Enantioselective Total Synthesis of Cerorubenic Acid-III via Type II [5+2] Cycloaddition Reaction

Article abstract of DOI:10.1021/acs.joc.1c00185

The first enantioselective total synthesis of cerorubenic acid-III is described in detail. Different strategies and attempts, based on a type II [5+2] cycloaddition reaction, leading to the bicyclo[4.4.1] ring system with a strained bridgehead double bond, are depicted. Furthermore, sodium naphthalenide was found to be efficient in the chemoselective reduction of 8-oxabicyclo[3.2.1]octene, with three transformations completed in one operation. An unusual SN1 transannular cyclization reaction was applied to construct the synthetically challenging vinylcyclopropane moiety. This strategy enabled the total synthesis of cerorubenic acid-III in 19 steps.

Full text of DOI:10.1021/acs.joc.1c00185

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Article
Enantioselective Total Synthesis of Cerorubenic Acid-III via Type II
[5+2] Cycloaddition Reaction
Xin Liu,# Junyang Liu,# Jianlei Wu, and Chuang-Chuang Li*
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ABSTRACT: The first enantioselective total synthesis of cerorubenic acid-III is described in detail. Different strategies and
attempts, based on a type II [5+2] cycloaddition reaction, leading to the bicyclo[4.4.1] ring system with a strained bridgehead
double bond, are depicted. Furthermore, sodium naphthalenide was found to be efficient in the chemoselective reduction of 8-
oxabicyclo[3.2.1]octene, with three transformations completed in one operation. An unusual SN1 transannular cyclization reaction
was applied to construct the synthetically challenging vinylcyclopropane moiety. This strategy enabled the total synthesis of
cerorubenic acid-III in 19 steps.
scarcity of these isolated natural samples, no further biological
activity of these compounds has been determined other than
their reported role in insect communication. Structurally,
cerorubenic acid-III (1), the most complex compound in this
family, possesses a unique 6/3/7/6 tetracyclic skeleton,
featuring a bridged bicyclo[4.4.1]undecene ring system (high-
lighted in red), and a highly strained vinylcyclopropane moiety
with the double bond at the bridgehead position.5 Furthermore,
seven contiguous stereocenters with an all-carbon quaternary
stereocenter (C3) make this molecule a formidable synthetic
challenge that has attracted much attention from the chemical
community.6 After a ten-year journey, Paquette and co-workers
finished their elegant total synthesis of cerorubenic acid-III
methyl ester (2) in 1998, comprising 30 steps with an overall
yield of 0.3%.6g However, the synthesis of 1 from 2 was still
unknown at the time. For the total synthesis of 1, the
development of an efficient method to construct the complex
ring system with high stereoselectivity, regioselectivity, and
enantioselectivity is a critical challenge. As part of our ongoing
endeavor toward the total synthesis of bioactive natural products
with a seven-membered ring,7 we reported herein an efficient
INTRODUCTION
■
Natural products from the sesterterpenoid family1 usually
present highly attractive targets for total synthesis owing to
their unusual structural features and interesting bioactivity.2
Cerorubenic acid-III (1, Figure 1), along with its four analogues
(3−6), were isolated from the secretion of Ceropiastes rubens
(Coccidae, a scale insect) by Naya and co-workers in 1983.3
These unusual sesterterpenoids were found to act as
kairomones,4 responsible for controlling the ovipositional
behavior of parasitic wasp Anicetus beneficus. Owing to the
Special Issue: Natural Products: An Era of Discovery
in Organic Chemistry
Received: January 23, 2021
Figure 1. Structures of cerorubenic acid-III and its analogues.
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Figure 2. Retrosynthetic analysis of cerorubenic acid-III (1).
Scheme 1. Preparation of Diol 19
Table 1. Optimization of Conditions for Oxidation and Olefination Reactions
B
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strategy for the enantioselective total synthesis of cerorubenic
acid-III,8 which was enabled by a type II [5+2] cycloaddition
reaction.
Scheme 2. First Attempt at Type II [5+2] Cycloaddition
Reaction
a
RESULT AND DISCUSSION
■
Retrosynthetic Analysis of Cerorubenic Acid-III (1).
Figure 2 shows our retrosynthetic analysis of cerorubenic acid-
III (1). We planned to install the tiglic acid side chain via the
homologation of aldehyde 7, followed by a Horner−Wads-
worth−Emmons (HWE) reaction.9 The challenging vinyl-
cyclopropane fragment was designed to be formed by a
radical-initiated cyclization10 from advanced intermediate 8.
Tricyclic core 8 could be achieved through a series of functional
group interconversions (FGIs) of 9. Bridged skeleton 9 was
proposed to be prepared by the type II [5+2] cycloaddition
reaction11 of 10. Acetoxypyranone 10 could be synthesized from
furan 11 using an Achmatowicz reaction12 after installing the
unsaturated ester. Finally, furan 11 could be readily prepared by
coupling lithium reagent 12 with enone 13, which would be
accessed from (−)-carvone.
Our synthetic work started with the synthesis of compound
19 (Scheme 1). The reported Tollens condensation reaction of
(−)-carvone was used to yield 14 with high stereoselectivity.13
Subsequent protection of the primary alcohol with trimethylsilyl
chloride (TMSCl) gave 15 in a moderate yield over two steps
and could be conducted on a 10 g scale. 2,4-Disubstituted furan
iodide 18 was prepared efficiently from known furan bromide
compound 1611b in two steps. Subsequent coupling of the two
fragments was realized using a 1,2-addition reaction, followed by
a mild deprotection of the TMS group to furnish diol compound
19 in 85% yield over two steps with 2:1 dr.
With diol 19 in hand, we focused on the installation of the
olefin moiety for the type II [5+2] cycloaddition while avoiding
the racemization at the C1 position and the elimination of
tertiary alcohol. The first challenge was to oxidize the primary
alcohol to aldehyde 20. Selective conditions (conditions 1) are
shown in Table 1. IBX and DMSO were finally found to be the
best conditions, resulting in an 88% yield and no racemization.
For the olefination reaction, different HWE and Wittig reaction
conditions were screened (conditions 2, Table 1), with the
condition shown in entry 4 giving ester 22 in high yield (90%)
with limited racemization.
Having secured a method for the synthesis of compound 22,
we proceeded to prepare acetoxypyranone 24, a precursor for
the type II [5+2] cycloaddition reaction (Scheme 2). The
tertiary alcohol was expected to be a good nucleophile in the
presence of the acetoxypyranone. Therefore, PCC-mediated
Babler oxidation of 22 provided the corresponding cyclo-
hexenone (23) in a good yield. Subsequent deprotection of the
TBS group using Olah’s reagent released furan alcohol (not
shown) smoothly. Achmatowicz rearrangement of the furan
alcohol initiated by m-CPBA, followed by acetylation, gave the
desired precursor 24 for the type II [5+2] cycloaddition in a high
yield. Fortunately, the key reaction furnished desired tricyclic
compound 25 successfully, with the structure confirmed by X-
ray crystallography. However, the yield was as low as about 10%,
with several attempts (different base and solvent) at improved
yields failing. After careful analysis of the byproducts, we found
that a possible four-membered ring structure related to the
unsaturated ester might contribute to the low cyclization yield.
Therefore, a modification of precursor 24 was proposed,
replacing the unsaturated ester with an allylic alcohol.
a
ORTEP drawing of 25 showing thermal ellipsoids at the 50%
probability level.
Starting from ester 22, reduction with DIBAL-H, protection
of the corresponding allylic alcohol with acetic anhydride
followed by Babler oxidation gave enone 26 in 63% overall yield
for three steps (Scheme 3). Another three-step transformation
from 26 gave modified precursor 28 efficiently. Subjecting 28 to
the standard conditions, the type II [5+2] cycloaddition of 28
afforded desired product 29 as a single diastereomer in an
improved yield of 71%, its structure was later confirmed by X-ray
crystallography.
With compound 29 in hand, the main skeleton of our target
natural product had been prepared, allowing us to proceed to the
next phase of our synthesis (Scheme 4). As the radical-initiated
reductive cleavage of C−O bonds (Li, MeNH2) in 8-
oxabicyclo[3.2.1]octene has been well studied by our group,11c
we initially planned to prepare triolefin 30 by directly reducing
the two enones in 29. After screening many different conditions,
treating 29 with NaBH3CN in the presence of BF3·Et2O,14 was
found to reduce the enones smoothly, giving alcohol 30 as a
single diastereomer in moderate yield. Next, a two-step Barton−
McCombie deoxygenation of 30 yielded a mixture of target
compound 32 and side-product 31 with the migration of the
bridgehead olefin. Selective cleavage of the C−O bond was
completed by treating this mixture with Li/MeNH2 to give diol
33, which was then protected to afford 34 in good yield. As the
subsequent installation of the cyclopropane moiety and a side
chain to create a chiral center at C15 from 34 proved to be
C
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cerorubenic acid-III could be generated from advanced
intermediate 35 through a selective cross-metathesis (CM)
reaction with methacrylic acid.15 The challenging cyclopropane
moiety16 in 35 could be prepared from tricyclic intermediate 36
through a key transannular cyclization reaction followed by a
series of FGIs. Aldehyde 36 was proposed to be obtained from
37 via a selective C−O bond cleavage.17 The well-studied type II
[5+2] cycloaddition of 38 would then yield tricyclic skeleton 37
stereoselectively according to our results above. Key reaction
precursor 38 would be accessed from 39 through an
Achmatowicz reaction. Finally, ketone 39 would be combined
in a one-step process via a cascade 1,4-addition−aldol reaction18
from enone 42, which could be prepared from commercially
available (S)-citronellal and methyl vinyl ketone (MVK).
This new approach started from the asymmetric synthesis of
enone 42 (Scheme 5). In contrast to reported work,19 we
employed more readily available proline-derived catalyst 44,20
prepared from (S)-(+)-α,α-diphenyl-2-pyrrolidinemethanol
(43) in one step, in the asymmetric Michael addition reaction
to afford 45 in 79% yield with 95% de from commercially
available (−)-citronellal. The subsequent aldol condensation
and dehydration provided enone 42 on a 20 g scale with 93% de.
Meanwhile, furan aldehyde 41 was synthesized on a gram scale
from alcohol 17 by oxidation using IBX, and the tin reagent 47
was prepared in two steps from propargyl alcohol (46)
according to the reported procedure.21
Scheme 3. Second Attempt at Type II [5+2] Cycloaddition
Reaction
a
With the building blocks 41, 42, and 47 in hand, we attempted
the three-component coupling reaction (Scheme 6). Copper-
catalyzed conjugate addition of the organolithium reagent,
prepared from 47 via tin−lithium exchange, to enone 42 yielded
silyl enol ether 48 smoothly after quenching the enolate with
TMSCl. Treatment of 48 with n-BuLi, followed by trapping of
the lithium enolate with aldehyde 41 in the presence of ZnBr2,
furnished β-hydroxyketone 49. Compound 49 was found to be
acid-sensitive and partially cyclized to give 50 during the workup
and purification. The β-hydroxyketone moiety in 49 was also
sensitive to base owing to a possible retro-aldol reaction. Careful
acetyl-protection of the hydroxy group and TBS group
deprotection then gave 51 in moderate yield. However, the
subsequent Achmatowicz reaction to prepare 52 gave undesired
products (such as 53 and 54) under different conditions. As the
ketone group in 49 was the main issue during synthesis, in situ
a
ORTEP drawing of 29 showing thermal ellipsoids at the 50%
probability level.
difficult, we turned to another approach to accomplish the
synthesis of cerorubenic acid-III.
