Total Synthesis of Nominal ent-Chlorabietol B

Article abstract of DOI:10.1021/acs.joc.0c00233

The nominal enantiomer of chlorabietol B was regio- and stereoselectively synthesized from (-)-abietic acid in 13 steps. Key features of the synthesis involved an oxidative [3+2] cycloaddition to install the dihydrobenzofuran moiety and an Aldol reaction, followed by elimination and reduction steps to introduce the long chain with three cis double bonds. However, obvious differences in the NMR spectra of the synthetic and natural samples suggested that the proposed structure of chlorabietol B should be revised carefully.

Full text of DOI:10.1021/acs.joc.0c00233

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Note
Total Synthesis of Nominal ent-Chlorabietol B
Yulong Li, Zhezhe Xu, Zhipeng Xie, Xingchao Guan, and Zhi-Xiang Xie
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00233 • Publication Date (Web): 26 Mar 2020
Downloaded from pubs.acs.org on March 26, 2020
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Total Synthesis of Nominal ent-Chlorabietol B
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Yulong Li, Zhezhe Xu, Zhipeng Xie, Xingchao Guan, and Zhixiang Xie*
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State Key Laboratory of Applied Organic Chemistry & College of Chemistry and Chemical Engineering, Lanzhou
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University, Lanzhou 730000, China
Abstract:
O
R
O
9
H
H
O
O
H
O
O
3+2
H
H
HO
H
HO
R
HO
(-)-abietinol
HO
OH
R =
OH
O
HO
OH
+
15
nominal ent-chlorabietol B
HO
OH
13
The nominal enantiomer of chlorabietol B was regio- and stereoselectively synthesized from
(-)-abietic acid in 13 steps. Key features of the synthesis involved an oxidative [3+2]
cycloaddition to install the dihydrobenzofuran moiety, and an Aldol reaction followed by
elimination and reduction steps to introduce the long chain with three cis double bonds. However,
obvious differences in the NMR spectra of the synthetic and natural samples suggested that the
proposed structure of chlorabietol B should be revised carefully.
Chlorabietol A-C (1-3) were isolated by Hu and co-workers1 from the extract of the roots of
Chloranthus oldhamii, which is a rare species native to China.2 (Figure 1) These compounds
represent a new class of natural products, featuring an abietane-type diterpenoid coupled with
different alkenyl phloroglucinol moiety by forming a 2,3-dihydrofuran ring. Bioactivity research
showed that chlorabietols A-C have moderate inhibitory activities against protein tyrosine
phosphatase 1B (PTP1B) with IC50 values of 12.6, 5.3, 4.9 μM, respectively. As the compounds
4-7 were isolated together with chlorabietols A-C from the same collected plant sample, these
compounds were envisioned to be the biogenetic precursors of the chlorabietols A-C. (Figure 1)
Their biosynthetic paths were proposed as an abietane-type diterpenoid such as compound 4,
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coupled with different alkenyl phloroglucinol moieties (such as compounds 5-7) by an oxidative
[3+2] cycloaddition reaction,3 which has been proven to be a powerful method for the preparation
of 2,3-dihydrofuran moiety with conjugated diene and phenol.4 The challenges for this biomimetic
[3+2] cycloaddition were reflected in two aspects. First, the methylene units positioned between
two double bonds on an aliphatic side chains are sensitive to oxidative conditions. Second, the
diene should be a conjugated one and distribute in a same ring. However, in this case the
conjugated diene of 4 are dispersed into two rings. The challenge of biomimetic synthesis,
unprecedented structures and the bioactivities stimulated our interest in their total synthesis.
Herein, we report the biomimetic total synthesis of nominal enantiomer of chlorabietol B by an
oxidative [3+2] cycloaddition reaction from (-)-abietic acid.
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13
OH
O
O
1
R2
OH
R = H, R2 = a
14
H
6
O
O
R1O
H
7
R3
OH
H
1
R2
5
6
7
H
HO
R1
1
2
R = CH3, R = a
HO
4
1
2
R = H, R = b
Chlroabietols A-C (1-3)
1
R = CH3, R2 = CH2OH, R3 = a
1
a =
b =
3
1
2
R = CH2OH, R = CH3, R3 = a
2
3
1
2
R = CH2OH, R = CH3, R3 = b
3
Figure 1. Proposed structures of chlorabietols A-C and their biosynthetic precursors 4-7
from C. oldhamii.
Scheme 1 outlines our retrosynthetic analysis of chlorabietol B (2). We favored the total
synthesis of chlorabietol B (2) to involve the late-stage coupling of the ketone 8 with C16 synthon
9 to introduce the long aliphatic chain, so that the oxidative [3+2] cycloaddition and epoxidation
procedure would proceed as hoped. The C16 building block 9 could be derived from commercially
available linolenic acid (10). The compound 8, contained all the stereocenters of the target
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molecule, could be achieved via a stereoselective epoxidation of compound 11. The key
intermediate 11 was envisioned to be synthesized via the powerful oxidative [3+2] cycloaddition
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reaction between (+)-abietinol (12) and 13 to install the 2,3-dihydrofuran ring skeleton.
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Scheme 1. Retrosynthetic Analysis of Chlorabietol B (2)
O
O
H
C15H25
O
O
H
O
O
O
+
9
H
H
C15H25
HO
HO
HO
OH
HO
OH
8
Chlroabietol B
HO
C15H25
O
10
linolenic acid (
)
H
H
[3+2] cycloaddition
H
O
O
HO
12
(+)-abietinol (
)
H
HO
+
HO
11
OH
OH
O
C15H25
=
HO
OH
13
As shown in Scheme 2, (+)-abietinol (12) was unavailable in commercial sources. However,
its enantiomer, (-)-abietinol (12) was easily obtained from commercially available (-)-abietic acid
(14) by treating with LiAlH4 in THF.5 Using available (-)-abietinol (12) as starting material, the
ent-chlorabietol B should be synthesized. Thus, we focused on the key oxidative [3+2]
cycloaddition reaction between diene 12 and 2',4',6'-trihydroxylacetophenone (13) for the
synthesis of enantiomer of chlorabietol B. Based on our previous work,4d Ag salts should be
benefit for getting the desired product which resulted from the ortho phenol group involved in the
cycloaddition process. So, Ag2O was chosen as oxidation reagent to initiate the reaction.
Pleasingly, treatment of (-)-abietinol (12) and 13 with Ag2O in MeCN gave the desired [3+2]
product 15 in moderate yield.
With compound 15 in hand, we tried to oxidize the double bond to achieve the epoxide product.
When using compound 15 or compound 15 protected OH groups by TBS or MOM, as substrates,
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t
6d
the double bond were failed to epoxidize by using H2O26a, m-CPBA6b, 6c, BuOOH/VO(acac)2
,
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tBuOOH/DBU6e, DMDO6f as oxidants. The stepwise epoxidation synthesis methods4b,7 were also
ineffective. We speculated that the benzene moiety in this kind of structure might be too
electron-rich to be untouched under the oxidative conditions.4a Thus, the phenols should be
protected by an electron-withdrawing group to lower the electron density of the benzene moiety
for epoxidation of double bond. So, compound 15 was treated with benzoyl chloride, NEt3 and
catalytic DMAP to afford benzoyl protected compound 16 smoothly in 85% yield.8 To our delight,
a single crystal of 16 was obtained, which allowed us to unambiguously confirm regioselectivity
and stereoselectivity of the oxidative [3+2] cycloaddition reaction by single crystal X-ray
diffraction. (for X-ray crystallography and detailed crystallographic data see SI) As hoped,
compound 16 was smoothly transferred to 17 by applying m-CPBA in DCM at room temperature.
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The relative stereochemistry of this epoxide was confirmed by NOE analysis. (Scheme 2)
Scheme 2. Synthesis of the Core 17 with All Stereocentras
OH
O
LiAlH4
HO
OH
13
H
H
THF
reflux
82%
Ag2O,MeCN
50%
H
H
HO2C
HO
brsm 65%
12
(-)-abietinol (
)
14
(-)-abietic acid (
)
BzCl, NEt3
DMAP
O
O
O
O
H
H
H
DCM
0 oC to r.t.
