Protecting-Group-Free Total Synthesis of (–)-Pallambins A—D

Article abstract of DOI:10.1002/cjoc.202100001

A full account of the total synthesis of (–)-pallambins A—D (1—6) is described. The strategy was devised by simulating their biosynthetic pathway. The left-part bicyclo[3.2.1]octane system of pallambins C and D was efficiently constructed via a palladium- catalyzed oxidative cyclization. For construction of the right-part tetrahydrofuran/γ-lactone moiety (C/D rings), initial attempts to synthesize the allylic alcohol 15 for an one-step Pd-mediated alkoxycarbonylation have failed. However, during the course of this work, an unprecedented CH₃Li-mediated method for conversion of bromoisoxazoline to the corresponding β-hydroxy nitrile has been discovered. Furthermore, a stepwise protocol was designed, namely an Eschenmoser-Claisen rearrangement/Lactonization to generate the C ring, and a non-classical Wittig reaction to form the D ring. During the course of this work, a palladium-catalyzed method for dehydrobromination of bromide ketone was developed. Finally, an individual transformation of pallambins C (3) and D (4) generated pallambins A (5) and B (6) under mild UV irradiation. Thus, the first enantioselective total syntheses of (–)-pallambins A—D have been achieved in 15 or 16 steps from the known chiral cyclohexenone 8. The described synthesis avoids protecting-group manipulations by designing highly chemo- and stereoselective transformations.

Full text of DOI:10.1002/cjoc.202100001

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Title: Protecting-Group-Free Total Synthesis of (–)-Pallambins A-D
Authors: Xiwu Zhang, Yuan Wang, Peng Chen, Xinxian Cai, and Yanxing Jia*
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Cite this paper: Chin. J. Chem. 2021, 39, XXX—XXX. DOI: 10.1002/cjoc.202100XXX
Protecting-Group-Free Total Synthesis of (–)-Pallambins A-D
Xiwu Zhang,‡ Yuan Wang,‡ Peng Chen, Xinxian Cai, and Yanxing Jia*
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing
100191, China
Keywords
Diterpenoid | Total synthesis | Enantioselective | Protecting-Group-Free | Bicyclo[3.2.1]octane
Main observation and conclusion
A full account of the total synthesis of (–)-pallambins A-D (1-6) are described. The strategy was devised by simulating their biosynthetic
pathway. The left-part bicyclo[3.2.1]octane system of pallambins C and D was efficiently constructed via a palladium-catalyzed oxidative
cyclization. For construction of the right-part tetrahydrofuran/γ-lactone moiety (C/D rings), initial attempts to synthesize the allylic
alcohol 15 for an one-step Pd-mediated alkoxycarbonylation have failed. However, during the course of this work, an unprecedented
CH3Li-mediated method for conversion of bromoisoxazoline to the corresponding β-hydroxy nitrile has been discovered. Furthermore,
a stepwise protocol was designed, namely an Eschenmoser-Claisen rearrangement/Lactonization to generate the C ring, and a non-
classical Wittig reaction to form the D ring. During the course of this work, a palladium-catalyzed method for dehydrobromination of
bromide ketone was developed. Finally, an individual transformation of pallambins C (3) and D (4) generated pallambins A (5) and B (6)
under mild UV irradiation. Thus, the first enantioselective total synthesis of (–)-pallambins A-D have been achieved in 15 or 16 steps
from the known chiral cyclohexenone 8. The described synthesis avoids protecting-group manipulations by designing highly chemo-
and stereoselective transformations.
Comprehensive Graphic Content
H
Me
H
Me
H
Me
O
H
H
Me
H
Me
Br
1,3-Diploar
Cycloaddition
O
CN
OH
CHO
OH
attempt 1
N
H
O
O
O
Me
O
Me
Me
Me
O
Me
H
O
H
H
O
H
O
O
H
Me
16
Me
26
Me
27
Me
14
13
H
MeO
OMe
N
H
H
Me
Me
Me
Me
Me
aq
H
2SO4
Hydroxylation
Pd(OAc)2
O
O
A
C
B
Lactone
Formation
Eschenmoser-Claisen
Rearrangement
O
O
H
Me
Pd-catalyzed
Me
N
Me
Me
O
O
H
O
O
Oxidative
OH
Me
39
Cyclization
8
13
37
36
attempt 2
O
H
O
O
O
H
Me
H
Me
H
Me
H
Me
H
Me
Pd-catalyzed
Debromination
Me
O
O
O
OH
O
Ph
Br
3P=C=C=O
D
O
O
O
O
O
O
Wittig
Me
H
H
H
Me
Me
Me
Me
H
H
H
H
O
H
O
H
O
O
O
H
H
H
Me
35
Me
Me
Me
52
Me
Z/E
)
C/D
pallambin
(
50
51
attempt 3
H
O
O
H
Me
H
Me
H
Me
H
O
H
hv
OH
OH
Me
Me
O
H
H
O
O
H
O
O
O
O
O
Me
H
Me
O
Me
H
H
H
O
H
O
H
O
O
H
H
H
Me
Me
45
OEt
Me
Me
14
Me
Z/E
)
A/B
48
pallambin
(
*E-mail: yxjia@bjmu.edu.cn
‡These authors contributed equally.
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Supporting Information
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CAS,
Shanghai,
&
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Zhang et al.
Report
eight-step total synthesis of phalarine,14 and 10-step total synthesis
of speradine C.15
Background and Originality Content
The liverworts, widely distributed all over the world, have been
found to be one of the most abundant sources of diterpenoids
which possess intriguing structure and interesting biological
activities. Since 1994, a group of extraordinarily complex 7,8-
secolabdane diterpenoids with a common furofuranone moiety
have been isolated and characterized from the liverworts, such as
pallavicinin (1), neopallavicinin (2), and pallambins A-D (3-6) (Figure
1).1-5 Structurally, these diterpenoids contain 4-6 congested rings
Results and Discussion
Scheme 1 Our Synthetic Strategy towards 1 to 6
Me
Me
Me
2
Pd
2
and
1
2
2
8
8
8
O
and 7-10 contiguous stereocenters including
2 all-carbon
4
TBSO
O
quaternary centers, representing formidable challenges for the
total synthesis.
8
9
10
Biosynthetically, these diterpenoids are derived from the same
labdane-type diterpenoid (Figure 1).2,5 The cleavage of C7-C8 bond
of the labdane-type diterpenoid gives the common labdane
precursor 7. Pallavicinin (1) and neopallavicinin (2) arise through
the reconstruction of C2-C8 bond via an intramolecular aldol
reaction. Pallambins C (3) and D (4) are formed through
demethylation at C4 position followed by the C4-C8 bond
reconstruction. In additiion, during the isolation of pallambins A-D
(3-6) by Lou and coworkers, they have demonstrated that
pallambins C (3) and D (4) could be convered to pallambins A (5)
and B (6) under UV irradiation through a diradical rearrangement
procedure.
Accordingly, these diterpenoids have attracted considerable at-
tention from the synthesis community.6-12 However, all reported
syntheses are racemic. The Wong group have reported the first total
synthesis of racemic pallavicinin (1) and neopallavicinin (2), pal-
lambins C (3) and D (4) in 2006 and 2012, respectively.6,8 The Car-
reira group achieved the first total synthesis of racemic pallambins
A (5) and B (6) in 2015.9 In the same year, we have accomplished
the first enantioselective synthesis of (+)-pallavicinin (1) and (-)-ne-
opallavicinin (2) from the known chiral cyclohexenone 8 (Scheme
1).10 In 2016, the Baran group reported a 11-step total synthesis of
racemic pallambins C (3) and D (4).12
H
Me
H
Me
H
Me
Pd
-
3 6
4
4
4
8
8
8
Me
Me
Me
O
TBSO
O
11
12
13
Inspired by the aforementioned biosynthetic pathway of 1-6, we
devised a biomimetic synthetic scheme to access 1-6 by simulating
the formation of different bicyclo[3.2.1]octane systems through
site-selective aldol cyclization (Scheme 1). We intend to use the
known chiral cyclohexenone 8 containing the chiral quaternity car-
bon center as the common intermediate (corresponding to inter-
mediate 7), and to construct different [3.2.1]octane systems 10 and
13 by site-selective palladium-catalyzed oxidative cyclization, finally
achieving the total synthesis of 1-6. In 2015, we have accomplished
the first enantioselective synthesis of (+)-(1) and (-)-(2) from 8.10 In
2019, we have achieved the first enantioselective synthesis of (-)-
(3-6) from 8.16 Herein, we describe the full details of our efforts to-
ward the synthesis of 3-6.
