Synthetic studies towards the mannolides: Construction of the bowl-shaped B/C/D ring system

Article abstract of DOI:10.1016/j.tet.2020.131629

The bowl-shaped tricyclo[6.3.1.0^4,12]dodecane moiety is the core feature of cephalotane-type diterpenoids. As part of our efforts directed towards a total synthesis of mannolide B, the bowl-shaped tricyclo[6.3.1.0^4,12]dodecane skelet

Full text of DOI:10.1016/j.tet.2020.131629

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthetic studies towards the mannolides: Construction of the bowl-
shaped B/C/D ring system
Kunkai Wang, Zhezhe Xu, Xiangchuang Tan, Zhixiang Xie*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, 222 Tianshui South Road, Lanzhou,
730000, China
a r t i c l e i n f o
a b s t r a c t
The bowl-shaped tricyclo[6.3.1.04,12]dodecane moiety is the core feature of cephalotane-type diterpe-
noids. As part of our efforts directed towards a total synthesis of mannolide B, the bowl-shaped tricyclo
[6.3.1.04,12]dodecane skeleton, a common intermediate of cephalotane-type diterpenoids bearing up to
five contiguous stereocenters including two quaternary carbon centers had been constructed. The syn-
thetic strategy was enabled by an efficient application of oxidative dearomatization/intramolecular Diels-
Alder reaction to access highly functionalized building block with the tricyclo[5.2.2.02,6]undecane unit
from commercially available materials. The key feature was firstly used the cyclic olefins with secondary
alcohol as dienophile for the intramolecular inverse electron demand Diels-Alder reaction. Further
synthetic studies led to construct ring D by a regioselective Aldol reaction.
Article history:
Received 26 August 2020
Received in revised form
23 September 2020
Accepted 27 September 2020
Available online xxx
Keywords:
Cephalotane-type diterpenoids
Mannolides
Oxidative dearomatization
Intramolecular Diels-Alder reaction
Aldol reaction
© 2020 Elsevier Ltd. All rights reserved.
1. Introduction
Due to the intriguing polycyclic structural features and exciting
biological activities, the cephalotane-type diterpenoids as
a
Cephalotaxus, as the sole member of the cephalotaxaceae family,
consists of nine species found around the world, of which seven
species are widely distributed in China and have been used against
leukemia in Chinese traditional medicine [1]. Chemical investiga-
tion have resulted in the isolation of the interesting secondary
metabolites such as alkaloids and terpenoids with a variety of
biological properties, particularly antitumor activity [2]. For
instance, the alkaloid homoharringtonine, from C. fortune, was
approved by the Food and Drug Administration for the treatment of
chronic myeloid leukemia in 2012. Be encouraged by this result,
studies on terpenoids, particularly cephalotane-type diterpenoids,
have drawn a great amount of attention from the phytochemist.
Before 2012, only five cephalotane-type diterpenoids had been
identified [3]. The first member of the cephalotane-type diterpe-
noids, harringtonolide (Fig. 1) was isolated and structurally char-
acterized from the seeds of C. harringtonia in 1978 by Buta and co-
workers [3a]. After 2012, Yue and co-workers have intensified
isolation efforts that led to the documentation of 31 additional
diterpenes and norditerpenoids [4]. (Fig. 1, selected examples).
compelling target, have attracted more and more attention from
the synthetic organic community. As the first example of
cephalotane-type diterpenoids, a great deal of synthetic strategies
has been developed for model studies on harringtonolide [5]. The
first total synthesis of hainanolidol was disclosed by Mander and
coworkers in 1998 [6]. The critical strategy featured an intra-
molecular arene cyclopropanation followed by a ring expansion to
construct the tropone moiety. In 2013, an intramolecular
oxidopyrylium-based [5 þ 2]-cycloaddition was developed by Tang
and coworkers as a highlight to finish the total synthesis of hai-
nanolidol [7]. The first asymmetric total synthesis of (þ)-harring-
tonolide was achieved by Zhai and coworkers by an intramolecular
Diels-Alder reaction and
a rhodium-complex-catalyzed intra-
molecular [3 þ 2]-cycloaddition as the key transformation [8].
Recently, Zhao and coworkers described the total synthesis of
cephanolides B and C enabled by palladium-catalyzed cascade
cyclization and late-stage sp3 CeH bond oxidation [9].
Mannolides A-C, three new C20 cephalotane-type diterpenoids,
were isolation by Yue and co-workers from Cephalotaxus mannii
Hook f. in 2016.[4a] (Fig. 1) Particularly noteworthy, this new C20
skeleton could serve as the key biosynthetic intermediate for the
coexistent antitumor troponoids (C19 cephalotane-type diterpe-
noids, such as harringtonolide). We became interested in
* Corresponding author.
E-mail address: xiezx@lzu.edu.cn (Z. Xie).
https://doi.org/10.1016/j.tet.2020.131629
0040-4020/© 2020 Elsevier Ltd. All rights reserved.
Please cite this article as: K. Wang, Z. Xu, X. Tan et al., Synthetic studies towards the mannolides: Construction of the bowl-shaped B/C/D ring
system, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131629

K. Wang, Z. Xu, X. Tan et al.
Tetrahedron xxx (xxxx) xxx
Fig. 1. The structure of select cephalotane-type diterpenoids.
mannolides A-C as a novel C20 cephalotane-type diterpenoids
possessing polycyclic carbon skeleton, and a more reasonable
biosynthetic intermediate for other cephalotane-type diterpenoids
from the biogenetic point of view. Here in, we report our progress
on the synthetic studies of construction of the bowl-shaped B/C/D
ring system of the mannolides A-C.
2. Results and discussion
From the viewpoint of molecular structure, a unique and bowl-
shaped tricyclo[6.3.1.04,12]dodecane moiety embodies the common
carbon skeleton of cephalotane-type diterpenoids (shown in Fig. 1.
red). This cis-fused tricarbocycle is designated as rings B, C, and D,
with five to seven contiguous stereocenters including at least one
all-carbon quaternary center. Moreover, ring D embeds a bridging
Scheme 1. Retrosynthetic analysis of mannolides B-C.
d-lactone unit ring E. The main structural differences of this class of
diterpenoids are both in left moiety combined with B/C rings and
the oxidation degree of the molecular architecture. Thus if we can
construct the bowl-shaped tricyclo[6.3.1.04,12]- dodecane moiety,
the cluster syntheses of cephalotane-type diterpenoids will be
achieved.
containing four continuous stereocenters including two quaternary
carbon centers, was built up by the inverse electron demand Diels-
Alder reaction. Thus, a model study of this reaction was need to
verify the performance and the stereochemistry. As shown in
Scheme 2, the masked o-benzoquinones 17, prepared from 2,5-
dimethylphenol (16) in four steps according to the literature [12],
was chose to attempt this D-A reaction with dienophile 9. To our
delight, a single product was obtained in reflux toluene with a
moderate yield. The relative stereochemistry of the compound 18
was determined by NOE and NOESY as shown in Scheme 2.
Although, the relative stereochemistry of 18 is not as expected, it
was remedied by selective oxidation cleavage of double bond and
reduction of ketone and ketal instead of the original design,
reduction of double bond and oxidation cleavage of ketone and
ketal.
