Divergent total synthesis of aspinolides B, E and J

Article abstract of DOI:10.1016/j.tet.2019.06.015

Stereoselective total synthesis of aspinolides B, E and J, naturally occurring 10-membered lactones, were accomplished by divergent strategies starting from the commercially available 2,3-O-isopropylidene-D-ribose and methyl D-lactate. The synthesis features rapid access to the both key fragments from chiral pool and the formation of 10-membered ring lactones containing trans double bond employing cross-metathesis reaction (CM) and intramolecular Shiina macrolactonization.

Full text of DOI:10.1016/j.tet.2019.06.015

Accepted Manuscript
Divergent total synthesis of aspinolides B, E and J
Caizhu Chang, Jialin Geng, Yuguo Du, Qingwei Lv, ZhiBing Dong, Jun Liu
PII:
S0040-4020(19)30668-4
https://doi.org/10.1016/j.tet.2019.06.015
TET 30407
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 April 2019
Revised Date: 4 June 2019
Accepted Date: 11 June 2019
Please cite this article as: Chang C, Geng J, Du Y, Lv Q, Dong Z, Liu J, Divergent total synthesis of
aspinolides B, E and J, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.06.015.
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ACCEPTED MANUSCRIPT
O
HO
O
HO
CH3
HO
H3C
O
O
OH
Aspinolide B
O
O
HO
HO
O
O
9-10 steps
O
CH3
OH
O
O
OH
HO
Aspinolide J
O
H3CO
CH3
HO
CH3
O
H3C
Aspinolide E
O

ACCEPTED MANUSCRIPT
Divergent Total Synthesis of Aspinolides B, E and J
Caizhu Changa,b, Jialin Genga,c, Yuguo Du a,c, Qingwei Lv a,c, ZhiBing Dong*b, Jun Liu*,a, c
aState Key Laboratory of Environmental Chemistry and Eco-toxicology, Research Center for
Eco-Environmental Sciences, Chinese Academy of Science, Beijing 100085, China;
bSchool of Chemistry and Environmental Engineering, Wuhan Institute of Technology, Wuhan
430205, China
cSchool of Chemical Sciences, University of Chinese Academy of Sciences, Beijing 100049,
China
Abstract
Stereoselective total synthesis of aspinolides B, E and J, naturally occurring 10-membered
lactones, were accomplished by divergent strategies starting from the commercially available
2,3-O-isopropylidene-D-ribose and methyl D-lactate. The synthesis features rapid access to the
both key fragments from chiral pool and the formation of 10-membered ring lactones containing
trans double bond employing cross-metathesis reaction (CM) and intramolecular Shiina
macrolactonization.
Introduction
Naturally occurring 10-membered lactones exhibit various important biological activities such as
antibacterial, antimalarial, cytotoxic, antitumor, antifungal, antifeedant, phytotoxic,
anti-microfilament, etc.1 Within this family, the 10-membered macrolide, aspinolide B, was
isolated from the cultures of Aspergillus ochraceus by Zeeck group, along with other aspinolides
in 1997 (Fig. 1).2 Subsequent exploration of the secondary metabolome of trichoderma
arundinaceum (Ta37) and TaꢀTri5 (harzianum A non-producer mutant) led to a second isolation
of aspinolides B (1), C (2) and characterization of new aspinolides D-J.3, 4 Architecturally,
aspinolides B (1), E (3) and J (4) have the same 10-membered lactone backbone and
stereochemistry, except for the ester on the side chain which attaches to C-8, respectively (Fig. 1).
The relative stereochemistry of aspinolide B was established by using X-ray crystallographic
diffraction analysis and the absolute configuration (4S,5R,8S,9R) was further established on the
basis of Helmchen’s method.2, 5 Preliminary biological studies on aspinolides indicated that
aspinolide B slightly repressed SA-related genes, while aspinolide C significantly induced the
SA-related genes PR1b1 and PR-P2 when their expression of plant defence-related genes
(50ꢁg/ml) was analysed.4
Fig. 1. Chemical structures of aspinolides (1-4).