Scheme 2 Retrosynthetic Analysis of Pallambins A-D
O
H
Me
O
hv
5
6
3
A
B
C
D
pallambin
pallambin
pallambin
pallambin
( )
( )
( )
4
( )
O
16
H
N
Me
Me
H
13
O
11
20
H
Me
14
H
Me
17
C2-C8
aldol
1
4
11
O
2
2
2
O
8
8
H
8
15
O
O
4
12
7
O
H
H
Me
O
Me
H
Pd-catalyzed
alkoxycarbonylation
Me
OH
Br
Me
19 18
Me
Vinylation
7
Labdane
1
pallavicinin ( )
-CH3
OH
O
C4-C8 aldol
Me
Me
O
O
H
H
Me
Me
15
Me
16
H
O
O
H
H
Me
H
Me
Me
O
Me
O
2
H
8
4
4
O
H
Me
Olefin isomerization/
1,3-diploar
8
8
Pd-catalyzed
Me
O
O
O
O
Me
Me
H
H
Me
O
Me
Oxidative
cycloaddition
H
H
H
Cyclization
O
H
Me
Me
Me
Me
O
3
D
4
2
C
pallambin ( )
pallambin ( )
neopallavicinin ( )
O
Me
O
hv
13
8
H
H
H
challenges:
Synthetic
4-6
H
O
O
♦
♦
rings
congested
Me
Me
O
Me
O
Our preliminary retrosynthetic analysis of pallambins A-D (3-6)
was illustrated in Scheme 2. As reported by Lou, pallambins A (5)
and B (6) could be readily accessed from pallambins C (3) and D (4)
through photoinduced interconversion.5 Pallambins C (3) and D (4)
could be prepared from the tetracycle 14. The tetrahydrofuran/γ-
lactone moiety of 14 might be constructed in one step by Pd-cata-
lyzed alkoxycarbonylation of the allylic alcohol 15. In turn, alcohol
15 could arise from bromoisoxazoline 16, which could be derived
from bicyclo[3.2.1]octane system 13 via a sequence of olefin isom-
erization and bromoisoxazoline formation. Bicycle 13 could be
eventually prepared from cyclohexenone 8 as shown in Scheme 2.
We intended to firstly explore the synthetic route with racemic
starting material, and then prepare the optical pure natural
7-10 contiguous
stereocenters
2 all-carbon
H
H
H
O
H
Me
♦
O
H
O
H
H
H
H
O
H
Me
Me
center
quaternary
Me
Me
5
A
B
6
pallambin ( )
pallambin ( )
Figure 1 Structures of pallavicinin (1), neopallavicinin (2), and pallambins
A-D (3-6) as well as their possible biosynthesis.
In connection with our long-term studies towards the concise
and efficient synthesis of structurally complex natural products, we
have developed several biomimetic strategies to construct the skel-
eton of several types of natural products and achieved their concise
total synthesis, such as five-step total synthesis of decursivine,13
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Chin. J. Chem. 2021, 39, XXX－XXX

Running title
Chin. J. Chem.
products with chiral cyclohexenone 8 which could be readily
prepared in 84% ee following the Stoltz’s procedure.17,18 As
illustrated in Scheme 3, our synthesis commenced with the
preparation of the known cyclohexenone 8. Sequential dialkylation
of the commercially available 3-ethoxy-2-cyclohexenone 17 with
allyl bromide and iodomethane provided 18 in 76% yield over 2
steps. Reduction of ketone 18 with LiAlH4 followed by acidic workup
gave the desired enone 8. Conjugate addition of a vinyl group to 8
mixture with a ratio of 3:1 at C5. Treatment of ketone 11 with Et3N
and TBSCl led to the corresponding thermodynamic TBS enol ether,
which subsequently underwent Pd-catalyzed oxidative cyclization
to give the desired bicyclo[3.2.1]octane system 13 in 64% yield.9,19-
31
With access to 13, we turned out to explore the 1,3-diploar
cycloaddition for the synthesis of bromoisoxazoline 16.9,32-37
Treatment of 13 with TfOH resulted in smoothly C8 olefin
isomerization to lead trisubstituted alkene 20. 1,3-Diploar
cycloaddition reaction of alkene 20 with bromonitrile oxide, in situ
generated from dibromoformaldoxime 21 in the presence of KHCO3,
smoothly provided the desired bromoisoxazoline 16 with exclusive
regio- and stereoselectivity. The excellent regioselectivity observed
in this reaction attributed to electron-rich trisubstituted double
bond in 20, and the stereoselectivity attributed to the hindered
bicyclo[3.2.1]octane system, which directed the attack of electro-
philic bromonitrile oxide to approach from the less hindered convex
face.
With bromoisoxazoline 16 in hand, we proceeded to prepare the
key precursor 15 of Pd-catalyzed alkoxycarbonylation,8,9,38-47 paving
the way for constructing the tetracyclic skeleton 14. Treatment of
16 with Zn/HCl delivered the desired β-hydroxy nitrile 22 (Scheme
4).48 With 22 in hand, we then turn our attention to reduce the cy-
ano group. At first, treatment of 22 with DIBAL-H, with complete
reduction of C-3 carbonyl, delivered the diol 24 as major product
with only trace amount of aldehyde 23. Unfortunately, attempts to
direct reduction of 24 under a variety of conditions were examined,
no reaction was found to occur.
Scheme 3 Preparation of Bromoisoxazoline 16
Br
1. LDA,
O
O
LiAlH4 Et
0 °C
2O,
,
2. LDA, MeI, -78 °C
then 25%
H SO
2 4
aq
90%
76% for 2 steps
EtO
EtO
17
18
H
Me
H
Me
19
5
MgBr
1.
2.
Et N
3
NaI, MeCN
TBSCl,
Me
-40 °C
CuBr•Me
2S,
then HMPA, MeI
=
O
,
Pd(OAc)2
DMSO, 85 °C
2
O
Me
Me
55%
3:1)
(dr
O
O
64% steps)
8
11
(2
13
Br
H
Me
H
Me
N
OH
Br
TfOH, 100 °C
1,4-dixoane
21
Br
N
KHCO3 25 °C
62% steps)
(2
,
O
Me
Me
O
H
O
Me
16
20
In order to decrease the effect of C3 ketone, protection of
ketone 16 with 1,2-bis(trimethylsilyloxy)ethane and TMSOTf was
followed by methylation afforded ketone 11 as a diastereomeric
Scheme 4 Attempts to Reduction of β-Hydroxy Nitrile
performed to afford ketal 25. Accidentally, in order to investigate
the electrophilicity of bromoisoxazoline 25, reaction of 25 with
CH3Li was carried out. Surpringly, the β-hydroxy nitrile 26 was ob-
tained in 99% yield. The structure of 26 was unambiguously
confirmed by single-crystal diffraction analysis. Although, several
methods for conversion of bromoisoxazoline to the correspond-
ing β-hydroxy nitrile have been reported,33,35,48-52 an
unprecedented CH3Li-mediated method has never been discovered.
This result meaned that a new method for conversion of bromoi-
soxazoline to the corresponding β-hydroxy nitrile has been devel-
oped. Mechanismly, it is most likely that CH3Li nucleophilicly attack
the Br atom of bromoisoxazoline and N-O bond cleavage to lead β-
hydroxy nitrile.
Frustratingly, the reduction of the β-hydroxy nitrile 26 under a
variety of conditions (DIBAL-H, LiAlH4, LiBH4, Red-Al,
Li(iBu)2(nBu)AlH, Ra-Ni/HCOOH, et al) varing with solvents,
Chin. J. Chem. 2021, 39, XXX－XXX
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
www.cjc.wiley-vch.de

Zhang et al.
Report
temperature and manipulations remained extremely sluggish, in
some cases, only trace 27 was produced with recovery of the
starting material 26. Based on above-mentioned results, we
speculated that the expsoed tertiary hydroxy at C8 position might
hamper the reduction of the cyano group. Therefore, protection of
C8 hydroxy group was performed. Pleasingly, upon CH3Li initated
ring open of the isoxazole 25, HMPA/TMS-Imidazole was added to
trap in situ generated oxygen anion in one-pot to deliver the
desired 28.53,54 Whereas, we were disappointed to find that no
significant improvement was achieved. Aldehyde 29 was obtained
in only 15% yield along with recovery of 28. What was worse was
that the yield of 29 decreased when the reaction was performed
on a relatively larger scale. In addition, treatment of 26 with TBAI
and MOMBr gave MOM-protected 30. Reduction of 30 gave similar
result (only trace product generated).
hydroxy aldehyde, we have to abandon this original synthetic plan
and turned out to explore an alternative approach featuring a
stepwise protocol to construct the fused furofuranone moiety (C/D
rings). The revised retrosynthetic analysis was shown in Scheme 6.
We envisioned that the tetracycle 14 could be formed from the
tricycle 35 through a Wittg reaction. Tricycle 35 could be formed
through the acid-mediated lactonization of amide 36 to furnish the
C ring, and subsequent hydroxylation with correct configuration.
Amide 36 could be generated via an Eschenmoser-Claisen
rearrangement of the allylic alcohol 37 which could be readily
prepared from bicycle 13.