85%
H
BzO
HO
BzO
OBz
HO
15
OH
16
NOE
O
NOE
m-CPBA
H
O
O
DCM
r.t.
62%
H
BzO
BzO
OBz
17
At this stage of our synthetic route, the next mission was to prepare the long C16 aliphatic
chain. Scheme 3 outlined the synthetic route of this chain. The commercially available linolenic
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acid (10) was reduced by LiAlH4 in THF to produce the primary alcohol 18, which was oxidized
to deliver the aldehyde 19. Compound 19 was treated with DIPEA, TMSOTf in DCM to give the
silyl enol ether intermediate, followed by adding Pd(OAc)2 and Na2CO3 to take part in a Saegusa
oxidation reaction to afford the α, β-unsaturated aldehyde 20.9 The electron deficient double bond
of 20 was selectively oxidized to deliver the desired epoxide product 21 in good yield using H2O2
under basic condition.10 Attempts to directly cleave the epoxide moiety of 21 was unsuccessful.
However, epoxide 21 was reduced by NaBH4 to give the epoxide primary alcohol 22, which was
successfully transferred to the C16 aldehyde 9 via cleaving C-C bond of the epoxide moiety with
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applying H5IO6 under acid condition.11
Scheme 3. Synthesis of C16 Long Aliphatic Aldehyde 9
HO
C15H25
LiAlH4
DMP, NaHCO3
HO
C15H25
THF, reflux
86%
DCM, r.t.
70%
O
10
18
linolenic acid (
)
i. DIPEA, TMSOTf,
DCM, -10 oC to r.t.
H2O2, NaHCO3
O
C15H25
O
C15H25
MeOH, r.t.
82%
ii. Pd(OAc)2,
NaCO3, MeCN, r.t.
19
20
72% in 2 steps
H5IO6
O
O
C15H25
HO
C15H25
NaBH4, MeOH
93%
O
O
3.5M H2SO4 (aq)
21
22
40%
brsm 60%
9
With the C16 building block 9 in hand, we then turned our attention to couple ketone 17 with
aldehyde 9. Treating with LDA or LiHMDS, the compound 17 underwent a Baker-Venkataraman
rearrangement12 instead of an aldol reaction with 9. Thus, the benzoyl group in compound 17
should be switched to another protecting group before attaching the long aliphatic chain. As
shown in Scheme 4, three benzoyl groups were removed by treating with NaOH in MeOH to
deliver alcohol 23 in high yield. The TES was chosen to replace benzoyl group. Treating with
TESCl, imidazole in DCM, the primary hydroxyl and two phenol hydroxyls were protected by
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TES. However, the TES group on the phenol in this compound turned out to be unstable. So, the
TES protected primary alcohol species 24 was obtained in moderate yield. Fortunately, treating
with LDA, the compound 24 was coupled with aldehyde 9 to produce a pair of diastereoisomers
25a and 25b,13 which could not be isolated by column chromatography. Following direct
deoxygenation of the β-hydroxyl group in 25a and 25b via Barton-McCombie deoxygenation
procedure14 did not work as expected. And attempts to eliminate the β-hydroxyl group to produce
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15b
the corresponding elimination product under different conditions such as p-TSA,15a,
MsCl/NEt3,15c py·SO3,15d TsCl/pyridine,15e SOCl2/NEt3 also failed to produce corresponding
15f
elimination products. It was envisioned that the phenol groups in the compounds 25a and 25b
should be protected before elimination step. Thus, the phenol groups in compounds 25a and 25b
were selectively protected with acetyl chloride and NEt3 to produce the corresponding desired
products, which was dehydrated with Burgess Reagent16 to obtain the compound 26.
Scheme 4. Synthesis of the Proposed Enantiomer of Chlorabietol B
O
NaOH
reflux
O
TESCl
O
O
MeOH,
88%
O
O
H
H
imidazole
DCM
58%
H
H
HO
BzO
HO
OH
BzO
OBz
23
17
O
O
LDA, THF
O
O
H
O
O
OH
H
O
C15H25
H
then
C15H25
TESO
H
9
TESO
HO
OH
50%
HO
25a
OH
25b
24
brsm 61%
and
O
n- Bu3SnH, Pd(PPh3)4
1. AcCl, NEt3, DMAP
O
O
H
THF, r.t.
C15H25
2. Burgess Reagent
42% two steps
H
TESO
50% brsm 70%
AcO
OAc
26
13
O
O
9
1
1. K2CO3, MeOH
8
14
O
O
O
H
O
H
2.TBAF, THF
82%
2'
7
C15H25
H
C17H29
H
3'
TESO
HO
2 steps
AcO
OAc
HO
OH
proposed ent-Chlorabietol B (28)
27
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The last challenge was to selectively reduce the electron deficient double bond in the presence
of three cis C=C bonds in the long side chain. In previous reports17 different metal hydrides
species were used to selectively reduce electron deficient double bonds via a 1,4-conjugated
addition mechanism. However, in this case different metal hydrides species such as Stryker’s
Reagent17a, MeCu/DIBAL-H17b, CuCl2·2H2O/PMHS17c, n-Bu3SnH17d could not reduce the
electron deficient double bond. Other reductive conditions such as NiCl2·6H2O/NaBH4,18a
(Ph3P)RhCl/Et3SiH18b and [IrCp*Cl2]2/i-PrOH18c led to over reduction: the electron deficient
double bond was reduced along with one of the three C=C bonds in the side chain. Reducing both
the deficient double bond and the epoxide apparently occurred by HSiCl3 under Lewis base
Ph3P=O or HMPA.19 Gratifyingly, the desired reducing compound 27 was achieved in an
acceptable yield by using Pd(PPh3)4/n-Bu3SnH.20 (Scheme 4) Finally, deprotecting all the
hydroxyl groups in 27 afforded the proposed ent-chlorabietol B (28).
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1
To our disappointment, the H and 13C NMR spectra of our synthetic sample 28 were not
coincident in all respects with the data reported by Hu and co-workers for the “natural”
chlorabietol B (2).1 Moreover, we carefully checked the effects of pH, concentration, temperature,
and impurities and excluded these reasons. By HMQC and HMBC experiment of the synthetic
sample 28 along with the previous compounds in our synthetic route, we confirmed which carbons
and hydrogens was different from the natural chlorabietol B (2). Significant differences (∆δ> 0.08
1
ppm) in the H NMR chemical shifts were observed between the synthesized ent-chlorabietol B
(28) and the “natural” chlorabietol B (2) for the hydrogen atoms at C1, C2, C6, C9, C11, C12, C15
and some clear discrepancies (∆δ>1.0 ppm) were also observed in the 13C NMR chemical shifts
for C2, C7, C8, C9, C11, C12, C20 and C3’. (See the part III in Supporting Information for details)
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And more, a positive specific rotation ([α]D = +26.0o (c 1.00, MeOH)) of synthetic sample was
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correlated with the reported specific rotation ([α]D = +18.7o (c 0.08, MeOH)). According to the
8
9
isolated paper,1 the only uncertainty of proposed structure of chlorabietol B (2) was the
configuration of C8. Therefore, we speculated that the original isolated sample of chlorabietol B
(2) structure was more likely to have difference at C8 with our synthetic sample’s structure which
was reported in the isolation paper. But unfortunately, the oxidative [3+2] cycloaddition between
(-)-abietinol (12) and compound 13 gave the sole product 15. Further studies on synthesis of C-8
epimer by new strategy are ongoing in our group.
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In summary, we have accomplished the total synthesis of nominal ent-chlorabietol B (28) in
13 steps with an overall yield of 3% (as the longest linear route from linolenic acid 10). An
oxidative [3+2] cycloaddition was applied to construct the main core of natural product. And the
long side chain was attached to the core by aldol reaction, followed by elimination and selective
reduction of electron deficient double bond. This synthetic strategy should pave a way to the
synthesis of natural products featuring a 2,3-dihydrofuran ring moiety. Additionally, this work
should be helpful to determine the real structure of chlorabietols.