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Their interesting biological profile combined with structural features has aroused the interest of
the synthetic community, and a few total syntheses of aspinolide have appeared accordingly.6
Since the first synthesis of aspinolide B reported by Pilli and coworkers6f through
Nozaki-Hiyama-Kishi reaction as the key step, many efforts have been made in the total synthesis
of aspinolides. In view of the structural feature of aspinolides B, E and J, it is therefore highly
desirable to develop an efficient synthetic approach, in which a readily accessible macrocyclic
lactone skeleton bearing suitable functionality would serve as a key intermediate for the divergent
total synthesis of these natural products as well their analogues. In particular, to the best of our
knowledge, the total synthesis of aspinolides C-J have not been reported so far. As part of our
interests in the total synthesis of various complex natural products based on carbohydrate
skeletons, 7 herein we disclose the divergent and stereoselective synthesis of aspinolides B, E and
J using readily available D-ribose as chiral pool.
Results and discussion
Scheme 1. Retrosynthetic analysis of aspinolides B, E and J
Retrosynthetic analysis of the target aspinolides is shown in Scheme 1. Generally cyclizations of
medium ring lactones are more difficult due to both enthalpic and entropic factors.8 Several routes
have been previously reported for synthesizing these 10-membered ring lactones containing trans
double bond employing ring-closing metathesis (RCM) in the final step.9 The major challenge in
the macrocyclic formation using the RCM strategy is the necessary optimization of reaction
conditions and controlling the double bond geometry.10 Macrolactonization has proven to be
particularly useful in the closing strained medium to large rings with the preservation of double
bond geometry in the final stage.11 Accordingly, we envisaged that aspinolides B, E and J could be
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elaborated from well functionalized macrocyclic lactone 5. The key intermediate 5 could be
obtained from building blocks 6 and 7, as the precursors of cross metathesis (CM) followed by
Shiina macrolactonization of the resulting CM product containing trans double bond. The ester 6
would be readily accessible obtained from 2,3-O-isopropylidene-D-ribose whereas the fragment 7
could be accessed from D-methyl lactate through reduction and Grignard addition by a one-pot
sequence.
Scheme 2. Synthesis of ester 6. Reagents and conditions: (a) Ph3P=CHCO2Et, PhCOOH(cat.),
DCM, reflux, 92%; (b) Pd-C, MeOH-EtOAc, H2; (c) I2, PPh3, imidazole, toluene, reflux, 67% for
2 steps;
As depicted in Scheme 2, the synthesis of fragment 6 was commenced with commercially
available 2,3-O-isopropylidene-D-ribose (8) which was subjected to chain extension with Wittig
olefination to afford α,β-unsaturated ester 10 according to the reported procedure.12a,b
Hydrogenation of 10 over 5% Pd-C in methanol and EtOAc gave the diol 11 in excellent yield.
According to the methodology developed by Garegg and Samuelsson,13 11 was then converted
into the teminal alkene 6 14 by using I2/TPP/imidazole in refluxing toluene.
The synthesis of fragment 7 was accessible from D-methyl lactate in 70% yield over two steps as
shown in Scheme 3. Protection of lactate with silyl group afforded the known compound 12 in
96% yield. 15a Reduction of ester 12 by DIBAL-H and subsequent treatment of the resulting
aldehyde with vinylmagnesium chloride in one-pot furnished the desired anti allylic alchol 7
(5.8:1 mixture of diastereoisomers from crude 1H NMR analysis). 15b-c
Scheme 3. Synthesis of compound 7. Reagents and conditions: (a) TBSCl, imidazole, DCM, rt,
96%; (b) DIBAL-H, Et2O, then vinylmagnesium chloride, -98 °C-rt, 73%;
With the required building blocks in hand, we then turned our attention to the construction of the
macrocyclic lactone skeleton following our retrosynthetic analysis (Scheme 4). The olefin
cross-metathesis between fragments 6 and 7 carried out smoothly using a catalytic amount of
Hoveyda-Grubbs Catalyst (2nd Generation)16 generated the desired olefin 13 in a satisfactory
yield of 75%. A small amount of homodimer of 7 (11%) was also observed.