Thus, we proceeded to construct the C ring via Eschenmoser-
Claisen rearrangement and lactonization (Scheme 7). Chemoselec-
tive epoxidation of electron-rich double bond of 13 with m-CPBA
provided the corresponding epoxide, which was
Scheme 5 Attempts to Functionalization of 25
Scheme 6 Revised Retrosynthetic Analysis of Pallambins A-D (3-6)
H
H
Me
O
Me
H
Me
H
Me
Br
Wittig
reaction
Lactone
formation
Cross
or
Coupling
OH
O
N
N
D
O
O
O
O
A
3-6
O
Nucleophilic
Substitution
Me
B
Me
C
O
O
H
O
H
O
Me
32
Me
25
H
Me
Me
H
H
O
H
H
O
Me
35
Me
14
MeONa, MeOH, 65 o
43% 62%)
C
(brsm
H
Me
H
Me
H
Me
Eschenmoser-Claisen
rearrangement
H
Me
H
Me
OMe
O
CO2Me
OH
H
N
O
O
O
H
Me
N
Me
Me
Me
Me
O
O
O
H
O
O
OH
Me
33
Me
34
36
37
13
Due to the failure of effective reduction of the β-hydroxy nitrile,
we have to make a slight adjustment of the previous synthetic plan,
that is, prior to N-O bond cleavage of the bromoisoxazoline, instal-
lation of the vinyl moiety to obtain compound 32 (Scheme 5). How-
ever, attempts to install the vinyl moiety on compound 25 through
both Pd-catalyzed cross-coupling and nucleophilic substitution
failed to produce the desired 32, instead, the β-hydroxy nitrile 26
was obtained as the sole product. For the formation of the β-hy-
droxy nitrile 26 under Pd-catalyzed cross-coupling, which presuma-
bly underwent oxidative addition of the N-O bond to Pd(0) species
and subsequent β–Br elimination. In addition, although bromide–
methoxide exchange of 25 could provide 33,9 the subsequent cleav-
age of N-O bond of 33 failed to give the desired ester 34 under a
variety of conditions (Zn/HCl, NaSEt, TMSCl/NaI, Mo(CO)6, Ra-
Ni/H2).
subsequently treated with PTSA in the presence of 1,3-dimethylim-
idazolidin-2-one (38) to provide the desired allylic alcohol 37.55
Eschenmoser-Claisen rearrangement of allylic alcohol 37 with N,N-
dimethylacetamide dimethyl acetal in toluene at 115 °C gave the
desired γ,δ-unsaturated amide 36 in 88% yield with remarkable ste-
reoselectivity,56 which was treated with H2SO4 in refluxing ethanol
afforded lactone 39 in 84% yield. IBX oxidation of 39 delivered the
desired ketone 40 in 40% yield.57-59 Although the yield is moderate,
this method is the most straightforward. In order to verify the struc-
ture of 40, conversion of 40 to the known Baran’s intermediate 41
was performed. DIBAL-H reduction of 40 followed by selective oxi-
dation of C3 allylic hydroxy with Dess-Martin reagent and methyla-
tion of the resultant hemiacetal delivered the intermediate 41 in 15%
overall yield. The spectrl data of 41 were identical to those reported
by Baran.12 Thus, the structure of 40 was unambiguously confirmed.
Consideration of the unacceptable efficiency of approach to β-
Scheme 7 Formal Syntheses of Pallambins C and D
H
Me
H
Me
MeO OMe
N
H
Me
H
Me
m
1. -CPBA
H
2SO4
EtOH/H2O
CH2Cl2 25 °C
,
O
O
100 °C
84%
2. TsOH, MDI 38
Toluene, 115 °C
88%
O
O
(
)
H
Me
Me
N
Me
Me
30 °C
O
CH2Cl2
H
,
O
O
O
OH
Me
39
40% steps)
(2
13
37
36
O
H
Me
H
Me
H
IBX
DMSO
1. DIBAL-H
2. DMP
Me
Me
3 steps
O
O
N
N
85 °C
40%
3.
HCl/MeOH
15%
O
O
O
OMe
H
Me
H
Me
Me
H
O
O
H
O
H
MDI 38
(
)
Me
Me
41
Me
40
3
Z
E
C
D
pallambin
pallambin
( ): ( )
4
( ): (
)
Scheme 8 Attempts to Preparation of Tetracyclic Framework 14 from Tricycle 39
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Chin. J. Chem. 2021, 39, XXX－XXX

Running title
Chin. J. Chem.
O
N
H
M
H
M
H
M
H
TM
C
2O
S
2C 2
Ph
43
SO2
e
(
)
e
e
2 l
H
,
Ph
TM Tf
SO
H
C
11
O
O
O
-
o
°C t 25 °C
O
O
7
8
LiHMD
S
O
O
O
e
e
M
e
M
M
-
,
OH
rsm
7
b
5
8 %
0%
O
O
O
.
H
H
H
THF 78 °C
99%
(
)
e
e
e
M
M
M
39
42
44
H
M
H
M
-
1 DMP
2 LiAlH Ot B
=
DIBAL H
e
e
Ph3P
H
Et
C
CO2
.
-
u
-
,
OH
OH
,
THF 40 °C
o uene
t l
(
)
3
90
°C
O
OH
O
O
53
%
O
O
89%
7
9%
e
M
e
M
H
H
O
O
H
H
e
e
M
M
45
46
O
H
H
M
H
M
H
M
e
e
e
,
,
OH
O
H
u n
o e e
O
DBU t l
25 °C
H
12
O
O
O
O
O
7
3%
H
O
O
O
e
M
e
M
e
M
H
H
Et
O
O
O
H
H
O
H
e
e
e
Et
M
M
M
47
48
14
With tricycle 45 in hand, we firstly investigated the construction
of D-ring through a sequence of intermolecular Wittig reaction/oxa-
Michael addition (Scheme 8). Reduction of lactone 45 with DIBAL-H
provided the hemiacetal 46 in 53% yield as an inseparable mixture
of diastereomers (dr = 2.3:1). To the best of our knowledge, the
precedence of these two cyclization depends on E/Z selectivity of
Wittig reaction.61-65 Initially, in order to obtain the Z-selectivity,
treatment of 46 with ethoxycarbonyl methylene triphenylphospho-
rane was carried out at room temperature, however, no reaction
occur. Given the fact that this reaction may demand for higher en-
ergy, the reaction temperature was gradually elevated to 90 oC. The
Wittig reaction occurred and produced the α,β-unsaturated ester
47, albeit with complete E-selectivity. The α,β-unsaturated ester 47
underwent an intramolecular Michael addition under basic condi-
tion to give tetrahydrofuran 48. However, the C12 chiral center in
48 is opposite to that required for natural products. Thus, a suitable
protocol should be devised.
With a robust route to tricycle 39, we focused on the installation
the C11 hydroxyl group with the correct configuration (Scheme 8).
Protection of the carbonyl group of 39 with TMSOTf and 1,2-bis(tri-
methylsilyloxy)ethane furnished lactone 42, which was confirmed
by single-crystal diffraction analysis. Direct α-hydroxylation of 42
with LiHMDS and Davis oxaziridine (43) provided the α-hydroxylac-
tone 44 in 99% yield as the sole product that is opposite to the ste-
reochemistry required for natural products.60 The stereoselectivity
is due to the convex face of 43 is more sterically hindered than its
concave face, and the hydroxylation can only occur on the less hin-
dered convex face. Thus, an oxidation/reduction strategy was im-
plemented to invert the configuration of C-11 hydroxyl group. Oxi-
dation of 44 with Dess-Martin reagent followed by an exclusively
stereoselective reduction with LiAlH(Ot-Bu)3 afforded the desired
alcohol 45. The structure of 45 was further confirmed by single-
crystal diffraction
analysis.
Scheme 9 Synthesis of Tetracyclic Skeleton 14
H
Me
O
H
O
H
Me
H
Me
Red-Al, CuI,
THF, 78 °C
PPh
3=C=C=O
-xylene
−
OH
O
O
m
O
O
O
195 °C
83%
O
then 2 M
HCl
O
O
Me
Me
49
Me
Me
H
H
H
H
H
O
O
O
H
H
91
%
Me
14
Me
45
−
H
Me
O
H
Me
43
1. LiHMDS,
78 °C
,
PPh
3=C=C=O
-xylene
Red-Al,
THF, 78 °C
CuI,
Me
−
OH
O
m
2. DMP, 25 °C 89%
,
O
O
−
160 °C
61%
O
H
O
O
3. LiAlH(Ot-Bu)3 78 °C
,
94
%
Me
Me
Me
H
H
O
O
O
H
H
87% for 3 steps
Me
50
Me
39
Me
35
In order to efficiently construct the trtracyclic framework, we
finally decide to perform a non-classical Wittig reation of 45 to
introduce the last D ring (Scheme 9).66,67 Heating 45 with
(triphenylphosphoranylidene)ketene in m-xylene at 195 oC
achieved the acyl hydroxyl group and subsequent intramolecular
Wittig reaction to furnish tetronic ester 49 in 83% yield. It is worth
to note that the reaction temperature and the reaction time was
critical for the high yield. Higher temperature and longer reaction
time resulted in lower yield. Chemo- and stereoselective reduction
of the tetronic ester double bond was then pursued. After extensive
experimentation, we were delighted to find that reduction of 49
with CuH, generated in suit by reaction of CuI with
Scheme 10 Total Syntheses of Pallambins A-D (3-6)
Chin. J. Chem. 2021, 39, XXX－XXX
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Zhang et al.
Report
O
H
O
H
O
H
H
Me
H
Me
H
Me
Pd(OAc)2
PPh3
O
O
O
Br
+
Et
DMSO
3N,
25 °C
O
O
O
O
Me
Me
Me
H
H
H
O
O
H
H
H
Me
51
Me
Me
52
53
(41%)
(38%)
AcOH, 25 °C
,
Py•HBr3
80%
O
O
O
H
O
O
H
Me
H
Me
H
Me
H
Me
1. LiHMDS, THF
IBX/DMSO
(1g/mL)
−
Me
O
O
O
78 °C, MeCHO
+
Me
85 °C
40%
2. Et
MsCl, DMAP
4
O
H
H
O
3N,
O
O
H
H
H
Me
Me
Me
Me
H
H
O
O
3
O
O
H
H
H
H
(30%), (51%)
Me
14
Me
52
Me
pallambin ( )
hv
Me
3
D
4
C
(41%)
pallambin ( )
hv
CH Cl
CH Cl
2 2
,
,
2
2
65%
70%
H
H
H
O
H
O
Me
Me
Me
O
O
H
H
H
H
Me
O
H
O
H
H
H
O
O
H
H
Me
Me
Me
Me
4
D
pallambin ( )
X-ray of
5
A
B
6
pallambin ( )
pallambin ( )
Red-Al, proceeded smoothly to give the desired product with a
highly selective 1,4-reduction.68 Upon completion of reduction, the
reaction was quenched and the protection group was removed with
2 M HCl solution to provide the desired product 14 in 91% yield. The
structure of 14 was verified by X-ray crystallography.