Our retrosynthetic analysis toward mannolides B-C (1e2) was
depicted in Scheme 1. We assumed that mannolide C (2) could be
accessed from mannolide B (1) through Barton-McCombie deoxy-
genation reducing secondary hydroxyl group. The mannolide B
could be derived from the acid 3 by utilizing C-H functionalization
of carboxylic-induced esterification [10], followed by stereo-
selective reduction ketone to secondary hydroxyl group. The acid 3
could be achieved via a sequence ring-closing metathesis [11] and
hydrolysis of ester of compound 4, which was prepared by alkyl-
ation with 6 from compound 5. The advanced intermediate 5,
containing the common carbon skeleton of cephalotane-type
diterpenoids and ring E, could be as a common intermediate for
preparing other cephalotane-type diterpenoids. The key interme-
Encouraged by the model study results, our synthesis started to
prepare the precursor 10 of Diels-Alder Reaction. As shown in
Scheme 3, the known alkenyl triflate 14 [15] was coupled with
allylic alcohol 15 through a redox-relay Heck reaction with Sig-
man’s procedure [14] to produce aldehyde 19 in 52% yield. How-
diate 5 was envisioned to be synthesized from a, b-unsaturated
ketone 7 via sequence oxidative cleavage of diketone, intra-
molecular oxa-Michael addition to install the ring E and esterifi-
cation. The ketone 7 should be prepared by sequence selective
reduction of disubstituent double bond, hydrolysis of acetal, fol-
ever, presumably for lack of substituents in both
a, b-unsaturated
ketone 14 ( -substituent) and allylic alcohol 15 (trisubstituted), the
a
enantioselectivity of this reaction was poor no matter what other
PyrOx-type ligands [14] and temperature we changed. In order to
lowed by Aldol reaction to install the a, b-unsaturated ketone. The
tricyclo[5.2.2.02,6]undecane unit 8 was traced back to phenol 10 via
the oxidative dearomatization, followed by inverse electron de-
mand Diels-Alder reaction [12] with cyclopent-3-en-1-ol (9). The
phenol 10 was considered to synthesis by alkylation of compound
13 to deliver b-keto ester 11, followed by decarboxylative aroma-
tization [13]. We reasoned that ketone 13, containing the first chiral
center, could be installed with compound 14 and allylic alcohol 15
through a redox-relay Heck reaction [14].
In our strategy, the tricyclo[5.2.2.02,6]undecane moiety,
Scheme 2. Model study of the inverse electron demand Diels-Alder reaction.
2

K. Wang, Z. Xu, X. Tan et al.
Tetrahedron xxx (xxxx) xxx
Scheme 3. Prepared the precursor 10 of Diels-Alder reaction.
verify the subsequent design, we continued to try the following
transformation. The compound 19 was selective protection of
aldehyde group in the presence of ketone with 1,2-
Bis(trimethylsilyloxy) ethane and catalytic TMSOTf (10%) to
obtain the glycol acetal 20 [16]. Notable, the glycol acetal 20 need
directly purifying by chromatography without any quenching,
otherwise it would lead to inverse reaction to recover the starting
material 19 completely. Elaboration of 20 to 3-methoxy-
saturated ketone 13 proceeded smoothly through two steps
transformations, including epoxidation of the -unsaturated
a, b-un-
Scheme 4. Synthetic studies of the Diels-Alder reaction.
a, b
ketone and one-pot sodium methoxide epoxide ring-opening [17]
with simultaneous hydroxyl group elimination to form the com-
pound 13.
In the following sequence, we should install butenyl side chain
at ketone a-carbon. Treating compound 13 with 4-bromobut-1-ene
12 in various bases and different solvents, we could not get the
satisfying results. We envisioned that introducing an active group
in 13 could make it to install the butenyl and followed aromatiza-
tion in conversion feasible. So, allyl carbonate was selected as the
active group and the efficient one-step removal of allyloxycarbonyl
groups at the aromatization using palladium chemistry. The active
group of 13 was introduced by utilizing allyl chloroformate in
enough activity to make this reaction occur. In addition, the
configuration of the side chain C-4-methyl in precursor 10 would be
predicated on the ability of exerting diastereofacial control, which
alcohol 9 attacked from less steric hindrance, in the oxidative
dearomatization step. Thus, we could establish the key four ster-
eocenters including two quaternary carbon centers in tricyclo
[5.2.2.02,6]undecane core of B/C-ring by the C-4-methyl chiral
inducing. To our knowledge, although tandem oxidative dear-
omatization/intramolecular Diels-Alder reaction of primary alcohol
had been reported in many total syntheses [19], there was still no
single report about secondary alcohol like this reaction. Obviously,
primary alcohol had much better activity than secondary in
oxidative dearomatization. In the initial attempt, treating a mixture
of 10 and excess 9 with oxidant bis(trifluoroacetoxy) iodobenzene
(PIFA) at room temperature led to a complex mixture, under
Mehta’s protocl [19a,c]. After extensive screening the oxidants,
solvents and reaction temperatures, the best result was delighted to
find (details see SI, Table S1). In the optimal condition, the ethers
24a and 24b were obtained in 77% overall yield. Unfortunately, the
stereocontrol of C-4 was poor due to single bond free rotation and
the ratio of 24a and 24b was about 1:1 dr. It was hard to determine
which compound had correct configuration for 24a and 24b, so we
made following conversion to this two diastereomers.
With 24a and 24b in hand, we attempted the intramolecular
Diels-Alder reaction to construct key intermediates 25a and 25b
(Scheme 4). Treating 24a and 24b in toluene at 95 ꢀC respectively,
complicated cage-like compound 25a and 25b was obtained in 95%
and 97% yield as colorless oil. However, the reaction time was too
long and need to shorten. Improving reaction temperature led to
another complex compound. Attempting various Lewis acid only
led to a complex mixture. In the presence of samarium (II) iodide
(0.1M in THF) [20], 25a and 25b were converted to compound 26a
and 26b in a high yield, respectively. Fortunately, the structure of
LiHMDS to deliver b-keto ester 21 [18]. Next, 21 was subjected to
alkylation with 12 to produce 11. After screening a number of bases
and additives, we were delighted to find that the best result was
carried out with Cs2CO3, catalytic tetrabutylammonium iodide and
excess 12 in DMF at room temperature, which could produce 11
smoothly in 83% yield. As expected, under the catalysis of Pd(OAc)2
and PPh3, decarboxylative aromatization proceeded smoothly in a
high yield to furnish phenol 10 [13b]. Notice, it was critical to use
PPh3 instead of dppe as ligand in this conversion, due to the coor-
dination of the ethylene glycol protecting group [13a].
With the desired phenol 10 in hand, we attempted the key
oxidative dearomatization/intermolecular Diels-Alder reaction to
construct the tricyclo[5.2.2.02,6]undecane unit, containing four-
contiguous stereocenter including two quaternary carbon centers.