EXPERIMENTAL SECTION
General Experimental Details: Unless otherwise noted, reactions were performed under an
atmosphere of argon with magnetic stirring and commercially available materials were used
without further purification. Solvents used for moisture sensitive operations were conducted
according to Purification of Laboratory Chemicals (W. L. Armarego, C. L. Chai, Elsevier Press:
Oxford, 2013). Flash chromatography (FC) was performed by using Yantai Chemicals (200–300
mesh). Reactions were monitored by thin-layer chromatography on plates (GF254), which were
purchased from Energy chemcal and visualized by UV or stained with the ethanolic solution of
phosphomolybdic acid and ferric chloride hexahydrate. Infrared spectra were recorded on a
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Nicolet Nexus 670 FT-IR spectrometer with wavenumbers expressed in cm-1 using samples
prepared as thin films between salt plates. Nuclear magnetic resonance (NMR) spectra were
recorded on a Varian Mercury-600BB, Brüker Advance III-400 and Brüker AVANCE CEO 600
spectrometer equipped with a BB-H&F-D-05 Z ET CryoProbe at operating frequencies of 400/600
MHz (1H NMR) or 100/150 MHz (13C NMR). Chemical shifts (δ) are given in ppm relative to
residual solvent (usually chloroform δ 7.27 for 1H NMR or δ 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, whereby the prefix app is applied in cases where the
true multiplicity is unresolved and br when the signal in question is broadened. HR-ESI-MS data
were performed on a Bruker APEX-II mass spectrometer. Optical rotations were measured on a
Rudolph Autopol IV polarimeter. The X-ray single-crystal determination was performed on an
Agilent SuperNova single crystal X-ray diffractometer.
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(-)-Abietinol (12) To a mixture of LiAlH4 (4.13 g, 108.8 mmol) and THF (80 ml) in a round
bottom flask under 0 oC was slowly added abietic acid (14) (4.63 g, 15.32 mmol) which solved in
o
THF (120 ml). The resulting reaction mixture was stirred at 0 C for 10 min, and then heated to
reflux for another one hour. After the abietic acid (14) was consumed confirmed by TLC analysis,
o
saturated potassium sodium tartrate solution was added to reaction mixture under 0 C. After gas
releasing ceased, the mixture was stirred at room temperature overnight. This mixture was
extracted by ethyl acetate. And the combined organic extract was washed with 2N HCl, saturated
NaHCO3 solution and brine. Separated organic layer was dried over Na2SO4 and concentrated in
vacuo. Purification was performed by column chromatography (petroleum ether/ethyl acetate =
4:1) and afforded (-)-abietinol5 (12) (3.62 g, 12.56 mmol, 82%) as a colorless oil: [α]D24 = -141.0o
(c 1.00, DCM); IR (thin film, ν cm-1): 3385, 2930, 2870, 1739, 1718, 1460, 1384, 1241, 1044 cm-1;
1H NMR (400 MHz, CDCl3): δ 5.77 (s, 1H), 5.40 (s, 1H), 3.35 (d, J = 10.9 Hz, 1H), 3.12 (d, J =
10.9 Hz, 1H), 2.22 (dt, J = 13.6, 6.8 Hz, 1H), 2.14 – 1.94 (m, 4H), 1.94 – 1.70 (m, 5H), 1.65 –
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1.48 (m, 3H), 1.45 – 1.30 (m, 2H), 1.28 – 1.14 (m, 1H), 1.02 (d, J = 3.9 Hz, 3H), 1.00 (d, J = 4.0
Hz, 3H), 0.87 (s, 3H), 0.83 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 145.1, 135.5, 122.4,
120.9, 72.0, 50.7, 43.5, 38.8, 37.4, 35.6, 34.8, 34.6, 27.5, 23.7, 22.6, 21.4, 20.8, 18.1, 17.6, 14.2;
HRMS (ESIMS) m/z: [M + K]+ Calcd for C20H32OK 327.2085; Found 327.1927.
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1-((4aR,4bS,8R,8aR,9aS,14aS)-10,12-Dihydroxy-8-(hydroxymethyl)-2-isopropyl-4b,8-dimeth
yl-4,4a,4b,5,6,7,8,8a,9,9a-decahydro-3H-phenanthro[8a,9-b]benzofuran-13-yl)ethan-1-one
(15) To a round bottom flask containing 2',4',6'-trihydroxylacetophenone (13) (1.52 g, 8.19 mmol)
and Ag2O (1.74 g, 7.51 mmol) equipped a magnetic stir bar was added (-)-abietinol (12) (1.97 g,
6.83 mmol) solved in MeCN (27 ml) under Ar atmosphere. After addition completion, the reaction
mixture was stirred at ambient temperature for 7 days. And then the mixture was filtered through a
pad of silica gel. The resulting organic solution was concentrated in vacuo. And the crude mixture
was purified by column chromatography (petroleum/ethyl acetate = 8:1) to afford the [3+2]
21
compound 15 (1.55 g, 3.41 mmol, 50%, brsm 65%) as a yellow solid: [α]D = 157.0o (c 1.00,
MeOH); m.p. 157–164 oC; IR (thin film, ν cm-1): 3430, 2928, 1740, 1614, 1433, 1364, 1298, 1262,
1181, 1062, 901 cm-1; 1H NMR (400 MHz, CDCl3): δ 13.12 (s, 1H), 9.58 (brs, 1H), 5.85 (s, 1H),
5.61 (s, 1H), 3.70 (d, J = 11.8 Hz, 1H), 3.48 (s, 1H), 2.98 (d, J = 11.8 Hz, 1H), 2.56 (s, 3H), 2.48
(d, J = 13.4 Hz, 1H), 2.30 (ddd, J = 26.9, 15.9, 7.8 Hz, 2H), 2.17 – 1.89 (m, 4H), 1.82 (d, J = 12.8
Hz, 1H), 1.72 – 1.46 (m, 6H), 1.18 (d, J = 8.5 Hz, 1H), 1.10 (s, 3H), 1.08 (s, 3H), 1.00 (s, 3H),
0.92 – 0.83 (m, 1H), 0.76 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 202.1, 164.6, 163.3, 158.9,
154.2, 122.0, 106.8, 103.3, 96.2, 90.3, 71.4, 49.1, 48.7, 41.0, 39.4, 37.5, 37.3, 35.3, 35.3, 31.4,
24.8, 21.4, 20.9, 20.0, 18.0, 17.9, 17.8, 15.6; HRMS (ESIMS) m/z: [M + H]+ Calcd for C28H39O5
455.2792; Found 455.2796.
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(4aR,4bS,8R,8aR,9aS,14aS)-13-Acetyl-8-((benzoyloxy)methyl)-2-isopropyl-4b,8-dimeth
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yl-4,4a,
4b,5,6,7,8,8a,9,9a-decahydro-3H-phenanthro[8a,9-b]benzofuran-10,12-diyl
dibenzoate (16) To a round bottom flask contained the triol compound 15 (1.88 g, 4.14 mmol)
was added DMAP (303.4 mg, 2.48 mmol). And then the flask was capped with a rubber stopper.