Given that protecting-group manipulations would adversely
affect synthetic efficiency and the ketone protection might be the
only one used in this total synthesis, we intended to achieve the
protecting-group-free total synthesis of these natural products.
Further visual inspection of the molecular models indicated that the
free C3 ketone group might not affect the hydroxylation and
subsequent reactions due to the sterically congested A/B ring
system shielding α-position of C3 ketone group. Therefore, we
audaciously attempted to direct conversion of 39 to 14 without
protection of C3 ketone (Scheme 9). Fortunately, all the reaction
worked well except that the reaction temperature of the non-
classical Wittig reation needed to be slightly decreased.
Finally, we conducted the conversion of pallambins C (3) and D
(4) to pallambins (5) and B (6) under UV irradiation. Interestingly,
we serendipitously disclosed that individual irradiation of
pallambins C (3) and D (4) under milder conditions (UV lamp, 8W)
in CH2Cl2 provided pallambins (5) and B (6), respectively, without
the cis/trans isomerization at ∆13(14) between pallambins (5) and
B (6) as well as pallambins C (3) and D (4). These results clearly
indicated that the cis/trans isomerization at ∆13(14) require higher
energy than the diradical rearrangement.
In addition, following the identical synthetic routes described
above, syntheses of (–)-pallambins A-D (3-6) were eventually
achieved from the chiral cyclohexenone 8. The physical data of our
synthesized products 3-6 are identical to those reported in the
literature (Supporting Information).5,8,9,12
Conclusions
After completion of tetracyclic framework, we proceeded to
introduce the C1,C2 double bond (Scheme 10). However, the
seemingly simple conversion proved exceptionally challenging. All
the reported direct methods failed to give any 52.69-76 For the
indirect method, only bromination of 14 with Py·HBr3 in HOAc gave
the desired 51 in 80% yield as a single stereoisomer.77 However,
attempts to dehydrobromination of 51 under a variety of conditions
also failed.78-83 Thus, alternative mild dehydrobromination method
was deemed necessary. Inspired by the mild reaction conditions
and reaction mechanism of palladium-catalyzed Heck reaction, we
envisioned that oxidative addition of the bromide ketone 51 to Pd(0)
species could give the corresponding alkylpalladium species, which
undergoes β–hydride elimination to provide the desired enone 52.
With this idea in mind and after extensive experimentation, we
found that treatment of 51 under the optimized conditions
(Pd(OAc)2, PPh3, and Et3N in DMSO) afforded the desired product
52 in 41% yield and the Heck-type product 53 in 38% yield.
Having obtained enone 52, considering oxidation of 39 with IBX
could give the enone 40, oxidation of 14 with IBX was examined
again. At first, following the same protocol, only trace amount of 52
was detected. And then we discovered that the desired enone 52
could be obtained in 40% yield when a large amount of oxidative
reagent (up to 1g IBX per mL DMSO) was used. Installation of the
ethylidene group furnished the target molecule pallambin C (3) in
30% yield and pallambin D (4) in 51% yield.
In summary, we have achieved the total synthesis of (–)-pallamb-
ins A-D (3-6) in 15 or 16 steps from the known chiral cyclohexenone
8 without the use of protecting groups. The success of this protect-
ing-group-free synthesis was mainly dependent on several highly
chemo- and stereoselective reactions.84 The present synthesis fea-
tures a palladium-catalyzed oxidative cyclization to assemble the
bicyclo[3.2.1]octane system, an Eschenmoser-Claisen rearrange-
ment/Lactonization sequence to construct the C ring, an intramo-
lecular Wittig reaction to form the D ring. During the course of this
work, an unprecedented CH3Li-mediated method for conversion of
bromoisoxazoline to the corresponding β-hydroxy nitrile, and a
mild method for dehydrobromination of bromide ketone were de-
veloped. We also found that pallambins C (3) and D (4) could be
individually converted to pallambins A (5) and B (6) under mild UV
conditions, respectively. This study is yet another example in which
natural product explorations catalyze the discovery of new reac-
tions.
Experimental
General All reagents were obtained from commercial suppliers
unless otherwise stated. Tetrahydrofuran (THF) was distilled from
potassium sodium alloys; Dichloromethane was distilled from
calcium hydride. Flasks were flame-dried under vacuum and cooled
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Chin. J. Chem. 2021, 39, XXX－XXX

Running title
Chin. J. Chem.
under a stream of argon. Flash chromatography was performed
using silica gel (200-300 mesh) with solvents distilled prior to use.
Nuclear magnetic resonance [1H and 13C NMR] spectra were
determined on Bruker AVIII-400 [1H NMR (400 MHz), 13C NMR (100
MHz)] and AVIII-600 [1H NMR (600 MHz), 13C NMR (150 MHz)]
spectrometers. The following abbreviations are used for the
multiplicities: s: singlet, d: doublet, t: triplet, q: quartet, quint:
quintet, m: multiplet, br d: broad doublet, br s: broad singlet for
proton spectra and carbon spectra. Coupling constants (J) are
reported in Hertz (Hz). Mass spectra were recorded using a Waters
Xevo G2 Q-TOF spectrometer.
was added to the faint brown solution, causing an immediate color
change to dark green. This dark green solution was stirred under –
40 °C for 20 min, upon a solution of compound 8 (3.00 g, 20 mmol,
1.0 eq.) in THF (5 mL) was added dropwise, the substrate was
consumed immediately. Then HMPA (10 mL, 60 mmol, 3.0 eq.) and
MeI (11 mL, 176 mmol, 8.8 eq.) was added and the reaction mixture
was warmed to 25 °C gradually with stirring for another 20 h before
NH4Cl (100 mL) was added. The mixture was extracted with EtOAc
(3 × 100 mL), and the combined organic layers were successively
washed with 20% ammonia solution (3 × 100 mL) and saturated
NaCl solution (3 × 100 mL), dried with anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified
by FCC (PE/EtOAc = 70:1) to provide the inseparable compound 11
and its epimer at C5 (2.11 g, 55%) with a diastereomeric ratio (dr =
3:1) as a faint yellow oil.
Compound 18. To a solution of 3-ethoxy-2-cyclohexenone 17 (10 g,
71.4 mmol, 1.0 eq.) in anhydrous THF (238 mL) at –78 °C under Ar
was added freshly prepared LDA (78.5 mmol, 1.1 eq.). The mixture
was sttirred for 30 min at this temperature and then allyl bromide
(13 mL, 150 mmol, 2.1 eq) was added dropwise. The mixture was
warmed gradually to – 60 °C and kept stirring for another 6 h before
NH4Cl (150 mL) was added. The mixture was extracted with EtOAc
(3 × 200 mL), and the combined organic layers were washed with
saturated NaCl solution (3 × 150 mL), dried with anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
passed through a short column of silica gel to provide the
corresponding allyl compound as a colorless oil.
To a solution of crude product above mentioned in THF (238 mL)
at –78 °C under Ar was added freshly prepared LDA (92.8 mmol, 1.3
eq.). The mixture was stirred for 30 min at this temperature and
then methyl iodide (6.7 mL, 107.1 mmol, 1.5 eq) was added
dropwise. The mixture was warmed gradually to 25 °C and kept
stirring for another 1 h before NH4Cl (150 mL) was added. The
mixture was extracted with EtOAc (3 × 200 mL), and the combined
organic layers were washed with saturated NaCl solution (3 × 150
mL), dried with anhydrous Na2SO4, filtered, and concentrated under
Compound 13. To a solution of 11 (230 mg, 1.2 mmol, 1.0 eq.) in
anhydrous MeCN (2 mL) was added Et3N (0.25 mL, 1.8 mmol, 1.5
eq.), TBSCl (271 mg, 1.8 mmol, 1.5 eq.) and NaI (271 mg, 1.8 mmol,
1.5 eq.). The reaction mixture was then stirred at 25 °C for 10 h.
Upon completion, H2O (2 mL) was added and the mixture was
extracted with Et2O (3 × 5 mL). The combined organic extracts were
washed with sat. NaCl solution (3 × 5 mL), dried with anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was used directly for the next step without further
purification.
To a solution of the above silyl enol ether in DMSO (24 mL) was
added Pd(OAc)2 (27.0 mg, 0.12 mmol, 0.10 eq.), and the resulting
solution was stirred under oxygen atmosphere (ballon with O2), at
85 °C for additional 7 h. Upon completion, H2O (20 mL) was added
and the mixture was extracted with EtOAc (3 × 40 mL). The
combined organic layers were washed with sat. NaCl solution (5 ×
30 mL), dried with anhydrous Na2SO4, filtered, and concentrated
reduced pressure. The residue was purified by FCC (PE/EtOAc = 20:1) under reduced pressure. The residue was purified by FCC (PE/CH2Cl2
to afford compound 18 (10.5 g, 76% for 2 steps) as a faint yellow oil.