As shown in Scheme 4, the phenol 10 was oxidized by PIDA in
MeOH to obtain o-benzoquinones 22 in 78% yield. To our disap-
pointment, we failed to obtain the desired compound 23 by treat-
ing diene 22 with dienophile 9. After extensively attempted
(including changed temperature, pressure and Lewis acid), the re-
sults were recovery of reactants or decomposed of diene 22. We
speculated that the intramolecular Diels-Alder reaction would have
3

K. Wang, Z. Xu, X. Tan et al.
Tetrahedron xxx (xxxx) xxx
26b was supported by X-ray diffraction, which allowed to deter-
mine 26a with the correct configuration.
a 1:2 inseparable isomers. In order to improve the yield and ratio of
32b, the reaction condition was extensive screening (details see SI,
Table S2). The best result was achieved that treating 31b with t-
BuONa in THF at 0 ꢀC for the Aldol reaction, the desired compound
32b was obtained as a single isomer in 40% yield [23]. (Method b)
Next, compound 32a was also synthesized from compound 26a
following the same procedure with 32% yield in three steps.
The compound 26b, with incorrect configuration, was used for
attempting the subsequent transformation to screen optimal con-
ditions. Attention was focused on the reduction of the ketone in
26b (Scheme 5). To our disappointment, it was all failed to reduce
the ketone after attempting several reducing systems [21] such as
TMSCl-mediated Clemmensen reduction (no reaction) [21a], Wolff-
Kishner reduction (decompose) and its Caglioti modification (no
reaction) [21b], and Lawesson’s reagent (no reaction). Next, we
turned our attention to transform ketone to alcoholic derivatives
followed by BartoneMcCombie deoxygenation or hydride reduc-
tion. Barton-McCombie reaction reducing precursor 28 was pre-
pared via three steps: 1) protected the secondary hydroxyl group
with TES, 2) reduced ketone to alcohol, 3) transformed the sec-
ondary alcohol to thioxoester derivative and deprotected hydroxyl
group. No desire product was detected by exposing 28 to tri-n-
butyltin hydride in refluxing toluene.
3. Summary
In conclusion, a synthesis of the BCD-ring system of mannolides
B-C via oxidative dearomatization/intramolecular Diels-Alder re-
action and regioselective Aldol reaction had been achieved.
Furthermore, we developed a novel strategy to synthesize poly-
substituted phenol compound from cyclohexen-1-one. The
following investigation toward total synthesis of mannolides B-C is
currently underway on the basis of present results in the laboratory.
After rigorous analysis, the conclusion drawn was that intra-
molecular Aldol reaction preferred to react at cyclopentanone
4. Experimental section
carbonyl
a-position (C-1) rather than cyclohexanone (C-6) because
4.1. General
of the steric hindrance. In order to verify this hypothesis, 26b was
oxidized with Dess-Martin periodinane reagent to deliver diketone
30b in quantity yield (Scheme 5). Inspired by Ito [22a]and Zhai
Oxygen- and moisture-sensitive reactions were carried out
under argon atmosphere. Solvents were purified and dried by
standard methods prior to use. All commercially available reagents
were used without further purification unless otherwise noted.
Column chromatography was performed on silica gel (200e300
mesh). NMR spectra were recorded on Bruker 400 MHz and Oxford
600 MHz spectrometers in the CDCl3. Chemical shifts are reported
€
[22b], it was quickly realized that Bronsted-acid could probably be a
better choice for deprotection of the cyclic acetal and Aldol reaction
in one-pots. However, treatment of 30b with p-toluenesulfonic acid
(PTSA) in toluene at room temperature to 80 ꢀC provided a complex
mixture. Under carefully screening, 10% HCl in THF at 50 ꢀC caused
the deprotection of the cyclic acetal to afford aldehyde 31b in 80%
yield. Moving forward, treating aldehyde 31b with p-toluene-
sulfonic acid monohydrate (PTSA$H2O) in benzene at 80 ꢀC for 3
days, (Method a) we obtained the expected product 32b and 33b in
5% yield, which was determined by 1H NMR, 13C NMR and HMBC, as
as
d values relative to internal chloroform (d
7.26 for 1H NMR and
77.00 for 13C NMR). High resolution mass spectra (HRMS) were
obtained on a 4G mass spectrometer by using electrospray ioni-
zation (ESI) analyzed by quadrupole time-of-flight (Q-TOF).
4.2. Experimental procedures and data of synthetic intermediates
4.2.1. 20-hydroxy-40,70-dimethyl-20,30,3a0,40,70,7a0-hexahydro-10H-
spiro[[1,3]dioxolane-2,8’-[4,7]ethanoinden]-90-one(18)
The solution of the compound 17 (41.7 mg, 0.23 mmol, 1.0
equiv.) and 9 (77.7 mg, 0.92 mmol, 4.0 equiv.) in 0.2 mL toluene was
stirred at 110 ꢀC for 24 h. The solvent was concentrated under
reduced pressure, and the resulting residue was purified by chro-
matography on silica gel (petroleum ether/ethyl acetate ¼ 8:1) to
afford the product compound 18 (29.3 mg, 65%) as yellow oil. 1H
NMR (400 MHz, CDCl3)
d
6.04 (dd, J ¼ 8.3, 0.8 Hz, 1H), 5.73 (dd,
J ¼ 8.3, 1.3 Hz, 1H), 4.41e4.23 (m, 3H), 4.09e3.94 (m, 2H), 2.85 (dd,
J ¼ 18.2,10.5 Hz,1H), 2.52 (dd, J ¼ 18.0, 9.5 Hz,1H),1.84 (dd, J ¼ 12.0,
7.6 Hz, 2H), 1.56 (s, 1H), 1.39e1.21 (m, 3H), 1.15 (s, 3H), 1.11 (s, 3H).
13C NMR (101 MHz, CDCl3)
d 209.04, 139.07, 131.84, 102.63, 73.44,
66.53, 66.36, 51.80, 45.36, 44.92, 43.27, 38.36, 38.33, 15.28, 14.66.
4.2.2. 3-(3-Oxocyclohex-1-en-1-yl)butanal (19)
A solution of 1,3-Cyclohexanedione (11.2 g, 100 mmol, 1.00
equiv.) and pyridine (15.70 g, 16.0 mL, 200 mmol, 2.00 equiv.) in
dichloromethane (500 mL) was cooled to ꢁ78 ꢀC. Tri-
fluoromethanesulfonic anhydride (20.0 mL, 120 mmol, 1.20 equiv.)
was added slowly and the reaction mixture was stirred at ꢁ78 ꢀC
for 10 min. The reaction mixture was warmed up to 0 ꢀC and after
consumption of the diketone (monitored by TLC). HCl (1 M, 200 mL)
was added. The reaction mixture was extracted with dichloro-
methane (3 ꢂ 250 mL), the organic layer was washed with satu-
rated NaHCO3 (100 mL), brine, dried over Na2SO4, filtered and the
solvents were evaporated under reduced pressure. The residue was
purified by column chromatography (silica gel, petroleum ether/
ethyl acetate ¼ 8:1) to yield compound 14 (21.47 g, 88 mmol, 88%)
Scheme 5. Synthesis of the bowl-shaped B/C/D ring system.