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Scheme 4. Syntheses of aspinolide J. Reagents and conditions: (a) Hoveyda-Grubbs Catalyst 2nd
Generation, dry DCM, reflux, 8 h, 75%; (b) crtonic anhydride, cat. DMAP, Py, rt, 5 h, 88%; (c)
LiOH, THF/H2O=3:2, 0oC to rt, 24 h; (d) HF-pyridine complex, THF/Py (10:1), rt, 24 h, 67% for
two steps; (e) MNBA, DMAP, toluene, 80oC, 18 h, 90%;
Esterification of 13 with crtonic anhydride in pyridine in the presence of DMAP to generate 14 in
88% yield. Regioselective hydrolysis of the ethyl ester of 14 with aqueous lithium hydroxide
afforded acid 15. Cleavage of the TBS group with weakly acidic HF-pyridine complex and
macrolactonization in the presence of MNBA and DMAP (Shiina's protcol)11b,17 furnished the key
intermediate 5 in excellent yield.
Scheme 5. Reagents and conditions: (a) 4N HCl, MeOH, rt, 2 h, 89%; (b) NaBH4, CuCl,
THF-EtOH (3:7), -40oC, 1 h, 76%; (c) 5% K2CO3, acetone, rt, 24 h; (d) 1N HCl, MeOH, rt, 3 h,
65% for two steps; (e) 5% K2CO3, acetone, rt. 40%;
With the key macrocyclic lactone 5 in hand, the stage was set for completion of the divergent total
synthesis of aspinolides B, E and J. Deprotection of the acetonide group in the lactone 5 with 4N
HCl afforded aspinolide B (1) in 89% yield. After considerable experimentation, selective
reduction of the crotonate to afford the corresponding butyrate ester, aspinolides E (3), was
accomplished by application of Narisada’s Cu(I)/ NaBH4 protocol.18 The crotonate ester in 5 was
selective hydrolyzed smoothly to afford 17 under 5% K2CO3 in acetone.4 The resulting alcohol 17,
without further purification, was subjected to 1N HCl underwent acetonide deprotection at
ambient temperature to deliver the desired macrolactone aspinolides J (4) in 65% overall yield
(Scheme 5). Alternatively, hydrolysis of the natural product aspinolide B (1) with 5% K2CO3 in
acetone also resulted in aspinolides J (4). The physical and spectroscopic data of aspinolides B, E
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and J were in good agreement with the data previously reported for the natural products. 2,3,4,19
Conclusions
In summary, we have successfully developed an efficient approach for the divergent total synthesis
of aspinolides B, E and J. In particular, aspinolides E and J, which are the first total synthesis so
far, were achieved in 10 linear steps with a 16.6% overall yield and with a 13.8% overall yields,
respectively. Further optimization of this strategy and the synthesis of other aspinolides as well as
the bioactivity evaluations are currently underway in our laboratory.
Experimental section
General Experimental
Unless noted otherwise, commercially available materials were used without further purification.
All solvents were dried according to the established procedures ahead of use. Flash
chromatography (FC) was performed using silica gel (200-300 meshes) according to the standard
protocol. All reactions under standard conditions were monitored by thin-layer chromatography
(TLC) on gel F254 plates. Optical rotations were measured using a polarimeter with a thermally
jacketed 5 cm cell at approximately 20 oC. Melting points were recorded in open capillary tubes
with a melting point apparatus (Buchi Melting Point M-560) and are uncorrected. IR(FT-IR)
spectra were recorded on a Perkin-Elmer BXII spectrometer with KBr pellets. High-resolution
mass spectrometry data (HRMS) were acquired using a Q-TOF analyzer in acetone or methanol as
1
solvent. H NMR, 13C NMR were measured on 400 MHz or 100 MHz spectrometers (NMR in
CDCl3 with TMS as an internal standard). Chemical shifts (δ) are given in ppm relative to residual
1
solvent (usually chloroform; δ 7.26 for H NMR or 77.0 for proton decoupled 13C NMR), and
coupling constants (J) in Hz. Multiplicity is tabulated as s for singlet, d for doublet, t for triplet, q
for quadruplet, and m for multiplet.