1H NMR (400 MHz, CDCl3) δ 5.70 (m, 1H), 5.21 (s, 1H), 5.03-4.99 (m,
2H), 3.84 (q, J = 6.8 Hz, 2H), 2.37 (t, J = 6.4 Hz, 2H), 2.31 (dd, J = 13.6
Hz, 7.2 Hz, 1H), 2.13 (dd, J = 13.6 Hz, 7.6 Hz, 1H), 1.87 (dt, J = 13.2
Hz, 6.4 Hz, 1H), 1.65 (dt, J = 12.8 Hz, 6.4 Hz, 1H), 1.31 (t, J = 6.8 Hz,
3H), 1.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 203.4, 175.7, 134.2,
117.8, 101.2, 64.0, 43.1, 41.4, 31.6, 25.9, 22.1, 14.1；HRMS (ESI)
m/z: [M + H]+ calcd for C12H19O2 195.1385, found 195.1378.
= 1:1) to afford the bicyclic compound 13 with desired
confirguration (146 mg, 64% for 2 steps) as a faint yellow oil. [α]D
25
+52.73 (c 0.20, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.46 (dt, J = 16.8,
10.0 Hz, 1H), 5.21 (dd, J = 10.0, 2.0 Hz, 1H), 5.13 (dd, J = 16.8, 2.0
Hz, 1H), 4.93 (t, J = 2.0 Hz, 1H), 4.86 (t, J = 2.4 Hz, 1H), 2.68 (d, J =
17.2 Hz, 1H), 2.59-2.50 (m, 2H), 2.22-2.16 (m, 2H), 1.82 (m, 1H),
1.65 (m, 1H), 1.09 (s, 3H), 1.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
210.7, 152.6, 133.2, 120.4, 107.2, 64.6, 61.9, 45.3, 40.6, 35.1, 33.7,
24.4, 16.2; HRMS (ESI) m/z: [M + H]+ calcd for C13H19O 191.1436,
found 191.1429.
Compound 8. A stirred solution of compound 18 (5.1 g, 26.3 mmol)
in Et2O (120 mL) was cooled to 0 °C under Ar. LiAlH4 (1.30 g, 34.2
mmol) was added slowly. After stirring at the same temperature for
30 min ，the reaction was quenched by slow addition of 25%
aqueous H2SO4 (320 mL) at 0 °C. The resulting biphasic system was
allowed to warm to ambient temperature and stirred vigorously for
an additional 1 h. The phases were separated and the aqueous
phase was extracted with Et2O (3 × 100 mL). The combined organic
phases were dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by FCC (PE/ Et2O = 10:1)
to afford cyclohexenone 8 (3.56 g, 90%) as a faint yellow oil. 1H NMR
(400 MHz, CDCl3) δ 6.66 (d, J = 10.0 Hz, 1H), 5.87 (d, J = 10.0 Hz, 1H),
5.77 (m, 1H), 5.13-5.06 (m, 2H), 2.46-2.42 (m, 2H), 2.19 (d, J = 7.2
Hz, 2H), 1.96 (m, 1H), 1.76 (m, 1H), 1.13 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 199.4, 158.5, 133.4, 127.5, 118.6, 45.2, 35.7, 34.0, 33.5,
24.6；HRMS (ESI) m/z: [M + H]+ calcd for C10H15O 151.1123, found
151.1132.
Compound 20. To a solution of 13 (570 mg, 3.0 mmol, 1.0 eq.) in
1,4-dioxane (60 mL) at 25 °C was added TfOH (0.26 μL, 3.0 mmol,
1.0 eq.) dropwise and the mixture was warmed to 100 °C gradually.
Upon the reaction mixture turns black brown, Sat. NaHCO3 (10 mL)
was added and the mixture was extracted by EtOAc (3 × 50 mL). The
combined organic layers were washed with brine (3 × 20 mL), dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by FCC (PE/EtOAc = 70:1) to afford 20 (382
mg, 67%) as a faint yellow oil. 1H NMR (400 MHz, CDCl3) δ 5.63 (s,
1H), 5.51 (dt, J = 16.8 Hz, 10.0 Hz, 1H), 5.19 (dd, J = 10.0 Hz, 1.2 Hz,
1H), 5.14 (dd, J = 16.8 Hz, 1.2 Hz, 1H), 2.59-2.48 (m, 2H), 2.20 (dd, J
= 18.0 Hz, 7.6 Hz, 1H), 1.79 (dt, J = 13.6 Hz, 8.0 Hz, 1H), 1.62-1.56
(m, 4H), 1.05 (s, 3H), 0.99 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 211.9,
143.7,136.7, 133.6, 120.4, 67.4, 63.6, 45.7, 34.8, 30.3, 22.4, 14.0,
13.1; HRMS (ESI) m/z: [M + H]+ calcd for C13H19O 191.1436, found
191.1427.
Compound 11. An over-dried round-bottom flask was charged with
CuBr·Me2S (8.22 g, 40 mmol, 2.0 eq.) and THF (80 mL). The turbid
liquid was stirred vigorously and cooled to –40 °C following with
Me2S (20 mL) was added in one portion. A solution of
vinylmagnesium bromide (1.0 M in THF, 80 mL, 80 mmol, 4.0 eq.)
Compound 16. To a solution of trisubstituted alkene 20 in EtOAc (10
mL) was added KHCO3 (500 mg, 5.0 mmol, 5.0 eq.) and
dibromoformaldoxine 21 (241 mg, 1.2 mmol, 1.2 eq.) at 25 °C. The
reaction mixture was then stirred for 10 h. Upon completion, H2O
(5 mL) was added and the mixture was extracted by EtOAc (2 × 10
Chin. J. Chem. 2021, 39, XXX－XXX
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
www.cjc.wiley-vch.de

Zhang et al.
Report
mL). The combined organic layers were washed with brine (3 × 5
mL), dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by FCC (PE/EtOAc = 20:1 to 10:1)
to afford 16 (261 mg, 84%) as a faint yellow semisolid. 1H NMR (400
MHz, CDCl3) δ 5.36 (dt, J = 16.8 Hz, 10.0 Hz, 1H), 5.25 (dd, J = 10.4
Hz, 2.0 Hz, 1H), 5.16 (dd, J = 16.4 Hz, 2.0 Hz, 1H), 3.17 (s, 1H), 2.51-
2.45 (m, 2H), 2.36 (ddd, J = 18.0 Hz, 10.8 Hz, 9.2 Hz, 1H), 1.86 (m,
1H), 1.74 (m, 1H), 1.31 (s, 3H), 1.19 (s, 3H), 1.06 (s, 3H); 13C NMR
Compound 28. To a solution of isoxazole 25 (36 mg, 0.10 mmol, 1.0
eq.) in anhydrous THF (2 mL) at –78 °C under Ar was added CH3Li
(0.11 mL, 1.0 M in THF, 0.11 mmol, 1.1 eq.). Upon completion of
addition, the substrate was consumed immediately. Then HMPA
(0.2 mL) and TMS-Imid. (0.15 mL, 1.0 mmol, 10.0 eq.) was added
and the reaction mixture was warmed to 25 °C gradually with
stirring for another 10 h before Sat. NH4Cl (100 mL) was added. The
mixture was extracted with EtOAc (2 × 5 mL) and the combined
(100 MHz, CDCl3) δ 209.8, 138.4, 131.2, 122.2, 97.2, 68.6, 63.8, 60.0, organic layers were washed with brine (2 × 5 mL), dried over Na2SO4,
47.0, 35.1, 33.8, 21.8, 18.3, 12.0; HRMS (ESI) m/z: [M + H]+ calcd for
C14H19BrNO2 312.0599, found 312.0563.
filtered, and concentrated under reduced pressure. The residue was
purified by FCC (PE/EtOAc = 10:1) to afford 28 (28.6 mg, 81%) as a
colorless semisolid. 1H NMR (400 MHz, CDCl3) δ 6.11 (dt, J = 16.8 Hz,
10.0 Hz, 1H), 5.10 (dd, J = 10.0 Hz, 2.8 Hz, 1H), 5.02 (dd, J = 16.8 Hz,
2.4 Hz, 1H), 3.97-3.88 (m, 2H), 3.83-3.72 (m, 2H), 2.90 (s, 1H), 2.52
(dd, J = 10.0 Hz, 1.2 Hz, 1H),1.78-1.69 (m, 2H), 1.57 (s, 3H), 2.96 (m,
1H), 1.22 (m, 1H), 1.08 (s, 3H), 0.80 (s, 3H), 0.23 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 135.6, 119.0, 118.3, 110.5, 84.2, 65.2, 63.9, 59.2,
58.6, 53.0, 42.2, 31.9, 30.7, 23.9, 23.3. 12.9, 2.7(t); HRMS (ESI) m/z:
[M + H]+ calcd for C19H32NO3Si 350.2151 found 350.2159.