4

K. Wang, Z. Xu, X. Tan et al.
Tetrahedron xxx (xxxx) xxx
as yellowish oil. Data is consistent with that reported in the liter-
ature. To a dry 500 mL Schlenk flask equipped with a stir bar was
added Pd2dba3 (3.15 g, 3.44 mmol, 0.05 equiv.), ligand (S) 2-t-
BuPyrOx (2.80 g, 10.31 mmol, 0.15 equiv.), 3 Å MS (13.74 g, 200 mg/
mmol), and ethyl pivalate (345 mL). To this flask, a three-way
adapter fitted with a balloon of Ar was added, and the flask was
evacuated via house vacuum and refilled with Ar three times while
stirring. The resulting mixture was stirred for 15 min. To this, the
corresponding alkenyl alcohol 15 (7.0 ml, 82.44 mmol, 1.2 equiv.),
alkenyl triflate 14 (16.76 g, 68.7 mmol, 1.0 equiv.) and Li2CO3 (7.61 g,
103.05 mmol, 1.5 equiv.) were added. The resulting mixture was
stirred for another 48 h at room temperature. The solvent was
concentrated under reduced pressure, and the resulting residue
was purified by chromatography on silica gel (petroleum ether/
ethyl acetate ¼ 2:1) to afford the product compound 19 (5.93 g, 52%,
59.87, 38.59, 37.98, 29.32, 24.37, 22.29, 18.95. HRMS (ESIMS) calcd
for C13H21Oþ4 [M þ H]þ 241.1434, found 241.1439.
4.2.5. Allyl 4-(1-(1,3-dioxolan-2-yl)propan-2-yl)-3-methoxy-2-
oxocyclohex-3-ene-1-carboxylate (21)
A solution of 1.06 M Lithium bis(trimethylsilyl)amide (43.70 mL,
46.31 mmol, 3.00 equiv.) in THF (78 mL) was cooled to ꢁ78 ꢀC. The
compound 13 (3.7048 g, 15.43 mmol, 1.0 equiv.) was added slowly.
The reaction mixture was stirred at ꢁ78 ꢀC for 2 h. Then, allyl
carbonochloridate (3.28 mL, 30.88 mmol, 2.0 equiv.) was added
quickly in one portion at ꢁ78 ꢀC. The reaction was quenched by
saturated NH4Cl and extracted with ethyl acetate. The combined
organic layers were washed with brine, dried with anhydrous
NaSO4. The solvent was concentrated under reduced pressure, and
the resulting residue was purified by chromatography on silica gel
(petroleum ether/ethyl acetate ¼ 4:1) to afford the product com-
pound 21 (4.52 g, 91%) as colorless oil. 1H NMR (400 MHz, CDCl3)
brsm 75%) as colorless oil. 1H NMR (400 MHz, CDCl3)
d 9.73 (t,
J ¼ 1.5 Hz, 1H), 5.87 (s, 1H), 2.88 (m, 1H), 2.66 (ddd, J ¼ 17.2, 6.5,
1.4 Hz, 1H), 2.52 (ddd, J ¼ 17.2, 7.5, 1.6 Hz, 1H), 2.42e2.29 (m, 4H),
2.06e1.93 (m, 2H), 1.16 (d, J ¼ 6.9 Hz, 3H). 13C NMR (101 MHz,
d
5.94e5.85 (m, 1H), 5.32 (dd, J ¼ 17.2, 1.3 Hz, 1H), 5.22 (d,
J ¼ 10.4 Hz, 1H), 4.76e4.73 (m, 1H), 4.70e4.58 (m, 2H), 3.93e3.86
(m, 2H), 3.82e3.75 (m, 2H), 3.63 (s, 3H), 3.43e3.39 (m, 1H),
3.35e3.30 (m, 1H), 2.49e2.24 (m, 3H), 2.19e2.11 (m, 1H), 1.85e1.69
(m, 2H), 1.07 (dd, J ¼ 6.8, 5.7 Hz, 3H). 13C NMR (101 MHz, CDCl3)
CDCl3)
d 200.25, 199.71, 168.32, 124.80, 48.41, 37.44, 35.32, 28.01,
22.77, 19.00. HRMS (ESIMS) calcd for C10H15Oþ2 [M þ H]þ 167.1067,
found 167.1071.
d
189.69,189.62,169.56,169.51,152.72,152.51,147.53,147.45,131.67,
4.2.3. 3-(1-(1,3-dioxolan-2-yl)propan-2-yl)cyclohex-2-en-1-one
(20)
118.50, 103.21, 103.11, 65.70, 64.81, 64.76, 64.73, 59.87, 59.84, 53.94,
53.82, 38.05, 37.94, 29.52, 25.40, 25.32, 22.71, 22.58, 19.10, 19.01.
HRMS (ESIMS) calcd for C17H25Oþ6 [M þ H]þ 325.1646, found
325.1649.
A solution of the compound 19 (5.93 g, 35.7 mmol, 1.0 equiv.)
and 1,2-bis-trimethylsilyloxyethane (8.84 g, 42.8 mmol, 1.2 equiv.)
in dichloromethane (140 mL) was cooled to ꢁ78 ꢀC and treated
with TMSOTf (0.65 mL, 3.57 mmol, 0.1 equiv.). The mixture was
stirred for 3 h at ꢁ78 ꢀC. The reaction was then directly purified by
chromatography on silica gel (petroleum ether/ethyl acetate ¼ 4:1)
to afford the product compound 20 (6.01 g, 80%) as colorless oil. 1H
4.2.6. Allyl 4-(-1-(1,3-dioxolan-2-yl)propan-2-yl)-1-(but-3-en-1-
yl)-3-methoxy-2-oxocyclohex-3-ene-1-carboxylate (11)
To a clean dry 100 ml flask with a magnetic stirring bar was
loaded compound 21 (3.54 g, 10.99 mmol, 1.0 equiv.), Cs2CO3
(4.29 g, 13.19 mmol, 1.2 equiv.), tetrabutylammonium iodide
(405.6 mg, 1.10 mmol, 0.1 equiv.) and DMF 55 mL. To the above
solution was added 4-bromobut-1-ene (4.46 mL, 43.96 mmol, 4.0
equiv.). The reaction was stirred at room temperature for 12 h. The
reaction mixture diluted with ethyl acetate, washed with water and
brine, dried with anhydrous NaSO4. The solvent was concentrated
under reduced pressure, and the resulting residue was purified by
chromatography on silica gel (petroleum ether/ethyl acetate ¼ 6:1)
to afford the product compound 11 (3.43 g, 83%) as colorless oil. 1H
NMR (400 MHz, CDCl3)
d
5.84 (s, 1H), 4.75 (t, J ¼ 4.8 Hz, 1H),
3.90e3.85 (m, 2H), 3.79e3.75 (m, 2H), 2.54e2.49 (m, 1H),
2.33e2.24 (m, 4H), 1.99e1.88 (m, 2H), 1.86e1.79 (m, 1H), 1.70e1.63
(m, 1H), 1.09 (d, J ¼ 6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 199.97,
169.99, 124.91, 102.81, 64.70, 64.69, 38.39, 37.51, 37.34, 26.76, 22.76,
19.25. HRMS (ESIMS) calcd for C12H19Oþ3 [M þ H]þ 211.1329, found
211.1332.
