety of 4 could serve as a
protected equivalent for requisite C3- and C19-hydroxy
groups. Site-selective transformations on the steroidal skeleton
followed by late-stage ring-opening of the bridged lactone
■
Cardiotonic steroids are attractive synthetic targets, as
1
2
privileged structures for drug discovery, due to their
3
interesting biological activities (Scheme 1). For instance,
uscharin strongly inhibited the Notch signaling pathway, which
could be important for the treatment of neurodegenerative
7
a
4
would afford known alkenyl iodide 5a
leading to
diseases, and a triazole-bearing derivative of ouabain was
(
+)-cannogenol (1). Herein, we disclose a total synthesis of
found to be a highly selective inhibitor of the α4-isoform of
+
+
(+)-1 from the versatile intermediate 4 to exemplify the utility
Na /K -ATPase and therefore may be suitable as a novel male
5
of our synthetic approach.
contraceptive. Some of biologically important cardiotonic
steroids, such as antiaroside B (which showed a strongly
positive inotropic effect with a large safety index) and
6
RESULTS AND DISCUSSION
■
cannogenol-3-O-α-L-rhamnoside (which exhibited potent
Initially, we carried out a multidecagram synthesis of
enantiopure CD-ring segment 3a based on our report
7b
anticancer activity) share as a common aglycone (+)-canno-
13
8
genol (1). Additionally, (+)-1 itself exhibited potent
although with several modifications (Scheme 2). O-Acylation
of 2-methyl-1,3-cyclopentanedione with freshly distilled acid
chloride 6, prepared from sorbic acid according to the reported
9
cytotoxicity against human cancer cell lines. Hence, a wide
variety of synthetic approaches have been developed in pursuit
7
,10,11
of cardiotonic steroids.
We anticipated that drug
17
procedure, and subsequent intramolecular Diels−Alder
candidates could be efficiently obtained if a versatile synthetic
intermediate allowing facile site-selective oxy-functionalization
on the steroidal skeleton became available. However, the
reported synthetic approaches to such intermediates lack
groups such as alkene, ketone, and hydroxy groups that are
important to facilitate the attachment of oxy-functionalities
onto the scaffold.
reaction of the resulting enol ester conducted at reflux in the
presence of BHT in o-dichlorobenzene provided desired
(
±)-endo-7 in 46% yield over the two steps. Sorbic acid was
used as a starting material instead of ethyl sorbate, to shorten
the sequence; the use of freshly distilled acid chloride 6
improved the reproducibility of the O-acylation; and o-
dichlorobenzene (bp = 178−180 °C) was used instead of
Recently, we successfully synthesized key intermediate 4 via
12
a Mizoroki−Heck reaction between 2-pyrone triflate 2 and
13
Received: December 18, 2020
Published: February 4, 2021
racemic CD-ring segment 3a, followed by an intramolecular
14
15
16
Diels−Alder (IMDA) reaction of 2-pyrone (Scheme 1).
Since 4 bears pendant alkenes and hydroxy groups for
subsequent site-selective oxy-functionalization, it could be
incorporated into synthetic approaches toward a wide variety
of natural and unnatural cardiotonic steroids. We sought to
©
2021 American Chemical Society
https://dx.doi.org/10.1021/acs.joc.0c02966
3
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Scheme 1. New Synthetic Approach to Cardiotonic Steroids
via Versatile Intermediate 4
due to separation of the diastereomers on a multidecagram
scale. Next, the ketone carbonyl group of (±)-endo-7 was
reduced using NaBH in CH Cl -MeOH to afford (±)-3a in
4
2
2
8
8% yield. Adjustments to the solvent and temperature
(
MeOH to CH Cl -MeOH (9:1) and 0 °C to −17 to −4
2
2
°
C) slightly improved the yield (82% in the previous report).
Although this solvent system did not affect its diastereose-
lectivity (90:10 in the previous report), an intrusive
evaporation of MeOH was not necessary during workup.
To obtain an enatiopure CD-ring segment 3a, the kinetic
resolution of (±)-3a was next carried out. Preparation of
13
enantiopure acetate 3b has been reported by our group;
however, the selective removal of the acetyl group without
ring-opening of the lactone proved impossible. Additionally,
the recrystallization step necessary to obtain enantiopure 3b
resulted in moderate yield (55% yield). Accordingly, we
investigated the enzymatic acetylation of (±)-3a followed by
enzymatic hydrolysis of the resulting 3b. The acetylation was
performed in toluene using 65 g of (±)-3a, from which 3b in
43% yield with 93% ee and ent-3a in 57% yield with 72% ee
were obtained. A bilayer solvent system (toluene/buffer)
containing the pH indicator bromothymol blue (BTB) was
found to be efficient for this hydrolysis, leading to 3a in 89%
yield as an enantiomerically pure form (>99% ee) along with
recovered 3b. The hydrolysis could be performed on a
decagram scale (15 g), and in total, 24 g of 3a was synthesized.
1
6
Based on our previous synthesis of the racemic 4,
enantiopure 4 was next synthesized from CD-ring segment
3
a with slight modifications (Scheme 3). Mizoroki−Heck
reaction of 3a and 2-pyrone triflate 2 as an A-ring segment with
PdCl and Et N provided 8 and its regioisomer 9 in 55 and
2
3
3
2% yields, respectively, as single diastereomers. This reaction
1
,2,4-trichlorobenzene (bp = 214 °C) for the intramolecular
could be performed on a multidecagram scale (20.9 g).
18
Diels−Alder reaction, the former being much easier to remove.
Comparing to the previous result using 1,2,4-trichlorobenzene
affording (±)-endo-7 in 66% yield, the lower yield was mainly
Employment of Herrmann’s palladacycle, an optimal catalyst
13
precursor in the previous bromoarene system, provided
13
desired 8 in 21% yield, although regioisomer 9 was not formed.
Scheme 2. Modified Synthesis of Enantiopure CD-Ring Segment 3a on a Multidecagram Scale
3
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Scheme 3. Synthesis of Versatile Intermediate 4 from
Enantiopure CD-Ring Segment 3a
Scheme 4. Synthesis of Alkenyl Iodide 5a from Intermediate
4
excellent yield without any decomposition. This bicyclic
lactone moiety was found to be stable enough to convert
into the final alkenyl iodide 5a. Since synthesis of (+)-1
required deoxygenation of the C6-hydroxy group, selective
deprotection of the TBS group at the C6 was performed by
using TBAF. The C17-siloxy group was found to be intact in
this condition probably due to its orientation on the congested
concave face on the cis-fused CD-ring system. Thiocarbony-
Treatment of 8 with lithium trimethylsilylacetylide in the
presence of BF ·OEt in THF led to the corresponding
3
2
1
9
ynone. Subsequent reduction of the carbonyl group with
Luche conditions followed by deprotection of the terminal
TMS group afforded propargyl alcohol 10 in 49% yield from 8.
The newly generated C6-stereogenic center of the major
diastereomer was determined at the stage of IMDA cyclo-
16,20
22
adduct to be R configuration.
A three-step sequence
lation of the resulting hydroxy group leading to 15 and
comprising half reduction of the alkyne in 10 using 3,6-dithia-
subsequent radical reduction afforded 16a in excellent overall
yield. Since the carbonyl group on the A-ring and the sterically
encumbered siloxy group at the C17 were anticipated to shield
both sides of the remaining alkene on the C-ring of 16a, the
TBS group was removed prior to hydrogenation of the alkene
using the Crabtree’s catalyst to afford 17 in extremely high
yield. To construct alkenyl iodide moiety, the hydroxy group at
the C17 was first oxidized by Dess−Martin periodinane, and
2
1
1
,8-ocatnediol instead of quinoline, intramolecular Diels−
Alder reaction of the resulting 11 in water, and protection with
TBS group of the crude cycloadducts furnished 4, 12, and 13,
in 32, 32, and 10% yields, respectively, after silica gel column
chromatography. TBS protection was necessary for easy
separation of each diastereomer. These transformations could
be run on a gram scale. Although LiCl in H O was the best
2
16
23
medium for this IMDA reaction, in this time, the reaction
was operated under the salt-free conditions to eliminate an
effort of its removal from the crude mixture of water-soluble
cycloadducts. The isolated yield of 4 was found to be the same
as the salt addition conditions.
subsequent two-step sequence reported by Barton et al. gave
19 without collapse of the bridged lactone moiety. Finally,
reductive ring-opening of the lactone gave alkenyl iodide 5a in
97% yield.