Retrosynthetic Analysis of Cerorubenic Acid-III (1):
Second Generation. A modified retrosynthetic analysis of
cerorubenic acid-III (1) is shown in Figure 3. We envisaged that
Scheme 4. Synthesis of Core Skeleton of Cerorubenic Acid
D
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Figure 3. Retrosynthetic analysis of cerorubenic acid-III.
Scheme 5. Gram-Scale Synthesis of Building Blocks 42, 41, and 47
reduction of the β-hydroxyketone using DIBAL-H after the aldol
reaction gave stable diol 55 efficiently with 50% overall yield
over two steps from 42.
excellent endo selectivity and diastereoselectivity. The structure
was confirmed by X-ray crystallographic analysis of its derivative
(60, Scheme 7), obtained from 58 in two steps, namely, a
reduction to give 59 and subsequent esterification. A suitable
quantity (20 g) of 59 was successfully prepared using this facile
synthetic route.
We next investigated the selective cleavage of the C−O bond
in the bridged ring system (Scheme 8). Our initial attempt
aimed to achieve direct cleavage of the C−O bond at the C4
position in enone 58 (Scheme 7). However, the treatment of
enone 58 with SmI2 in various solvents failed to give the desired
product. Accordingly, bromide 61, prepared from alcohol 59 in
After successful installation of the furan and olefin, we
proceeded to the type II [5+2] cycloaddition (Scheme 7).
Acetalization of diol 55 with acetone by TsOH, followed by
removal of TBS protecting group with TBAF, afforded 56 in
good yield. VO(acac)2 and TBHP were found to be the best
reagents for the oxidative rearrangement of 56. Protection of the
anomeric hydroxyl group with Ac2O in one pot afforded
precursor 57 in 71% yield. The type II intramolecular [5+2]
cycloaddition of 57 gave target product 58 in 72% yield with
E
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Scheme 6. Attempts at a Three-Component Coupling Reaction
Scheme 7. Construction of the Tricycle Skeleton via Type II [5+2] Cycloaddition
one step, was treated with SmI2 or t-BuLi to give diene 62 with
cleavage of the oxygen bridge. However, the yield was relatively
low and difficult to repeat (21%−35%). Subsequently, we
switched to treatment of 61 with Na-naphthalenide in THF−
H2O, which smoothly afforded diol 64 in 78% yield. Notably,
when the reaction was conducted in anhydrous THF solution
(gram scale), diene compound 63 was obtained as a major
product. The diene intermediate could also be converted to 64
by subjecting to the Na-naphthalenide conditions again, but the
yield was lower than that of the one-pot process. Therefore, this
remarkable reaction successfully cleaved the C4−O bond,
removed the benzyl group, and reduced the less hindered C4−
C5 double bond of the diene intermediate. The structure of diol
64 was finally confirmed by 2D-NMR.
F
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Scheme 8. Selective C−O Bond Cleavage
Scheme 9. Proposed SN2 and Radical Cyclization Pathways for Cyclopropanation
Scheme 10. Discovery of an Unusual SN1 Cyclization
As shown in Scheme 9, two cyclopropanation pathways (SN2
and radical cyclization) were proposed for accessing compound
65 from 64. In the SN2 pathway, the stereocenter at C24 needed
to be inverted from R (64) to S (66), then cyclized to give 65 via
intermediate 67. In the radical cyclization pathway, the external
olefin in 68 needed to be installed first, with subsequent radical-
G
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initiated cyclization9b affording compound 65 via intermediate
69.
hindered hydroxyl group (left) in 77 was selectively protected by
low-temperature acetylation. The remaining alcohol was
oxidized by DMP in one pot to give the corresponding ketone
in a high yield. Base-mediated elimination was conducted
carefully with KHMDS to give target enone 78 in 80% yield over
two steps. The next task was the crucial 1,4-reduction of enone
78 to complete the final chiral center. Fortunately, 78 was
reduced by NaBH4 and NiCl2 to afford the corresponding
ketone efficiently.23 Subsequent olefination of the carbonyl
group afforded triene 35. The endgame and completion of the
total synthesis were realized by cross-metathesis (CM) to install
the side chain. The designed CM reaction of 35 with methacrylic
acid catalyzed by Grubbs II reagent failed to give the natural
product. However, an alternative CM reaction with methacry-
laldehyde using Grubbs II catalyst proceeded well, with
subsequent oxidation by in situ generated Ag2O giving 1 in
27% overall yield from 78. To confirm this result, treatment of 1
with TMSCHN2 afforded cerorubenic acid-III methyl ester (2)
in 95% yield.24 Therefore, the enantioselective total synthesis of
cerorubenic acid-III was completed.
The radical cyclization pathway was studied first. We
attempted to install the terminal alkene at C3 through selective
iodination of the primary alcohol in 64, which seemed
theoretically feasible, followed by elimination of the hydrogen
halide under basic conditions. To our surprise, subjecting diol
64 to Ph3P/I2/imidazole conditions afforded ring closure
product 71, containing a tetrahydrofuran moiety, in 83% yield
(Scheme 10). We reasoned that the activated primary alcohol in
64 was attacked by the hydroxyl group (blue) at C24. Therefore,
the secondary alcohol needed to be protected in advance. Two-
step protection of the two hydroxyl groups furnished 72 in 57%
yield, followed by deprotection of the TBDPS group.
Surprisingly, when 72 was treated with TBAF, byproduct 71
was obtained in 10%−15% yield, along with the target product in
45% yield. Regarding the mechanism, this reaction proceeded
via an SN1 pathway through cation intermediate 73, with the
oxygen in the tetrahydrofuran moiety originating from the
primary alcohol (red).
Inspired by this observation, a more direct and feasible
method for cyclopropanation via a cationic intermediate was
proposed. Aldehyde 36 was prepared from 64 in moderate yield
over two steps (Scheme 11). As expected, the cyclization
CONCLUSIONS
■
In summary, we have accomplished the first enantioselective
total synthesis of cerorubenic acid-III in 19 steps after two
different synthetic strategies were studied. This work features a
powerful type II [5+2] cycloaddition reaction. The synthetically
challenging bicyclo[4.4.1] ring system with a strained bridge-
head double bond was constructed efficiently. Besides, a
chemoselective cascade cleavage of 8-oxabicyclo[3.2.1]octene
was realized using sodium naphthalenide condition. This
reaction largely improved the synthetic efficiency as three
transformations occurred in one operation. Finally, the vinyl-
cyclopropane moiety was installed using an unusual trans-
annular cyclization reaction with retention of the desired
stereochemistry. The detailed efficient and diastereoselective
approach described above can also be extended to the
asymmetric synthesis of other cerorubenic acids, cerorubenols,
and their derivatives and provide materials for further biological
research.
Scheme 11. Cyclopropanation via an SN1 Pathway
EXPERIMENTAL SECTION
■
General Experimental Information. Unless otherwise men-
tioned, all reactions were carried out under a nitrogen atmosphere
under anhydrous conditions, and all reagents were purchased from
commercial suppliers without further purification. Solvent purification
was conducted according to Purification of Laboratory Chemicals
(Perrin, D. D.; Armarego, W. L. and Perrins, D. R., Pergamon Press:
Oxford, 1980). Yields refer to chromatographically and spectroscopi-
cally (1H NMR) homogeneous materials, unless otherwise stated.
Reactions were monitored by thin-layer chromatography on plates
(GF254) supplied by Yantai Chemicals (China) using UV light as a
visualizing agent, an ethanolic solution of phosphomolybdic acid, or
basic aqueous potassium permanganate (KMnO4), and heat as
developing agents. If not specially mentioned, flash column
chromatography uses silica gel (200−300 mesh) supplied by Tsingtao
Haiyang Chemicals (China). NMR spectra were recorded on Bruker
AV-500 and calibrated using a residual undeuterated solvent as an
proceeded smoothly under basic conditions to afford 76
diastereoselectively in 78% yield. Regarding the mechanism,
cationic intermediate 75, stabilized by the adjacent vinyl group,
was proposed to be generated when treated with t-BuOK, which
was then attacked by the enolate to yield the desired
vinylcyclopropane.
Our total synthesis of cerorubenic acid-III now entered the
final stages. First, a one-pot Wolff−Kishner reduction22
(Scheme 12) and deprotection using acetic acid was conducted
to afford diol 77 in a high yield. Subsequently, the less sterically
1
internal reference (CHCl3, δ 7.26 ppm H NMR, δ 77.16 13C NMR;
CH2Cl2, δ 5.32 ppm 1H NMR, δ 54.00 13C NMR; C6D6, δ 7.15 ppm 1H
NMR, δ 128.00 13C NMR). The following abbreviations were used to
explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet,
b = broad, m = multiplet, td = triplet of doublets, dt = doublet of triplets.
High-resolution mass spectrometric (HRMS) data were recorded on a
Bruker Apex IV RTMS instrument using a quadrupole analyzer or on a
̈
Thermo Scientific Q Exactive using an orbitrap analyzer. X-ray
H
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Scheme 12. Total Synthesis of Cerorubenic Acid-III
diffraction data were collected at 100 K on a Bruker-D8 venture
microsource diffractometer.
in anhydrous Et2O (10 mL) was added dropwise. The reaction mixture
was left to stir at −78 °C until completion (30 min), and it was
quenched by saturated NH4Cl and extracted with Et2O (3 × 30 mL).
The combined organic layers were washed with brine (15 mL), dried
over anhydrous Na2SO4, and concentrated under reduced pressure to
give a crude product. The crude product was redissolved in the MeOH
(50 mL), and a catalytic amount of K2CO3 (138 mg, 1.0 mmol) was
added to the solution at room temperature; the mixture was stirred for 1
h at the same temperature. The reaction was quenched by saturated
NH4Cl. Then, MeOH was removed under reduced pressure, and the
aqueous was extracted with EtOAc (3 × 30 mL). The combined organic
layers were washed with brine (20 mL), dried over anhydrous Na2SO4,
concentrated in vacuo, and purified by flash chromatography on silica
gel (hexane/EtOAc = 20:1) to afford 19 (1.79 g, 85%, dr = 2:1, partly
separable) as a colorless oil. Note that to be accurate and for
convenience, two diastereisomers of 19 were characterized by NMR
spectroscopy and mass spectrometry independently (named 19a and
19b), but their relative configuration has not been determined. The
same situation obtains compounds 20, 21, and 22: HRMS (ESI) m/z
[M + Na]+ calcd for C24H40NaO4Si 443.2588, found 443.2588.
Procedures and characterization data for compounds 16, 17, 35, 42,
45, 55, 56, 57, 58, 59, 61, 64, 76, and 78 were reported previously.8
(5R,6R)-2-Methyl-5-(prop-1-en-2-yl)-6-(((trimethylsilyl)oxy)-
methyl)cyclohex-2-en-1-one (15). To a solution of 14 (5.0 g, 27.78
mmol) in anhydrous DCM (60 mL) was added imidazole (2.8 g, 41.67
mmol) at 0 °C. After the mixture was stirred at the same temperature for
5 min, chlorotrimethylsilane (3.6 g, 33.34 mmol) was added to the
reaction slowly. The mixture was warmed to 25 °C and stirred for 2 h.