Under Ar atmosphere DCM (30 ml) was added to the flask in one portion, followed by NEt3 (2.6
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o
ml, 1.89 g, 18.64 mmol). The resulted pale yellow reaction mixture was cooled to 0 C. At this
temperature, BzCl (1.9 ml, 2.27 g, 16.15 mmol) was added dropwisely to the flask. After addition
completion, the reaction mixture was allowed to warm to the room temperature and stirred over
night. After completely consumption of triol compound 15 monitored by TLC, the reaction was
quenched with saturated NH4Cl solution. The aqueous layer was extracted by ethyl acetate three
times. And the combined organic layer was washed with saturated NaHCO3 solution, water, brine
in sequence and dried over Na2SO4. The separated organic solution was concentrated in vacuo to
give the crude product which was purified by column chromatography (petroleum/ethyl acetate =
8:1) to afford pure compound 16 (2.70 g, 3.52 mmol, 85%) as a colorless solid: [α]D24 = +77.0o (c
1.00, DCM); m.p. 132–135 oC; IR (thin film, ν cm-1): 3407, 2960, 1741, 1601, 1465, 1404, 1244,
1084, 708 cm-1; 1H NMR (400 MHz, CDCl3): δ 8.18 (t, J = 7.7 Hz, 4H), 7.93 (d, J = 7.2 Hz, 2H),
7.62 (dd, J = 6.4, 1.8 Hz, 2H), 7.51 (dd, J = 8.9, 6.6 Hz, 5H), 7.43 (t, J = 7.4 Hz, 2H), 6.17 (s, 1H),
5.68 (s, 1H), 4.00 (d, J = 11.0 Hz, 1H), 3.77 (dd, J = 15.1, 7.3 Hz, 2H), 2.60 (s, 3H), 2.29 (ddd, J =
24.9, 13.6, 6.2 Hz, 2H), 2.11 (dt, J = 22.1, 11.0 Hz, 4H), 1.89 (d, J = 12.7 Hz, 1H), 1.78 – 1.49 (m,
5H), 1.44 (s, 2H), 1.09 (dd, J = 6.6, 4.5 Hz, 6H), 1.03 (s, 3H), 1.00 – 0.94 (m, 1H), 0.82 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 196.6, 166.5, 164.8, 163.5, 160.2, 153.8, 149.5, 149.2, 134.1,
133.4, 132.7, 130.4, 130.4, 130.1, 130.1, 129.5, 129.3, 129.3, 128.8, 128.8, 128.5, 128.5, 128.4,
128.4, 128.0, 122.3, 122.2, 114.7, 109.3, 90.3, 72.3, 51.1, 48.9, 43.4, 39.5, 36.9, 36.5, 35.6, 35.1,
35.1, 32.1, 24.6, 21.3, 20.8, 20.4, 18.1, 17.6, 17.5, 15.7; HRMS (ESIMS) m/z: [M + Na]+ Calcd
for C49H50O8Na 789.3398; Found 789.3395.
CCDC 1972686 contains the supplementary crystallographic data for 16 and is available free
of
charge
from
the
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
(2aR,2bS,6R,6aR,7aS,12aS,12bS,13aR)-11-Acetyl-6-((benzoyloxy)methyl)-13a-isopropyl-2
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b,6-dimethyl-2,2a,2b,3,4,5,6,6a,7,7a,12b,13a-dodecahydro-1H-oxireno[2',3':7,8]phenanthro[
8a,9-b]benzofuran-8,10-diyl dibenzoate (17) The compound 16 (1.93 g, 2.51 mmol) was solved
in DCM (42 ml). The resulted clear solution was added m-CPBA (75 %, 927.3 mg, 4.03 mmol) in
one portion. After m- CPBA was added, the reaction mixture was stirred at room temperature for
8h. Saturated NaHCO3 aqueous solution was applied to quench the reaction. The resulted mixture
was extracted with ethyl acetate three times. The combined organic layer was washed by water
and brine in sequence and dried over Na2SO4. The organic solution was concentrated in vacuo and
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resulted crude product which was purified by column chromatography (petroleum/ethyl acetate =
24
6:1) to afford epoxide compound 17 (1.22 g, 1.56 mmol, 62%) as a colorless viscous oil: [α]D
=
1
+10.0o (c 1.00, DCM); IR (thin film, ν cm-1): 3424, 2930, 1727, 1462, 1071, 987, 725 cm-1; H
NMR (400 MHz, CDCl3): δ 8.21 (d, J = 7.4 Hz, 2H), 8.15 (d, J = 7.3 Hz, 2H), 7.87 (d, J = 7.3 Hz,
2H), 7.70 – 7.59 (m, 2H), 7.53 (dt, J = 14.7, 7.6 Hz, 5H), 7.43 (t, J = 7.5 Hz, 2H), 6.22 (s, 1H),
3.98 (d, J = 11.1 Hz, 1H), 3.88 (d, J = 5.5 Hz, 1H), 3.80 (d, J = 11.0 Hz, 1H), 3.16 (s, 1H), 2.64 (s,
3H), 2.16 (d, J = 14.2 Hz, 1H), 1.98 – 1.73 (m, 6H), 1.73 – 1.64 (m, 1H), 1.56 (d, J = 11.8 Hz, 3H),
1.45 (s, 3H), 1.28 (t, J = 12.8 Hz, 1H), 1.08 (s, 3H), 1.02 (s, 3H), 1.01 (d, J = 6.7 Hz, 3H), 0.86 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 196.5, 166.5, 164.8, 163.4, 159.3, 149.6, 149.4, 134.2,
134.2, 133.4, 132.8, 130.5, 130.5, 130.2, 130.0, 129.5, 129.3, 129.3, 128.9, 128.9, 128.5, 128.5,
128.5, 128.5, 128.0, 121.8, 114.6, 109.8, 89.8, 72.1, 64.0, 63.0, 51.1, 47.5, 42.8, 39.6, 36.5, 36.1,
35.5, 33.9, 32.3, 21.6, 21.2, 19.0, 18.3, 17.7, 17.7, 17.3, 15.7; HRMS (ESIMS) m/z: [M + Na]+
Calcd for C49H50O9Na 805.3347; Found 805.3352.
(9Z,12Z,15Z)-octadeca-9,12,15-trien-1-ol (18) To a round bottom flask containing LiAlH4
(5.96 g, 157.1 mmol) and THF (180 ml) equipped with a magnetic stir bar was added commercial
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available linolenic acid 10 (6.16 g, 22.13 mmol) in THF (110 ml) slowly at 0 oC. After all the acid
was added, the reaction mixture was heated to reflux for 1h. Then the reaction was cooled to 0 oC.
At this temperature, saturated potassium sodium tartrate aqueous solution was applied to quench
the reaction. Then the mixture was stirred overnight at ambient temperature. The mixture was
extracted with ethyl acetate. Combined organic extracts were washed by 2N HCl, sat. NaHCO3
and brine in sequence, dried over Na2SO4. The volatile was evaporated in vacuo to give the crude
product which was purified by column chromatography (petroleum/ethyl acetate = 8:1) to afford
alcohol 1821 (5.03 g, 19.03 mmol, 86%) as a colorless viscous oil: IR (thin film, ν cm-1): 3341,
2927, 2374, 1655, 1461, 1056, 722 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.42 – 5.28 (m, 6H), 3.61
(t, J = 6.7 Hz, 2H), 2.85 – 2.75 (m, 4H), 2.11 – 2.02 (m, 4H), 1.82 (brs, 1H), 1.59 – 1.52 (m, 2H),
1.38 – 1.25 (m, 10H), 0.97 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 131.9, 130.3,
128.2, 128.2, 127.6, 127.0, 63.0, 32.7, 29.6, 29.5, 29.4, 29.2, 27.2, 25.7, 25.6, 25.5, 20.5, 14.2;
HRMS (ESIMS) m/z: [M + H]+ Calcd for C18H33O 265.2526; Found 265.2527.
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(9Z,12Z,15Z)-octadeca-9,12,15-trienal (19) To a round bottom flask containing alcohol 18
(1.09 g, 4.11 mmol) equipped with a stir bar was added DCM (21 ml), followed by NaHCO3
(691.3 mg, 8.23 mmol). This mixture was stirred at room temperature. And then DMP (2.62 g,
6.17 mmol) was added to the reaction vow in portions. After the substrate 18 was consumed,
monitored by TLC analysis, the reaction was quenched by sat. sodium thiosulfate aqueous
solution. The resulted mixture was extracted by DCM. Combined organic layer was washed with
water and brine in sequence, followed by drying over Na2SO4. The extract was concentrated in
vacuo to give the crude product. The crude product was purified by flash column chromatography
(petroleum/ethyl acetate = 60:1) to afford aldehyde 1922 (755.8 mg, 2.88 mmol, 70%) as a
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colorless oil: IR (thin film, ν cm-1): 3433, 2960, 1727, 1461, 1269, 1069, 727 cm-1; 1H NMR (400
MHz, CDCl3) δ 9.76 (s, 1H), 5.43 – 5.28 (m, 6H), 2.82 – 2.79 (m, 4H), 2.42 (td, J = 7.4, 1.6 Hz,
2H), 2.11 – 2.03 (m, 4H), 1.64 (dd, J = 14.3, 7.4 Hz, 2H), 1.32 (m, 8H), 0.98 (t, J = 7.5 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 202.7, 131.9, 130.1, 128.2, 128.2, 127.7, 127.1, 43.8, 29.5,
29.2, 29.1, 29.0, 27.1, 25.6, 25.5, 22.0, 20.5, 14.2; HRMS (ESIMS) m/z: [M + H]+ Calcd for
C18H31O 263.2369; Found 263.2367.