4.2.4. 3-(1-(1,3-dioxolan-2-yl)propan-2-yl)-2-methoxycyclohex-2-
en-1-one (13)
NMR (400 MHz, CDCl3)
d 5.89e5.73 (m, 2H), 5.30e5.25 (m, 1H),
To a cooled (0 ꢀC) and stirred solution of the compound 20
(6.01 g, 28.57 mmol, 1.0 equiv.) in 140 mL methanol was added
(14.5 mL, 142.90 mmol, 5.0 equiv.) of 30% hydrogen peroxide and
10% sodium hydroxide (12.5 mL, 31.43 mmol, 1.1 equiv.) during
30 min. The mixture was stirred for 4 h at 0 ꢀC, then the reaction
was quenched with saturated NH4Cl solution, and the mixture was
extracted with ethyl acetate. The combined organic layers were
washed with brine, dried with anhydrous NaSO4, filtered and the
solvents were evaporated under reduced pressure to leave the
residue that was taken directly to the next step as crude. To a so-
lution of above residue in 570 mL methanol was added 1M (in
methanol) sodium methoxide (42.9 mL, 42.86 mmol, 1.5 equiv.) and
the mixture was refluexed for 36 h, the solution was evaporated
under reduced pressure, saturated NH4Cl solution was added, and
the mixture was extracted with ethyl acetate. The solvent was
concentrated under reduced pressure, and the resulting residue
was purified by chromatography on silica gel (petroleum ether/
ethyl acetate ¼ 4:1) to afford the product compound 13 (3.70 g,
5.20 (d, J ¼ 10.4 Hz, 1H), 5.01 (dd, J ¼ 17.1, 1.3 Hz, 1H), 4.93 (d,
J ¼ 10.2 Hz, 1H), 4.72 (dt, J ¼ 14.1, 4.8 Hz, 1H), 4.65e4.52 (m, 2H),
3.94e3.85 (m, 2H), 3.80e3.74 (m, 2H), 3.59 (d, J ¼ 1.3 Hz, 3H),
3.31e3.22 (m, 1H), 2.51e2.21 (m, 3H), 2.14e1.60 (m, 8H), 1.05 (dd,
J ¼ 7.0, 4.9 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 191.86, 191.60,
171.20, 171.03, 150.44, 150.09, 147.50, 147.30, 137.90, 137.86, 131.56,
131.51, 118.77, 118.70,114.84, 114.82, 103.30, 103.22, 65.67, 64.78,
64.75, 64.71, 59.40, 59.23, 56.95, 56.74, 38.07, 37.92, 33.10, 32.53,
29.85, 29.52, 29.47, 28.87, 28.76, 21.46, 21.32, 19.14, 19.06. HRMS
(ESIMS) calcd for C21H31O6þ [M þ H]þ 379.2115, found 379.2120.
4.2.7. 3-(1-(1,3-dioxolan-2-yl)propan-2-yl)-6-(but-3-en-1-yl)-2-
methoxyphenol (10)
In a dry argon-purged flask were placed Pd(OAc)2 (204.8 mg,
0.91 mmol, 0.1 equiv.) and PPh3 (119.6 mg, 0.46 mmol, 0.05 equiv.)
in dry acetonitrile (180 mL). The mixture was stirred at room
temperature for 30 min. The compound 11 (3.43 g, 9.12 mmol, 1.0
equiv) in dry acetonitrile (10 ml) was added and the reaction was
refluxed for 1 h. The resulting mixture was then concentrated in
vacuo and chromatographed on silica gel (petroleum ether/ethyl
acetate ¼ 8:1) to give the compound 10 (2.40 g, 90%) as colorless oil.
54%) as yellowish oil. 1H NMR (400 MHz, CDCl3)
d
4.71 (t, J ¼ 4.8 Hz,
1H), 3.90e3.84 (m, 2H), 3.78e3.73 (m, 2H), 3.58 (s, 3H), 3.34e3.25
(m, 1H), 2.39e2.35 (m, 2H), 2.30e2.26 (m, 2H), 1.90e1.83 (m, 2H),
1.80e1.73 (m, 1H), 1.70e1.64 (m, 1H), 1.03 (d, J ¼ 7.0 Hz, 3H). 13C
1H NMR (400 MHz, CDCl3)
J ¼ 8.0 Hz, 1H), 5.95e5.85 (m, 1H), 5.69 (s, 1H), 5.06 (dd, J ¼ 17.1,
d
6.87 (d, J ¼ 8.0 Hz, 1H), 6.68 (d,
NMR (101 MHz, CDCl3) d 195.08, 152.56, 148.10, 103.16, 64.65, 64.63,
5

K. Wang, Z. Xu, X. Tan et al.
Tetrahedron xxx (xxxx) xxx
1.5 Hz, 1H), 4.97 (d, J ¼ 10.2 Hz, 1H), 4.71 (dd, J ¼ 6.2, 4.0 Hz, 1H),
3.98e3.90 (m, 2H), 3.84e3.76 (m, 5H), 3.37e3.28 (m, 1H),
2.71e2.68 (m, 2H), 2.40e2.34 (dd, J ¼ 15.1, 7.2 Hz, 2H), 2.04e1.97
(m, 1H), 1.89e1.82 (m, 1H), 1.26 (d, J ¼ 6.9 Hz, 3H). 13C NMR
4.2.10. 4a-(1-(1,3-dioxolan-2-yl)propan-2-yl)-7-(but-3-en-1-yl)-
8a-methoxy-3,4,4a,8a-tetrahydro-2H-4,7,2 (epiethane[1,1,2]triyl)
chromen-8(7H)-one (25a) and its isomer 25b
The solution of the compound 24a (390 mg,1.04 mmol) in 20 mL
toluene was stirred at 95 ꢀC for 14 days. The solvent was concen-
trated under reduced pressure, and the resulting residue was pu-
rified by chromatography on silica gel (petroleum ether/ethyl
acetate ¼ 8:1) to afford the product compound 25a (372 mg, 95%)
(101 MHz, CDCl3)
d 146.72, 144.32, 138.57, 137.01, 126.11, 125.60,
117.26, 114.54, 103.36, 64.79, 64.65, 61.75, 41.55, 33.73, 29.30, 27.94,
22.78. HRMS (ESIMS) calcd for C17H24O4Naþ [M þ Na]þ 315.1567,
found 315.1575.
as colorless oil. 1H NMR (400 MHz, CDCl3)
d 6.25 (s, 1H), 5.90e5.80
4.2.8. 5-(1-(1,3-dioxolan-2-yl)propan-2-yl)-2-(but-3-en-1-yl)-6,6-
dimethoxycyclohexa-2,4-dien-1-one (22)
(m, 2H), 5.04 (dd, J ¼ 17.1,1.5 Hz,1H), 4.97e4.91 (m, 2H), 4.37 (s,1H),
3.98e3.89 (m, 2H), 3.85e3.79 (m, 2H), 3.63 (s, 3H), 2.45 (t,
J ¼ 9.0 Hz, 1H), 2.45 (t, J ¼ 9.0 Hz, 1H), 2.27e1.79 (m, 8H), 1.56e1.49
(m, 1H), 1.45e1.32 (m, 3H), 1.10 (t, J ¼ 5.7 Hz, 3H). 13C NMR
In a dry argon-purged flask was placed compound 10 (8.2 mg,
0.028 mmol, 1.0 equiv.) in dry MeOH (0.7 mL). The mixture was
stirred at 0 ꢀC for 5 min. PIDA (11.8 mg, 0.036 mmol, 1.3 equiv.) was
added. Then the reaction was warmed up to rt. The reaction
mixture was extracted with ethyl acetate, the organic layer was
washed with brine, dried over Na2SO4, filtered and the solvents
were evaporated under reduced pressure. The residue was purified
by column chromatography (silica gel, petroleum ether/ethyl
acetate ¼ 8:1) to yield compound 22 (7.1 mg, 78%) as yellow oil. 1H
(101 MHz, CDCl3)
d 206.34, 138.41, 138.41, 130.03, 114.56, 104.61,
94.83, 75.58, 64.71, 64.42, 53.72, 52.17, 49.25, 43.06, 37.56, 37.01,
36.59, 32.50, 28.61, 28.19, 17.27. HRMS (ESIMS) calcd for
C
22H30O5Naþ [M þ Na]þ 397.1985, found 397.1985.