The reaction was quenched by the addition of saturated NH4Cl (50
mL). Then the aqueous layer was extracted with DCM (3 × 50 mL).
The combined organic layers were washed with brine (30 mL) and
dried over Na2SO4. The dried solution was filtered and concentrated.
The residue obtained was purified by flash column chromatography on
silica gel (hexane/EtOAc = 30:1) to afford 15 (6.3 g, 90%) as a colorless
oil: Rf = 0.65 (hexane/EtOAc = 10:1); HRMS (ESI) m/z [M + H]+
calcd for C14H25O2Si 253.1618, found 253.1615; 1H NMR (500 MHz,
CDCl3) δ 6.66 (ddt, J = 5.6, 3.0, 1.4 Hz, 1H), 4.83−4.76 (m, 2H), 4.07
(dd, J = 9.7, 3.4 Hz, 1H), 3.58 (dd, J = 9.7, 3.5 Hz, 1H), 2.97−2.89 (m,
1H), 2.33 (ddt, J = 18.5, 11.6, 3.0 Hz, 3H), 1.79−1.73 (m, 3H), 1.70 (d,
J = 1.2 Hz, 3H), 0.03 (d, J = 1.2 Hz, 9H); 13C{1H} NMR (126 MHz,
CDCl3) δ 199.1, 145.6, 143.8, 135.6, 112.9, 59.0, 51.6, 43.7, 30.4, 19.6,
16.2, −0.5.
tert-Butyl((4-(2-iodoethyl)furan-2-yl)methoxy)-
dimethylsilane (18). I2 (3.0 g, 12 mmol), triphenylphosphine (3.1 g,
12 mmol), and imidazole (1.0 g, 15 mmol) were dissolved in anhydrous
DCM (50 mL), and the mixture was stirred at room temperature for 5
min. A solution of compound 17 (2.6 g, 10.0 mmol) in anhydrous DCM
(5 mL) was added dropwise to the mixture. The reaction was stirred at
rt for 3 h. The mixture was quenched with saturated Na2S2O3 solution
(50 mL) and extracted with CH2Cl2 (3 × 30 mL). The combined
organic layers were washed with brine (15 mL). After drying over
Na2SO4, the solution was concentrated in vacuo and purified by flash
chromatography on silica gel quickly (hexane/EtOAc = 80:1) to afford
18 (3.3 g, 90%) as a colorless oil: Rf = 0.3 (hexane/EtOAc = 50:1);
HRMS (ESI) m/z [M + H]+ calcd for C13H23IO2Si 367.0585, found
367.0588; 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 1.0 Hz, 1H), 6.14
(d, J = 0.9 Hz, 1H), 4.60 (d, J = 0.7 Hz, 2H), 3.27 (t, J = 7.5 Hz, 2H),
2.97 (td, J = 7.6, 0.8 Hz, 2H), 0.91 (s, 9H), 0.08 (s, 6H); 13C{1H} NMR
(101 MHz, CDCl3) δ 154.7, 138.7, 124.4, 107.9, 58.2, 29.7, 25.9, 18.4,
4.8, −5.3.
1
Compound 19a: Rf = 0.30 (hexane/EtOAc = 5:1); H NMR (500
MHz, CDCl3) δ 7.17 (d, J = 1.1 Hz, 1H), 6.18−6.12 (m, 1H), 5.54 (dt, J
= 3.1, 1.5 Hz, 1H), 4.80−4.69 (m, 2H), 4.58 (s, 2H), 3.81−3.69 (m,
2H), 3.31 (s, 1H), 2.90 (d, J = 4.6 Hz, 1H), 2.52−2.35 (m, 3H), 2.14−
1.88 (m, 5H), 1.77 (d, J = 1.9 Hz, 3H), 1.68 (d, J = 1.1 Hz, 3H), 0.91 (s,
9H), 0.09 (s, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 154.6, 146.6,
138.1, 137.4, 126.1, 124.3, 112.9, 108.7, 77.0, 63.7, 58.4, 47.5, 42.8,
36.9, 30.4, 26.1, 21.4, 18.6, 17.8, 17.5, −5.1. Compound 19b: Rf = 0.28
(hexane/EtOAc = 5:1); 1H NMR (500 MHz, CDCl3) δ 7.14 (d, J = 1.1
Hz, 1H), 6.10 (d, J = 0.9 Hz, 1H), 5.69 (dq, J = 5.7, 1.7 Hz, 1H), 4.99−
4.80 (m, 2H), 4.64−4.51 (m, 2H), 4.04 (dd, J = 11.9, 2.2 Hz, 1H), 3.73
(dd, J = 12.0, 3.3 Hz, 1H), 2.96 (d, J = 0.0 Hz, 2H), 2.71 (ddd, J = 12.0,
10.8, 5.7 Hz, 1H), 2.25−2.12 (m, 2H), 2.11−1.97 (m, 4H), 1.72 (t, J =
1.9 Hz, 6H), 1.65 (dtd, J = 12.2, 3.4, 2.2, 0.0 Hz, 1H), 0.90 (s, 9H), 0.07
(s, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 154.7, 147.5, 138.0,
135.7, 127.2, 125.3, 113.0, 108.5, 76.7, 61.1, 58.4, 42.9, 40.0, 36.7, 31.2,
26.0, 20.6, 19.1, 18.5, 17.9, −5.1.
(1S,6R)-2-(2-(5-(((tert-Butyldimethylsilyl)oxy)methyl)furan-
3-yl)ethyl)-2-hydroxy-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-
ene-1-carbaldehyde (20). To a solution of 19 (1.68 g, 4.0 mmol) in
DMSO (40 mL) was added IBX (2.8 g, 10.0 mmol) at room
temperature, and the mixture was stirred for 1 h. The reaction was
quenched by saturated Na2SO3. The mixture was diluted with water
(200 mL) and extracted with Et2O (3 × 50 mL). The combined organic
layers were washed with water (100 mL) again and then washed with
brine (50 mL), dried over anhydrous Na2SO4, concentrated in vacuo,
and purified by flash chromatography on silica gel (hexane/EtOAc =
15:1) to afford 20 (1.47 g, 88%) as a colorless oil: HRMS (ESI) m/z
(5R,6R)-1-(2-(5-(((tert-Butyldimethylsilyl)oxy)methyl)furan-
3-yl)ethyl)-6-(hydroxymethyl)-2-methyl-5-(prop-1-en-2-yl)-
cyclohex-2-en-1-ol (19). To a solution of 18 (2.01 g, 5.5 mmol) in
anhydrous Et2O (30 mL) under an argon atmosphere was added
dropwise tBuLi (8.5 mL, 11.0 mmol, 1.3 M solution in pentane) at −78
°C. After stirring at −78 °C for 1 h, a solution of 15 (1.26 g, 5.0 mmol)
I
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Article
calcd for [M + NH4]+ C24H42NO4Si 436.2878, found 436.2878.
Compound 20a: Rf = 0.55 (hexane/EtOAc = 5:1); H NMR (500
123.6, 113.3, 108.7, 75.4, 58.4, 52.3, 51.7, 44.7, 38.1, 29.5, 26.1, 20.6,
18.6, 18.5, 18.4, −5.1. Compound 22b: Rf = 0.5 (hexane/EtOAc = 5:1);
1H NMR (500 MHz, CDCl3) δ 7.13 (d, J = 1.1 Hz, 1H), 6.93 (dd, J =
1
MHz, CDCl3) δ 9.77 (d, J = 3.4 Hz, 1H), 7.13 (d, J = 1.1 Hz, 1H), 6.09
(s, 1H), 5.54−5.45 (m, 1H), 4.90−4.80 (m, 2H), 4.57 (s, 2H), 2.91
(ddd, J = 11.8, 9.1, 6.7 Hz, 1H), 2.69−2.61 (m, 2H), 2.54−2.35 (m,
2H), 2.31−2.21 (m, 1H), 2.12−2.04 (m, 1H), 1.97 (ddd, J = 14.1, 12.2,
5.5 Hz, 1H), 1.86 (ddd, J = 14.1, 12.6, 4.5 Hz, 1H), 1.78 (d, J = 1.8 Hz,
3H), 1.74−1.70 (m, 3H), 0.90 (s, 9H), 0.08 (s, 6H); 13C{1H} NMR
(126 MHz, CDCl3) δ 206.3, 154.7, 146.4, 138.2, 137.6, 125.5, 123.7,
113.1, 108.5, 75.5, 59.1, 58.4, 40.5, 38.4, 30.1, 26.0, 20.8, 19.9, 18.6,
17.9, −5.1. Compound 20b: Rf = 0.55 (hexane/EtOAc = 5:1); 1H NMR
(500 MHz, CDCl3) δ 9.61 (d, J = 4.6 Hz, 1H), 7.15 (d, J = 1.0 Hz, 1H),
6.12 (d, J = 0.9 Hz, 1H), 5.74 (dt, J = 5.8, 1.7 Hz, 1H), 4.85 (dt, J = 5.6,
1.6 Hz, 2H), 4.62−4.50 (m, 2H), 2.94 (dt, J = 11.9, 5.9 Hz, 1H), 2.44
(ddd, J = 17.8, 9.4, 4.8 Hz, 2H), 2.20−2.12 (m, 1H), 2.07−1.99 (m,
3H), 1.94 (ddd, J = 9.6, 6.0, 2.6 Hz, 2H), 1.76−1.73 (m, 3H), 1.69 (d, J
= 1.2 Hz, 3H), 0.90 (s, 9H), 0.08 (s, 6H); 13C{1H} NMR (126 MHz,
CDCl3) δ 206.2, 154.7, 145.4, 138.2, 135.3, 127.6, 125.0, 113.8, 108.6,
75.0, 58.4, 55.3, 39.6, 37.4, 30.9, 26.1, 20.3, 19.6, 18.6, 17.4, −5.1.