With alkenyl iodide 5a in hand, the total synthesis of (+)-1
was completed according to the reaction sequence by Bhattarai
With enantiomerically pure samples of intermediate 4 in
hand, our attention turned to the synthesis of alkenyl iodide
7a
and Nagorny (Scheme 5). Protection of the 3- and 19-
hydroxy groups by TBS groups afforded 5b. Stereocontrolled
introduction of butenolide at the C17 was accomplished
5
a, a synthetic intermediate for (+)-cannogenol (1) (Scheme
4
). It was anticipated that the bridged allylic ester moiety on
24
the A-ring of 4 would be labile and induce undesired side
according to the procedure reported by Inoue et al. Stille
15
7a
reactions such as decarboxylation. To improve the stability of
the A-ring, the alkene moiety was reduced using Pd/C at 1 atm
of hydrogen to afford saturated bicyclic lactone 14a in
coupling of 5b with tributylstannyl butenolide 20 led to 21a.
After protection of the hydroxy group at C14 by a TMS group,
hydrogenation of alkene on the D-ring, proceeded from the α-
3
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chromatography. A Chromatorex PSQ 100B (spherical, particle
size: 0.110 mm, Fuji Silysia Chemical Ltd.) was used for PSQ 100B
silica gel open column chromatography. Preparative TLC separations
were carried out on 0.5 mm silica gel plates 60F254 (Merck). An oil
bath was used as the heat source. Dry THF and CH Cl were
Scheme 5. Total Synthesis of (+)-Cannogenol (1)
2
2
purchased from Kanto Chemical Co., Inc. Diisopropylamine was
distilled from CaH and stored over KOH. DMF was distilled from
2
CaH and stored over MS 4A. DMSO was distilled from CaH and
2
2
stored over MS 4A. Pyridine was distilled from CaH and stored over
2
MS 4A. Et N was distilled from CaH and stored over KOH. Celite
3
2
(Hyflo Super-Cel Celite) was purchased from Nacalai Tesque, Inc.
Florisil was purchased from Kanto Chemical Co., Inc. Lipase MY-30
was purchased from Meito Sangyo Co., Inc. All other commercially
available reagents were used as received.
Acid Chloride 6. This compound was prepared according to the
17
reported procedure with slight modifications. A solution of LDA
was prepared by the slow addition of n-BuLi (2.80 M solution in
hexane, 630 mL, 1.76 mol) to a solution of dry diisopropylamine (250
mL, 1.78 mol) in dry THF (1.8 L), and the internal temperature was
maintained in a range from −15 to 0 °C. After being cooled to −10
°
C, a solution of sorbic acid (90.1 g, 803 mmol) in dry THF (500
mL) was added dropwise to the LDA solution in a range from −10 to
0 °C, and then the resulting orange solution was warmed to room
2
temperature. After being stirred at room temperature for 1 h, the
reaction mixture was cooled (<5 °C) and then poured into a vigorous
stirred cold 3 N aqueous solution of HCl (1.8 L). The organic layer
side, established the stereochemistry at C17, giving 22 as a
single diastereomer. The final removal of all silyl groups
furnished (+)-1. The H and C{ H} NMR spectra of (+)-1
was separated and washed with H O (500 mL). The aqueous layer
2
was extracted with Et O (3 × 500 mL). The combined organic layer
1
13
1
2
was dried over Na SO and concentrated under reduced pressure to
2
4
were consistent with those reported by Bhattarai and
afford a crude mixture (89.8 g) as a pale yellow oil. This material was
used for the next reaction without further purification. A crude
mixture of carboxylic acid (89.8 g) was dissolved in dry CH Cl (800
7
a
Nagorny.
In conclusion, the total synthesis of (+)-cannogenol (1) via
the versatile intermediate 4 has been accomplished. Since each
alkene and hydroxy group on the steroidal rings could be
readily discriminated during the synthesis, the functionalization
of 4 is expected to be facile and yield a wide variety of highly
oxy-functionalized cardiotonic steroids. Such studies are
currently underway in our laboratory; the results will be
reported in due course.
2
2
mL). To this solution was added DMF (0.20 mL, 2.6 mmol) followed
by thionyl chloride (117 mL, 1.61 mol) at room temperature. The
reaction mixture was stirred at room temperature until the starting
1
material was consumed, monitoring by H NMR analysis of a small
aliquot of the reaction mixture. After being stirred for 3 h, the reaction
mixture was concentrated under reduced pressure. The residue was
purified by distillation to afford acid chloride 6 (53.6 g, bp 80 °C/50
1
mmHg, 51% yield in two steps) as a colorless oil. H NMR spectrum
17
was identical to that reported for this compound.
±)-endo-7. This compound was prepared according to the
EXPERIMENTAL SECTION
General Techniques. Infrared spectra (IR) were recorded on a
(
■
13
reported procedure with slight modifications. Acid chloride 6
(53.6 g, 410 mmol) was dissolved in dry CH Cl (430 mL). This
solution was added rapidly to a solution of 2-methyl-1,3-cyclo-
pentanedione (46.0 g, 410 mmol) and dry Et N (62 mL, 0.45 mol) in
dry CH Cl (820 mL), and the internal temperature was maintained
JASCO FT/IR-4100 type A spectrophotometer and are reported in
2
2
−
1
1
wavenumber (cm ). Proton nuclear magnetic resonance ( H NMR)
spectra were recorded on a Varian Gemini-2000 (300 MHz) or a
Bruker Avance-400 (400 MHz) spectrometer. Chemical shifts of all
compounds are reported in parts per million (ppm) relative to the
residual undeuterated solvent (CDCl as δ = 7.26, CD OD as δ =
3
2
2
in a range from −17 to 0 °C. After being stirred at −10 °C for 1 h, the
reaction mixture was allowed to warm to room temperature. Then,
3
3
3
.31). Data were reported as follows: chemical shift, multiplicity (s =
the reaction mixture was washed with H
aqueous solution of NaHCO (1 × 450 mL) and brine (1 × 450 mL).
The organic layer was passed through the short plug of neutral silica
gel, and the product was eluted with solvent(s) (CH Cl (1 L) and
CH Cl /Et O = 7:3 (1 L)). The filtrate was concentrated under
O (1 × 450 mL), a saturated
2
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br =
broadened), integration, coupling constant(s), and assignment.
Carbon nuclear magnetic resonance ( C{ H} NMR) spectra were
recorded on a Bruker Avance-400 (100 MHz) spectrometer.
Chemical shifts of all compounds are reported in ppm relative to
the solvent (CDCl as δ = 77.0, CD OD as δ = 49.0). All NMR were
3
1
3
1
2
2
2
2
2
reduced pressure to afford a crude mixture (83.3 g) as an orange oil.
To a hot o-dichlorobenzene (1.6 L) were added BHT (3.61 g, 16.0
mmol) and a solution of the crude mixture obtained above in o-
dichlorobenzene (500 mL) at 130 °C. The reaction mixture was
heated to reflux and then stirred at that temperature for 6 h. The
reaction mixture was concentrated under reduced pressure at 57 °C
(11 mmHg). The residue was filtered through a pad of Celite eluted
3
3
measured at 300 K. High-resolution mass spectra (HRMS) were
recorded on an Agilent 6220 Accurate-Mass TOF and reported in
mass-to-charge ratio (m/z). Melting points (mp) were recorded on a
Yanaco MP-S3 melting point apparatus and are not corrected. Optical
rotations were measured on a JASCO DIP-370 digital polarimeter.
All reactions were monitored by thin-layer chromatography (TLC)
on 0.25 mm silica gel-coated glass plates 60F254 (Merck,
with CH Cl to remove insoluble materials, and the filtrate was
2 2
concentrated under reduced pressure. The mixture was dissolved in
toluene and charged onto a short pad of silica gel, and remaining o-
dichlorobenzene was washed out by elution of hexane (1 L).
Remaining compounds were eluted with solvent(s) (CH Cl to
#
1.05715.0001) otherwise noted. Visualization was achieved by
using UV light (254 nm) and an appropriate reagent (ethanolic
phosphomolybdic acid or p-anisaldehyde solution in H SO /AcOH/
2
4
2
2
EtOH), followed by heating. Silica gel 60 (particle size: 0.063−0.200
mm, Merck, #1.07734.9025) was used for silica gel open-column
chromatography. Silica gel 60 (spherical, particle size: 0.04−0.05 mm,
Kanto, #37562−84) was used for silica gel flash column
CH Cl /Et O = 9:1 to 4:1), and the resulting filtrate was
2 2 2
concentrated under reduced pressure to afford a wet yellow solid
(57.7 g) involving cycloadducts ((±)-endo-7/(±)-exo-7 = 81:19).