In the same procedure, 24b (452 mg, 1.20 mmol) was trans-
formed to 25b (438.6 mg) with 97% as colorless oil. 1H NMR
(400 MHz, CDCl3)
d
6.29 (d, J ¼ 8.5 Hz, 1H), 5.93e5.82 (m, 2H),
NMR (400 MHz, CDCl3)
d
6.66 (d, J ¼ 6.5 Hz, 1H), 6.16 (d, J ¼ 6.5 Hz,
5.09e5.05 (m, 1H), 5.00e4.95 (m, 2H),4.37 (s, 1H), 4.00e3.90 (m,
2H), 3.87e3.82 (m, 2H), 3.68 (s, 3H), 2.49e2.45 (m, 2H), 2.26e2.22
(m, 1H), 2.19e2.12 (m, 3H), 2.04 (d, J ¼ 12.0 Hz, 1H), 1.98e1.81 (m,
1H), 5.78 (ddt, J ¼ 16.8, 10.2, 6.6 Hz, 1H), 4.98 (t, J ¼ 13.7 Hz, 2H),
4.89 (t, J ¼ 5.0 Hz, 1H), 4.02e3.91 (m, 2H), 3.88e3.76 (m, 2H), 3.20
(d, J ¼ 2.5 Hz, 6H), 2.92e2.77 (m, 1H), 2.36 (t, J ¼ 7.5 Hz, 2H), 2.21
(dd, J ¼ 14.1, 7.1 Hz, 2H), 1.96 (dt, J ¼ 13.7, 5.2 Hz, 1H), 1.73 (ddd,
J ¼ 13.9, 8.8, 5.1 Hz, 1H), 1.21 (d, J ¼ 6.9 Hz, 3H). 13C NMR (101 MHz,
2H),1.58e1.51 (m,1H),1.45e1.31 (m, 3H),1.06 (d, J ¼ 6.5 Hz, 3H). 13
C
NMR (101 MHz, CDCl3)
d 207.21, 138.51, 138.51, 130.72, 114.64,
105.50, 94.70, 75.40, 64.73, 64.33, 53.77, 52.29, 49.99, 43.80, 39.55,
36.96, 36.67, 32.69, 28.68, 28.25, 17.65. HRMS (ESIMS) calcd for
CDCl3) d 197.07, 155.13, 137.70, 136.69, 134.98, 121.71, 115.21, 103.56,
95.15, 64.79, 64.56, 50.86, 50.80, 40.96, 32.54, 29.18, 27.91, 21.54.
C
22H30O5Naþ [M þ Na]þ 397.1985, found 397.1984.
4.2.9. 5-(1-(1,3-dioxolan-2-yl)propan-2-yl)-2-(but-3-en-1-yl)-6-
(cyclopent-3-en-1-yloxy)-6-methoxycyclohexa-2,4-dien-1-one
(24a) and its isomer 24b
4.2.11. (3a,4,7a)-4-(1-(1,3-dioxolan-2-yl)propan-2-yl)-7-(but-3-
en-1-yl)-2-hydroxy-2,3,3a,4,7,7a-hexahydro-1H-4,7-ethanoinden-
8-one (26a)
In a dry argon-purged flask was placed K2CO3 (973.4 mg,
7.05 mmol, 1.2 equiv.), cyclopent-3-en-1-ol 9 (5.0 mL, 58.69 mmol,
10 equiv.) and compound 10 (1.72 g, 5.87 mmol, 1.0 equiv.) in dry
THF (1.2 mL). The mixture was stirred at ꢁ78 ꢀC for 5 min [Bis(-
trifluoroacetoxy)iodo]benzene (3.43 g, 9.12 mmol, 1.0 equiv.) in dry
THF (10 ml) was dropwise added. Then the reaction was warmed up
to 0 ꢀC in 8 h. The reaction mixture was extracted with ethyl ace-
tate, the organic layer was washed with saturated NaHCO3, brine,
dried over Na2SO4, filtered and the solvents were evaporated under
reduced pressure. The residue was purified by column chroma-
tography (silica gel, petroleum ether/ethyl acetate ¼ 32:1) to yield
compound 24a (773.4 mg, 35%) and 24b (925.7 mg, 42%) as yellow
oil.
The compound 25a (360 mg, 0.96 mmol, 1.0 equiv.) was dis-
solved in the methanol. The reaction mixture was degassed 3 times.
0.1M (in THF) SmI2 (57.6 mL, 5.76 mmol, 6.0 equiv.) was injected
into the reaction at room temperature. After the solution was stir-
red for 1 h, it was exposed to air until dark color disappeared. Brine
was added, the reaction mixture was extracted with ethyl acetate,
the organic layer was dried over Na2SO4, filtered and the solvents
were evaporated under reduced pressure. The residue was purified
by column chromatography (silica gel, petroleum ether/ethyl
acetate ¼ 2:1) to yield compound 26a (331.4 mg, 90%) as colorless
oil. 1H NMR (400 MHz, CDCl3)
d
6.38 (d, J ¼ 8.5 Hz, 1H), 6.03 (d,
J ¼ 8.5 Hz, 1H), 5.90e5.80 (m, 1H), 5.04 (dd, J ¼ 17.1, 1.5 Hz, 1H),
4.97e4.91 (m, 2H), 4.21e4.12 (m, 1H), 4.0e3.93 (m, 2H), 3.88e3.81
(m, 2H), 2.33e1.84 (m, 9H), 1.84e1.72 (m, 3H), 1.58e1.45 (m, 2H),
1.26e1.18 (m, 2H),1.02 (d, J ¼ 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3)
24a: 1H NMR (400 MHz, CDCl3)
d
6.65 (d, J ¼ 6.5 Hz, 1H), 6.12 (d,
J ¼ 6.5 Hz, 1H), 5.85e5.74 (m, 1H), 5.62e5.59 (m, 1H), 5.57e5.54 (m,
1H), 5.03e4.96 (m, 3H), 4.87 (t, J ¼ 5.1 Hz, 1H), 3.96e3.88 (m, 2H),
3.82e3.77 (m, 2H), 3.08 (s, 3H), 2.91e2.83 (m, 1H), 2.63e2.57 (m,
1H), 2.54e2.42 (m, 2H), 2.40e2.29 (m, 2H), 2.26e2.13 (m, 2H),
2.05e1.96 (m, 2H), 1.68e1.61 (m, 1H), 1.19 (d, J ¼ 7.0 Hz, 3H). 13C
d
213.06, 138.95, 138.77, 132.07, 114.41, 103.82, 73.83, 64.90, 64.65,
56.23, 46.11, 43.42, 40.63, 39.94, 37.36, 35.83, 35.43, 31.27, 28.58,
28.31, 15.64. HRMS (ESIMS) calcd for C21H31Oþ4 [M þ H]þ 347.2217,
found 347.2224.