Synthesis of ethyl 3-((4S,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)propanoate (6)
A catalytic amount of 10% Pd/C (10 mg) was added to a solution of 10 (195 mg, 0.75 mmol) in
MeOH/EtOAc (1:1, 12 mL). The mixture was stirred at room temperature for 1 h under H2
atmosphere. After completion of reaction (TLC), the catalyst was removed by filtration, washed
twice with ethyl acetate and the combined filtrate was concentrated to afford 11 as a colorless oil
which was used for the next step without further purification.
To a solution of the crude 11 in dry toluene (7 mL) was added triphenylphosphine (786 mg, 3.0
mmol) followed by imidazole (204 mg, 3.0 mmol) and stirred vigorously. To the resulting solution
was added iodine (571 mg, 2.25 mmol) portion wise and the mixture was refluxed for 3 h. After
completion of reaction, the mixture was cooled to room temperature and poured into saturated
aqueous Na2S2O3 (20 mL), and then was extracted with EtOAc (3
× 20 mL). The combined
organic phase was dried over Na2SO4, and concentrated under reduced pressure. The crude was
purified by flash column chromatography (petroleum ether/EtOAc 20:1) to give 6 as a colorless
5

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oil (114 mg, 67% for two steps). [α]D20 -4.6 (c 0.54, CHCl3); 1H NMR (400 MHz, Chloroform-d) δ
5.81 (ddd, J = 17.5, 10.3, 7.6 Hz, 1H), 5.35 - 5.24 (m, 2H), 4.53 (t, J = 6.9 Hz, 1H), 4.17 - 4.10 (m,
3H), 2.51 - 2.32 (m, 2H), 1.77 - 1.71 (m, 2H), 1.47 (s, 3H), 1.35 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H);
13C NMR (100 MHz, Chloroform-d) δ 173.3, 133.8, 118.6, 108.4, 79.5, 77.2, 60.4, 30.9, 28.1,
26.1, 25.6, 14.2. HRMS (ESI-TOF) m/z: [M + Na]+Calcd for C12H20O4Na 251.1259; Found
251.1273; IR (KBr) 2893, 2933, 1738, 1370, 1255, 1211, 1159, 1065, 1044, 932, 867 cm-1.
Synthesis of (3S,4R)-4-((tert-butyldimethylsilyl)oxy)pent-1-en-3-ol (7)
To a solution of TBS-protected lactate 12 (2.6 g, 11.9 mmol) in dry ether (60 mL) was added
slowly DIBAL-H (1.0 M, 13.1 mL, 13.1 mmol) via syringe at −98 °C under N2 atmosphere and
stirred for 15 min. After completion of reaction (TLC), vinylmagnesium chloride (1.0 M, 29.7 mL,
29.7 mmol) was added dropwise into the mixture via syringe. The solution was then warmed to
room temperature and stirred for 2 h. After completion, the reaction was quenched with saturated
sodium potassium tartarate (30 mL) and stirred overnight. The aqueous layer was extracted with
ether (3 × 80 mL). The combined organic phase was washed with brine, dried over Na2SO4, and
concentrated. The crude residue was purified by flash column chromatography (petroleum
ether/ethyl acetate 80: 1) to give 7 (1.87 g, 73%) as a colorless oil; [α]D20 - 19.4 (c 1.0, CHCl3); 1H
NMR (400 MHz, Chloroform-d) δ 5.81 (ddd, J = 17.1, 10.6, 6.2 Hz, 1H), 5.31 - 5.17 (m, 2H),
4.02 (ddt, J = 6.3, 3.6, 1.4 Hz, 1H), 3.84 (qd, J = 6.3, 3.6 Hz, 1H), 1.07 (d, J = 6.3 Hz, 3H), 0.89 (s,
9H), 0.08 (s, 6H); 13C NMR (100 MHz, Chloroform-d) δ 136.5, 116.5, 76.6, 71.2, 25.8, 18.0, 17.6,
-4.4, -4.9. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C18H28O3SiNa 343.1705; Found 343.1711;
IR (KBr) 2956, 2930, 2886, 2857, 1472, 1381, 1256, 1096, 1007, 935, 836, 773 cm-1.