The resulting mixture was recrystallized from cyclohexane/EtOAc
3
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(
5:1) from 80 °C to room temperature. Then, the obtained solid was
for 3 h, to the resulting mixture was added dropwise a 1.0 M aqueous
solution of NaOH (15 mL). After being stirred at room temperature
for 12 h, to the resulting mixture was added dropwise a 1.0 M aqueous
solution of NaOH (25 mL). After being stirred at room temperature
for 28.5 h, the resulting mixture was filtered through a pad of Celite
eluted with EtOAc. The organic layer was separated, and the aqueous
layer was extracted with EtOAc. The combined organic layer was
dried over Na SO and concentrated under reduced pressure. The
washed by Et O to afford a mixture of (±)-endo-7 and (±)-exo-7
2
(
36.2 g) as a pale yellow solid. Further recrystallization and silica gel
flash column chromatography (hexane/Et O = 1:1) afforded
2
1
(
±)-endo-7 (39.2 g, 46% in two steps) as an off-white solid. H
NMR spectrum of (±)-endo-7 was identical to that reported for this
13
compound.
±)-Alcohol 3a. This compound was prepared according to the
(
2
4
13
reported procedure with slight modifications. To a solution of
±)-endo-7 (40.4 g, 196 mmol) in CH Cl /MeOH (3.27 L, 9:1) was
residue was purified by PSQ 100B silica gel open column
(
chromatography (hexane/CH Cl /EtOAc = 6:1:3 to 5:1:3 to
2
2
2
2
added NaBH (28.9 g, 764 mmol) at −15 °C. After being stirred at
EtOAc) to afford alcohol 3a (11.1 g, 89% yield, >99% ee) as a
white solid and acetate 3b (1.43 g, 10% yield, 18% ee) as a white solid.
An enantiomeric excess was determined by chiral HPLC analysis.
Chiral HPLC analysis for 3a (CHIRALPAK IB column, hexane/2-
propanol = 90/10, flow rate = 0.5 mL/min, detection 200 nm light, 30
4
−
15 °C for 2 h, the reaction was quenched with a cold 1 N aqueous
solution of HCl (1.62 L) and then the mixture was allowed to warm
to room temperature. The organic layer was separated, and the
aqueous layer was extracted with CH Cl (3 × 500 mL). The
2
2
combined organic layer was dried over Na SO and concentrated
°C) t = 22.5 min (major isomer), 24.4 min (minor isomer). Chiral
2
4
R
under reduced pressure. The residue was passed through a short pad
of silica gel eluted with EtOAc, and the filtrate was concentrated
under reduced pressure to afford a mixture of alcohols (±)-3a and
HPLC analysis for 3b (CHIRALPAK IB column, hexane/2-propanol
= 90/10, flow rate = 0.5 mL/min, detection 200 nm light, 30 °C) t =
R
19.8 min (major isomer), 21.8 min (minor isomer). 3a: Anal. Calcd
2
8
(±)-epi-3a (39.6 g, 97%, (±)-3a/(±)-epi-3a = 92:8) as a white solid.
for C H O : C, 69.21; H, 7.74; found: C, 69.19; H, 7.70. [α] − 2.7
1
2
16
3
D
The second reaction using (±)-endo-7 (32.8 g, 159 mmol) was
conducted following the same procedure to afford a mixture of
alcohols (±)-3a and (±)-epi-3a (31.6 g, 98%, (±)-3a/(±)-epi-3a =
(c 1.015, CHCl3).
Mizoroki−Heck Reaction of 2 and 3a. This reaction was
conducted according to the reported procedure with slight
16
9
1:9) as a white solid. The two batches were combined, and the
modifications. To a solution of triflate 2 (3.78 g, 15.5 mmol),
resulting mixture of (±)-3a and (±)-epi-3a (71.2 g) was recrystallized
from refluxed solution in cyclohexane/EtOAc (3:1) to afford pure
alkene 3a (2.80 g, 13.4 mmol), and PdCl (238 mg, 1.34 mmol) in
2
DMF (27 mL) was added Et N (5.6 mL, 40.4 mmol) at room
3
(
±)-3a (51.4 g, 70%) as a white crystalline and a mixture of (±)-3a
temperature. The resulting mixture was degassed by three freeze−
and (±)-epi-3a (20.8 g, 77:23) as a yellowish solid. The mixture was
purified by silica gel column chromatography (hexane/EtOAc = 2:1
to 1:1) to afford (±)-3a (11.1 g, 15%) as an off-white solid and a
mixture of (±)-3a and (±)-epi-3a (6.71 g). Further purification by
silica gel flash column chromatography (hexane/EtOAc = 2:1 to 1:1)
afforded (±)-3a (2.78 g, 3%) as an off-white solid. H NMR spectrum
of (±)-3a was identical to that reported for this compound.
thaw cycles, and the flask was filled with N . After being stirred at
2
room temperature for 37 h, the resulting mixture was diluted with
EtOAc (60 mL) and then poured into a stirred mixture of a saturated
aqueous solution of NaHCO (100 mL), H O (100 mL), and EtOAc
3
2
(40 mL). The organic layer was separated, and the aqueous layer was
extracted with EtOAc (2 × 100 mL). The combined organic layer was
washed with brine (400 mL). The brine layer was extracted with
EtOAc (100 mL). The combined organic layer was dried over
Na SO and concentrated under reduced pressure. The residue was
1
13
Enzymatic Acetylation of (±)-Alcohol 3a. This reaction was
conducted according to the reported procedure with slight
2
4
13
modifications. To a solution of (±)-3a (65.2 g, 313 mmol) in
toluene (3.27 L) were added vinyl acetate (242 g, 2.16 mmol) and
lipase MY-30 (188 g) at room temperature. The reaction was
monitored by TLC and H NMR analyses of a small aliquot of the
filtered reaction mixture. After being stirred at room temperature for
purified two times by PSQ 100B silica gel open column
chromatography (CH Cl /hexane/EtOAc = 1:1:1 to 1:1:2) to afford
2
2
8 (2.22 g, 55% yield) as an off-white solid and 9 (1.30 g, 32% yield) as
1
1
13
1
a pink solid. H and C{ H} NMR spectra of 8 and 9 were identical
16
27
to those reported for these compounds. 8: [α]D −18.2 (c 1.125,
23
7
3.5 h, to the resulting mixture was added lipase MY-30 (94.2 g) at
CHCl ). 9: [α] −3.60 (c 1.01, CHCl ).
3
D
3
room temperature. After being stirred at room temperature for 29.5 h,
the reaction mixture was filtered through a filter paper. Compounds
were washed out with EtOAc, and combined filtrate was concentrated
under reduced pressure. The residue was purified three times by silica
gel open-column chromatography (hexane/CH Cl /EtOAc = 6:1:3 to
Multidecagram-Scale Synthesis of 8. To a solution of triflate 2
(28.2 g, 115 mmol), alkene 3a (20.9 g, 100 mmol), and PdCl (1.78 g,
2
10.1 mmol) in DMF (200 mL) was added Et N (42 mL, 303 mmol)
3
at room temperature. The resulting mixture was degassed by three
freeze−thaw cycles, and the flask was filled with N . After being
2
2
2
5
:1:3 to 4:1:3 to EtOAc) to afford acetate 3b (33.6 g, 43% yield, 93%
stirred at room temperature for 38 h, the resulting mixture was poured
into a stirred mixture of a saturated aqueous solution of NaHCO3
ee) as a white solid and alcohol ent-3a (38.2 g, 57% yield, 72% ee) as a
white solid. An enantiomeric excess was determined by chiral HPLC
analysis. Chiral HPLC analysis for acetate 3b (CHIRALPAK IB
column, hexane/2-propanol = 90/10, flow rate = 0.5 mL/min,
detection 200 nm light, 30 °C) t = 19.9 min (major isomer), 22.2
min (minor isomer). Chiral HPLC analysis for alcohol ent-3a
(600 mL) and H O (600 mL). The resulting mixture was extracted
2
with EtOAc (5 × 200 mL). The combined organic layer was washed
with brine (500 mL). The brine layer was extracted with EtOAc (2 ×
200 mL). The combined organic layer was dried over Na SO and
R
2
4
concentrated under reduced pressure. The residue was purified by
silica gel flash column chromatography (CH Cl /hexane/EtOAc =
(
CHIRALPAK IB column, hexane/2-propanol = 90/10, flow rate =
2
2
0
.5 mL/min, detection 200 nm light, 30 °C) t = 23.1 min (minor
1:1:1 to 1:1:2 to 1:1:3) to afford 8 (15.9 g, 52% yield) as an off-white
solid and a mixture of 8 and 9 (10.7 g, 35% yield, 8/9 = 18:82,
determined by H NMR analysis) as a red-purple solid.
R
1
isomer), 24.5 min (major isomer). H NMR spectrum of 3b was
identical to that reported for this compound.