NMR (101 MHz, CDCl3)
d 198.32, 155.76, 137.76, 136.74, 134.78,
128.59, 128.04, 121.08, 115.20, 103.56, 95.09, 71.80, 64.76, 64.46,
51.75, 42.04, 41.14, 40.81, 32.52, 29.69, 28.07, 21.03. HRMS (ESIMS)
calcd for C22H30O5Naþ [M þ Na]þ 397.1985, found 397.1992.
4.2.12. (3a,4,7a)-4-(1-(1,3-dioxolan-2-yl)propan-2-yl)-7-(but-3-
en-1-yl)-2-hydroxy-2,3,3a,4,7,7a-hexahydro-1H-4,7-ethanoinden-
8-one (26b)
24b: 1H NMR (400 MHz, CDCl3)
d
6.65 (d, J ¼ 6.5 Hz, 1H), 6.10 (d,
As prepared for 26a, the 25b (430.6 mg, 1.15 mmol) was trans-
J ¼ 6.5 Hz,1H), 5.85e5.75 (m,1H), 5.63e5.56 (m, 2H), 5.05e4.85 (m,
4H), 3.99e3.93 (m, 2H), 3.86e3.80 (m, 2H), 3.11 (s, 3H), 2.92e2.83
(m, 1H), 2.63e2.47 (m, 2H), 2.43e2.31 (m, 3H), 2.26e2.16 (m, 2H),
2.10e2.05 (m, 1H), 1.95e1.89 (m, 1H), 1.78e1.71 (m, 1H), 1.20 (d,
formed to 26b (358.3 mg) with 90% as a white solid; mp 99e101 ꢀC.
1H NMR (400 MHz, CDCl3)
d
6.37 (d, J ¼ 8.5 Hz, 1H), 6.01 (d,
J ¼ 8.4 Hz, 1H), 5.90e5.80 (m, 1H), 5.03 (d, J ¼ 17.1 Hz, 1H),
4.96e4.90 (m, 2H), 4.21e4.13 (m,1H), 3.98e3.92 (m, 2H), 3.87e3.81
(m, 2H), 2.29e1.92 (m, 9H), 1.82e1.68 (m, 3H), 1.59e1.45 (m, 2H),
1.32e1.23 (m, 1H), 1.03 (d, J ¼ 6.8 Hz, 3H). 13C NMR (101 MHz,
J ¼ 6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 198.24, 155.65, 137.78,
136.67, 134.83, 128.53, 128.10, 120.98, 115.19, 103.52, 95.50, 72.09,
64.80, 64.60, 51.56, 41.24, 40.73, 40.60, 32.50, 29.34, 28.07, 22.26.
HRMS (ESIMS) calcd for C22H30O5Naþ [M þ Na]þ 397.1985, found
397.1992.
CDCl3)
d 213.05, 139.21, 138.76, 131.92, 114.41, 103.81, 73.83, 64.89,
64.62, 56.29, 45.96, 43.26, 40.56, 40.15, 37.27, 36.69, 35.50, 31.58,
28.56, 28.29, 15.35. HRMS (ESIMS) calcd for C21H31Oþ4 [M þ H]þ
6

K. Wang, Z. Xu, X. Tan et al.
Tetrahedron xxx (xxxx) xxx
347.2217, found 347.2226.
137.70, 135.16, 131.76, 114.70, 58.69, 57.88, 43.41, 42.59, 41.40, 39.96,
39.73, 34.51, 28.83, 28.42, 18.65.
4.2.13. (3a,4,7a)-4-(-1-(1,3-dioxolan-2-yl)propan-2-yl)-7-(but-3-
en-1-yl)-1,3,3a,4,7,7a-hexahydro-2H-4,7-ethanoindene-2,8-dione
(30b)
4.2.16. (2a,2a1,3,5a,6)-3-(but-3-en-1-yl)-6-methyl-2a,2a1,6,7-tetra
hydro-3H-3,5a-ethanoacenaphthylene-1,10(2H)-dione (32b)
Method b: In a dry argon-purged flask, the solution of the above
aldehyde 31b (24 mg, 0.08 mmol) in 1.9 mL THF was added sodium
tert-butoxide (11.2 mg, 0.12 mmol, 1.2 equiv) at 0 ꢀC. After 5 min,
saturated NH4Cl solution was added, and the mixture was extracted
with ethyl acetate. the organic layer was dried over Na2SO4, filtered
and the solvents were evaporated under reduced pressure, and the
resulting residue was purified by chromatography on silica gel
(petroleum ether/ethyl acetate ¼ 4:1) to afford the product com-
pound 32b (10.9 mg, 40%) as a colorless oil.
To a solution of the compound 26b (358.3 mg, 1.03 mmol, 1.0
equiv.) in dichloromethane (20 mL) was cooled to 0 ꢀC and treated
with DMP (873.7 mg, 2.06 mmol, 2.0 equiv.). The mixture was
stirred for 8 h at room temperature. The reaction was then directly
purified by chromatography on silica gel (petroleum ether/ethyl
acetate ¼ 3:1) to afford the product compound 30b (354.5 mg,
>99%) as colorless oil. 1H NMR (400 MHz, CDCl3)
d 6.43 (d,
J ¼ 8.5 Hz, 1H), 6.09 (d, J ¼ 8.5 Hz, 1H), 5.87e5.77 (m, 1H), 5.02 (dd,
J ¼ 17.1, 1.3 Hz, 1H), 4.89 (dd, J ¼ 5.8, 3.7 Hz, 1H), 3.95e3.88 (m, 2H),
3.84e3.77 (m, 2H), 2.62e2.52 (m, 2H), 2.37e2.23 (m, 3H),
2.23e2.09 (m, 2H), 2.05e2.196 (m, 1H), 1.90 (d, J ¼ 18.9 Hz, 1H),
4.2.17. (3a,4,7a)-4-(-1-(1,3-dioxolan-2-yl)propan-2-yl)-7-(but-3-
en-1-yl)-1,3,3a,4,7,7a-hexahydro-2H-4,7-ethanoindene-2,8-dione
(30a)
1.85e1.76 (m, 2H), 1.69e1.45 (m, 4H), 1.02 (d, J ¼ 6.6 Hz, 3H). 13
C
NMR (101 MHz, CDCl3)
d 216.47, 211.21, 138.30, 138.30, 131.58,
114.64, 103.49, 64.86, 64.58, 56.48, 46.28, 40.62, 39.93, 39.30, 38.92,
38.15, 36.57, 31.03, 28.50, 28.44, 15.43. HRMS (ESIMS) calcd for
C
In the same procedure, 26a (280.0 mg, 0.81 mmol,1.0 equiv) was
transformed to 30a (278.2 mg) with 99% as colorless oil. 1H NMR
21H29Oþ4 [M þ H]þ 345.2060, found 345.2069.