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(2E,9Z,12Z,15Z)-octadeca-2,9,12,15-tetraenal (20). To a round bottom flask equipped a
magnetic stir bar was added aldehyde 19 (714.4 mg, 2.72 mmol) in DCM (30 ml). This flask was
o
o
placed in a – 10 C ice-salt bath. After the aldehyde solution was cooled to – 10 C, DIPEA (1.9
ml, 1.41 g, 10.89 mmol) and TMSOTf (0.99 mol, 1.21 g, 5.44 mmol) was added via a syringe in
sequence. Then the reaction mixture was allowed to warm to room temperature and stirred
overnight. And sat. NaHCO3 aqueous solution was added to quench the reaction. The resulted
mixture was extracted by DCM three times. Combined organic layer was washed by H2O and
brine in sequence and dried over Na2SO4. The extract was concentrated in vacuo to afford the
desired crude silyl enol ether product which was used in the next transformation without any
purification.
To a round bottom flask containing the obtained silyl enol ether was added MeCN (39 ml) to
form a solution followed by addition of Na2CO3 (577.1 mg, 5.44 mmol) and Pd(OAc)2 (611.2 mg,
2.72 mmol). The resulted reaction mixture was stirred at room temperature for 8h. After the total
consumption of substrate monitored by TLC, the reaction mixture was filtered through a pad of
silica gel. The filtration was concentrated in vacuo to give the crude α, β-unsaturated aldehyde
which was purified by flash column chromatography (petroleum/ethyl acetate = 60:1) to afford
desired aldehyde 20 (510.4 mg, 1.96 mmol, 72% over 2 steps) as a colorless oil: IR (thin film, ν
cm-1): 3365, 2931, 1693, 1460, 1267, 1129, 976, 717 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.49 (d,
J = 7.9 Hz, 1H), 6.86 – 6.80 (m, 1H), 6.14 – 6.08 (m, 1H), 5.39 – 5.32 (m, 6H), 2.80 (m, 4H), 2.33
(dd, J = 13.5, 6.7 Hz, 2H), 2.14 – 2.00 (m, 4H), 1.60 – 1.47 (m, 2H), 1.46 – 1.30 (m, 4H), 0.97 (t,
J = 7.5 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 194.0, 158.7, 133.0, 131.9, 129.8, 128.3,
128.1, 128.0, 127.0, 32.6, 29.2, 28.7, 27.7, 27.0, 25.6, 25.5, 20.5, 14.2; HRMS (ESIMS) m/z: [M
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+ Na]+ Calcd for C18H28ONa 283.2032; Found 283.2032.
3-((6Z,9Z,12Z)-pentadeca-6,9,12-trien-1-yl)oxirane-2-carbaldehyde
(21).
The
α,
7
8
9
β-unsaturated aldehyde 20 (323.7 mg, 1.24 mmol) was solved in MeOH (5.0 ml) followed by
adding NaHCO3 (104.4 mg, 1.24 mmol) and H2O2 (30%, 0.38 ml, 126.8 mg, 3.73 mmol) in
sequence. The resulting reaction was stirred at room temperature for 2h. After the adehyde
substrate consumed, sat. sodium thiosulfate aqueous solution was added to quench the reaction.
The resulted mixture was extracted by ethyl acetate. Combined organic solvents were washed with
water and brine in sequence, followed by drying over Na2SO4. This washed extract was
concentrated in vacuo to give the crude epoxide product which was purified by flash column
chromatography (petroleum/ethyl acetate = 60:1) to afford the desired epoxide 21 (281.7 mg, 1.02
mmol, 82%) as a colorless oil: IR (thin film, ν cm-1): 3432, 2929, 1729, 1460, 1265, 1070, 851,
722 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.02 (d, J = 6.3 Hz, 1H), 5.46 – 5.30 (m, 6H), 3.23 (dd, J
= 7.6, 3.3 Hz, 1H), 3.14 (dd, J = 6.2, 1.7 Hz, 1H), 2.87 – 2.70 (m, 4H), 2.14 – 2.01 (m, 4H), 1.76 –
1.61 (m, 2H), 1.53 – 1.36 (m, 6H), 0.98 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
198.4, 132.0, 129.9, 128.3, 128.1, 128.0, 127.0, 59.0, 56.7, 31.2, 29.4, 28.8, 27.0, 25.7, 25.6, 25.5,
20.5, 14.3; HRMS (ESIMS) m/z: [M + Na]+ Calcd for C18H28O2Na 299.1982; Found 299.1983.
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(3-((6Z,9Z,12Z)-pentadeca-6,9,12-trien-1-yl)oxiran-2-yl)methanol (22). To
a round
bottom flask containing NaBH4 (109.3 mg, 2.89 mmol) was added MeOH (4.1 ml) and placed in
an ice-warter bath. After cooling to 0 oC the epoxide 21 (228.1 mg, 0.83 mmol) in MeOH (10.3 ml)
o
was added dropwisely. The reaction was maintained at 0 C for 10 min. Sat. NH4Cl aqueous
solution was added to quench the reaction. The resulted mixture was extracted with ethyl acetate.
Combined organic layer was washed by water and brine in sequence followed by drying over
Na2SO4. The dried extract was concentrated in vacuo to give a crude desired reduction product
which was purified by column chromatography (petroleum/ethyl acetate = 4:1) to afford primary
alcohol 22 (183.0 mg, 0.77 mmol, 93%) as a colorless oil: IR (thin film, ν cm-1): 3401, 2928, 1655,
1
1460, 1029, 885, 717 cm-1; H NMR (400 MHz, CDCl3) δ 5.43 – 5.27 (m, 6H), 3.90 (ddd, J =
12.5, 5.3, 2.1 Hz, 1H), 3.65 – 3.55 (m, 1H), 2.98 – 2.89 (m, 2H), 2.85 – 2.70 (m, 4H), 2.19 – 2.13
(m, 1H), 2.12 – 2.02 (m, 4H), 1.62 – 1.52 (m, 2H), 1.48 – 1.34 (m, 6H), 0.97 (t, J = 7.5 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 131.9, 130.0, 128.3, 128.1, 127.8, 127.0, 61.7, 58.5, 55.9,
31.5, 29.4, 29.0, 27.0, 25.8, 25.5, 25.5, 20.5, 14.2; HRMS (ESIMS) m/z: [M + Na]+ Calcd for
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C18H30O2Na 301.2138; Found 301.2138.