13
1
Enzymatic Hydrolysis of Acetate 3b. To a solution of acetate 3b
15.0 g, 60.0 mmol, 93% ee) in toluene (225 mL) was added a 0.1 M
Propargyl Alcohol 10. This compound was synthesized according
16
(
to the reported procedure. To a solution of trimethylsilylacetylene
(27.5 mL, 199 mmol) in dry THF (800 mL) was added n-BuLi (2.80
M solution in hexane, 65 mL, 182 mmol) at −78 °C. After being
stirred at −78 °C for 20 min, to the cold solution was added a
solution of 8 (13.6 g, 44.9 mmol) in dry THF (500 mL). After being
stirred at −78 °C for 30 min, to the reaction mixture was added
dropwise BF ·OEt (11.3 mL, 90.0 mmol). After being stirred at −78
sodium phosphate buffer (375 mL, pH = 7) involving with 0.01% (w/
w) bromothimol blue (BTB) as a pH indicator at room temperature.
To this mixture was added lipase MY-30 (15.0 g), and the resulting
suspension was stirred vigorously at room temperature. The pH was
monitored by BTB and was controlled in a range from 6 to 7 by
dropping a 1.0 M aqueous solution of NaOH. The conversion was
3
2
1
monitored by TLC and H NMR analysis of a small aliquot of the
°C for 2.5 h, the reaction mixture was poured into a cold mixture of a
filtered reaction mixture. After being stirred at room temperature for 1
h, to the resulting mixture was added dropwise a 1.0 M aqueous
solution of NaOH (15 mL). After being stirred at room temperature
saturated aqueous solution of NH Cl (1 L), brine (1 L), H O (600
4
2
mL), and EtOAc (1 L) at 0 °C. The resulting mixture was allowed to
warm to room temperature. The organic layer was separated and
3
609
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J. Org. Chem. 2021, 86, 3605−3614

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
washed with brine (1 L). The aqueous layer was extracted with
EtOAc (1 L), and the organic layer was washed with brine layer. The
combined organic layer was dried over Na SO and concentrated
a saturated aqueous solution of NaHCO (90 mL), H O (100 mL),
3 2
and Et O (90 mL). The organic layer was separated, and the aqueous
2
layer was extracted with Et O (90 mL). The combined organic layer
2
4
2
under reduced pressure. The residue was purified by PSQ 100B silica
gel open column chromatography (hexane/EtOAc = 2:1 to 1:1 to 1:2
to 1:3) to afford the corresponding ynone (9.60 g) as a light brown
solid. This material was used for the next reaction without further
purification. To a solution of the ynone (9.60 g) in MeOH (800 mL)
was added CeCl ·7H O (13.7 g, 36.0 mmol) at 0 °C. After being
was washed with brine (90 mL), dried over Na SO , and concentrated
2
4
under reduced pressure. The residue was purified by PSQ 100B silica
gel open column chromatography (hexane/EtOAc = 10:1 to 7:1 to
1:5 to EtOAc) to afford 4 (553 mg, 32% yield in three steps), 12 (437
mg, 32% yield in three steps), and 13 (173 mg, 10% yield in three
steps) as a white amorphous solid, respectively. Analytically pure
sample of 13 was obtained by recrystallization from refluxed n-hexane
3
2
stirred at 0 °C for 30 min to dissolve the CeCl ·7H O, the reaction
3
2
1
13
1
mixture was cooled to −78 °C. To the cold solution was added
cooled to 4 °C. H and C{ H} NMR spectra of 4, 12, and 13 were
16
27
NaBH (3.59 g, 95.0 mmol) at −78 °C. After being stirred at −78 °C
identical to those reported for these compounds. 4: [α]D − 18.6 (c
4
2
7
27
D
for 40 min, the reaction mixture was allowed to warm to 0 °C in 50
1.035, CHCl ). 12: [α] + 52.1 (c 1.06, CHCl ). 13: [α] + 82.9 (c
3
D
3
min, and then the reaction was quenched with acetone (14 mL) at 0
1.00, CHCl3).
°
C. The resulting mixture was poured into a mixture of a 1 N aqueous
Hydrogenation of 4. To a solution of 4 (48.0 mg, 0.0856 mmol) in
EtOH (2.5 mL) was added Pd/C (5.2 mg, 4.9 μmol) at room
temperature. The reaction mixture was stirred under an atmosphere of
hydrogen (1 atm) at room temperature for 5.5 h and then filtered
through a pad of Celite eluted with EtOAc. The filtrate was
concentrated under reduced pressure. The residue was purified by
PSQ 100B silica gel open column chromatography (hexane/EtOAc =
9:1 to 7:1) to afford 14a (48.2 mg, quantitative yield) as a crystalline
white solid. Peak assignment was performed by NMR spectroscopy
solution of HCl (800 mL) and H O (1.6 L). The aqueous layer was
2
extracted with EtOAc (3 × 1 L), and each organic layer was washed
with brine (1 L), respectively. Combined organic layer was dried over
Na SO and concentrated under reduced pressure to afford propargyl
alcohol S1 (9.69 g) as a brown solid. This material was used for the
next reaction without further purification. Analytically pure sample of
S1 (6R/6S = 81:19 determined by H NMR analysis) was obtained
by PSQ 100B silica gel open column chromatography (hexane/EtOAc
2
4
1
1
13
1
1
13
1
1
=
1:1 to 1:2) as a pale yellow solid. H and C{ H} NMR spectra of
( H, C{ H}, COSY, HSQC, and HMBC). mp 205−207 °C. H
16
28
S1 were identical to those reported for this compound. [α]D
+
NMR (CDCl , 400 MHz): δ 5.75 (dd, 1H, J = 10, 2.5 Hz,
3
1
26.1 (c 1.11, CH OH). To a solution of propargyl alcohol S1 (9.69
CH CCHCH), 5.55 (dd, 1H, J = 10, 2 Hz, CH CCHCH), 4.76
3
3
3
g) in MeOH (800 mL) was added KF (13.9 g, 240 mmol) at room
temperature. After being stirred at room temperature for 26.5 h, the
reaction mixture was concentrated under reduced pressure. To the
residue were added H O (200 mL) and MeOH (50 mL), and the
resulting mixture was extracted with CHCl /2-PrOH (8 × 100 mL,
(m, 1H, OCOCH), 4.11 (dd, 1H, J = 8.5, 8 Hz, CH CCHOSi),
3
3.90 (ddd, 1H, J = 11.5, 8, 7.5 Hz, OCCCHCHOSi), 2.23 (m, 1H,
OCOCHCH H CH), 2.18−2.05 (m, 2H, OCCCHCHOSi-
A
B
2
CH H ), 1.97−1.64 (m, 9H, 2 × CH, 7 × CH H ), 1.42 (ddd,
A
B
A
B
3
1H, J = 14, 9.5, 6.5 Hz, OCOCHCH H CH), 1.36 (dd, 1H, J =
A
B
3
:1). The combined organic layer was dried over Na SO and
13.5, 9 Hz, CH CCHOSiCH CH H ), 1.32−1.19 (m, 2H,
2
4
3 2 A B
concentrated under reduced pressure. The residue was purified by
CH CCHOSiCH H , OH), 1.06 (s, 3H, CH ), 0.88 (s, 9H,
3 A B 3
PSQ 100B silica gel open column chromatography (CH Cl /MeOH
=
as an off-white solid. H and C{ H} NMR spectra were identical to
those reported for this compound. 10: [α]D + 150.3 (c 1.045,
C(CH ) ), 0.86 (s, 9H, C(CH ) ), 0.06 (s, 3H, OSiCH ), 0.05 (s,
3 3 3 3 3
2
2
1
3
1
20:1) to afford 10 (7.23 g, 49% yield in three steps, 6R/6S = 82:18)
3H, OSiCH ), 0.04 (s, 3H, OSiCH ), 0.01 (s, 3H, OSiCH ). C{ H}
3 3 3
1
13
1
NMR (CDCl , 100 MHz): δ 174.9, 128.7, 124.5, 81.6, 78.3, 74.2,
3
16
29
67.3, 49.8, 43.1, 42.3, 41.6, 35.6, 34.3, 29.9, 28.7, 28.6, 27.7, 25.8,
CH OH).
25.7, 23.1, 18.4, 18.0, 17.9, −3.90, −4.44, −4.87, −4.97. IR (KBr) v
3
max
−
1
Allylic Alcohol 11. This compound was synthesized according to
3468, 1747, 1471, 1462, 1252, 1088, 979 cm . HRMS-ESI (m/z):
16
+
the reported procedure with slight modifications. To a solution of
propargyl alcohol 10 (1.02 g, 3.09 mmol, 6R/6S = 82:18) in MeOH
[M + Na] calcd for C H O Si Na, 585.3402; found, 585.3407.