(400 MHz, CDCl3)
d
6.47 (d, J ¼ 8.5 Hz, 1H), 6.13 (d, J ¼ 8.5 Hz, 1H),
5.90e5.85 (m, 1H), 5.05 (dd, J ¼ 17.1, 1.6 Hz, 1H), 4.97 (dd, J ¼ 10.2,
1.4 Hz, 1H), 4.92 (dd, J ¼ 6.2, 3.3 Hz, 1H), 3.99e3.92 (m, 2H),
3.88e3.81 (m, 2H), 2.70e2.54 (m, 2H), 2.45e2.29 (m, 2H),
2.24e2.12 (m, 3H), 2.08e1.99 (m, 1H), 1.93 (d, J ¼ 19.0 Hz, 1H),
4.2.14. 3-((3aS,4S,7S,7aR)-7-(but-3-en-1-yl)-2,8-dioxo-1,2,3,3a, 7,
7a-hexahydro-4H-4,7-ethanoinden-4-yl) butanal (31b)
To a stirred solution of the compound 30b (33.5 mg, 0.10 mmol,
1.0 equiv.) in 1.8 mL THF was added 0.68 mL10% HCl. The mixture
was stirred for 2 h at 50 ꢀC, then the reaction was quenched with
saturated NaHCO3 solution, and the mixture was extracted with
ethyl acetate. The combined organic layers were washed with
brine, dried with anhydrous NaSO4, filtered and the solvents were
evaporated under reduced pressure to leave the aldehyde 31b
1.90e1.70 (m, 4H), 1.63e1.48 (m, 2H), 1.05 (d, J ¼ 6.8 Hz, 3H). 13
C
NMR (101 MHz, CDCl3)
d 216.59, 211.59, 138.36, 138.31, 131.87,
114.74, 103.46, 64.96, 64.72, 56.52, 46.51, 41.11, 40.05, 39.22, 39.04,
38.41, 35.80, 30.87, 28.58, 28.54, 15.83. HRMS (ESIMS) calcd for
C
21H29Oþ4 [M þ H]þ 345.2060, found 345.2065.
(24 mg, 80%). 1H NMR (400 MHz, CDCl3)
d
9.79 (d, J ¼ 1.6 Hz, 1H),
4.2.18. (2a,2a1,3,5a,6)-3-(but-3-en-1-yl)-6-methyl-2a,2a1,6,7-
tetrahydro-3H-3,5a-ethanoacenaphthylene-1,10(2H)-dione (32a)
In the same procedure, 30a (30.5 mg, 0.09 mmol, 1.0 equiv) was
transformed to 32a (10.2 mg) as a white solid with 32% yield in two
6.44 (d, J ¼ 8.6 Hz, 1H), 6.17 (d, J ¼ 8.5 Hz, 1H), 5.85 (dd, J ¼ 17.0,
10.3 Hz, 1H), 5.11e4.94 (m, 2H), 2.72e2.48 (m, 3H), 2.48e2.28 (m,
4H), 2.28e2.10 (m, 2H), 2.10e2.01 (m, 1H), 1.99 (m, 1H), 1.94e1.76
(m, 2H), 1.65 (m, 1H), 1.54 (m, 1H), 1.03 (d, J ¼ 6.9 Hz, 3H). 13C NMR
steps. 1H NMR (400 MHz, CDCl3)
d
6.65 (d, J ¼ 8.4 Hz, 1H), 6.57 (dd,
(101 MHz, CDCl3)
d 215.97, 210.47, 200.80, 138.23, 137.51, 132.36,
J ¼ 7.4, 3.1 Hz, 1H), 6.13 (d, J ¼ 8.4 Hz, 1H), 5.93e5.83 (m, 1H), 5.08
(dd, J ¼ 17.2, 1.3 Hz, 1H), 5.00 (d, J ¼ 10.1 Hz, 1H), 2.83e2.80 (m, 1H),
2.66e2.45 (m, 3H), 2.18e1.99 (m, 5H), 1.89e1.79 (m, 2H), 1.73 (dd,
114.88, 56.61, 46.86, 45.79, 40.68, 39.96, 39.39, 39.05, 38.12, 29.37,
28.55, 28.52, 15.59.
J ¼ 18.3, 1.5 Hz, 1H), 1.61e1.54 (m, 1H), 1.13 (d, J ¼ 7.1 Hz, 3H). 13
C
4.2.15. (2a,2a1,3,5a,6)-3-(but-3-en-1-yl)-6-methyl-2a,2a1,6,7-tetra
hydro-3H-3,5a-ethanoacenaphthylene-1,10(2H)-dione (32b); 4-
(but-3-en-1-yl)-8-methyl-1,3a,4,7,8,8b-hexahydro-2H-4,8a-
etheno-as-indacene-2,5(3H)-dione (33b)
NMR (101 MHz, CDCl3)
d 211.63, 205.33, 139.64, 138.46, 138.16,
132.82, 131.44, 114.77, 56.61, 42.84, 41.62, 39.52, 38.45, 37.31, 32.48,
30.53, 28.66, 28.13, 17.96. HRMS (ESIMS) calcd for C19H23Oþ2 [M þ
H]þ 283.1693, found 283.1701.
Method a: In a dry argon-purged flask, the solution of the
aldehyde 31b (16 mg, 0.053 mmol) in 0.53 mL benzene was added
PTSA (3.0 mg, 0.016 mmol, 0.3 equiv.) at 80 ꢀC for 3 days. The
mixture was extracted with ethyl acetate. the organic layer was
dried over Na2SO4, filtered and the solvents were evaporated under
reduced pressure, and the resulting residue was purified by chro-
matography on silica gel (petroleum ether/ethyl acetate ¼ 4:1) to
afford the product compound 32b:33b ¼ 1:2 inseparable isomer
(0.8 mg, 5%).
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgments
32b: 1H NMR (400 MHz, CDCl3)
d 6.61e6.59 (m, 2H), 6.14 (d,
We gratefully acknowledge financial support from the NNSFC
(Grants 21672088, 21772079 and 21971096) and the Natural Sci-
ence Foundation of Gansu Province (18JR4RA003).
J ¼ 8.4 Hz, 1H), 5.92e5.82 (m, 1H), 5.10e5.05 (m, 1H), 4.99 (d,
J ¼ 9.8 Hz, 1H), 2.74e2.58 (m, 3H), 2.46 (dd, J ¼ 19.5, 10.1 Hz, 1H),
2.24e2.16 (m, 2H), 2.12e2.02 (m, 1H), 1.94e1.80 (m, 5H), 1.59e1.51
(m, 1H), 1.07 (d, J ¼ 6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 211.75,
Appendix A. Supplementary data
205.30, 140.28, 138.50, 138.48, 133.89, 131.34, 114.74, 56.69, 46.19,
42.76, 39.58, 38.32, 35.44, 33.86, 32.91, 28.71, 28.35, 16.10. HRMS
(ESIMS) calcd for C19H23O2þ [M þ H]þ 283.1693, found 283.1700.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131629.
33b: 1H NMR (400 MHz, CDCl3)
1H), 6.09 (d, J ¼ 8.4 Hz, 1H), 5.94e5.79 (m, 1H), 5.03 (dd, J ¼ 34.4,
13.6 Hz, 2H), 2.88 (m, 1H), 2.76e1.71 (m, 12H), 1.23 (d, J ¼ 7.2 Hz,
d
6.76 (d, J ¼ 8.4 Hz, 1H), 6.56 (s,
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8