Ethyl (E)-3-((1S,6R)-2-(2-(5-(((tert-Butyldimethylsilyl)oxy)-
methyl)furan-3-yl)ethyl)-2-hydroxy-3-methyl-6-(prop-1-en-2-
yl)cyclohex-3-en-1-yl)acrylate (21). n-BuLi (1.1 mL, 2.2 mmol, 2.0
M solution in pentane) was slowly added to a solution of
triethylphosphonoacetate 20 (449 mg, 2.0 mmol) in THF (20 mL)
at −78 °C. After 5 min, aldehyde (418 mg, 1.0 mmol) was slowly added,
and the resulting mixture was stirred at −78 °C for 10 min and then at
room temperature for 1 h. The reaction was quenched with the addition
of brine (5 mL), and the mixture was diluted with ether (10 mL),
washed with brine (3 × 10 mL), and dried with anhydrous Na2SO4. The
solvent was evaporated under reduced pressure and purified by flash
chromatography on silica gel (hexane/EtOAc = 10:1) to afford 21 (288
mg, 59%; dr = 1.5:1) as a colorless oil. Note that data of two target
(major) diastereisomers were shown. Compound 21a: Rf = 0.5
(hexane/EtOAc = 5:1); 1H NMR (400 MHz, CDCl3) δ 7.19−7.14 (m,
1H), 6.93−6.84 (m, 1H), 6.12 (s, 1H), 5.97 (d, J = 15.6 Hz, 1H), 5.60
(d, J = 1.8 Hz, 1H), 4.86−4.76 (m, 2H), 4.59 (s, 2H), 4.21 (qd, J = 7.1,
0.7 Hz, 2H), 2.68−2.58 (m, 2H), 2.52−2.40 (m, 2H), 2.15 (dq, J = 6.4,
2.5 Hz, 2H), 1.92 (ddd, J = 13.8, 12.2, 5.7 Hz, 2H), 1.84 (s, 1H), 1.80
(q, J = 1.9 Hz, 3H), 1.78−1.69 (m, 2H), 1.67 (d, J = 1.4 Hz, 1H), 1.30
(dd, J = 7.2, 0.8 Hz, 3H), 0.92 (d, J = 0.8 Hz, 9H), 0.10 (d, J = 0.8 Hz,
6H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.9, 154.5, 147.8, 146.5,
138.1, 136.7, 125.6, 124.3, 123.9, 113.1, 108.5, 75.2, 60.4, 58.3, 52.1,
44.6, 38.0, 29.3, 25.9, 20.5, 18.5, 18.4, 18.3, 14.3, −5.2. Compound 21b:
Rf = 0.5 (hexane/EtOAc = 5:1); 1H NMR (400 MHz, CDCl3) δ 7.15
(d, J = 1.1 Hz, 1H), 6.94 (dd, J = 15.9, 10.4 Hz, 1H), 6.11 (d, J = 1.0 Hz,
1H), 5.81 (d, J = 15.9 Hz, 1H), 5.79−5.70 (m, 1H), 4.86−4.69 (m,
2H), 4.60 (s, 2H), 4.20 (qd, J = 7.1, 1.3 Hz, 2H), 2.62 (td, J = 11.3, 5.5
Hz, 1H), 2.41 (dd, J = 11.8, 10.4 Hz, 1H), 2.33 (ddd, J = 10.8, 8.5, 5.7
Hz, 1H), 2.17−1.96 (m, 4H), 1.94−1.80 (m, 3H), 1.77 (dt, J = 2.5, 1.5
Hz, 3H), 1.75 (s, 1H), 1.64 (s, 1H), 1.31 (t, J = 7.2 Hz, 3H), 0.92 (s,
9H), 0.10 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 166.1, 154.6,
148.2, 145.9, 137.9, 135.2, 127.6, 124.9, 123.1, 113.2, 108.5, 74.4, 60.3,
58.3, 48.0, 42.6, 36.6, 30.7, 25.9, 20.1, 18.7, 18.5, 18.1, 14.3, −5.2.
Methyl (E)-3-((1S,6R)-2-(2-(5-(((tert-Butyldimethylsilyl)oxy)-
methyl)furan-3-yl)ethyl)-2-hydroxy-3-methyl-6-(prop-1-en-2-
yl)cyclohex-3-en-1-yl)acrylate (22). To a solution of 20 (1.25 g, 3.0
mmol) in DCE (50 mL) was added phosphorus ylide (5.0 g, 15 mmol)
at rt. Then, the mixture was warmed to 80 °C and stirred at the same
temperature overnight. After the reaction finished, the mixture was
concentrated in vacuo and purified by flash chromatography on silica
gel (hexane/EtOAc = 10:1) to afford 22 (1.28 g, 90%; dr ≥ 20:1) as a
colorless oil: HRMS (ESI) m/z [M + NH4]+ calcd for C27H46NO5Si
492.3140, found 492.3140. Compound 22a: Rf = 0.5 (hexane/EtOAc =
5:1); 1H NMR (500 MHz, CDCl3) δ 7.14 (d, J = 1.0 Hz, 1H), 6.86 (dd,
J = 15.6, 9.9 Hz, 1H), 6.10 (s, 1H), 5.95 (d, J = 15.7 Hz, 1H), 5.58 (td, J
= 3.8, 1.7 Hz, 1H), 4.78 (dt, J = 3.8, 1.5 Hz, 2H), 4.57 (s, 2H), 3.73 (s,
3H), 2.68−2.55 (m, 2H), 2.52−2.33 (m, 2H), 2.15−2.09 (m, 2H), 1.89
(ddd, J = 14.0, 12.3, 5.6 Hz, 1H), 1.78 (q, J = 2.0 Hz, 4H), 1.73−1.67
(m, 1H), 1.61 (s, 3H), 0.90 (s, 9H), 0.08 (s, 6H); 13C{1H} NMR (126
MHz, CDCl3) δ 166.5, 154.6, 148.2, 146.6, 138.2, 136.9, 125.7, 124.5,
15.9, 10.4 Hz, 1H), 6.08 (d, J = 0.9 Hz, 1H), 5.80 (d, J = 15.9 Hz, 1H),
5.75−5.65 (m, 1H), 4.84−4.68 (m, 2H), 4.57 (s, 2H), 3.72 (s, 3H),
3.67−3.63 (m, 1H), 2.59 (td, J = 11.3, 5.3 Hz, 1H), 2.39 (dd, J = 11.8,
10.3 Hz, 1H), 2.34−2.24 (m, 1H), 2.09−2.00 (m, 3H), 1.89−1.79 (m,
2H), 1.77−1.74 (m, 3H), 1.57 (t, J = 1.0 Hz, 3H), 0.90 (s, 9H), 0.08 (s,
6H); 13C{1H} NMR (126 MHz, CDCl3) δ 166.6, 154.7, 148.6, 146.0,
138.1, 135.3, 127.8, 125.0, 122.9, 113.4, 108.6, 74.5, 58.4, 51.6, 48.1,
42.7, 36.7, 30.8, 26.1, 20.2, 18.8, 18.6, 18.2, −5.1.
Methyl (E)-3-((1S,6R)-2-(2-(5-(((tert-Butyldimethylsilyl)oxy)-
methyl)furan-3-yl)ethyl)-3-methyl-4-oxo-6-(prop-1-en-2-yl)-
cyclohex-2-en-1-yl)acrylate (23). To a slurry solution of pyridinium
chlorochromate (1.5 g, 7.0 mmol) and 4 Å MS in dichloromethane (50
mL) was added a solution of alcohol 22 (1.66 g, 3.5 mmol) in
dichloromethane (10 mL) at rt, and the resulting dark red mixture was
stirred at the same temperature for 2 h. The reaction was worked up by
the addition of ether (20 mL), and the formed solution was first filtered
through a silica gel pad and washed with ether (3 × 30 mL). The
combined organic phases were sequentially washed with an aqueous
solution of NaOH (5%, 50 mL), an aqueous solution of HCl (5%, 50
mL), and a saturated aqueous solution of NaHCO3 (2 × 40 mL), and
finally dried over anhydrous Na2SO4. The solvent was removed in
vacuo, and the residue was purified by a flash chromatography on silica
gel (hexane/EtOAc = 15:1) to afford 23 (1.28 g, 78%) as a colorless oil:
Rf = 0.6 (hexane/EtOAc = 5:1); HRMS (ESI) m/z [M + NH4]+ calcd
1
for C27H44NO5Si 490.2983, found 490.2982; H NMR (500 MHz,
chloroform-d) δ 7.11 (s, 1H), 6.89 (dd, J = 15.6, 8.5 Hz, 1H), 6.09 (s,
1H), 5.92−5.79 (m, 1H), 4.83 (s, 1H), 4.66 (s, 1H), 4.57 (s, 2H), 3.75
(s, 3H), 3.25 (t, J = 6.8 Hz, 1H), 2.65 (q, J = 5.6 Hz, 1H), 2.61−2.54 (m,
2H), 2.47 (ddt, J = 28.0, 15.4, 5.1 Hz, 3H), 2.25 (ddd, J = 12.4, 9.8, 5.8
Hz, 1H), 1.80 (d, J = 1.5 Hz, 3H), 1.69 (s, 3H), 0.90 (s, 9H), 0.08 (s,
6H); 13C{1H} NMR (126 MHz, CDCl3) δ 197.8, 166.4, 155.0, 153.3,
148.1, 144.5, 138.5, 133.4, 124.4, 123.4, 113.5, 108.4, 58.3, 51.9, 46.4,
45.5, 39.2, 34.2, 26.0, 22.9, 21.0, 18.6, 11.1, −5.1.
Methyl (E)-3-((1S,6R)-2-(2-(2-Acetoxy-5-oxo-5,6-dihydro-2H-
pyran-3-yl)ethyl)-3-methyl-4-oxo-6-(prop-1-en-2-yl)cyclohex-
2-en-1-yl)acrylate (24). To a solution of 23 (944 mg, 2.0 mmol) in
THF (20 mL) was added pyridine hydrofluoride (1.29 mL, 10 mmol, aq
70% HF) at 0 °C. Then, the mixture was warmed to rt and stirred at the
same temperature stirred for 1 h. After the reaction finished, the mixture
was cooled to 0 °C and quenched slowly with saturated NaHCO3 (50
mL) until the pH was 7. The resulting mixture was extracted with
EtOAc (3 × 20 mL). The combined organic layers were washed with
brine (20 mL), dried over anhydrous Na2SO4, concentrated in vacuo,
and purified by flash chromatography on silica gel (hexane/EtOAc =
5:1) to give the corresponding free alcohol (651 mg, 91%).
To a solution of the alcohol prepared above (537 mg, 1.5 mmol) in
DCM (10 mL) was added 3-chloroperoxybenzoic acid (m-CPBA, 75%
purity, 414 mg, 1.8 mmol) at rt. Then, the mixture was warmed to 38 °C
and stirred at the same temperature for 1.5 h. After the reaction finished,
the mixture was quenched with saturated Na2SO3 (50 mL). The result
mixture was extracted with DCM (3 × 10 mL). The combined organic
layers were washed with brine (10 mL), dried over anhydrous Na2SO4,
and concentrated in vacuo to give a crude product, which was used in
the next step without further purification. The crude product was
dissolved in anhydrous DCM (10 mL) and cooled to 0 °C. Et3N (0.32
mL, 2.3 mmol), 4-dimethylaminopyridine (DMAP, 92 mg, 0.75 mmol),
and acetic anhydride (Ac2O, 0.22 mL, 2.3 mmol) were added to the
reaction in sequence. Then mixture was stirred at the same temperature
until the end of reaction. The reaction was quenched by saturated
NH4Cl (10 mL), and the mixture was extracted with DCM (3 × 10
mL). The combined organic layers were washed with brine (10 mL)
and dried over Na2SO4. The dried solution was filtered and
concentrated and purified by flash chromatography on silica gel
(hexane/EtOAc = 8:1) to afford 24 (530 mg, 85% for two steps; totally
77% for three steps from 23, dr ≈ 1:1) as a colorless oil: Rf = 0.52
(hexane/EtOAc = 2:1); HRMS (ESI) m/z [M + NH4]+ calcd for
C23H32NO7 434.2173, found 434.2172; 1H NMR (500 MHz, CDCl3) δ
J
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6.86 (dt, J = 15.7, 8.6 Hz, 1H), 6.43 (d, J = 2.7 Hz, 1H), 6.05 (d, J = 5.8
Hz, 1H), 5.89 (ddd, J = 15.6, 8.0, 0.9 Hz, 1H), 4.85 (d, J = 1.5 Hz, 1H),
4.71−4.61 (m, 1H), 4.41 (dd, J = 17.0, 1.2 Hz, 1H), 4.17 (d, J = 17.0 Hz,
1H), 3.76 (d, J = 0.7 Hz, 3H), 3.23 (q, J = 7.1 Hz, 1H), 2.67 (ddd, J =
7.6, 5.1, 2.4 Hz, 1H), 2.62−2.46 (m, 3H), 2.30−2.20 (m, 3H), 2.16 (d, J
= 4.2 Hz, 3H), 1.82 (dd, J = 5.2, 1.5 Hz, 3H), 1.73−1.70 (m, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 197.4, 197.3, 193.2, 193.2, 169.9,
169.8, 166.2, 166.2, 156.3, 156.3, 151.3, 151.2, 147.3, 144.1, 144.1,
134.0, 125.4, 125.3, 123.8, 123.8, 113.9, 113.8, 88.4, 88.3, 66.5, 66.5,
52.0, 46.7, 46.5, 45.8, 45.6, 39.4, 39.3, 30.9, 30.6, 30.2, 30.1, 21.0, 21.0,
20.9, 20.8, 11.2.