Synthesis of ethyl 3-((4R,5R)-5-((3S,4R,E)-4-((tert-butyldimethylsilyl)oxy)-3-hydroxypent-
1-en-1-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)propanoate (13)
Hoveyda-Grubbs Catalyst 2nd Generation (4 mg, 0.006 mmol) was added to a mixture of 6 (50
mg, 0.22 mmol) and 7 (95 mg, 0.44 mmol) in dry DCM (15 mL). The mixture was refluxed for 8
h. After completion of reaction (TLC), the solution was concentrated and purified by flash column
20
chromatography (petroleum ether/EtOAc 8:1) to give 13 as a colorless oil (68 mg, 75%). [α]D
-4.1 (c 0.3, CHCl3); 1H NMR (400 MHz, Chloroform-d) δ 5.75 - 5.73 (m, 2H), 4.58 - 4.55 (m, 1H),
4.17 - 4.07 (m, 4H), 3.86 (qd, J = 6.3, 3.4 Hz, 1H), 2.50 -2.32 (m, 2H), 1.77 - 1.72 (m, 2H), 1.46 (s,
3H), 1.35 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.06 (d, J = 6.3 Hz, 3H), 0.89 (s, 9H), 0.07 (d, J = 1.1
Hz, 6H); 13C NMR (100 MHz, Chloroform-d) δ 173.2, 132.8, 127.7, 108.4, 78.7, 77.4, 75.5, 71.2,
60.4, 30.9, 28.2, 26.1, 25.8, 25.7, 18.0, 17.6, 14.2, -4.5, -4.9; HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C21H40O6SiNa 439.2492; Found 439.2482; IR (KBr) 3473, 2956, 2930, 2855, 1735,
1469, 1373, 1258, 1216, 1154, 1094, 1008, 976, 833, 776, 736 cm-1.
Synthesis of (3S,4R,E)-4-((tert-butyldimethylsilyl)oxy)-1-((4R,5R)-5-(3-ethoxy-3-oxopropyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)pent-1-en-3-yl (E)-but-2-enoate (14)
To a solution of 13 (400 mg, 0.96 mmol) in pyridine (10 mL), crtonic anhydride (0.5 mL, 3.36
mmol) and catalytic amount of DMAP was added, and the mixture kept at room temperature for 5
h. The reaction was quenched by the addition of MeOH (1 mL). The solution was concentrated
with toluene and poured into saturated aqueous NaHCO3 (20 mL) and then extracted with EtOAc
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(2 × 20 mL). The combined organic phase was washed with saturated aqueous CuSO4, water, and
dried over Na2SO4, and concentrated under reduced pressure. The crude was purified by flash
column chromatography (petroleum ether/EtOAc 10:1) to give 14 as a colorless oil (408 mg, 88%).
[α]D20 -9.0 (c 2.3, CHCl3); 1H NMR (400 MHz, Chloroform-d) δ 6.97 (dq, J = 15.6, 6.9 Hz, 1H),
5.90 - 5.80 (m, 2H), 5.71 (dd, J = 15.6, 7.0 Hz, 1H), 5.17 (dd, J = 7.3, 3.3 Hz, 1H), 4.57 (t, J = 6.6
Hz, 1H), 4.17 - 4.09 (m, 3H), 3.97 (qd, J = 6.4, 3.3 Hz, 1H), 2.48 - 2.32 (m, 2H), 1.88 (dd, J = 6.9,
1.7 Hz, 3H), 1.74 - 1.68 (m, 2H), 1.46 (s, 3H), 1.34 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H), 1.10 (d, J =
6.4 Hz, 3H), 0.87 (s, 9H), 0.03 (d, J = 3.8 Hz, 6H); 13C NMR (100 MHz, Chloroform-d) δ 173.2,
165.5, 144.8, 130.5, 128.5, 122.8, 108.4, 78.3, 77.4, 77.3, 69.5, 60.3, 30.8, 28.1, 26.0, 25.7 (3C),
25.6, 19.9, 18.02, 19.78, 14.2, -4.7, -4.8; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C25H44O7SiNa 507.2749; Found 507.2741; IR (KBr) 2959, 2933, 2857, 1733, 1652, 1446, 1373,
1258,1216, 1180, 1102, 1003, 966, 836, 773, 739 cm-1.