3
1
54
5
2
2
7
[α] − 61.3 (c 0.94, CHCl ).
D
3
(308 mL) were added 3,6-dithia-1,8-octanediol (5.7 mg, 0.031 mmol)
Diol 14b. To a solution of 14a (70.0 mg, 0.124 mmol) in dry THF
(2.5 mL) was added TBAF (1.0 M solution in THF, 0.6 mL, 0.6
mmol) at room temperature. After being stirred at room temperature
for 2.5 h, to the reaction mixture were added H O (10 mL) and Et O
and a Lindlar catalyst (lead poisoned, 329 mg, 0.154 mmol) at room
temperature. After being stirred under an atmosphere of hydrogen (1
atm) at room temperature for 1.5 h, the reaction mixture was filtered
through a pad of Celite eluted with MeOH, and the filtrate was
concentrated under reduced pressure to afford a crude mixture of 11
2
2
(10 mL). The organic layer was separated, and the aqueous layer was
extracted with Et O (10 mL). The combined organic layer was
2
(
1.10 g). This material was used for the next reaction without further
washed with brine, dried over Na SO , and concentrated under
2
4
purification. Analytically pure sample of 11 (6R/6S = 90:10
reduced pressure. The residue was purified by PSQ 100B silica gel
1
determined by H NMR analysis) was obtained by PSQ 100B silica
open column chromatography (Et O to EtOAc) to afford 14b (55.8
2
gel open column chromatography (hexane/EtOAc = 1:1 to 1:2 to 1:3
to EtOAc to EtOAc/MeOH = 2:1) as a pale yellow amorphous solid.
mg, quantitative yield) as a white solid. Peak assignment was
performed by NMR spectroscopy ( H, C{ H}, COSY, HSQC, and
1
13
1
1
13
1
1
H and C{ H} NMR spectra were identical to those reported for
HMBC). mp 198−201 °C. H NMR (CDCl , 400 MHz): δ 5.74 (dd,
3
16
28
this compound. [α]D + 128.8 (c 1.01, CH OH).
1H, J = 10, 2.5 Hz, CH CCHCH), 5.54 (dd, 1H, J = 10, 1 Hz,
3
3
Silylated Cycloadducts 4, 12, and 13. These compounds were
CH CCHCH), 4.71 (m, 1H, OCOCH), 4.10 (dd, 1H, J = 9, 8
3
16
synthesized according to the reported procedure. To the crude
Hz, CH CCHOSi), 3.90 (ddd, 1H, J = 12, 8, 8 Hz, O
3
mixture of allylic alcohol 11 (1.10 g) was added deionized H O (206
CCCHCHOH), 2.29 (m, 1H, OCOCHCH H CH), 2.14 (ddd,
2
A
B
mL), and the resulting mixture was well-suspended by sonication.
After being stirred vigorously at room temperature for 204 h, the
1H, J = 11.5, 11, 7.5 Hz, CHCHCHCH), 2.08−1.75 (m, 9H, CH, 7
× CH H , OH), 1.75−1.60 (m, 2H, CHCHCHCHCH H ), 1.54
A
B
A
B
1
completion of the reaction was confirmed by TLC and H NMR
(dd, 1H, J = 13.5, 9 Hz, OCOCHCH H CH), 1.42 (ddd, 1H, J =
A
B
analysis of a small aliquot of the reaction mixture. The reaction
mixture was concentrated under reduced pressure to afford a crude
mixture of cycloadducts (1.08 g) as a pale yellow solid. The ratio of
14.5, 9.5, 6.5 Hz, CH CCHOSiCH CH H ), 1.35−1.15 (m, 2H,
3 2 A B
CH CCHOSiCH H , OH), 1.06 (s, 3H, CH ), 0.88 (s, 9H,
3
A
B
3
1
3
1
C(CH ) ), 0.04 (s, 3H, OSiCH ), 0.01 (s, 3H, OSiCH ). C{ H}
3
3
3
3
1
cycloadducts was determined by H NMR analysis as 43:40:17 for
NMR (CDCl , 100 MHz): δ 175.3, 128.9, 124.3, 81.7, 78.2, 74.5,
3
presilylated compounds corresponding to 4, 12, and 13, respectively.
This material was used for the next reaction without further
purification. To a solution of cycloadducts (1.08 g) in DMF (30
mL) were added imidazole (1.27 g, 18.5 mmol) and TBSCl (1.43 g,
66.8, 49.9, 43.3, 42.3, 41.8, 35.5, 34.2, 29.9, 28.9, 28.4, 27.1, 25.8,
23.0, 18.7, 18.0, −4.44, −4.96. IR (KBr) v 3407, 1736, 1112, 1077
max
−
1
+
cm . HRMS-ESI (m/z): [M + Na] calcd for C H O SiNa,
2
5
40
5
2
7
471.2537; found, 471.2537. [α] − 64.5 (c 1.04, CHCl ).
Thiocarbonate 15. Diol 14b (45.0 mg, 0.100 mmol) was dried
azeotropically with toluene (2×) and dissolved in dry CH Cl (1.0
D
3
9
.29 mmol) at room temperature. After being stirred at room
temperature for 9 h, the reaction mixture was poured into a mixture of
2
2
3
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J. Org. Chem. 2021, 86, 3605−3614

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
mL). To this solution were added phenyl chlorothionoformate (0.020
mL, 0.15 mmol) and dry pyridine (0.025 mL, 0.31 mmol) at room
temperature. After being stirred at room temperature for 19 h, the
reaction was quenched with a 1 N aqueous solution of HCl (5 mL).
hexane/EtOAc = 3:1 to 1:1 to 1:3) to afford 16a (36.6 mg, 99%
yield) as a white solid. Peak assignment was performed by NMR
1
13
1
spectroscopy ( H, C{ H}, COSY, HSQC, and HMBC). mp 128−
1
129 °C. H NMR (CDCl , 400 MHz): δ 5.75 (dd, 1H, J = 10, 2.5 Hz,
3
The aqueous layer was extracted with Et O (2 × 5 mL). The
CH CCHCH), 5.58 (dd, 1H, J = 10, 2 Hz, CH CCHCH), 4.62
2
3
3
combined organic layer was washed with brine, dried over Na SO ,
(m, 1H, OCOCH), 4.11 (dd, 1H, J = 8.5, 8.5 Hz, CH CCHOSi),
2
4
3
and concentrated under reduced pressure. The residue was purified by
silica gel flash chromatography (hexane/EtOAc = 5:1 to 3:1) to afford
2.19 (m, 1H, OCOCHCH H CH), 2.03 (m, 1H, O
A
B
CCCHCH ), 1.96 (m, 1H, CHCHCHCH), 1.92−1.70 (m, 8H,
2
1
5 (53.3 mg, 91% yield) as a white solid. Peak assignment was
CH, 7 × CH H ), 1.65 (ddd, 1H, J = 13.5, 9, 3 Hz, O
A
B
1
13
1
performed by NMR spectroscopy ( H, C{ H}, COSY, HSQC, and
CCCHCH H ), 1.53 (dddd, 1H, J = 13.5, 13.5, 10, 9 Hz, O
A
B
1
HMBC). mp >100 °C (decomposed). H NMR (CDCl , 400 MHz):
CCCHCH H ), 1.45−1.32 (m, 2H, OCCCHCH CH H ,
3
A B 2 A B
δ 7.42 (dd, 2H, J = 8.5, 7.5 Hz, phenyl H-3′), 7.30 (tt, 1H, J = 7.5, 1
CH CCHOSiCH CH H ), 1.27 (m, 1H, CH CCHOSiCH H ),
3 2 A B 3 A B
Hz, phenyl H-4′), 7.08 (dd, 2H, J = 8.5, 1 Hz, phenyl H-2′), 5.80 (dd,
1.19 (dd, 1H, J = 13, 9 Hz, OCOCHCH H CH), 1.06 (s, 3H,
CH ), 0.88 (s, 9H, C(CH ) ), 0.04 (s, 3H, OSiCH ), 0.01 (s, 3H,
3 3 3 3
A
B
1
H, J = 10, 2.5 Hz, CH CCHCH), 5.70−5.51 (m, 2H, SCOCH,
3
1
3
1
CH CCHCH), 4.73 (m, 1H, OCOCH), 4.13 (dd, 1H, J = 9, 8
OSiCH3). C{ H} NMR (CDCl , 100 MHz): δ 175.8, 128.6, 125.1,
3
3
Hz, CH CCHOSi), 2.49 (ddd, 1H, J = 12, 10, 9 Hz, SCOCHCH),
82.1, 78.3, 74.3, 50.1, 43.3, 42.5, 35.2, 34.8, 29.9, 29.7, 28.94, 28.85,
3
2
.38−2.18 (m, 3H, OCOCHCH H CHCH, SCOCH-
25.8, 22.1, 21.7, 20.4, 18.4, 18.0, −4.44, −4.97. IR (KBr) v 3471,
A
B
max
−
1
+
CH H CH), 2.07−1.80 (m, 8H, CH, 7 × CH H ), 1.60 (m, 1H,
1748 cm . HRMS-ESI (m/z): [M + Na] calcd for C H O SiNa,
A
B
A
B
25 40 4
2
7
OCOCHCH H CH), 1.45 (m, 1H, CH CCHOSiCH CH H ),
455.2588; found, 455.2588. [α] − 63.2 (c 0.905, CHCl ).