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(7Z,10Z,13Z)-hexadeca-7,10,13-trienal (9). To a round bottom flask equipped a magnetic
stir bar, primary alcohol 22 (181.9 mg, 0.43 mmol) in Et2O (7.0 ml) was added followed by
adding H2SO4 (3.5 M, 2.0 ml) and H5IO6 (1.36 g, 5.98 mmol) in sequence. The resulted two phase
solution was stirred vigorously at room temperature for 4h. Then sat. NaHCO3 aqueous solution
was added to the solution until gas releasing ceased. The aqueous phase was separated and
extracted with Et2O. The combined organic extracts were washed by water and brine in sequence
and dried over MgSO4. The dried extract was concentrated in vacuo to give the desired crude
aldehyde which was purified by column chromatography (petroleum/ethyl acetate = 60:1 to 4:1) to
afford aldehyde 923 (40.1 mg, 0.17 mmol, 40%, brsm 60%) as a colorless oil: IR (thin film, ν
9
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cm-1): 3431, 2932, 2370, 1727, 1461, 1392, 1242, 1069, 918, 713 cm-1; H NMR (400 MHz,
CDCl3) δ 9.76 (t, J = 1.7 Hz, 1H), 5.43 – 5.27 (m, 6H), 2.87 – 2.73 (m, 4H), 2.42 (td, J = 7.4, 1.7
Hz, 2H), 2.11 – 2.02 (m, 4H), 1.77 – 1.59 (m, 2H), 1.43 – 1.33 (m, 4H), 0.97 (t, J = 7.5 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 202.6, 131.9, 129.8, 128.3, 128.1, 128.0, 127.0, 43.8, 29.3,
28.7, 26.9, 25.6, 25.5, 21.9, 20.5, 14.2; HRMS (ESIMS) m/z: [M + H]+ Calcd for C16H27O
235.2056; Found 235.2056.
1-((2aR,2bS,6R,6aR,7aS,12aS,12bS,13aR)-8,10-Dihydroxy-6-(hydroxymethyl)-13a-isopr
opyl-2b,6-dimethyl-2,2a,2b,3,4,5,6,6a,7,7a,12b,13a-dodecahydro-1H-oxireno[2',3':7,8]phena
nthro [8a,9-b]benzofuran-11-yl)ethan-1-one (23). To a round bottom flask containing epoxide
compound 17 (1.21 g, 1.55 mmol) was added MeOH (52 ml) and NaOH (644.3 mg, 16.11 mmol).
And then the reaction mixture was heated to reflux for 6h. After the compound 17 was consumed
completely monitored by TLC, 1N HCl was applied to quench the reaction. The mixture was
extracted by ethyl acetate three times. Combined organic layer was washed with sat. NaHCO3,
H2O and brine sequencelly, dried over Na2SO4. The organic solution was concentrated in vacuo to
give crude product. The crude product was purified by column chromatography (petroleum/ethyl
24
acetate = 2:1) to afford compound 23 (641.4 mg, 1.36 mmol, 88%) as a yellowish solid: [α]D
=
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+56.0o (c 1.00, DCM); m.p. 115–118 C; IR (thin film, ν cm-1): 3338, 2926, 1614, 1438, 1366,
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1300, 1263, 1183, 1065, 822 cm-1; H NMR (400 MHz, CDCl3): δ 13.17 (s, 1H), 9.41 (s, 1H),
5.81 (s, 1H), 3.62 (s, 1H), 3.53 (d, J = 11.6 Hz, 1H), 3.11 – 3.00 (m, 2H), 2.60 (s, 3H), 2.54 (d, J =
14.0 Hz, 1H), 1.93 (m, 2H), 1.80 – 1.61 (m, 5H), 1.61 – 1.32 (m, 6H), 1.23 (dd, J = 19.7, 9.8 Hz,
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1H), 1.05 (s, 3H), 1.00 (dd, J = 11.8, 6.9 Hz, 6H), 0.96 – 0.86 (m, 1H), 0.80 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 202.3, 164.6, 162.2, 159.2, 106.6, 103.0, 96.4, 89.4, 71.8, 64.1, 62.7,
49.1, 47.6, 41.2, 39.3, 37.2, 36.6, 35.0, 34.0, 31.3, 22.0, 20.4, 18.9, 18.3, 18.0, 17.6, 17.6, 15.4;
HRMS (ESIMS) m/z: [M + Na]+ Calcd for C28H38O6Na 493.2561; Found 493.2563.
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1-((2aR,2bS,6R,6aR,7aS,12aS,12bS,13aR)-8,10-Dihydroxy-13a-isopropyl-2b,6-dimethyl-
6-(((triethylsilyl)oxy)methyl)-2,2a,2b,3,4,5,6,6a,7,7a,12b,13a-dodecahydro-1H-oxireno[2',3':7,8
] phenanthro[8a,9-b]benzofuran-11-yl)ethan-1-one (24). To a round bottom flask containing
compound 23 (136.5 mg, 0.29 mmol) was added imidazole (177.7 mg, 2.61 mmol) and DCM (5.0
ml). And then the flask was placed in a ice-water bath and treated with TESCl (0.12 ml, 104.9 mg,
0.70 mmol). The resulted reaction mixture was allowed to warm to room temperature and stirred
overnight. After the consumption of substrate 23 monitored by TLC analysis, 2N HCl was added
and stirred for 20 min. The mixture was extracted by ethyl acetate. The combined organic solvent
was washed with sat. NaHCO3, water and brine in sequence. Separated organic layer was dried
over Na2SO4 and concentrated in vacuo to give crude product 24. The crude product was purified
by column chromatography (petroleum/ethyl acetate = 8:1) to afford compound 24 (98.4 mg, 0.17
mmol) as a colorless oil: [α]D25 = +45.0o (c 1.00, DCM); IR (thin film, ν cm-1): 3324, 2956, 1740,
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1614, 1437, 1366, 1301, 1263, 1183, 1097, 822, 742 cm-1; H NMR (400 MHz, CDCl3): δ 13.14
(s, 1H), 6.94 (s, 1H), 5.91 (s, 1H), 3.58 (d, J = 5.0 Hz, 1H), 3.24 (d, J = 9.9 Hz, 1H), 3.13 (d, J =
9.9 Hz, 1H), 3.04 (s, 1H), 2.63 (s, 3H), 2.38 (d, J = 14.3 Hz, 1H), 1.96 – 1.87 (m, 2H), 1.85 – 1.71
(m, 4H), 1.64 (dq, J = 13.2, 6.6 Hz, 1H), 1.51 (m, 2H), 1.45 – 1.38 (m, 2H), 1.33 – 1.18 (m, 3H),
1.04 (s, 3H), 1.01 (s, 3H), 0.99 (s, 3H), 0.89 – 0.84 (m, 13H), 0.61 – 0.43 (m, 6H); 13C{1H} NMR
(100 MHz, CDCl3): δ 202.5, 164.9, 161.8, 159.6, 108.3, 102.8, 97.4, 89.7, 72.6, 64.7, 63.2, 50.4,
45.6, 42.6, 39.9, 37.6, 37.6, 36.3, 35.5, 34.1, 31.4, 22.8, 21.6, 19.1, 18.3, 17.7, 17.7, 16.1, 6.7, 6.7,
6.7, 4.3, 4.3, 4.3; HRMS (ESIMS) m/z: [M + H]+ Calcd for C34H53O6Si 585.3606; Found
585.3606.
(9Z,12Z,15Z)-1-((2aR,2bS,6R,6aR,7aS,12aS,12bS,13aR)-8,10-dihydroxy-13a-isopropyl-
2b,6-dimethyl-6-(((triethylsilyl)oxy)methyl)-2,2a,2b,3,4,5,6,6a,7,7a,12b,13a-dodecahydro-1H-
oxireno[2',3':7,8]phenanthro[8a,9-b]benzofuran-11-yl)-3-hydroxyoctadeca-9,12,15-trien-1-o
ne (25a and 25b). To a flame-dried round bottom flask equipped with a magnetic stir bar was
added THF (freshly distilled, 1.0 ml) followed by diisopropylamine (0.16 ml, 111.3mg, 1.1 mmol)
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under Ar atmosphere. After this mixture was cooled to 0 oC, n-BuLi (2.5M in hexane, 0.4 ml, 1.0
mmol) was added through a syringe. The resulted mixture was stirred at the same temperature for
30 min. The LDA solution formed here was used directly in the next procedure.