Synthesis of 3-((4R,5R)-5-((3S,4R,E)-3-(((E)-but-2-enoyl)oxy)-4-hydroxypent-1-en-1-yl)-2,2-
dimethyl-1,3-dioxolan-4-yl)propanoic acid (16)
o
A cooled (0 C) solution of ester 14 (100 mg, 0.21 mmol) in THF/H2O (3:2, 8mL) was treated
with LiOH (13 mg, 0.31 mmol). The reaction mixture was stirred at room temperature for 24 h.
After completion of the reaction (monitored by TLC), the reaction mixture was acidified with 1N
HCl until pH = 3 and was extracted with ethyl acetate (3 × 10 mL). The combined organic layer
was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure.
The crude acid 15 was used for the next step without further purification.
o
To a cooled (0 C) solution of the above crude 15 in THF/pyridine (10:1, 11 mL) was added
HF-pyridine complex (0.43 ml，3.15 mmol) dropwise and stirred at room temperature for 24 h.
After completion of reaction (TLC), it was quenched with saturated NH4Cl solution, extracted
with EtOAc (3 × 10 mL), washed with saturated aqueous CuSO4, brine and dried over Na2SO4.
The combined organic phase was evaporated under reduced pressure and purified by flash column
chromatography (dichloromethane/MeOH 30:1) to give 16 as a colorless oil (47 mg, 67% for two
steps). 1H NMR (400 MHz, Chloroform-d) δ 7.01 (dq, J = 14.1, 6.8 Hz, 1H), 5.90 - 5.80 (m, 3H),
5.27 (dd, J = 5.6, 3.5 Hz, 1H), 4.60 (t, J = 5.9 Hz, 1H), 4.18 (dt, J = 8.7, 5.6 Hz, 1H), 3.98 (qd, J =
6.5, 3.6 Hz, 1H), 2.54 - 2.38 (m, 2H), 1.89 (dd, J = 7.0, 1.7 Hz, 3H), 1.77 - 1.67 (m, 2H), 1.47 (s,
3H), 1.35 (s, 3H), 1.19 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, Chloroform-d) δ 178.4, 165.6,
145.7, 131.0, 127.9, 122.3, 108.6, 78.0, 77.2, 77.0, 69.0, 30.4, 28.0, 25.8, 25.5, 18.04, 18.01;
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C17H26O7Na 365.1576; Found 365.1568; IR (KBr)
3447, 2925, 1717, 1655, 1443, 1378, 1263, 1180, 1101, 1063, 974, 867, 736 cm-1.
Synthesis of (3aS,8R,9S,11aR,E)-2,2,8-trimethyl-6-oxo-3a,5,6,8,9,11a-hexahydro-4H-[1,3]di-
oxolo-[4,5-e]oxecin-9-yl (E)-but-2-enoate (5)
To a solution of the seco acid 16 (50 mg, 0.146 mmol) in toluene (35 mL) was slowly added a
solution of MNBA (65 mg, 0.19 mmol) and DMAP (107 mg, 0.876 mmol) in toluene (35 mL) at
o
80 C with a mechanically driven syringe over a 18 h period under a nitrogen atmosphere. After
completion of reaction (TLC), the mixture cooled to room temperature and concentrated under
reduced pressure. The crude was purified by flash column chromatography (petroleum
1
ether/EtOAc 5:1) to give 5 as a colorless oil (42 mg, 90%). [α]D20 -41.0 (c 1.0, CHCl3); H NMR
(400 MHz, Chloroform-d) δ 6.99 (dq, J = 15.5, 6.7 Hz, 1H), 5.86 - 5.80 (m, 1H), 5.71 - 5.61 (m,
7

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2H), 5.11 - 5.02 (m, 2H), 4.75 (d, J = 6.9 Hz, 1H), 4.38 - 4.34 (m, 1H), 2.56 - 2.49 (m, 1H), 2.15 -
2.07 (m, 2H), 2.06 - 2.00 (m, 1H), 1.88 (dd, J = 6.9, 1.7 Hz, 3H), 1.57 (s, 3H), 1.34 (d, J = 5.4 Hz,
6H); 13C NMR (100 MHz, Chloroform-d) δ 173.4, 165.5, 145.7, 129.7, 126.0, 122.2, 108.6, 79.4,
76.8, 74.9, 70.1, 29.7, 26.7, 26.4, 24.8, 18.1, 17.3; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C17H24O6Na 347.1471; Found 347.1463; IR (KBr) 2988, 2938, 1728, 1655, 1446, 1383, 1258,
1174, 1109, 1062, 1018 cm-1.