Deoxygenation of 15 (0.655 mmol Scale). To a solution of
thiocarbonate 15 (383 mg, 0.655 mmol) in toluene (100 mL) were
A
B
3
2
A
B
D
3
1.31 (m, 1H, CH CCHOSiCH H ), 1.09 (s, 3H, CH ), 0.89 (s, 9H,
3
A
B
3
1
3
1
C(CH ) ), 0.06 (s, 3H, OSiCH ), 0.03 (s, 3H, OSiCH ). C{ H}
3
3
3
3
NMR (CDCl , 100 MHz): δ 194.8, 174.2, 153.3, 129.6, 129.0, 126.7,
added AIBN (53.8 mg, 0.328 mmol) and n-Bu SnH (0.62 mL, 2.3
mmol) at room temperature. The resulting mixture was degassed by
3
3
1
2
v
24.0, 121.8, 81.5, 80.3, 78.2, 74.0, 49.9, 43.0, 42.7, 39.1, 35.7, 29.84,
9.78, 29.0, 28.3, 26.9, 25.8, 23.4, 18.5, 18.0, −4.41, −4.95. IR (KBr)
three freeze−thaw cycles, and the flask was filled with N . After being
2
−
1
+
3466, 1755, 1204 cm . HRMS-ESI (m/z): [M + Na] calcd for
stirred at reflux for 2 h, the reaction mixture was allowed to cool to
room temperature. The resulting mixture was directly purified by 10%
(w/w) K CO containing silica gel open chromatography (toluene to
max
2
7
C H O SSiNa, 607.2520; found, 607.2526. [α] − 76.9 (c 1.24,
32
44
6
D
CHCl3).
2
3
Sequential Synthesis of Thiocarbonate 15 from 4. To a solution
of 4 (435 mg, 0.808 mmol) in EtOH (23 mL) was added Pd/C (86.3
mg, 0.0811 mmol) at room temperature. The reaction mixture was
stirred under an atmosphere of hydrogen (1 atm) at room
temperature for 2.5 h and then filtered through a pad of Celite
eluted with EtOAc. The filtrate was concentrated under reduced
pressure to afford a crude mixture of 14a as a white solid. To a
solution of the crude mixture of 14a in dry THF (16 mL) was added
TBAF (1.0 M solution in THF, 4,0 mL, 4.0 mmol) at room
temperature. After being stirred at room temperature for 2 h, to the
reaction mixture were added H O (45 mL) and Et O (30 mL). The
hexane/EtOAc = 3:1 to 1:1 to 1:3) to afford 16a (276 mg, 97% yield)
as a white solid.
Diol 16b. To a solution of 16a (276 mg, 0.638 mmol) in CH Cl /
2
2
MeCN (10 mL, 1:1) was added a 48% (w/w) aqueous solution of HF
(110 μL, 6.38 mmol) at room temperature. After being stirred at
room temperature for 19 h, to the reaction mixture was added CaCO3
(640 mg, 6.40 mmol). After being stirred at room temperature for 1 h,
the resulting mixture was filtered through a pad of Celite eluted with
EtOAc, and the filtrate was concentrated under reduced pressure. The
residue was purified by PSQ 100B silica gel open column
chromatography (EtOAc) to afford 16b (198 mg, 97% yield) as a
white solid. Peak assignment was performed by NMR spectroscopy
2
2
organic layer was separated, and the aqueous layer was extracted with
1
13
1
1
Et O (30 mL). The combined organic layer was washed with brine,
( H, C{ H}, COSY, HSQC, and HMBC). mp 228−230 °C. H
2
dried over Na SO , and concentrated under reduced pressure to
NMR (CD OD, 400 MHz): δ 5.60 (d, 1H, J = 10.5 Hz, CHCH),
2
4
3
afford a crude mixture of 14b as an off-white solid. The crude mixture
of 14b was dried azeotropically with toluene (3×) and dissolved in
5.57 (d, 1H, J = 10.5 Hz, CHCH), 4.64 (m, 1H, OCOCH), 4.10
(dd, 1H, J = 9.5, 8 Hz, CH CCHOH), 2.19 (m, 1H, O
3
dry CH Cl2 (80 mL). To this solution were added phenyl
COCHCH H CH), 2.09−1.98 (m, 3H, 2 × CH, CH H ), 1.98−
2
A
B
A
B
chlorothionoformate (0.13 mL, 0.97 mmol) and dry pyridine (0.16
mL, 2.0 mmol) at room temperature. After being stirred at room
temperature for 16 h, to the reaction mixture were added phenyl
chlorothionoformate (0.035 mL, 0.26 mmol) and dry pyridine (0.040
mL, 0.50 mmol) at room temperature. After being stirred at room
temperature for 25 h, to the reaction mixture were added phenyl
chlorothionoformate (0.055 mL, 0.41 mmol) and dry pyridine (0.10
mL, 1.2 mmol) at room temperature. After being stirred at room
temperature for 22 h, the reaction mixture was concentrated under
1.78 (m, 7H, CH, 6 × CH H ), 1.71−1.58 (m, 2H, CH ), 1.46−1.35
A
B
2
(m, 2H, 2 × CH H ), 1.35−1.24 (m, 2H, 2 × CH H ), 1.07 (s, 3H,
A
B
A
B
1
3
1
CH ). C{ H} NMR (CD OD, 100 MHz): δ 178.9, 128.8, 127.3,
3
3
83.4, 79.0, 76.6, 51.0, 44.9, 43.6, 36.9, 35.4, 30.5, 29.8 (two carbons),
−
1
29.3, 23.0, 22.9, 21.3, 19.1. IR (KBr) v 3455, 1736 cm . HRMS-
max
+
ESI (m/z): [M + Na] calcd for C H O Na, 341.1723; found,
1
9
26
4
2
7
341.1723. [α] − 84.8 (c 1.015, CH OH).
D
3
Hydrogenation of 16b. To a solution of 16b (198 mg, 0.620
mmol) in dry CH Cl (30 mL) was added a Crabtree’s catalyst (24.8
2
2
reduced pressure. The residue was dissolved in Et O (20 mL), and
then to the resulting mixture was added a 1 N aqueous solution of
mg, 0.0308 mmol) at room temperature. After being stirred under an
atmosphere of hydrogen (1 atm) at room temperature for 24 h, to the
reaction mixture was added the Crabtree’s catalyst (25.1 mg, 0.0312
mmol) at room temperature. The reaction mixture was stirred under
an atmosphere of hydrogen (1 atm) at room temperature for another
23 h and then filtered through Florisil eluted with EtOAc. The filtrate
was concentrated under reduced pressure. The residue was purified by
PSQ 100B silica gel open column chromatography (CH Cl /MeOH
2
HCl (20 mL). The aqueous layer was extracted with Et O (2 × 20
2
mL). The combined organic layer was washed with brine, dried over
Na SO , and concentrated under reduced pressure. The residue was
2
4
purified by silica gel flash chromatography (hexane/EtOAc = 5:1 to
:1) to afford diol 14b (45.2 mg, 12% yield in three steps) as a white
3
solid and thiocarbonate 15 (303 mg, 64% yield in three steps) as a
white solid.