Compound 22. To a solution of 16 (62 mg, 0.20 mmol, 1.0 eq.) in
MeOH (5 mL) was added freshly prepared zinc powder (390 mg, 6.0
mmol, 30.0 eq.) and 6% HCl (1 mL) at 60 °C. The resulting solution
was kept stirring until TLC indicated complete consumption of the
substrate. Then H2O (5 mL) was added and the mixture was
extracted by EtOAc (2 × 10 mL). The combined organic layers were
washed with brine (3 × 5 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
FCC (PE/EtOAc = 7:1 to 3:1) to afford nitrile 22 (44 mg, 95%) as a
colorless semisolid. 1H NMR (400 MHz, CDCl3) δ 5.38 (dt, J = 16.4 Hz,
10.0 Hz, 1H), 5.28-5.19 (m, 2H), 3.19 (s, 1H), 2.82 (dd, J = 9.6 Hz, 1.2
Hz, 1H), 2.53 (dd, J = 19.2 Hz, 8.0 Hz, 1H), 2.28 (dt, J = 19.2 Hz, 10.0
Hz, 1H), 2.12 (s, 1H), 1.91 (m, 1H), 1.64 (m, 1H), 1.30 (s, 3H), 1.29 (s,
3H), 1.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 210.7, 131.8, 122.0,
117.2, 78.9, 64.9, 59.6, 51.9, 43.5, 35.1, 33.2, 23.2, 23.0, 12.7;
HRMS (ESI) m/z: [M + H]+ calcd for C14H20NO2 234.1494, found
234.1489.
Compound 29. To a solution of nitrile 28 (21 mg, 0.06 mmol, 1.0 eq.)
in anhydrous toluene (3 mL) was cooled to –78 °C under Ar, then
DIBAL-H (0.16 mL, 1.1 M in THF, 0.18 mmol, 3.0 eq.) was added
dropwise. After 30 min, sat. NH4Cl (1 mL) was added and the
mixture was kept stirred for another 20 min at 25 °C. Then the
mixture was extracted with EtOAc (2 × 5 mL). The combined organic
layers were washed with brine (2 × 5 mL), dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by FCC (PE/EtOAc = 20:1) to afford aldehyde 29 (3.2 mg,
1
15%) as a white semisolid with 28 (15.8 mg, 75%) recovered. H
Compound 25. To a solution of 16 (187 mg, 0.60 mmol, 1.0 eq.) and
1,2-bis(trimethylsilyloxy)ethane (0.58 mL, 2.4 mmol, 4.0 eq.) in
anhydrous CH2Cl2 (6 mL) at –78 °C under Ar was added TMSOTf (22
μL, 0.12 mmol, 0.2 eq.). The mixture was gradually warmed to 25 °C
and kept stirring for 72 h at this temperature. Sat. NaHCO3 (2 mL)
was added and the mixture was extracted by CH2Cl2 (2 × 10 mL). The
combined organic layers were washed with brine (2 × 5mL), dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by FCC (PE/EtOAc = 20:1 to 10:1) to afford
25 (136 mg, 64%) as a white solid with 17 (34 mg, 18%) recovered.
mp : 115-116 °C; 1H NMR (400 MHz, CDCl3) δ 6.10 (dt, J = 16.8 Hz,
10.0 Hz, 1H), 5.08 (dd, J = 10.0 Hz, 2.4 Hz, 1H), 5.01 (dd, J = 16.8 Hz,
2.0 Hz, 1H), 3.98 (m, 1H), 3.92 (m, 1H), 3.84-3.74 (m, 2H), 2.84 (s,
1H), 2.15 (d, J = 10.0 Hz, 1H), 1.75-1.67 (m, 2H), 1.58 (m, 1H), 1.49
(s, 3H), 1.35 (m, 1H), 1.01 (s, 3H), 0.94 (s, 3H); 13C NMR (100 MHz,
NMR (400 MHz, CDCl3) 1H NMR (400 MHz, CDCl3) δ 9.62 (d, J = 5.2
Hz, 1H), 6.19 (dt, J = 17.2 Hz, 10.4 Hz, 1H), 5.11-5.04 (m, 2H), 3.98-
3.88 (m, 2H), 3.84-3.72 (m, 2H), 2.84 (d, J = 10.4 Hz, 1H), 2.26 (d, J
= 5.2 Hz, 1H), 1.67-1.60 (m, 3H), 1.54 (s, 3H), 1.19 (m, 1H), 0.93 (s,
3H), 0.82 (s, 3H), 0.10 (9H); 13C NMR (100 MHz, CDCl3) δ 205.2,
136.4, 117.6, 111.0, 87.9, 66.8, 65.1, 63.8, 60.8, 58.5, 42.4, 33.2,
30.3, 24.4, 20.7, 12.7, 2.6(t); HRMS (ESI) m/z: [M + H]+ calcd for
C19H33O4Si 353.2148, found 353.2151.
Compound 30. To a solution of lactone 26 (28 mg, 0.10 mmol, 1.0
eq.) in anhydrous Toluene (3 mL) at 25 °C was added TBAI (56 mg,
0.1 mmol, 1.5 eq.), DIPEA (0.22 mL, 1.3 mmol, 13.0 eq.) and MOMBr
(16 μL, 0.20 mmol, 2.0 eq.). The mixture was gradually warmed to
90 °C and kept stirring for 7 h at this temperature. Sat. NH4Cl (1 mL)
was added and the mixture was extracted by EtOAc (2 × 5 mL). The
CDCl3) δ138.8, 135.0, 118.7, 110.1, 99.2, 67.7, 65.2, 64.2, 59.4, 56.4, combined organic layers were washed with brine (2 × 5mL), dried
45.7, 32.1, 30.5, 22.3, 19.6, 11.2; HRMS (ESI) m/z: [M + H]+ calcd for
C16H23BrNO3 356.0861, found 356.0869.
over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by FCC (PE/EtOAc = 20:1) to afford 30 (29.3
mg, 93%) as a white semisolid. 1H NMR (400 MHz, CDCl3) δ 6.10 (dt,
J = 16.8 Hz, 10.0 Hz, 1H), 5.11-5.05 (m, 2H), 4.92 (d, J = 8.4 Hz, 1H),
4.84 (d, J = 8.0 Hz, 1H), 3.97-3.88 (m, 2H), 3.84-3.73 (m, 2H), 3.48 (s,
3H), 2.92 (s, 1H), 2.60 (d, J = 10.0 Hz, 1H), 1.79-1.71 (m, 2H), 1.61(s,
Compound 26. To a solution of isoxazole 25 (71 mg, 0.20 mmol, 1.0
eq.) in anhydrous THF (4 mL) at –78 °C under Ar was added CH3Li
(0.22 mL, 1.0 M in THF, 0.22 mmol, 1.1 eq.). Upon completion of
addition, the substrate was consumed immediately. Sat. NH4Cl (1mL) 3H), 1.52 (m, 1H), 1.24 (m, 1H), 1.11 (s, 3H), 0.85 (s, 3H); 13C NMR
was added and the mixture was extracted by EtOAc (2 × 5 mL). The
combined organic layers were washed with brine (2 × 5 mL), dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by FCC (PE/EtOAc = 5:1) to afford 26 (55
(100 MHz, CDCl3) δ 135.3, 118.8, 118.6, 110.3, 92.1, 86.3, 65.2, 63.9,
59.2, 58.9, 56.3, 52.1, 42.4, 31.8, 30.6, 23.8, 18.6, 12.4; HRMS (ESI)
m/z: [M + H]+ calcd for C18H28NO4 322.2018, found 322.2022.
mg, 99%) as a white solid. mp: 132-133 °C; 1H NMR (400 MHz, CDCl3) Compound 33. To a solution of 25 (356 mg, 1.0 mmol, 1.0 eq.) in
δ 6.12 (dt, J = 16.8 Hz, 10.0 Hz, 1H), 5.12-5.05 (m, 2H), 3.99-3.89 (m,
2H), 3.85-3.73 (m, 2H), 2.97 (s, 1H), 2.56 (d, J = 10.4 Hz, 1H), 1.78-
1.74 (m, 3H), 1.57-1.45 (m, 4H), 1.25 (m, 1H), 1.12 (s, 3H), 0.87 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 135.1, 118.8, 118.2, 110.3, 79.5,
65.2, 64.0, 59.2, 57.4, 51.1, 42.4, 31.8, 30.7, 24.4, 23.6, 11.6; HRMS
(ESI) m/z: [M + H]+ calcd for C16H24NO3 278.1756, found 278.1759.
Crystallographic data for 26 has been deposited with the Cambridge
Crystallographic Data Center, accession number CCDC 1915894.
anhydrous MeOH (10 mL) was added freshly prepared
MeONa/MeOH (10 mmol, 2 mL) and the mixture was stirred at
65 °C under Ar for 7 days before Sat. NH4Cl (5 mL) was added. The
mixture was extracted with EtOAc (2 × 10 mL) and the combined
organic layers were washed with brine (2 × 10 mL), dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by FCC (PE/EtOAc = 10:1) to afford 33 (132 mg,
1
43%) a white semisolid with 25 (68 mg, 19%) recovered. H NMR
(400 MHz, CDCl3) δ 6.13 (dt, J = 16.8 Hz, 10.0 Hz, 1H), 5.09-5.01 (m,
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© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
Chin. J. Chem. 2021, 39, XXX－XXX

Running title
Chin. J. Chem.
2H), 3.99-3.89 (m, 2H), 3.84-3.75 (m, 5H), 2.62 (s, 1H), 2.30 (dd, J =
10.0 Hz, 1H), 1.75-1.66 (m, 3H), 1.59 (m, 1H), 1.47 (s, 3H), 0.91 (s,
3H), 0.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.1, 135.7, 118.1,
110.5, 97.2, 65.1, 64.2, 61.2, 59.1, 57.1, 56.7, 44.7, 32.0, 30.6, 21.6,
19.6, 10.8; HRMS (ESI) m/z: [M + H]+ calcd for C17H26NO4 308.1862,
found 308.1868.