Synthesis of Aspinolide B (1)
To a solution of 5 (40 mg，0.123 mmol) in MeOH (4 mL) was added a drop of 4N HCl. The
reaction mixture was stirred at 30 oC for 2 h, then the reaction was neutralized with triethylamine
and concentrated under reduced pressure. The crude was purified by flash column chromatography
(hexane/EtOAc/ dichloromethane 1:1:1) to give Aspinolide B (1) as a white solid (31 mg, 89%).
1
m.p.: 99-101 oC, lit. 102-103 6f; [α]D20 -44.4 (c 1.0, MeOH), lit. [α]D20 -44.0 (c 1.0, MeOH) 6f; H
NMR (400 MHz, Chloroform-d) δ 7.01 (dq, J = 15.5, 6.9 Hz, 1H), 5.85 (dq, J = 15.6, 1.7 Hz, 1H),
5.67 (dd, J = 15.9, 1.9 Hz, 1H), 5.57 (ddd, J = 15.9, 8.1, 2.3 Hz, 1H), 5.09 (dq, J = 9.2, 6.3 Hz,
1H), 4.95 (t, J = 8.7 Hz, 1H), 4.53 - 4.52 (m, 1H), 3.65 (dt, J = 11.2, 2.7 Hz, 1H), 2.47 (ddd, J =
15.6, 9.9, 1.3 Hz, 1H), 2.29 (dtd, J = 14.8, 11.4, 1.3 Hz, 1H), 2.11 - 2.04 (m, 1H), 1.90 (dd, J = 6.9,
1.7 Hz, 3H), 1.80 - 1.74 (m, 1H), 1.33 (d, J = 6.3 Hz, 3H); 13C NMR (100 MHz, Chloroform-d) δ
175.4, 165.6, 146.0, 131.4, 127.5, 122.0, 78.6, 75.2, 72.7, 71.8, 32.5, 27.1, 18.1, 16.7; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C14H21O6 285.1338; Found 285.1331; IR (KBr) 3447, 2980,
2938, 1723, 1655, 1446, 1360, 1180, 1151, 1065, 1018 cm-1.
Synthesis of Aspinolide E (3)
To a stirred solution of Aspinolide B (1, 20 mg，0.07 mmol) and cuprous chloride (7 mg, 0.07
mmol) in the mixture of THF (1.2 mL) and EtOH (2.8 mL) was added NaBH4 (26 mg, 0.7 mmol)
portion wise at -40 oC. The reaction mixture was stirred at the same temperature for 1 h. Then the
reaction mixture was concentrated under reduced pressure. The residue was diluted with water and
extracted with ethyl acetate (3 × 10 mL). The organic layer was separated, washed with water,
brine, dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by
flash column chromatography (petroleum ether/EtOAc/dichloromethane 1:1:1) to give Aspinolide
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E (3) as a white amorphous solid (15 mg, 76%). [α]D -24.6 (c 0.24, CHCl3); lit.3 [α]D -14.5 (c
0.24, CHCl3); 1H NMR (400 MHz, Chloroform-d) δ 5.65 (dd, J = 15.9, 1.9 Hz, 1H), 5.54 (ddd, J =
15.9, 8.3, 2.3 Hz, 1H), 5.07 (dq, J = 9.3, 6.3 Hz, 1H), 4.90 (t, J = 8.8 Hz, 1H), 4.52 (s, 1H), 3.65
(dt, J = 11.1, 2.6 Hz, 1H), 2.46 (dd, J = 15.5, 9.4 Hz, 1H), 2.33 - 2.24 (m, 3H), 2.07 ((dd, J = 15.6,
11.5 Hz, 1H), 1.74 - 1.81 (m, 1H), 1.65 (dq, J = 14.8, 7.4 Hz, 2H), 1.32 (d, J = 6.3 Hz, 3H), 0.95 (t,
J = 7.4 Hz, 3H); 13C NMR (100 MHz, Chloroform-d) δ 175.47, 172.78, 131.23, 127.74, 78.67,
75.13, 72.86, 71.84, 36.18, 32.44, 27.28, 18.37, 16.70, 13.64; HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C14H22O6Na 309.1314; Found 309.1307; IR (KBr) 3457, 2959, 2928, 1728, 1438, 1373,
1180, 1157, 1070, 1000 cm-1.