Deoxygenation of 15 (0.0855 mmol Scale). To a solution of
2
2
= 19:1 to 9:1) to afford 17 (188 mg, 95% yield) as a white solid. Peak
1
13
1
assignment was performed by NMR spectroscopy ( H, C{ H},
1
thiocarbonate 15 (50.0 mg, 0.0855 mmol) in toluene (13 mL) were
COSY, HSQC, and HMBC). mp 117−119 °C. H NMR (CD OD,
3
added AIBN (6.9 mg, 0.042 mmol) and n-Bu SnH (0.080 mL, 0.30
400 MHz): δ 4.61 (m, 1H, OCOCH), 4.15 (dd, 1H, J = 8.5, 8.5
3
mmol) at room temperature. The resulting mixture was degassed by
Hz, CH CCHOH), 2.71 (m, 1H, CH CCH CH H ), 2.19 (ddd, 1H,
3
3
2
A
B
three freeze−thaw cycles, and the flask was filled with N . After being
J = 13, 10, 6 Hz, OCOCHCH H CH), 2.06 (m, 1H,
CH CCHOHCH H ), 1.98 (m, 1H, CH CCHOHCH CH H ),
3 A B 3 2 A B
2
A
B
stirred at reflux for 2 h, the reaction mixture was allowed to cool to
room temperature. The resulting mixture was directly purified by 10%
1.96−1.85 (m, 3H, 2 × CH, CH H ), 1.85−1.73 (m, 4H, 4 ×
A
B
(
w/w) K CO containing silica gel open chromatography (toluene to
CH H ), 1.61−1.37 (m, 7H, 7 × CH H ), 1.29 (dd, 1H, J = 13, 9
2
3
A
B
A
B
3
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Hz, OCOCHCH H CH), 1.23−1.08 (m, 2H, CH, CH H ), 1.06
1.5 h, the reaction was quenched with a 1 N aqueous solution of HCl
(10 mL). The aqueous layer was extracted with EtOAc (3 × 5 mL).
The combined organic layer was washed with a saturated aqueous
solution of NaHCO followed by brine, dried over Na SO , and
A
B
A
B
13
1
(
s, 3H, CH ). C{ H} NMR (CD OD, 100 MHz): δ 179.8, 86.0,
3
3
8
2
1.4, 76.4, 48.7, 44.6, 42.5, 38.5, 38.0, 31.0, 30.6, 29.7, 29.4, 28.2,
−
1
3.9, 23.2, 21.9, 20.9, 16.7. IR (KBr) v 3432, 3318, 1715 cm .
max
3
2
4
+
HRMS-ESI (m/z): [M + Na] calcd for C H O Na, 343.1880;
concentrated under reduced pressure. The residue was purified by
silica gel flash chromatography (EtOAc) to afford 5a (17.7 mg, 97%
1
9
28
4
2
6
found, 343.1880. [α]D − 149.5 (c 1.04, CH OH).
Ketone 18. To a solution of 17 (32.0 mg, 0.100 mmol) in dry
CH Cl (10 mL) was added Dess−Martin periodinane (50.9 mg,
3
1
13
1
yield) as a white solid. H and C{ H} NMR spectra were identical
7a
to those reported for this compound. mp >120 °C (decomposed).
2
2
1
0.120 mmol) at room temperature. After being stirred at room
H NMR (CD OD, 400 MHz): δ 6.06 (br s, 1H), 4.03 (br s, 1H),
3
temperature for 1 h, the reaction was quenched with a mixture of
saturated aqueous solutions of NaHCO and Na S O (10 mL, 1:1),
and the resulting mixture was stirred at that temperature for 30 min.
3.83 (d, 1H, J = 11 Hz), 3.41 (d, 1H, J = 11 Hz), 2.59 (d, 1H, J = 16.5
Hz), 2.25−2.12 (m, 2H), 1.96 (ddd, 1H, J = 14, 14, 2 Hz), 1.91−1.45
(m, 9H), 1.44−1.35 (m, 2H), 1.30 (m, 1H), 1.24 (m, 1H), 1.12−0.90
3
2
2
3
1
3
1
The aqueous layer was extracted with CH Cl (2 × 5 mL). The
(m, 2H), 1.01 (s, 3H). C{ H} NMR (CD OD, 100 MHz): δ 134.8,
2
2
3
combined organic layer was washed with a saturated aqueous solution
of NaHCO , dried over Na SO , and concentrated under reduced
111.6, 83.5, 67.4, 66.1, 55.7, 43.0, 42.7, 40.5, 39.5, 37.3, 34.1, 29.7,
2
4
3
2
4
28.3, 27.2, 24.2, 21.7, 20.9, 18.6. [α] + 21.9 (c 0.885, CH OH).
D
3
pressure. The residue was purified by PSQ 100B silica gel open
column chromatography (CH Cl /MeOH = 19:1) to afford 18 (28.0
Silylation of 5a. This reaction was conducted according to the
reported procedure. To a solution of triol 5a (13.9 mg, 0.0322
7a
2
2
mg, 88% yield) as a white solid. Peak assignment was performed by
mmol) in dry CH Cl (1.6 mL) were added dropwise 2,6-lutidine
2
2
1
13
1
NMR spectroscopy ( H, C{ H}, COSY, HSQC, and HMBC). mp
(0.045 mL, 0.39 mmol) and TBSOTf (0.040 mL, 0.17 mmol) at −78
°C. The resulting suspension was warmed to −20 °C within 10 min
and then stirred at −20 °C for 2.5 h. To the resulting clear solution
1
>
1
210 °C (decomposed). H NMR (CDCl , 400 MHz): δ 4.61 (m,
3
H, OCOCH), 2.82 (dddd, 1H, J = 14, 14, 13, 4 Hz,
CH CCH CH H ), 2.45−2.32 (m, 2H, CH CCOCH ), 2.22 (m,
was added a saturated aqueous solution of NaHCO (5 mL). The
3
2
A
B
3
2
3
1
H, OCOCHCH H CH), 2.10−1.70 (m, 9H, 2 × CH, 6 ×
aqueous layer was extracted with CH Cl (3 × 5 mL). The combined
A
B
2
2
CH H , OH), 1.70−1.57 (m, 3H, 3 × CH H ), 1.52 (ddd, 1H, J =
organic layer was washed with H O, dried over Na SO , and
A
B
A
B
2 2 4
1
1
3, 10.5, 8 Hz, CH H ), 1.45 (m, 1H, CH CCH CH H ), 1.38 (ddd,
concentrated under reduced pressure. The residue was purified by
PSQ 100B silica gel open column chromatography (hexane/EtOAc =
19: 1) to afford 5b (21.1 mg, 99% yield) as a white amorphous solid.
A
B
3
2
A
B
H, J = 14, 4, 3 Hz, CH CCH H ), 1.23 (ddd, 1H, J = 14, 14, 3 Hz,
3
A
B
CH CCH H ), 1.20 (dd, 1H, J = 13.5, 9 Hz, OCOCH-
3
A
B
1
13
1
CH H CH), 1.16 (ddd, 1H, J = 13, 13, 4.5 Hz, OCCCHCH),
H and C{ H} NMR spectra were identical to those reported for
A
B
1
3
1
7a
1
1
2
.12 (s, 3H, CH ). C{ H} NMR (CDCl , 100 MHz): δ 221.1,
this compound.
3
3
76.7, 83.0, 74.3, 54.3, 42.9, 41.5, 37.1, 36.5, 32.6, 32.1, 30.2, 28.6,
Stille Coupling. This reaction was conducted according to the
−
1
7a
7.3, 22.5, 21.7, 20.8, 19.5, 12.3. IR (KBr) v 3449, 1732 cm .
reported procedure. To a flask with 5b (9.4 mg, 0.014 mmol) were
max
+
HRMS-ESI (m/z): [M + Na] calcd for C H O Na, 341.1723;
found, 341.1722. [α]D − 148.3 (c 0.995, CHCl ).
added LiCl (13.0 mg, 0.307 mmol), CuCl (24.6 mg, 0.248 mmol),
1
9
26
4
2
5
3
and Pd(PPh ) (1.8 mg, 0.0016 mmol) under argon flow followed by
3 4
Alkeneyl Iodide 19. To a solution of ketone 18 (11.5 mg, 0.0360
the addition of stannane 20 (0.028 M solution in dry DMSO, 1.6 mL,
0.045 mmol) at room temperature. The resulting mixture was
degassed by three freeze−thaw cycles, and the flask was filled with
argon. After being stirred at 70 °C for 2 h, the reaction mixture was
allowed to cool to room temperature and quenched with pH 7
phosphate buffer (3 mL). The resulting mixture was then filtered
through cotton filter to remove solid residue, and the aqueous layer
was extracted with EtOAc (3 × 5 mL). The combined organic layer
was washed with brine, dried over Na SO , and concentrated under
mmol) in EtOH (3.6 mL) were added Et N (0.10 mL, 0.72 mmol)
3
and N H ·H O (0.035 mL, 0.72 mmol) at room temperature. The
2
4
2
reaction mixture was heated to 50 °C and stirred at that temperature
for 3 h. The resulting mixture was concentrated under reduced
pressure to afford the crude mixture as a white solid. The crude
mixture was dissolved in dry THF (3.6 mL), and to this solution were
added Et N (0.10 mL, 0.72 mmol) and solid I (18.9 mg, 0.0745
3
2
mmol) at room temperature. After being stirred at room temperature
for 30 min, the reaction was quenched with a mixture of saturated
aqueous solutions of NaHCO3 and Na S O (4 mL, 1:1). The
2
4
reduced pressure. The residue was purified by silica gel flash
chromatography (hexane/EtOAc = 3:1) followed by 10% (w/w) of
K CO containing silica gel open chromatography (hexane/EtOAc =
2
2
3
resulting mixture was extracted with EtOAc (2 × 5 mL). The
combined organic layer was washed with a saturated aqueous solution
of NaHCO , dried over Na SO , and concentrated under reduced
2
3
1
3:2) to afford 21a (5.4 mg, 61% yield) as a white amorphous solid. H
1
3
1
3
2
4
and C{ H} NMR spectra were identical to those reported for this
7a
pressure. The residue was purified by PSQ 100B silica gel open
column chromatography (hexane/EtOAc = 2:1 to 1:1) to afford 19
compound.