from 22) as a colorless oil: Rf = 0.7 (hexane/EtOAc = 5:1); HRMS
(ESI) m/z [M + Na]+ calcd for C28H42NaO5Si 509.2694, found
509.2698; 1H NMR (500 MHz, CDCl3) δ 7.14 (s, 1H), 6.11 (s, 1H),
5.74−5.59 (m, 2H), 4.80 (t, J = 1.5 Hz, 1H), 4.64 (s, 1H), 4.56 (d, J =
7.8 Hz, 4H), 3.11 (t, J = 5.9 Hz, 1H), 2.62−2.52 (m, 3H), 2.52−2.37
(m, 3H), 2.31 (td, J = 10.9, 10.5, 5.2 Hz, 1H), 2.05 (s, 3H), 1.78 (d, J =
1.3 Hz, 3H), 1.69 (s, 3H), 0.90 (s, 9H), 0.08 (s, 6H); 13C{1H} NMR
(126 MHz, CDCl3) δ 198.4, 170.9, 155.3, 154.8, 145.1, 138.5, 135.1,
132.5, 127.0, 124.7, 113.0, 108.5, 64.5, 58.4, 46.7, 46.2, 39.3, 34.1, 26.0,
22.9, 21.1, 21.0, 18.6, 11.1, −5.1.
(E)-3-((1S,6R)-2-(2-(5-(Hydroxymethyl)furan-3-yl)ethyl)-3-
methyl-4-oxo-6-(prop-1-en-2-yl)cyclohex-2-en-1-yl)allyl Ace-
tate (27). To a solution of 26 (1.46 g, 3.0 mmol) in THF (30 mL)
was added pyridine hydrofluoride (1.94 mL, 10 mmol, aq 70% HF) at 0
°C. Then, the mixture was warmed to rt and stirred at the same
temperature for 2 h. After the reaction finished, the mixture was cooled
to 0 °C and quenched slowly with saturated NaHCO3 until the pH was
7. The result mixture was extracted with EtOAc (3 × 20 mL). The
combined organic layers were washed with brine (20 mL) and dried
over anhydrous Na2SO4, concentrated in vacuo, and purified by flash
chromatography on silica gel (hexane/EtOAc = 4:1) to afford 27 (1.08
g, 97%) as a colorless oil: Rf = 0.15 (hexane/EtOAc = 5:1); HRMS
(ESI) m/z [M + Na]+ calcd for C22H28NaO5 395.1829, found
395.1827; 1H NMR (500 MHz, CDCl3) δ 7.17 (s, 1H), 6.18 (s, 1H),
5.73−5.56 (m, 2H), 4.80 (d, J = 1.9 Hz, 1H), 4.64 (s, 1H), 4.55 (s, 4H),
3.11 (t, J = 6.1 Hz, 1H), 2.57 (tq, J = 15.5, 5.1 Hz, 3H), 2.52−2.39 (m,
3H), 2.32 (td, J = 10.8, 10.3, 5.0 Hz, 1H), 2.05 (s, 4H), 1.78 (d, J = 1.4
Hz, 3H), 1.69 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 198.4,
170.9, 155.2, 154.6, 145.1, 139.0, 135.0, 132.5, 127.1, 124.9, 113.0,
109.0, 64.5, 57.7, 46.7, 46.2, 39.4, 34.1, 22.8, 21.1, 21.0, 11.1.
(E)-3-((1S,6R)-2-(2-(2-Acetoxy-5-oxo-5,6-dihydro-2H-pyran-
3-yl)ethyl)-3-methyl-4-oxo-6-(prop-1-en-2-yl)cyclohex-2-en-1-
yl)allyl Acetate (28). To a solution of compound 27 (744 mg, 2.0
mmol) in THF (21.0 mL) and H2O (7.0 mL) were added NaHCO3
(336 mg, 4.0 mmol), NaOAc (164 mg, 2.0 mmol), and NBS (374 mg,
2.1 mmol) sequentially at 0 °C, and the mixture was stirred at the same
temperature for 30 min. The reaction was worked up by the addition of
water (8.0 mL), followed by extraction with EtOAc (3 × 10 mL). The
combined organic layers were washed with brine (10 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo to give a crude product,
which was used in the next step without further purification. The crude
product was dissolved in anhydrous DCM (15 mL) and cooled to 0 °C.
Et3N (0.42 mL, 3.0 mmol), 4-dimethylaminopyridine (DMAP, 120 mg,
1.0 mmol), and acetic anhydride (Ac2O, 0.29 mL, 3.0 mmol) were
added to the reaction in sequence. Then mixture was stirred at the same
temperature until the end of reaction. The reaction was quenched by
saturated NH4Cl (10 mL), and the mixture was extracted with DCM (3
× 15 mL). The combined organic layers were washed with brine (15
mL) and dried over Na2SO4. The solvents were removed under a
vacuum, and the residue was purified by a flash column chromatography
on silica gel (hexane/EtOAc = 15:1) to afford 28 (817 mg, 95% for two
steps, dr ≈ 1:1) as a colorless oil: Rf = 0.55 (hexane/EtOAc = 2:1);
HRMS (ESI)) m/z [M + H]+ calcd for C24H31O7 431.2064, found
431.2061; 1H NMR (500 MHz, CDCl3) δ 6.45 (d, J = 2.5 Hz, 1H), 6.07
(s, 1H), 5.69−5.63 (m, 2H), 4.81 (s, 1H), 4.63 (s, 1H), 4.55 (ddt, J =
17.9, 13.2, 5.8 Hz, 2H), 4.41 (d, J = 17.0 Hz, 1H), 4.16 (d, J = 17.0 Hz,
1H), 3.07 (d, J = 6.5 Hz, 1H), 2.60−2.55 (m, 2H), 2.54−2.44 (m, 2H),
2.38−2.23 (m, 3H), 2.16 (3H), 2.06 (3H), 1.79 (s, 3H), 1.69 (3H);
13C{1H} NMR (126 MHz, CDCl3) δ 197.9, 193.3, 193.3, 170.9, 169.9,
Methyl (2S,10R,10aR,11S,11aR,12S)-7-Methyl-3,8-dioxo-10-
(prop-1-en-2-yl)-2,3,5,6,8,9,10,10a,11,11a-decahydro-2,11-
methanobenzo[5,6]cyclohepta[1,2-b]pyran-12-carboxylate
(25). To a dried sealed tube with anhydrous acetonitrile (CH3CN, 50
mL) were added 24 (208 mg, 0.5 mmol) and 2,2,6,6-tetramethylpiper-
idine (TMP, 0.12 mL, 0.75 mmol). Then the mixture was heated at 170
°C for 20 h. The reaction was worked up by transferring the solution to
a round-bottomed flask; the solvents were removed under reduced
pressure, and the residue was purified by flash column chromatography
on silica gel (hexane/EtOAc = 10:1) to afford 25 (17.8 mg, about 10%)
as a white solid. Crystals suitable for X-ray analysis were obtained from
dissolving 25 in CH2Cl2 followed by the addition of hexane and then
allowing the solvent to evaporate slowly: Rf = 0.55 (hexane/EtOAc =
2:1); HRMS (ESI) m/z [M + H]+ calcd for C21H25O5 357.1697, found
357.1694; 1H NMR (500 MHz, CDCl3) δ 6.86 (dt, J = 15.7, 8.6 Hz,
1H), 6.43 (d, J = 2.7 Hz, 1H), 6.05 (d, J = 5.8 Hz, 1H), 5.89 (ddd, J =
15.6, 8.0, 0.9 Hz, 1H), 4.85 (d, J = 1.5 Hz, 1H), 4.71−4.61 (m, 1H),
4.41 (dd, J = 17.0, 1.2 Hz, 1H), 4.17 (d, J = 17.0 Hz, 1H), 3.76 (d, J = 0.7
Hz, 3H), 3.23 (q, J = 7.1 Hz, 1H), 2.67 (ddd, J = 7.6, 5.1, 2.4 Hz, 1H),
2.62−2.46 (m, 3H), 2.30−2.20 (m, 3H), 2.16 (d, J = 4.2 Hz, 3H), 1.82
(dd, J = 5.2, 1.5 Hz, 3H), 1.73−1.70 (m, 3H); 13C{1H} NMR (126
MHz, CDCl3) δ 197.0, 194.5, 172.7, 165.9, 152.9, 145.3, 132.9, 123.1,
112.7, 84.4, 81.0, 53.3, 51.9, 48.5, 48.0, 43.1, 36.7, 35.5, 33.1, 29.5, 22.5.
(E)-3-((1S,6R)-2-(2-(5-(((tert-Butyldimethylsilyl)oxy)methyl)-
furan-3-yl)ethyl)-3-methyl-4-oxo-6-(prop-1-en-2-yl)cyclohex-
2-en-1-yl)allyl Acetate (26). To a solution of 22 (2.8 g, 6.0 mmol) in
anhydrous DCM (50 mL) was added DIBAL-H (1.5 M in toluene, 10.0
mL, 15.0 mmol) dropwise at −78 °C. After the mixture was stirred at
the same temperature for 15 min, the reaction was quenched by the
addition of potassium sodium tartrate saturated solution (100 mL).
The mixture was warmed to 25 °C and stirred for 3 h. Then it was
transferred to a separatory funnel, and the aqueous layer was extracted
with EtOAc (3 × 50 mL). The combined organic layers were washed
with brine (30 mL), dried over Na2SO4, and concentrated in vacuo to
give a crude product, which was used in the next step without further
purification. The crude product was dissolved in anhydrous DCM (50
mL) and cooled to 0 °C. Et3N (1.25 mL, 9.0 mmol), 4-
dimethylaminopyridine (DMAP, 73.6 mg, 0.75 mmol), and acetic
anhydride (Ac2O, 0.86 mL, 9.0 mmol) were added to the reaction in
sequence. The mixture was stirred at the same temperature until the end
of the reaction. The reaction was quenched by saturated NH4Cl (30
mL), and the mixture was extracted with DCM (3 × 30 mL). The
combined organic layers were washed with brine (20 mL) and dried
over Na2SO4. The dried solution was filtered, concentrated, and
purified by flash chromatography on silica gel (hexane/EtOAc = 20:1)
to afford the acetate (2.49 g, 85%) as a colorless oil.