94.1, 64.0, 59.7, 51.6, 43.0, 35.5, 34.3, 31.0, 21.7, 19.6, 12.6; HRMS
(ESI) m/z: [M + H] + calcd for C15H21O3 249.1491, found 249.1493.
Compound 40. To a solution of lactone 39 (100 mg, 0.4 mmol, 1.0
eq.) in anhydrous DMSO (4.0 mL) was added IBX (1.46 g, 5.2 mmol,
13.0 eq.) at 85 °C. After 14 h, sat. NaHCO3 ( 5 mL) was slowly added
and the mixture was extracted with EtOAc (2 × 10 mL). The
combined organic layers were washed with NaHCO3 (3 × 10 mL),
brine (3 × 10 mL), dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by FCC (PE/EtOAc
= 5:1) to afford unsaturated ketone 40 (39.7 mg, 40%) as a faint
Compound 37. To a stirred solution of compound 13 (190 mg, 1.0
mmol, 1.0 eq.) in CH2Cl2 (10 mL) at 0 °C, m-CPBA (70%-75%, 297 mg,
1.2 mmol, 1.2 eq.) was added in several portions. The resulting
solution was warmed to 25 °C and kept stirring until TLC indicated
complete consumption of the substrate. Then sat. Na2SO3 (3 mL)
was added and the mixture was extracted with CH2Cl2 (2 × 10 mL).
The combined organic layers were washed with 0.1 M aq. NaOH (2
× 10 mL) and brine (3 × 10 mL), dried over Na2SO4, filtered and
concentrated under reduced pressure which was used directly for
next step without further purification.
1
yellow semisolid. H NMR (400 MHz, CDCl3) δ 6.82 (dd, J = 9.6 Hz,
2.0 Hz, 1H), 6.01 (d, J = 9.6 Hz, 1H), 5.55 (dt, J = 16.8 Hz, 10.0 Hz,
1H), 5.22-5.15 (m, 2H), 2.82 (dd, J = 19.6 Hz, 11.2 Hz, 1H), 2.66 (dd,
J = 19.6 Hz, 3.6 Hz, 1H), 2.60 (dd, J = 11.2 Hz, 3.6 Hz, 1H), 2.38 (dd,
J = 9.2 Hz, 2.0 Hz, 1H), 1.30 (s, 3H), 1.14 (s, 3H), 1.12 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 199.4, 175.7, 157.7, 131.4, 127.7, 122.0,
93.2, 63.7, 62.7, 51.9, 46.3, 30.1, 23.3, 19.5, 13.3; HRMS (ESI) m/z:
[M + H]+ calcd for C15H19O3 247.1334, found 247.1339.
To a solution of MDI (0.22 mL, 2.0 mmol, 2.0 eq.) and the above
o
epoxide in CH2Cl2 (10 mL) at 30 C, TsOH (86 mg, 0.50 mmol, 0.50
eq.) was added in several portions. The reaction mixture was stirred
for about 2.5 h. Upon completion, sat. NaHCO3 (3 mL) was added
and the mixture was extracted with CH2Cl2 (2 × 10 mL). The
combined organic layers were washed with brine (3 × 10 mL), dried
over Na2SO4, filtered and concentrated under reduced pressure.
The residue was purified by FCC (PE/EtOAc = 6:1) to afford the
Compound 41. To a solution of 40 (37 mg, 0.15 mmol, 1.0 eq.) in
anhydrous THF (3 mL) was cooled to –78 °C under Ar, then DIBAL-H
(0.75 mL, 1.0 M in THF, 0.75 mmol, 5.0 eq.) was added dropwise.
After 5 min, sat. NH4Cl (2 mL) was added and the mixture was
warmed to 25 °C and stirred for another 20 min. The mixture was
extracted with EtOAc (2 × 10 mL) and the combined organic layers
were washed with brine (3 × 5 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was used
directly without purification.
To a solution of the above diol in CH2Cl2 (3 mL) was added DMP
(95 mg, 0.225 mmol, 1.5 eq.) and NaHCO3 (38 mg, 0.45 mmol, 3.0
eq.). After 10 min, sat. Na2SO3 (2 mL) was added and the mixture
was extracted with CH2Cl2 (2 × 5 mL). The combined organic layers
were washed with brine (2 × 5 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was used
directly without purification.
25
alcohol 37 (82 mg, 40% for 2 steps) as a colorless semisolid. [α]D
+213.33 (c 0.27, CHCl3);1H NMR (400 MHz, CDCl3) δ 5.94 (s, 1H),
5.50 (dt, J = 16.8, 10.4 Hz, 1H), 5.23 (dd, J = 10.4, 2.0 Hz, 1H), 5.17
(dd, J = 16.8, 2.0 Hz, 1H), 4.16 (d, J = 14.0 Hz, 1H), 4.08 (d, J = 14.0
Hz, 1H), 2.66 (ddd, J = 18.0, 10.0, 8.8 Hz, 1H), 2.57 (d, J = 10.0 Hz,
1H), 2.25 (dd, J = 18.0, 7.6 Hz, 1H), 1.83 (dt, J = 13.8, 8.4 Hz, 1H),
1.64 (m, 1H), 1.10 (s, 3H), 1.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
211.7, 147.1, 137.1, 132.8, 121.0, 67.9, 62.1, 59.4, 46.0, 34.8, 30.1,
22.3, 14.0; HRMS (ESI) m/z: [M - H]- calcd for C13H17O2 205.1229,
found 205.1233.
Compound 36. To a solution of allyl alcohol 37 (206 mg, 1.0 mmol,
1.0 eq.) in toluene (10 mL) was added N, N- dimethylacetamide
acetal (1.63 mL, 10 mmol, 10 eq.) and the mixture was heated to
115 oC for 2 h. The reaction mixture was concentrated under
reduced pressure. The residue was purified by FCC (PE/EtOAc = 5:1
To a solution of the obtained crude in MeOH (1 mL) was added 1
M HCl in MeOH (2 mL). After 5 min, sat. NaHCO3 (3 mL) was added
and the mixture was extracted with EtOAc (2 × 5 mL). The combined
organic layers were washed with brine (2 × 5 mL), dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
to 2:1) to afford the single diastereomer dimethyl amide 36 (242 mg, purified by FCC (PE/EtOAc = 10:1) to afford 41 (5.9 mg, 15% for 3
88%) as a faint green oil. [α]D25 +150.07 (c 0.70, CHCl3); 1H NMR (400
MHz, CDCl3) δ 5.46 (dt, J = 16.6, 10.0 Hz, 1H), 5.21 (dd, J = 10.0, 1.6
Hz, 1H), 5.12 (dd, J = 16.6, 1.6 Hz, 1H), 5.03 (d, J = 1.6 Hz, 1H), 4.92
(d, J = 2.0 Hz, 1H), 3.45 (t, J = 7.0 Hz, 1H), 3.03 (s, 3H), 2.98 (s, 3H),
2.66-2.55 (m, 2H), 2.29 (dd, J = 16.0, 6.4 Hz, 1H), 2.23-2.15 (m, 2H),
1.82-1.72 (m, 2H), 1.07 (s, 3H), 0.89 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 210.7, 171.9, 157.7, 133.1, 120.6, 108.5, 62.0, 61.0, 47.5,
42.9, 37.4, 37.2, 35.8, 34.8, 34.7, 20.6, 16.7; HRMS (ESI) m/z: [M +
H]+ calcd for C17H26NO2 276.1964, found 276.1968.
steps) as a white semisolid. 1H NMR (400 MHz, CDCl3) δ 6.72 (dd, J
= 9.6 Hz, 1.6 Hz, 1H), 5.90 (d, J = 9.6 Hz, 1H), 5.58 (dt, J = 16.8 Hz,
10.0 Hz, 1H), 5.16-5.11 (m, 2H), 5.09 (d, J = 5.2 Hz, 1H), 3.31 (s, 3H),
2.58 (t, J = 8.4 Hz, 1H), 2.43 (d, J = 9.6 Hz, 1H), 2.07 (dd, J = 13.2 Hz,
9.6 Hz, 1H), 1.91 (ddd, J = 13.6 Hz, 8.0 Hz, 5.6 Hz, 1H), 1.22 (s, 3H),
1.05 (s, 3H), 1.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 201.8, 157.2,
132.9, 126.9, 120.7, 106.9, 92.7, 63.6, 62.2, 54.6, 54.4, 46.2, 35.5,
25.4, 19.2, 13.0; HRMS (ESI) m/z: [M + H]+ calcd for C16H23O3
263.1647, found 263.1653.