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The compound 24 (158.2 mg, 0.23 mmol) was solved in THF (0.8 ml) and added to another
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flame-dried flask under Ar atmosphere. After this solution was cooled to -78 C, the freshly
prepared LDA (1.2 ml, 0.70 mmol) was added via a syringe dropwisely. The reaction mixture was
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stirred for 50 min at -78 C. And then aldehyde 9 (63.6 mg, 0.27 mmol) solved in THF (0.8 ml)
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was added to the flask by syringe. The reaction mixture was kept at -78 C for another 1h. Then
sat. NH4Cl aqueous solution was used to quench the reaction. The mixture was extracted with
ethyl acetate. Combined organic layer was washed with water and brine in sequence, dried over
Na2SO4. The organic solution was concentrated in vacuo to give a crude product. The crude
product was purified by column chromatography (petroleum/ethyl acetate = 8:1 to 4:1) to afford
compound 25a and 25b (1:1.1, inseparable) contained two diastereoisomers (94.2 mg, 0.12 mmol,
50 %, brsm 61%) as a colorless oil. Compounds 25a and 25b: [α]D25 = +50.0o (c 1.00, DCM); IR
(thin film, ν cm-1): 3195, 2961, 2927, 1638, 1612, 1431, 1261, 1095, 1020, 800, 739, 568 cm-1.
HRMS (ESIMS) m/z: [M + Na]+ Calcd for C50H78O7SiNa 841.5409; Found 841.5416.
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Compound 25a: H NMR (400 MHz, CDCl3): δ 13.09 (s, 1H), 7.06 (brs, 1H), 5.91 (s, 1H),
5.44 – 5.27 (m, 6H), 4.18 (brs, 1H), 4.05 – 4.03 (m, 1H), 3.64 (d, J = 4.6 Hz, 1H), 3.48 – 3.38
(m, 1H), 3.27 (d, J = 4.9 Hz, 1H), 3.15 (d, J = 6.0 Hz, 1H), 3.10 (s, 1H), 2.94 (d, J = 8 Hz, 1H),
2.82 – 2.77 (m, 4H), 2.48 (d, J = 16 Hz, 1H), 2.12 – 2.05 (m, 4H), 1.94 – 1.87 (m, 2H), 1.86 –
1.71 (m, 5H), 1.66 (d, J = 8 Hz, 1H), 1.60 – 1.55 (m, 3H), 1.53 – 1.47 (m, 3H), 1.42 – 1.20 (m,
8H), 1.04 (s, 3H), 1.01 – 0.96 (m, 9H), 0.91 – 0.85 (m, 12H), 0.57 – 0.50 (m, 6H); 13C{1H} NMR
(100 MHz, CDCl3): δ 203.9, 165.5, 161.5, 159.9, 131.9, 130.3, 128.3, 127.6, 127.1, 108.3, 102.9,
98.0, 89.8, 72.7, 69.9, 68.4, 65.3, 64.6, 63.4, 51.5, 50.3, 49.5, 46.1, 42.8, 39.8, 37.6, 37.0, 36.3,
35.5, 34.2, 29.7, 29.4, 27.3, 25.6, 25.5, 22.7, 21.5, 20.5, 19.1, 18.3, 17.7, 17.6, 16.0, 14.3, 6.7, 6.7,
6.7, 4.3, 4.3, 4.3.
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Compound 25b: H NMR (400 MHz, CDCl3): δ 12.91 (s, 1H), 7.06 (brs, 1H), 5.90 (s, 1H),
5.44 – 5.27 (m, 6H), 4.02 (brs, 1H), 3.59 (d, J = 4.6 Hz, 1H), 3.51 (brs, 1H), 3.48 – 3.38 (m, 1H),
3.25 (d, J = 4.9 Hz, 1H), 3.13 (d, J = 6.0 Hz, 1H), 3.02 (s, 1H), 2.90 (d, J = 8.0 Hz, 1H), 2.82 –
2.77 (m, 4H), 2.41 (d, J = 16 Hz, 1H), 2.12 – 2.05 (m, 4H), 1.94 – 1.87 (m, 2H), 1.86 – 1.71 (m,
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5H), 1.62 (d, J = 8 Hz, 1H), 1.60 – 1.55 (m, 3H), 1.53 – 1.47 (m, 3H), 1.42 – 1.20 (m, 8H), 1.04 (s,
3H), 1.01 – 0.96 (m, 9H), 0.91 – 0.85 (m, 12H), 0.57 – 0.50 (m, 6H); 13C{1H} NMR (100 MHz,
CDCl3): δ 203.2, 165.1, 161.1, 159.9, 131.9, 130.3, 128.3, 127.6, 127.1, 108.1, 102.9, 97.7, 89.6,
72.7, 69.9, 68.4, 65.3, 64.6, 63.1, 51.5, 50.2, 49.5, 45.7, 42.8, 39.7, 37.6, 37.0, 36.3, 35.5, 34.2,
29.7, 29.4, 27.3, 25.5, 25.4, 22.4, 21.4, 20.5, 19.1, 18.3, 17.7, 17.6, 15.9, 14.3, 6.7, 6.7, 6.7, 4.3,
4.3, 4.3.
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(2E,9Z,12Z,15Z)-1-((2aR,2bS,6R,6aR,7aS,12aS,12bS,13aR)-8,10-Dihydroxy-13a-isopro
pyl-2b,6-dimethyl-6-(((triethylsilyl)oxy)methyl)-2,2a,2b,3,4,5,6,6a,7,7a,12b,13a-dodecahydro-
1H-oxireno[2',3':7,8]phenanthro[8a,9-b]benzofuran-11-yl)octadeca-2,9,12,15-tetraen-1-one
(26). The adol products 25a and 25b (67.9 mg, 0.083 mmol) were solved in DCM (3.0 ml) and
transferred to a round bottom flask containing DMAP (2.0 mg, 0.01658 mmol) via syringe. After
the reaction mixture was cooled to 0 oC, NEt3 (34.6 μl, 25.2 mg, 0.25 mmol) and AcCl (23.6 μl,
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26 mg, 0.33 mmol) were added in sequence. The resulted mixture was stirred at 0 C for another
1h. After the totally consumption of compounds 25a and 25b, sat. NaHCO3 aqueous solution was
used to quench the reaction. The aqueous phase was extracted by DCM. The combined organic
layer was washed with water and brine in sequence, dried over Na2SO4 followed by concentrating
in vacuo to give crude product. The crude product was purified by column chromatography
(petroleum/ethyl acetate = 16:1 to 8:1) to afford corespoding diacetyl protected products (49.7 mg,
0.055 mmol, 66%) as a colorless oil.
To a round bottom flask equipped with a stir bar was added Burgess reagent (24.3 mg, 0.10
mmol) solved in toluene (0.6 ml). And the diacetyl protected products (30.7 mg, 0.034 mmol) in
toluene (0.8 ml) was added to the reaction system via syringe. The resulted mixture was placed in
a 50 oC oil bath and stirred for 8h. After the total consumption of the substrates, water was added
to quench the reaction. Resulted mixture was extracted by ethyl acetate. The combined organic
phase was washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude
product. The crude product was purified by column chromatography (petroleum/ethyl acetate =
16:1 to 8:1) to afford α, β-unsaturated ketone 26 (18.9 mg, 0.021 mmol, 63%) as a colorless oil:
[α]D25 = +13.0o (c 1.00, DCM); IR (thin film, ν cm-1): 3395, 2928, 1775, 1670, 1617, 1461, 1413,
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1367, 1192, 1096, 825, 728 cm-1; H NMR (400 MHz, CDCl3) δ 6.86 (dt, J = 15.4, 6.6 Hz, 1H),
6.69 (d, J = 15.6 Hz, 1H), 6.40 (s, 1H), 5.43 – 5.28 (m, 6H), 3.59 (dd, J = 7.1, 1.8 Hz, 1H), 3.14 (q,
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J = 9.5 Hz, 2H), 2.99 (s, 1H), 2.82 – 2.77 (m, 4H), 2.30 (s, 3H), 2.26 – 2.21 (m, 5H), 2.11 – 2.06
(m, 4H), 1.97 (d, J = 14.1 Hz, 1H), 1.87 – 1.69 (m, 6H), 1.60 (dd, J = 13.8, 6.9 Hz, 1H), 1.55 –
1.44 (m, 4H), 1.39 – 1.23 (m, 9H), 1.03 (s, 3H), 1.00 – 0.95 (m, 8H), 0.90 – 0.83 (m, 13H), 0.56 –
0.47 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 188.7, 169.1, 167.3, 158.7, 149.8, 149.1, 148.6,
131.9, 130.5, 130.1, 128.3, 128.2, 127.7, 127.1, 121.9, 114.2, 109.5, 89.8, 71.7, 63.9, 62.9, 50.7,
46.0, 42.8, 39.6, 37.7, 35.9, 35.4, 34.0, 32.5, 29.5, 29.0, 27.8, 27.1, 25.6, 25.5, 22.3, 21.4, 20.9,
20.9, 20.5, 19.1, 18.3, 17.7, 17.6, 17.2, 15.9, 14.2, 6.8, 6.8, 6.8, 4.3, 4.3, 4.3; HRMS (ESIMS) m/z:
[M + Na]+ Calcd for C54H80O8SiNa 907.5515; Found 907.5516.