To a slurry solution of pyridinium chlorochromate (1.6 g, 7.5 mmol)
and 4 Å MS in dichloromethane (50 mL) was added a solution of
acetate prepared above (2.44 g, 5.0 mmol) in dichloromethane (10 mL)
at rt, and the resulting dark red mixture was stirred at the same
temperature for 2 h. The reaction was worked up by the addition of
ether (20 mL), and the formed solution was first filtrated through a
silica gel pad and washed with ether (3 × 30 mL). The combined
organic phases were sequentially washed with an aqueous solution of
NaOH (5%, 50 mL), an aqueous solution of HCl (5%, 50 mL), and a
saturated aqueous solution of NaHCO3 (2 × 40 mL) and finally dried
over anhydrous Na2SO4. The solvent was removed in vacuo, and the
residue was purified by a flash chromatography on silica gel (hexane/
EtOAc = 20:1) to afford 26 (1.79 g, 74%; totally 63% for three steps
169.8, 156.8, 156.7, 153.1, 153.1, 144.8, 144.7, 134.4, 134.4, 133.2,
133.1, 127.7, 127.6, 125.2, 125.1, 113.3, 88.5, 88.4, 66.5, 64.3, 47.0,
46.7, 46.4, 46.3, 39.5, 39.5, 30.6, 30.2, 30.1, 21.1, 21.0, 20.9, 20.8, 11.2.
((2S,10R,10aR,11S,11aR,12R)-7-Methyl-3,8-dioxo-10-(prop-
1-en-2-yl)-2,3,5,6,8,9,10,10a,11,11a-decahydro-2,11-
methanobenzo[5,6]cyclohepta[1,2-b]pyran-12-yl)methyl Ace-
tate (29). To a dried sealed tube with anhydrous acetonitrile (CH3CN,
50 mL) were added 28 (430 mg, 1.0 mmol) and 2,2,6,6-
tetramethylpiperidine (TMP, 0.24 mL, 1.5 mmol). Then the mixture
was heated at 170 °C for 20 h. The reaction was worked up by
transferring the solution to a round-bottomed flask, the solvents were
K
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Article
removed under reduced pressure, and the residue was purified by flash
column chromatography on silica gel (hexane/EtOAc = 8:1) to afford
29 (262 mg, 71%) as a white solid. Crystals suitable for X-ray analysis
were obtained from dissolving 29 in CH2Cl2, followed by the addition
of hexane, and then allowing the solvent to evaporate slowly: Rf = 0.50
(hexane/EtOAc = 2:1); HRMS (ESI)) m/z [M + H]+ calcd for
C22H27O5 371.1853, found 371.1851; 1H NMR (500 MHz, CDCl3) δ
6.03 (s, 1H), 4.79 (s, 1H), 4.50−4.44 (m, 2H), 4.34 (s, 1H), 4.25 (dd, J
= 11.0, 6.5 Hz, 1H), 4.10 (dd, J = 10.9, 8.7 Hz, 1H), 3.10 (ddd, J = 12.8,
6.5, 2.4 Hz, 1H), 2.85 (d, J = 17.2 Hz, 2H), 2.77 (ddd, J = 12.0, 6.6, 2.3
Hz, 1H), 2.63 (d, J = 17.1 Hz, 1H), 2.49 (ddd, J = 11.0, 7.1, 4.2 Hz, 1H),
2.45−2.38 (m, 1H), 2.15 (d, J = 10.5 Hz, 1H), 2.09 (s, 3H), 2.08−2.03
(m, 1H), 1.87 (td, J = 12.6, 6.6 Hz, 1H), 1.80 (s, 3H), 1.67 (s, 3H);
13C{1H} NMR (126 MHz, CDCl3) δ 196.7, 195.3, 170.9, 165.9, 153.6,
(m, 2H), 4.34 (ddd, J = 7.6, 4.5, 1.6 Hz, 1H), 4.25 (d, J = 5.4 Hz, 1H),
4.19−4.14 (m, 2H), 4.08 (d, J = 5.9 Hz, 1H), 4.01−3.95 (m, 2H),
3.26−3.17 (m, 1H), 2.85 (ddd, J = 13.0, 5.6, 2.5 Hz, 1H), 2.70 (ddd, J =
17.4, 5.4, 2.6 Hz, 1H), 2.55−2.48 (m, 1H), 2.37 (d, J = 11.4 Hz, 1H),
2.31 (ddd, J = 12.4, 5.7, 2.5 Hz, 1H), 2.28−2.23 (m, 2H), 2.23−2.16
(m, 2H), 2.14−2.09 (m, 2H), 2.06 (s, 6H), 1.95 (dtd, J = 13.8, 7.1, 6.6,
4.8 Hz, 4H), 1.89−1.81 (m, 6H), 1.79 (d, J = 4.3 Hz, 1H), 1.74 (s, 3H),
1.72 (s, 3H), 1.69−1.67 (m, 1H), 1.64 (td, J = 7.6, 2.6 Hz, 4H), 1.56 (s,
3H), 1.52 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ 171.1, 171.0,
147.2, 147.2, 142.3, 142.3, 130.2, 129.8, 129.4, 129.3, 128.0, 126.6,
115.7, 109.8, 109.8, 81.4, 80.0, 77.7, 75.1, 68.0, 67.0, 55.9, 53.8, 52.5,
51.5, 45.7, 44.4, 43.0, 42.2, 40.6, 35.1, 34.4, 33.4, 30.2, 29.7, 28.9, 28.2,
28.2, 27.9, 26.9, 22.6, 22.6, 21.0, 21.0, 20.3, 19.2, 18.9, 17.5, 13.6.
(4aR,13R,13aS,14S,14aR)-3,3,10-Trimethyl-13-(prop-1-en-2-
yl)-4a,5,8,9,11,12,13,13a,14,14a-decahydro-1H-7,14-
methanobenzo[4,5]cyclodeca[1,2-d][1,3]dioxine (34). Freshly
cut lithium slices (28.0 mg, 4.0 mmol) were added rapidly to a solution
of 31 and 32 (68.4 mg, 0.2 mmol) in ethylamine (5 mL) at 25 °C. The
mixture turned blue and was vigorously stirred for further 45 min. The
reaction was quenched with cyclopentadiene (1 mL) and saturated
NH4Cl (aq) (3 mL). Water (1 mL) was added to the mixture, which
was extracted with EtOAc (100 mL). The combined organic extracts
were washed with 1 M HCl (aq), brine, dried over anhydrous Na2SO4,
and concentrated in vacuo to give a crude product of 33 (hard to
purify), which was used in the next step.
The crude product was dissolved again in DCM (5 mL) at rt. Then,
2,2-dimethoxypropane (0.24 mL, 2.0 mmol) and p-toluenesulfonic acid
(PTSA, 8.6 mg, 0.05 mmol) were added to the solution sequence, and
the resulting mixture was stirred at the same temperature overnight.
The reaction was quenched with saturated NaHCO3 (1 mL) and
filtered with Celite. The solution was extracted with EtOAc (3 × 5 mL).
The combined organic extracts were washed with brine and dried over
anhydrous Na2SO4. The solution was concentrated in vacuo, and the
residue was chromatographed on silica gel (hexane/EtOAc = 8:1) to
afford a mixture of 34 (18 mg, 70% for two steps from 32) as a foam: Rf
= 0.50 (hexane/EtOAc = 2:1); HRMS (ESI) m/z [M + H]+ calcd for
C23H35O2 343.2632, found 343.2630; 1H NMR (500 MHz, CDCl3) δ
5.38−5.34 (m, 1H), 4.75 (t, J = 1.8 Hz, 1H), 4.53 (s, 1H), 4.07 (td, J =
7.8, 3.4 Hz, 1H), 3.89−3.77 (m, 2H), 2.91 (dt, J = 12.7, 3.7 Hz, 1H),
2.63−2.50 (m, 2H), 2.39 (dt, J = 14.7, 7.5 Hz, 1H), 2.21−2.16 (m, 2H),
2.04−1.89 (m, 3H), 1.86−1.78 (m, 4H), 1.72 (d, J = 1.3 Hz, 3H),
1.70−1.65 (m, 2H), 1.62 (s, 3H), 1.44 (s, 3H), 1.42 (s, 3H), 1.40−1.36
(m, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ 147.5, 145.2, 130.0,
128.4, 117.6, 110.2, 98.6, 70.0, 63.3, 49.2, 47.0, 43.5, 37.5, 36.6, 36.1,
32.0, 31.7, 29.9, 28.7, 28.7, 22.3, 22.0, 19.2.
(2S,3S,4S)-3-((E)-3-(Benzyloxy)prop-1-en-1-yl)-2-((S)-2-(5-
(((tert-butyldimethylsilyl)oxy)methyl)furan-3-yl)-1-hydrox-
yethyl)-4-((S)-6-methylhept-5-en-2-yl)cyclohexan-1-one (49).
n-BuLi (2.4 M in hexanes, 10.5 mL, 25 mmol) was added dropwise
to a solution of (E)-(3-(benzyloxy)prop-1-en-1-yl)tributylstannane 47
(10.6 g, 24.5 mmol) in anhydrous THF (80 mL) at −50 °C, and the
mixture was stirred at the same temperature for 1 h. The resultant
solution was transferred via cannula to another flask containing a
suspension of copper cyanide (CuCN, 2.1 g, 24.5 mmol) in anhydrous
THF (50 mL, also cooled to −50 °C). The mixture was stirred for 15
min and then treated with MeLi (1.6 M in diethyl ether, 15.5 mL, 24.5
mmol), stirred for an additional 15 min, and cooled to −78 °C. A
solution of enone 42 (2.5 g, 12 mmol) in THF (15 mL) was added over
30 min, and the mixture was stirred for an additional 30 min.
Chlorotrimethylsilane (TMSCl, 2.1 mL, 24.5 mmol) was then added,
and after 15 min, this was followed by TEA (4.2 mL, 30 mmol). The
reaction was quenched by pouring into a 10% aqueous solution of
NH4Cl (100 mL). The mixture was filtrated through a pad of Celite
with the aid of EtOAc. The organic layer of the filtrate was extracted
with EtOAc (2 × 100 mL). The combined organic layers were washed
with brine, dried over Na2SO4, and concentrated under reduced
pressure. The residue was passed through a short silica gel column with
EtOAc/hexane (1:100−1:50) quickly. The eluate was concentrated to
give the trimethylsilyl enol ether 48, which was used for the next step
without further purification.
145.3, 132.6, 123.4, 112.7, 84.1, 80.8, 66.1, 48.3, 47.5, 46.6, 42.9, 36.6,
35.6, 33.1, 22.5, 21.0, 10.8.