Silylation of 21a. This reaction was conducted according to the
7a
(
14.5 mg, 94% yield in two steps) as a white solid. Peak assignment
reported procedure. To a solution of 21a (5.4 mg, 0.0087 mmol) in
dry DMF (1 mL) were added imidazole (37.0 mg, 0.543 mmol) and
TMSCl (0.030 mL, 0.22 mmol) at room temperature. After being
stirred at room temperature for 13 h, to the reaction mixture was
added TMSCl (0.010 mL, 0.079 mmol) at room temperature. After
being stirred at room temperature for 2.5 h, the reaction was
1
13
1
was performed by NMR spectroscopy ( H, C{ H}, COSY, HSQC,
and HMBC). mp >111 °C (decomposed). H NMR (CDCl , 400
1
3
MHz): δ 6.09 (dd, 1H, J = 3, 2 Hz, ICCH), 4.61 (m, 1H, O
COCH), 2.51 (dd, 1H, J = 16.5, 2, Hz, ICCHCH H ), 2.44 (m,
A
B
1
H, CH CCH CH H ), 2.23 (m, 1H, OCOCHCH H CH), 2.22
3
2
A
B
A
B
(
dd, 1H, J = 16.5, 3 Hz, ICCHCH H ), 2.06−1.95 (m, 2H, O
quenched with a saturated aqueous solution of NaHCO (10 mL).
A B
3
CCCHCH , OCCCHCH), 1.95−1.67 (m, 6H, O
The aqueous layer was extracted with CH Cl (3 × 5 mL). The
2
2
2
COCHCH CH , OCCCHCH CH H , CH CCH H ), 1.67−
combined organic layer was washed with brine, dried over Na SO ,
2
2
2
A
B
3
A
B
2 4
1
.57 (m, 2H, OCCCHCH H , OH), 1.56−1.35 (m, 3H, O
and concentrated under reduced pressure. The residue was purified by
silica gel flash chromatography (hexane/EtOAc = 9:1) to afford 21b
along with recovery of 21a (0.7 mg, 13% yield). Since 21b was
obtained with concomitant of impurities, this material was used
without further purification.
A
B
CCCHCH H CH H , CH CCH CH H ), 1.18 (dd, 1H, J = 13, 9
A
B
A
B
3
2
A
B
Hz, OCOCHCH H CH), 1.09 (s, 3H, CH ), 1.08 (m, 1H, O
A
B
3
CCCHCH), 1.00 (ddd, 1H, J = 14, 12, 3 Hz, CH CCH H ).
3
A
B
13
1
C{ H} NMR (CDCl , 100 MHz): δ 176.5, 133.5, 111.3, 82.7, 74.2,
3
5
1
5.2, 43.3, 43.1, 41.6, 36.8, 35.9, 35.7, 30.3, 28.7, 23.4, 22.9, 21.1,
Hydrogenation of 21b. This reaction was conducted according to
the reported procedure. To a solution of 21b in EtOAc (1 mL) was
added Pd/C (2.9 mg, 0.0027 mmol) at room temperature. The
reaction mixture was stirred under an atmosphere of hydrogen (1
atm) at room temperature for 20 min and then filtered through a pad
of Celite eluted with EtOAc. The filtrate was concentrated under
reduced pressure. The residue was purified by silica gel flash
−
1
7a
9.9, 18.5. IR (KBr) v 3448, 1733, 1077, 754 cm . HRMS-ESI
max
+
(
4
m/z): [M + Na] calcd for C H IO Na, 451.0741; found,
1
9
25
3
51.0740. [α]2 − 113.9 (c 0.875, CHCl ).
5
D
3
Reduction of 19. To a solution of lactone 19 (18.1 mg, 0.0423
mmol) in dry THF (4.2 mL) was added DIBAL (1.00 M solution in
toluene, 0.42 mL, 0.42 mmol) at 0 °C. After being stirred at 0 °C for
3
612
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chromatography (hexane/EtOAc = 9:1) to afford 22 (5.2 mg, 87%
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1
(
3
(
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.03 (d, 1H, J = 18 Hz), 4.91 (d, 1H, J = 18 Hz), 4.04 (m, 1H), 3.83
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(m, 3H), 2.00−1.43 (m, 12H), 1.43−1.33 (m, 2H), 1.33−1.18 (m,
1
3
1
4
1
3
0
H), 0.88 (s, 3H). C{ H} NMR (CD OD, 100 MHz): δ 178.4,
3
2
(
453−2461.
77.3, 117.8, 86.6, 75.4, 67.5, 66.1, 52.1, 51.1, 42.5, 41.3, 40.5, 36.4,
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3
ASSOCIATED CONTENT
sı Supporting Information
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2
(
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The Supporting Information is available free of charge at
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1H and 13C{1H} NMR spectra for all new compounds
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3b (18% ee) (PDF)
AUTHOR INFORMATION
Corresponding Author
Atsuo Nakazaki − Graduate School of Bioagricultural Sciences,
Nagoya University, Nagoya 464-8601, Japan; orcid.org/
■
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000-0002-0025-0523; Email: nakazaki@agr.nagoya-
2
(
430.
u.ac.jp
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Shogo Watanabe − Graduate School of Bioagricultural
Sciences, Nagoya University, Nagoya 464-8601, Japan
Toshio Nishikawa − Graduate School of Bioagricultural
Sciences, Nagoya University, Nagoya 464-8601, Japan;
orcid.org/0000-0003-1955-6618
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02966
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
This work was financially supported by a Grant-in-Aid for
Scientific Research (B) (no. 19H02896) and (C) (no.
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Nagoya University Graduate Program of Transformative
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(
14) For reviews of approaches to steroid synthesis using Diels−
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(
(
1
2
2
992, 48, 9111−9171. (b) Goel, A.; Ram, V. J. Natural and synthetic
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(
16) Watanabe, S.; Nishikawa, T.; Nakazaki, A. Synthesis of Oxy-
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(
17) Martin, S. F.; Tu, C.-Y.; Chou, T.-S. Novel Intramolecular [4 +
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] Cycloaddition Reactions of Enamines and Enamides with
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̈
(18) (a) Herrmann, W. A.; Brossmer, C.; Ofele, K.; Reisinger, C.-P.;
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Defined Catalysts for the Heck Olefination of Chloro- and
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(
b) Herrmann, W. A.; Brossmer, C.; Reisinger, C.-P.; Riermeier, T.
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(19) Other conditions using lithium trimethylsilylacetylide with
anhydrous CeCl or without any additive resulted in the inferior yield
3
and low reproducibility probably owing to the nucleophilic addition
to the 2-pyrone moiety. Employment of bromomagnesium
trimethylsilylacetylide afforded the ynone in a low yield (∼20%),
and starting 8 was mainly recovered.
(
20) Reduction of the ynone with Li(t-BuO) AlH in THF at 0 °C
3
provided the same sense of diastereoselectivity (6R/6S = 72:28). In
contrast, the use of NaBH in MeOH at −78 °C gave opposite
4
diastereoselectivity (6R/6S = 31:69). The origin of stereoinduction is
still obscure at this time; however, some chelation might be formed to
achieve acceptable diastereoselectivity.
(
21) Lindlar, H.; Dubuis, R. Palladium Catalyst for Partial Reduction
of Acetylenes. Org. Synth. 1966, 46, 89−92.
22) Three-step sequential transformations from key intermediate 4
(
to thiocarbonate 15 could be performed on a larger scale. For details,
see the Experimental Section.
(
23) Barton, D. H. R.; O’brien, R. E.; Sternhell, S. 88. A New
Reaction of Hydrazones. J. Chem. Soc. 1962, 470−476.
24) Mukai, K.; Urabe, D.; Kasuya, S.; Aoki, N.; Inoue, M. A
(
convergent total synthesis of 19-Hydroxysarmentogenin. Angew.
Chem., Int. Ed. 2013, 52, 5300−5304.
3
614
https://dx.doi.org/10.1021/acs.joc.0c02966
J. Org. Chem. 2021, 86, 3605−3614