Synthesis of Aspinolide J (4)
Method A: Compound 5 (30 mg，0.093 mmol) was dissolved in acetone (5 mL) and treated with a
aqueous solution of K2CO3 (5%) (3 mL). The reaction mixture was stirred at room temperature for
24 h. After completion of reaction (monitored by TLC), the mixture was neutralized with saturated
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ammonium chloride solution and extracted with ethyl acetate. Evaporation of the solvent gave a
crude extract. The crude was used for the next step without further purification.
To a solution of the above crude in MeOH (5 mL) was added a drop of 1N HCl. The reaction
mixture was stirred at room temperature for 3 h, then the reaction was directly concentrated under
reduced pressure. The crude was purified by flash column chromatography (hexane/EtOAc/MeOH,
5:5:1) to give Aspinolide J (4) as a white amorphous solid (13 mg, 65% for two steps).
Method B: Aspinolide B (1, 25 mg，0.088 mmol) was dissolved in acetone (5 mL) and treated
with a aqueous solution of K2CO3 (5%) (2 mL). The reaction mixture was stirred at room
temperature for 6 h. After completion of reaction (monitored by TLC), the mixture was neutralized
with saturated ammonium chloride solution, extracted with ethyl acetate and dried over Na2SO4.
The organic phase was evaporated under reduced pressure and purified by flash column
chromatography hexane/EtOAc/MeOH, 5:5:1) to give Aspinolide J (4) as a white amorphous solid
(7.6 mg, 40%). [α]D -16.7 (c 0.1, CHCl3); lit.4 [α]D -14.9 (c 0.1, CHCl3); H NMR (400 MHz,
Chloroform-d) δ 5.69 (ddd, J = 15.9, 8.5, 2.2 Hz, 1H), 5.54 (dd, J = 15.6, 1.8 Hz, 1H), 4.89 (dq, J
= 8.8, 6.4 Hz, 1H), 4.54 (s, 1H), 3.87 (t, J = 8.6 Hz, 1H), 3.64 (d, J = 11.1 Hz, 1H), 2.45 (dd, J =
15.6, 9.7 Hz, 1H), 2.33 - 2.24 (m, 1H), 2.05 (dd, J = 15.5, 11.5 Hz, 1H), 1.80 - 1.74 (m, 1H), 1.42
(d, J = 6.3 Hz, 3H); 13C NMR (100 MHz, Chloroform-d) δ 176.2, 32.9, 27.5, 73.3, 79.2, 130.5,
131.3, 75.5, 74.7, 16.9; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C10H16O5Na 239.0895;
Found 239.0890; IR (KBr) 3447, 2925, 1728, 1370, 1266, 1222, 1156, 1049, 1007, 969, 859, 737
cm-1.
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Acknowledgements
This work was supported by the National Key Research and Development Program of China
(2016YFA0203102), the National Basic Research Program of China (Grant 2015CB931903), the
Strategic Priority Research Program of Chinese Academy of Sciences (Grant XDB14040201) and
Natural Science Foundation of China (Projects 21302150 and 21602082).We thank Dr. Miao
Chen and Xinyu Zhang for HRMS measurements.
Appendix A. Supplementary data
Supplementary data associated with this article can be found in the online version, at
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