((2S,3S,10R,10aR,11S,11aR,12R)-3-Hydroxy-7-methyl-10-
(prop-1-en-2-yl)-2,3,5,6,8,9,10,10a,11,11a-decahydro-2,11-
methanobenzo[5,6]cyclohepta[1,2-b]pyran-12-yl)methyl Ace-
tate (30). To a solution of compound 29 (185 mg, 0.5 mmol) in
anhydrous THF (10.0 mL) was added boron trifluoride etherate (1.1
mL, 9.0 mmol) at rt, and the mixture was stirred at the same
temperature for 5 min. Then, sodium cyanoborohydride (NaBH3CN,
471 mg, 7.5 mmol) was added, and the mixture was stirred at rt
overnight. The reaction was quenched by added saturated NaHCO3 (5
mL), and the mixture was extracted with EtOAc (3 × 5 mL). The
combined organic layers were washed with brine (15 mL) and dried
over Na2SO4. The solvents were removed under reduced pressure, and
the residue was purified by flash column chromatography on silica gel
(hexane/EtOAc = 5:1) to afford 30 (100 mg, 56%) as a foam: Rf = 0.60
(hexane/EtOAc = 1:1); HRMS (ESI) m/z [M + H]+ calcd for
C22H31O4 359.2217, found 359.2214; 1H NMR (500 MHz, CDCl3) δ
5.31 (d, J = 1.9 Hz, 1H), 4.76−4.70 (m, 2H), 4.48 (dq, J = 1.8, 0.9 Hz,
1H), 4.24 (dd, J = 10.8, 5.2 Hz, 1H), 4.20−4.15 (m, 1H), 4.11 (d, J = 6.2
Hz, 1H), 4.00 (dd, J = 10.8, 9.3 Hz, 1H), 2.86 (ddd, J = 13.1, 5.5, 2.7 Hz,
1H), 2.54−2.47 (m, 1H), 2.33−2.24 (m, 2H), 2.14 (d, J = 9.0 Hz, 1H),
2.11−2.07 (m, 1H), 2.06 (s, 3H), 2.04−1.98 (m, 1H), 1.91 (dd, J = 7.0,
5.6 Hz, 1H), 1.87−1.83 (m, 2H), 1.78−1.74 (m, 1H), 1.73−1.71 (m,
3H), 1.55 (d, J = 1.1 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ
171.3, 146.9, 144.8, 128.8, 128.4, 120.6, 110.1, 81.7, 80.4, 68.1, 67.7,
53.0, 45.3, 44.6, 43.3, 34.7, 33.7, 28.3, 22.7, 21.1, 21.0, 19.3.
((2R,10R,10aR,11S,11aR,12R)-7-Methyl-10-(prop-1-en-2-yl)-
2,3,5,6,8,9,10,10a,11,11a-decahydro-2,11-methanobenzo-
[5,6]cyclohepta[1,2-b]pyran-12-yl)methyl Acetate (32). NaH
(20.8 mg, 0.52 mmol, 60% suspension in mineral oil) was washed twice
with hexanes and added slowly to a well-stirred and precooled (0 °C)
solution of alcohol 30 (71.6 mg, 0.2 mmol) in anhydrous THF (10
mL). Immediately thereafter, CS2 (36 μL, 0.6 mmol) was added, and
the red-orange solution was allowed to warm at 25 °C, at which
temperature it was stirred over a period of 3 h. The reaction mixture was
then recooled at 0 °C and treated with methyl iodide (64 μL, 1.1
mmol). After the mixture was stirred at 25 °C for an additional 30 min,
the colorless solution was quenched with ice−water (5 mL) and
extracted with ethyl ether (3 × 10 mL). The combined ethereal layers
were washed with aqueous saturated sodium bicarbonate (10 mL) and
brine (10 mL). The organic layers were combined, dried over MgSO4,
and concentrated under reduced pressure. The crude residue was
subjected to chromatography (0−20% ether in hexanes) to afford the
corresponding xanthate as a light-yellow liquid. This liquid was
dissolved in dry benzene (10 mL) and treated with Bu3SnH (0.41 mL,
1.5 mmol). The reaction mixture was preheated at 80 °C and treated
with AIBN (3.28 mg, 0.02 mmol) added in four portions over a period
of 2 h. After the end of the reaction, the solvent was removed under
reduced pressure and the crude residue was purified through flash
chromatography on silica gel (hexane/EtOAc = 30:1) to afford a
mixture of 31 and 32 (38 mg, 56%, 31/32 = 1.6:1, detected by crude
NMR) as a foam: Rf = 0.2 (hexane/EtOAc = 20:1); HRMS (ESI) m/z
1
[M + H]+ calcd for C22H31O3 343.2268, found 343.2270; H NMR
(500 MHz, CDCl3) δ 5.82 (ddd, J = 9.8, 4.1, 2.8 Hz, 1H), 5.65 (dt, J =
9.8, 1.9 Hz, 1H), 5.37−5.33 (m, 1H), 4.76−4.71 (m, 2H), 4.53−4.47
L
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To a solution of the crude trimethylsilyl enol ether 48 (about 20
mmol) in anhydrous THF (40 mL) was added n-BuLi (2.4 M in
hexanes, 5.0 mL, 12 mmol) at −78 °C, and stirring was continued at
−30 °C for 1 h. Then, the mixture was cooled to −78 °C, and a solution
of ZnBr2 (3.0 g, 13.2 mmol) in THF (15 mL) was added dropwise.
After the mixture was stirred at the same temperature for 30 min, a
solution of aldehyde 41 (3.1 g, 12 mmol) in THF (6 mL) was added
over 30 min, and the mixture was stirred for an additional 5 min. The
reaction was quenched by pouring into a saturated aqueous solution of
NaHCO3 (100 mL) at 0 °C. The aqueous layer was extracted with
EtOAc (3 × 50 mL). The combined organic layers were washed with
brine (50 mL) and dried over Na2SO4. The dried solution was filtered
and concentrated. The residue obtained was purified by flash column
chromatography on silica gel (hexane/EtOAc = 10:1) to afford 49
(about 45−60% for two steps) as a foam: Rf = 0.45 (hexane/EtOAc =
5:1); HRMS (ESI) m/z [M + Na]+ calcd for C37H56NaO5Si 631.3789,
found 631.3787; 1H NMR (500 MHz, CDCl3) δ 7.36−7.28 (m, 5H),
7.12 (s, 1H), 6.03 (s, 1H), 5.71 (dt, J = 15.5, 5.5 Hz, 1H), 5.30 (ddt, J =
15.6, 9.7, 1.6 Hz, 1H), 5.08−5.00 (m, 1H), 4.52 (d, J = 11.5 Hz, 4H),
4.03 (dd, J = 5.5, 1.6 Hz, 2H), 3.87−3.77 (m, 1H), 3.17 (d, J = 11.4 Hz,
1H), 2.87 (ddd, J = 14.4, 7.0, 1.2 Hz, 1H), 2.76−2.66 (m, 2H), 2.36 (tt,
J = 13.1, 7.1 Hz, 2H), 2.24 (d, J = 11.4 Hz, 1H), 2.06−1.99 (m, 2H),
1.84−1.75 (m, 2H), 1.74−1.68 (m, 1H), 1.64 (d, J = 1.4 Hz, 3H), 1.55
(d, J = 1.3 Hz, 3H), 1.49−1.40 (m, 2H), 0.94 (d, J = 7.0 Hz, 4H), 0.89
(s, 9H), 0.06 (s, 6H); 13C{1H} NMR (126 MHz, CDCl3) δ 215.2,
154.7, 139.3, 138.4, 133.8, 131.6, 130.3, 128.5, 127.7, 127.7, 124.7,
122.7, 108.9, 72.1, 70.9, 70.0, 58.4, 55.6, 48.9, 47.4, 43.2, 32.8, 32.0,
29.9, 26.4, 26.3, 26.0, 25.9, 18.7, 18.6, 17.7, −5.1.
(S)-1-((1S,2S,3S)-2-((E)-3-(Benzyloxy)prop-1-en-1-yl)-3-((S)-
6-methylhept-5-en-2-yl)-6-oxocyclohexyl)-2-(5-
(hydroxymethyl)furan-3-yl)ethyl Acetate (51). To a solution of
49 (1.4 g, 2.3 mmol) in DCM (30 mL) at 0 °C was added Et3N (0.49
mL, 3.5 mmol) and DMAP (146 mg, 1.2 mmol) subsequently. Then
Ac2O (0.24 mL, 2.5 mmol) was added to the solution and stirred at rt
for 15 min before the reaction was quenched by saturated NH4Cl (10
mL). Then the aqueous layer was extracted with DCM (3 × 20 mL).
The combined organic layers were washed with brine (20 mL) and
dried over Na2SO4. The dried solution was filtered and concentrated.
The residue obtained was purified by flash column chromatography on
silica gel (hexane/EtOAc = 15:1) to afford the corresponding acetate as
a foam.
The acetate prepared above (1.1 g, 1.6 mmol) was dissolved in
CH3CN (30 mL) and cooled to 0 °C. Then, imidazole (1.6 g, 23 mmol)
and triethylamine trihydrofluoride (1.5 g, 9.2 mmol) were added
subsequently. After the mixture was stirred at the same temperature for
2 h, the reaction was quenched by a saturated aqueous solution of
NaHCO3 (20 mL) at 0 °C. The aqueous layer was extracted with
EtOAc (3 × 20 mL). The combined organic layers were washed with
brine (20 mL) and dried over Na2SO4. The dried solution was filtered
and concentrated. The residue obtained was purified by flash column
chromatography on silica gel (hexane/EtOAc = 5:1) to afford 51 (789
mg, 64% for two steps) as a foam: Rf = 0.2 (hexane/EtOAc = 2:1);
HRMS (ESI) m/z [M + H]+ calcd for C33H45O6 537.3211, found
537.3210; 1H NMR (500 MHz, CDCl3) δ 7.35 (d, J = 5.6 Hz, 4H), 7.15
(s, 1H), 6.13 (s, 1H), 5.51 (dt, J = 15.5, 5.5 Hz, 1H), 5.36−5.27 (m,
1H), 5.13 (td, J = 7.5, 1.8 Hz, 1H), 5.04 (tt, J = 6.5, 5.0, 2.0 Hz, 1H),
4.57−4.50 (m, 2H), 4.47−4.44 (m, 2H), 4.03 (ddd, J = 5.5, 3.9, 1.4 Hz,
2H), 2.99 (dd, J = 14.0, 7.9 Hz, 1H), 2.81 (dd, J = 14.1, 6.9 Hz, 1H),
2.47−2.37 (m, 3H), 2.31−2.24 (m, 1H), 2.03 (s, 3H), 1.95 (ddd, J =
9.4, 6.1, 3.2 Hz, 1H), 1.88 (t, J = 6.2 Hz, 1H), 1.82−1.72 (m, 2H), 1.56
(d, J = 1.2 Hz, 3H), 1.47 (ddd, J = 24.5, 12.2, 3.8 Hz, 2H), 1.34−1.21
(m, 3H), 0.93 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3) δ
209.6, 170.7, 154.6, 140.1, 138.4, 133.5, 131.7, 129.6, 128.5, 127.8,
127.8, 124.6, 121.7, 109.5, 72.9, 72.1, 70.2, 57.7, 54.0, 47.0, 46.7, 42.1,
32.6, 29.7, 27.0, 26.3, 25.9, 24.5, 21.4, 18.5, 17.8.
M, 0.24 mL, 0.15 mmol). Then, the mixture was stirred at the same
temperature for 15 min before the reaction was quenched by saturated
NH4Cl (5 mL). Then the aqueous layer was extracted with EtOAc (3 ×
5 mL). The combined organic layers were washed with brine (5 mL)
and dried over Na2SO4. The dried solution was filtered and
concentrated. The residue obtained was purified by flash column
chromatography on silica gel (hexane/EtOAc = 15:1) to afford 62 (7.8
mg, 30%) as a foam: Rf = 0.5 (hexane/EtOAc = 5:1); 1H NMR (400
MHz, CDCl3) δ 7.39−7.27 (m, 5H), 6.33 (d, J = 10.1 Hz, 1H), 6.18−
6.12 (m, 1H), 5.90 (s, 1H), 5.09 (d, J = 7.2 Hz, 1H), 4.58−4.42 (m,
2H), 4.14−4.01 (m, 2H), 3.68−3.59 (m, 1H), 3.50 (d, J = 3.2 Hz, 2H),
2.61 (dd, J = 11.0, 3.2 Hz, 1H), 2.46 (d, J = 5.0 Hz, 3H), 2.15 (s, 1H),
2.03−1.91 (m, 2H), 1.75 (d, J = 11.2 Hz, 2H), 1.70−1.68 (m, 3H), 1.62
(d, J = 1.3 Hz, 3H), 1.57−1.46 (m, 3H), 1.38 (s, 3H), 1.36 (s, 3H),
1.28−1.15 (m, 4H), 1.06 (dd, J = 12.3, 4.8 Hz, 1H), 0.90 (d, J = 6.7 Hz,
3H).