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(9Z,12Z,15Z)-1-((2aR,2bS,6R,6aR,7aS,12aS,12bS,13aR)-8,10-Dihydroxy-13a-isopropyl-
2b,6-dimethyl-6-(((triethylsilyl)oxy)methyl)-2,2a,2b,3,4,5,6,6a,7,7a,12b,13a-dodecahydro-1H-
oxireno[2',3':7,8]phenanthro[8a,9-b]benzofuran-11-yl)octadeca-9,12,15-trien-1-one (27). To
a round bottom flask equipped with a magnetic stir bar, Pd(PPh3)4 (1.0 mg, 0.00082 mmol) was
added followed by adding unsaturated ketone 26 (24.3 mg, 0.02745 mmol) in THF (3.0 ml). After
Pd-catalyst solved to give a pale yellow solution, n-Bu3SnH (22.2 μl, 24.0 mg, 0.08234 mmol)
was added via a syringe. The resulted reaction mixture was stirred at room temperature for 24h.
And then water was added to quench. The aqueous phase was extracted with ethyl acetate three
times. Combined organic layer was washed by brine and dried over Na2SO4, followed by
concentrating in vacuo to provide a mixture of 26 and 27. This mixture was purified by column
chromatography (petroleum/ethyl acetate = 16:1) to afford selectively reduced product 27 (12.2
mg, 0.014 mmol, 50%, brsm 70%) as a colorless oil: [α]D25 = +11.0o (c 1.00, DCM); IR (thin film,
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ν cm-1): 3399, 2927, 1775, 1671, 1616, 1460, 1412, 1367, 1192, 1095, 727 cm-1; H NMR (400
MHz, CDCl3) δ 6.36 (s, 1H), 5.44 – 5.27 (m, 6H), 3.61 (dd, J = 7.0, 1.7 Hz, 1H), 3.18 – 3.10 (m,
2H), 3.01 (s, 1H), 3.00 – 2.85 (m, 2H), 2.84 – 2.72 (m, 4H), 2.30 (s, 3H), 2.26 (s, 3H), 2.12 – 2.03
(m, 4H), 2.01 – 1.95 (m, 1H), 1.90 – 1.84 (m, 2H), 1.81 – 1.72 (m, 3H), 1.67 – 1.59 (m, 4H), 1.52
– 1.46 (m, 2H), 1.40 – 1.25 (m, 13H), 1.04 (s, 3H), 1.00 – 0.96 (m, 8H), 0.90 – 0.83 (m, 13H),
0.54 – 0.47 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 199.6, 169.4, 167.3, 158.9, 149.6, 148.8,
131.9, 130.4, 128.3, 128.2, 127.5, 127.1, 121.9, 114.2, 109.6, 89.9, 71.7, 64.1, 63.0, 50.8, 46.2,
43.9, 42.7, 39.6, 37.7, 35.9, 35.4, 34.0, 29.7, 29.4, 29.3, 29.2, 27.3, 25.6, 25.5, 24.0, 22.1, 21.4,
21.0, 20.9, 20.5, 19.2, 18.3, 17.7, 17.6, 17.2, 15.9, 14.3, 6.8, 6.8, 6.8, 4.3, 4.3, 4.3; HRMS
(ESIMS) m/z: [M + Na]+ Calcd for C54H82O8SiNa 909.5671; Found 909.5665.
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Nominal ent-Chlorabietol B (28). The compound 27 (10 mg, 0.011 mmol) was solved in
MeOH (1.6 ml) followed by addition of K2CO3 (9.3 mg, 0.068 mmol). The resulting reaction
mixture was stirred at room temperature for 8h. After the complete consumption of substrate 27,
water was added to the reaction vow. The resulting aqueous solution was extracted with ethyl
acetate. Combined organic layer was washed by brine, dried over Na2SO4. The organic solvent
was evaporated in vacuo to give the crude deacetylation product which was used without any
purification.
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The crude deacetylation product was solved in THF (1.6 ml) followed by addition of TBAF
(1.0M in THF, 11.0 μl, 0.11 mmol). The resulting solution was stirred at room temperature for
another 3h. After the fully consumption of the substrate, water was added to quenching. The
aqueous solution was extracted with ethyl acetate three times. Combined organic layer was
washed with brine, dried over Na2SO4. The organic solution was concentrated in vacuo to give a
crude product 28. This crude product was purified by flash column chromatography
(petroleum/ethyl acetate = 3:1) to afford compound 28 (6.2 mg, 0.0090 mmol, 82% over 2 steps)
23
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as a white solid: [α]D = +26.0o (c 1.00, MeOH); m.p. 95–102 C; IR (thin film, ν cm-1): 3389,
2930, 2840, 1633, 1616, 1449, 1262, 1026, 824, 692 cm-1; 1H NMR (400 MHz, CDCl3) δ 13.38 (s,
1H), 9.18 (brs, 1H), 5.85 (s, 1H), 5.42 – 5.31 (m, 6H), 3.66 (s, 1H), 3.61 (d, J = 12.0 Hz, 1H), 3.07
(s, 1H), 3.04 (d, J = 12.0 Hz, 1H), 2.99 (d, J = 12.0 Hz, 2H), 2.81 – 2.77 (m, 4H), 2.58 (d, J = 12.0
Hz, 1H), 2.11 – 2.02 (m, 4H), 1.98 – 1.89 (m, 2H), 1.80 – 1.72 (m, 4H), 1.71 – 1.63 (m, 4H), 1.61
– 1.57 (m, 1H), 1.57 – 1.50 (m, 2H), 1.42 (d, J = 12.0 Hz, 1H), 1.40 – 1.31 (m, 9H), 1.21 (d, J =
12.0 Hz, 1H), 1.08 (s, 3H), 1.03 (d, J = 6.0 Hz, 3H), 1.01 (d, J = 6.0 Hz, 3H), 0.98 (t, J = 6.0 Hz,
3H), 0.91-0.89 (m, 1H), 0.82 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 205.2, 165.0, 162.0,
158.6, 131.9, 130.4, 128.3, 128.2, 127.6, 127.1, 106.3, 103.0, 96.5, 89.4, 71.7, 63.7, 62.6, 49.1,
47.7, 42.8, 40.9, 39.4, 37.3, 36.8, 35.0, 34.0, 29.7, 29.5, 29.4, 29.3, 27.3, 25.6, 25.5, 24.6, 22.2,
20.5, 20.3, 18.9, 18.4, 18.1, 17.7, 17.6, 15.4, 14.3; HRMS (ESIMS) m/z: [M + Na]+ Calcd for
C44H64O6Na 711.4595; Found 711.4600.
ASSOCIATED CONTENT
1
Supporting Information. Copies of H and 13C NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Accession Codes
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CCDC 1972686 contains the supplementary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
9
AUTHOR INFORMATION
Corresponding Author
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*E-mail: xiezx@lzu.edu.cn.
ORCID
Zhixiang Xie: 0000-0001-5809-3084
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge financial support from the NNSFC (Grants 21672088, 21772079
and 21971096) and the Natural Science Foundation of Gansu Province (18JR4RA003).
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