(1S,3aS,3a1R,6aS,8aR,11R,11aS,11bR)-5,5-Dimethyl-1-((S)-6-
methylhept-5-en-2-yl)-1,2,3,3a,3a1,6a,7,8a,10,11,11a,11b-do-
decahydro-4,6,9-trioxa-8,11-(epipropan[1]yl[3]ylidene)-
naphtho[1,8-ef ]azulene (71). To a solution of 64 (43.2 mg, 0.1
mmol) in DCM (10 mL) at rt was added triphenylphosphine (39.3 mg,
0.15 mmol) and iodide (30.5 mg, 0.12 mmol) subsequently. Then, the
mixture was stirred at rt for 50 min before the reaction was quenched by
saturated Na2SO3 (5 mL). Then the aqueous layer was extracted with
DCM (3 × 20 mL). The combined organic layers were washed with
brine (20 mL) and dried over Na2SO4. The dried solution was filtered
and concentrated. The residue obtained was purified by flash column
chromatography on silica gel (hexane/EtOAc = 15:1) to afford 71 (34.4
mg, 83%) as a foam: Rf = 0.5 (hexane/EtOAc = 10:1). Compound 71
was isolated as a byproduct from the deprotection reaction of
1
compound 72: H NMR (500 MHz, CDCl3) δ 5.71 (dd, J = 9.0, 4.1
Hz, 1H), 5.14 (tt, J = 7.0, 1.5 Hz, 1H), 4.50 (d, J = 7.9 Hz, 1H), 4.09 (d,
J = 7.8 Hz, 1H), 3.97−3.89 (m, 2H), 3.31 (ddd, J = 10.9, 9.4, 5.4 Hz,
1H), 2.68 (dd, J = 16.5, 12.8 Hz, 1H), 2.55 (q, J = 5.1 Hz, 1H), 2.42 (dd,
J = 11.3, 5.4 Hz, 1H), 2.16−2.05 (m, 3H), 1.93−1.71 (m, 8H), 1.69 (d,
J = 1.4 Hz, 3H), 1.60 (s, 3H), 1.52 (ddd, J = 14.0, 6.5, 3.3 Hz, 2H),
1.44−1.38 (m, 3H), 1.37 (s, 3H), 1.33 (s, 3H), 1.16−1.13 (m, 1H),
0.96 (d, J = 6.8 Hz, 3H).
(S,E)-2-Methyl-6-((1R,1aR,4aS,8S,8aS,8bR)-1-methyl-5-
methylene-1a,3,4,4a,5,6,7,8,8a,8b-decahydro-1H-1,2-
(epipropan[1]yl[3]ylidene)benzo[a]cyclopropa[c][7]annulen-
8-yl)hept-2-enoic Acid (1).8 To a solution of 35 in anhydrous DCM
(20 mL) were added methacrylaldehyde (0.29 mL, 3.5 mmol) and
Grubbs II catalyst (81 mg, 0.1 mmol) subsequently. The reaction was
sealed and heated at 52 °C for 15 h. After the mixture was cooled to 25
°C, the volatiles were removed under vacuo, and the residue was
redissolved in EtOH (10 mL). To the vigorously stirred solution was
added Ag2O (prepared in situ from a solution of silver nitrate (82 mg,
0.48 mmol) in water (1 mL) by the addition of a solution of sodium
hydroxide (38 mg, 0.96 mmol) in water (1 mL) dropwise). After
stirring for 1 h, the mixture was carefully acidified with AcOH and
filtered. The filtrate was concentrated in vacuo, and the residue was
extracted with ether. The combined organic layers were washed with
brine (5 mL) and dried over Na2SO4. The dried solution was filtered
and concentrated. The residue obtained was purified quickly by flash
column chromatography on silica gel (hexane/EtOAc = 3:1) to afford 1
as a colorless oil (32 mg, 27% for three steps): Rf = 0.45 (hexane/EtOAc
= 5:1); [α]2D5 −38 (c 0.32, CH2Cl2); HRMS (ESI) m/z [M + H]+ calcd
for C25H37O2 369.2788, found 369.2788; 1H NMR (500 MHz,
CD2Cl2) δ 6.90 (t, J = 7.6 Hz, 1H), 5.69−5.62 (m, 1H), 4.76 (d, J = 2.0
Hz, 1H), 4.70 (d, J = 2.1 Hz, 1H), 2.49−2.42 (m, 1H), 2.34−2.29 (m,
1H), 2.29−2.23 (m, 1H), 2.25−2.08 (m, 5H), 2.03−1.94 (m, 1H), 1.84
(m, 1H), 1.83 (s, 3H), 1.81−1.76 (m, 1H), 1.72−1.60 (m, 3H), 1.59−
1.53 (m, 2H), 1.50−1.45 (m, 1H), 1.39−1.32 (m, 1H), 1.21−1.17 (m,
1H), 1.16−1.12 (m, 1H), 1.10 (s, 3H), 0.96 (d, J = 9.2 Hz, 1H), 0.91 (d,
J = 6.7 Hz, 3H), 0.68 (t, J = 9.9 Hz, 1H); 13C{1H} NMR (126 MHz,
CD2Cl2) δ 173.2, 152.3, 146.1, 140.9, 127.1, 124.6, 106.4, 45.0, 40.8,
36.5, 33.0, 32.9, 32.8, 32.6, 31.2, 29.1, 28.9, 27.5, 27.1, 25.0, 24.3, 24.2,
21.0, 18.2, 12.3.
(3aS,3a1R,6S,6aS,7S,13aS,14R)-8-((Benzyloxy)methyl)-
2,2,14-trimethyl-6-((S)-6-methylhept-5-en-2-yl)-
3a,3a1,4,5,6,6a,7,8,13,13a-decahydro-1,3-dioxa-7,12-
methanocyclodeca[de]naphthalen-14-ol (62). To a solution of 61
(30.0 mg, 0.05 mmol) in Et2O (5 mL) at −78 °C was added t-BuLi (1.6
M
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Article
Methyl (S,E)-2-Methyl-6-((1R,1aR,4aS,8S,8aS,8bR)-1-methyl-
5-methylene-1a,3,4,4a,5,6,7,8,8a,8b-decahydro-1H-1,2-
(epipropan[1]yl[3]ylidene)benzo[a]cyclopropa[c][7]annulen-
8-yl)hept-2-enoate (2).8 To a solution of 1 (10 mg, 0.03 mmol) in
hexane (2.5 mL) and MeOH (2.5 mL) was added a solution of
TMSCHN2 (2 M in hexane, 27 μL, 0.05 mmol). The solution was
stirred at rt for 40 min and quenched with AcOH until no bubbles came
out. The volatiles were removed under a vacuum, and the residue was
purified by flash column chromatography on silica gel (hexane/EtOAc
= 20:1) to afford the cerorubenic acid-III methyl ester (2) as a colorless
oil (9.8 mg, 95%): Rf = 0.59 (hexane/EtOAc = 20:1); [α]2D5 −50 (c 1.0,
CH2Cl2), [α]2D5 −22 (c 0.16, CHCl3); −28 (c 0.054, CHCl3); {lit.6g
[α]2D0 −139 (c 0.16, CHCl3); lit.6g −124 (c 0.001, CHCl3); lit.3 [α]2D4
−60 (c 0.001, CHCl3)}; HRMS (ESI) m/z [M + H]+ calcd for
Technology, Shenzhen 518055, China; orcid.org/0000-
0002-4622-5200
Jianlei Wu − Shenzhen Key Laboratory of Small Molecule Drug
Discovery and Synthesis, Shenzhen Grubbs Institute,
Department of Chemistry, Guangdong Provincial Key
Laboratory of Catalysis, Southern University of Science and
Technology, Shenzhen 518055, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00185
Author Contributions
#X.L. and J.L. contributed equally to this work.
1
C26H39O2 383.2945, found 383.2944; H NMR (500 MHz, C6D6) δ
Notes
6.93 (dt, J = 1.5, 8.0 Hz, 1H), 5.71−5.65 (m, 1H), 4.95 (s, 1H), 4.89 (d,
J = 1.8 Hz, 1H), 3.45 (s, 3H), 2.53−2.46 (m, 1H), 2.25−2.13 (m, 5H),
2.11−2.03 (m, 1H), 2.00 (m, 1H), 1.90 (m, 1H), 1.87 (s, 3H), 1.83 (dt,
J = 10.3, 5.2 Hz, 1H), 1.80−1.73 (m, 1H), 1.66−1.31 (m, 8H), 1.19 (dt,
J = 6.7, 4.4 Hz, 1H), 1.05 (s, 3H), 0.92 (d, J = 8.5 Hz, 1H), 0.81 (d, J =
6.7 Hz, 3H), 0.71 (dd, J = 10.5, 9.1 Hz, 1H); 13C{1H} NMR (126 MHz,
C6D6) δ 168.1, 151.3, 142.6, 140.5, 127.7, 124.4, 106.9, 51.3, 44.9, 40.6,
36.3, 32.9, 32.8, 32.6, 32.2, 31.1, 28.9, 28.6, 27.3, 26.5, 24.8, 24.2, 23.9,
20.7, 18.1, 12.6. (127.7, the signal of the enoate carbon 19, is obscured
by solvent peaks, and it was elucidated by the correlations of H21 and
C19 in the HMBC spectrum).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21971105), the Guangdong Basic and
Applied Basic Research Foundation (2019A1515111071 and
2021A1515010188), Guangdong Provincial Key Laboratory of
Catalysis (2020B121201002), the Shenzhen Science and
T e c h n o l o g y I n n o v a t i o n C o m m i t t e e
(JCYJ20190809181011411 and ZDSYS20190902093215877),
and the Shenzhen Peacock Plan (KQTD2016053117035204).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00185.
■
sı
REFERENCES
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AUTHOR INFORMATION
Corresponding Author
■
Chuang-Chuang Li − Shenzhen Key Laboratory of Small
Molecule Drug Discovery and Synthesis, Shenzhen Grubbs
Institute, Department of Chemistry, Guangdong Provincial Key
Laboratory of Catalysis, Southern University of Science and
Technology, Shenzhen 518055, China; orcid.org/0000-
0003-4344-0498; Email: ccli@sustech.edu.cn
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Authors
Xin Liu − Shenzhen Key Laboratory of Small Molecule Drug
Discovery and Synthesis, Shenzhen Grubbs Institute,
Department of Chemistry, Guangdong Provincial Key
Laboratory of Catalysis, Southern University of Science and
Technology, Shenzhen 518055, China
Junyang Liu − Shenzhen Key Laboratory of Small Molecule
Drug Discovery and Synthesis, Shenzhen Grubbs Institute,
Department of Chemistry, Guangdong Provincial Key
Laboratory of Catalysis and Academy for Advanced
Interdisciplinary Studies, Southern University of Science and
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