Compound 39. To a solution of dimethyl amide 36 (115 mg, 0.42
Compound 42. To a solution of lactone 39 (500 mg, 2.0 mmol, 1.0
eq.) and 1,2-bis(trimethylsilyloxy)ethane (0.20 mL, 0.80 mmol, 0.4
eq.) in anhydrous CH2Cl2 (10 mL) at –78 °C under Ar was added
TMSOTf (73 μL, 0.4 mmol, 0.2 eq.). The mixture was gradually
warmed to 25 °C and kept stirring for 72 h at this temperature. Sat.
mmol, 1.0 eq.) in EtOH/H2O (5/0.5 mL) in a seal tube was added 6
o
M H2SO4 (1.1 mL, 16 eq.). The mixture was heated to 100 C for
about 16 h. Upon completion, sat. NaHCO3 (3 mL) was added and
the mixture was extracted with EtOAc (3 × 5 mL). The combined
organic layers were washed with brine (3 × 5 mL), dried over Na2SO4, NaHCO3 (2 mL) was added and the mixture was extracted by CH2Cl2
filtered and concentrated under reduced pressure. The residue was
(2 × 10 mL). The combined organic layers were washed with brine
(2 × 5mL), dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by FCC (PE/EtOAc = 7:1
to 3:1) to afford 42 (412 mg, 70%) as a white solid with 39 (75 mg,
15%) recovered. mp: 109-110 °C; 1H NMR (400 MHz, CDCl3) δ 6.14
(dt, J = 16.8 Hz, 10.0 Hz, 1H), 5.06 (dd, J = 10.0 Hz, 2.4 Hz, 1H), 4.98
(dd, J = 16.8 Hz, 2.4 Hz, 1H), 4.00-3.90 (m, 2H), 3.86-3.74 (m, 2H),
2.74 (dd, J = 19.2 Hz, 10.4 Hz, 1H), 2.61 (dd, J = 19.2 Hz, 1.2 Hz, 1H),
2.34 (dd, J = 10.4 Hz, 1.2 Hz, 1H), 1.98 (dd, J = 10.0 Hz, 1.2 Hz, 1H),
purified by FCC (PE/EtOAc = 5:1) to afford the lactone 39 (87 mg,
25
84%) as a faint yellow semisolid. [α]D +89.23 (c 0.65, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 5.39 (dt, J = 16.8, 10.0 Hz, 1H), 5.23 (dd, J
= 10.0, 1.6 Hz, 1H), 5.14 (dd, J = 16.8, 1.6 Hz, 1H), 2.87 (dd, J = 19.0,
10.0 Hz, 1H), 2.77 (dd, J = 19.0, 2.0 Hz, 1H), 2.64 (dd, J = 10.0, 1.6
Hz, 1H), 2.50 (dd, J = 18.0, 8.0 Hz, 1H), 2.43-2.34 (m, 2H), 1.90 (ddd,
J = 13.6, 11.1, 8.0 Hz, 1H), 1.63 (m, 1H), 1.35 (s, 3H), 1.04 (s, 3H),
1.01 (s, 3H);13C NMR (100 MHz, CDCl3) δ 210.1, 175.7, 131.7, 121.6,
Chin. J. Chem. 2021, 39, XXX－XXX
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
www.cjc.wiley-vch.de

Zhang et al.
Report
1.79-1.60 (m, 3H), 1.55 (s, 3H), 1.23 (m, 1H), 0.91 (s, 3H), 0.82 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 176.9, 135.3, 118.1, 110.4, 96.6,
65.1, 64.1, 59.0, 56.3, 50.3, 41.4, 32.6, 30.8, 30.4, 22.1, 21.1, 11.8;
HRMS (ESI) m/z: [M + H]+ calcd for C17H25O4 293.1753, found
293.1762.
Crystallographic data for 42 has been deposited with the Cambridge
Crystallographic Data Center, accession number CCDC 1916443.
semisolid with a ratio of 2.3:1. 1H NMR (400 MHz, CDCl3) δ 6.15 (m,
1H), 5.37 (d, J = 4.8 Hz, 1H), 5.20 (d, J = 6.8 Hz, 1H), 5.07-4.97 (m,
2H), 4.58 (br s, 1H), 4.39 (t, J = 7.2 Hz, 1H), 3.95-3.87 (m, 2H), 3.83-
3.70 (m, 2H), 3.46 (br s, 1H), 3.04 (d, J = 10.0 Hz, 1H), 2.39 (m, 1H),
2.30 (d, J = 8.4 Hz, 1H), 2.24-2.22 (m, 2H), 1.67-1.56 (m, 4H), 1.48 (s,
3H), 1.34 (s, 3H), 1.10 (s, 3H), 1.09 (s, 3H), 0.86 (s, 3H), 0.84 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 137.5, 136.8, 117.5, 117.1, 111.3, 111.0,
101.8, 94.4, 94.0, 92.9, 80.7, 76.6, 65.0, 65.0, 63.9, 61.5, 57.3, 57.0,
55.9, 55.2, 54.3, 42.3, 42.3, 34.6, 34.2, 30.8 30.7, 22.8, 22.7, 22.3,
11.2, 11.2; HRMS (ESI) m/z: [M - H]- calcd for C17H25O5 309.1702,
found 309.1711.
Compound 44. To a solution of lactone 42 (292 mg, 1.0 mmol, 1.0
eq.) in anhydrous THF (10 mL) at –78 °C under Ar was added LiHMDS
(1.8 mL, 1.0 M in THF, 1.8 mmol, 1.8 eq.) and the mixture was kept
stirring for 30 min at this temperature. Davis’ oxaziridine 43 (391
mg, 1.5 mmol, 1.5 eq.) in THF (1.5 mL) was added dropwise and the
reaction mixture was stirred for additional 1 h. Upon completion,
sat. NH4Cl (2 mL) was added and the mixture was extracted by
EtOAc (2 × 10 mL). The combined organic layers were washed with
brine (2 × 10 mL), dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by FCC (PE/EtOAc
= 10:1 to 3.5:1) to afford 44 (305 mg, 99%) as a white solid. mp: 156-
158 °C; 1H NMR (400 MHz, CDCl3) δ 6.14 (dt, J = 16.8 Hz, 10.0 Hz,
1H), 5.05 (dd, J = 10.0 Hz, 2.0 Hz, 1H), 4.95 (dd, J = 16.8 Hz, 2.0 Hz,
1H), 4.40 (d, J = 1.2 Hz, 1H), 4.00-3.91 (m, 2H), 3.86-3.74 (m, 2H),
2.89 (d, J = 2.8 Hz, 1H), 2.27 (s, 1H), 1.82 (dd, J = 9.6 Hz, 2.0 Hz, 1H),
1.77-1.64 (m, 6H), 1.34 (m, 1H), 0.91 (s, 3H), 0.90 (s, 3H); 13C NMR
Compound 47. To a solution of lactone 46 (31 mg, 0.1 mmol, 1.0
eq.) in anhydrous Toluene (3 mL) was added ethoxycarbonyl
methylene triphenylphosphorane (105 mg, 0.3 mmol, 3.0 eq.) at
25 °C. The mixture was warmed to 90 °C and srirred for 2 h, and
concentrated under reduced pressure. The residue was purified by
FCC (PE/EtOAc = 3:1) to afford unsaturated ester 47 (27.7 mg, 79%)
as a white semisolid. 1H NMR (400 MHz, CDCl3) δ 7.27 (dd, J = 15.6
Hz, 3.6 Hz, 1H), 6.22-6.09 (m, 2H), 5.08-5.01 (m, 2H), 4.53-4.45 (m,
2H), 4.21 (q, J = 7.2 Hz, 2H), 3.95 (m, 1H), 3.89 (m, 1H), 3.81 (m, 1H),
3.71 (m, 1H), 2.48 (d, J = 10.4 Hz, 1H), 1.90 (d, J = 2.4 Hz, 1H), 1.71-
1.64 (m, 2H), 1.61-1.56 (m, 2H), 1.44 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H),
1.17 (dd, J = 11.6 Hz, 5.2 Hz, 1H), 1.13 (s, 3H), 0.78 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 177.5, 135.0, 118.2, 110.3, 97.6, 71.7, 65.1, 64.1, (100 MHz, CDCl3) δ 166.8, 153.0, 136.9, 119.6, 117.4, 111.2, 86.2,
59.7, 58.6, 55.7, 41.0, 32.7, 30.4 ,22.4, 22.2, 11.7; HRMS (ESI) m/z:
72.7, 65.0, 63.8, 60.3, 59.9, 56.8, 56.4, 42.3, 33.6, 30.6, 25.6, 21.4,
14.3, 11.5; HRMS (ESI) m/z: [M - H]- calcd for C21H31O6 379.2121,
found 379.2117.
[M - H]- calcd for C17H23O5 307.1545, found 307.1552.
Compound 45. To a solution of 44 (308 mg, 1.0 mmol, 1.0 eq.) in
CH2Cl2 (10 mL) was added DMP (636 mg, 1.5 mmol, 1.5 eq.) at 25 °C
and the reaction was kept stirring until TLC indicated complete
consumption of the substrate. Then sat. Na2SO3 (5 mL) was added
and the mixture was extracted with CH2Cl2 (2 × 10 mL). The
combined organic layers were washed with Na2SO3 (2 × 5 mL), brine
(3 × 10 mL), dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was passed through a short column
of silica gel to provide the corresponding allyl compound as a
colorless oil.
Compound 48. To a solution of 47 (19 mg, 0.05 mmol, 1.0 eq.) in
anhydrous Toluene (2 mL) was added DBU (15 μL, 0.10 mmol, 2.0
eq.) at 25 °C under Ar and the mixture was warmed to 60 °C and
srirred for 30 min, then sat. NH4Cl (1 mL) was added and the mixture
was extracted with EtOAc (2 × 5 mL) and the combined organic
layers were washed with brine (2 × 5 mL), dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by FCC (PE/EtOAc = 5:1) to afford ester 48 (13.9 mg, 73%)
as a white semisolid. 1H NMR (400 MHz, CDCl3) δ 1H NMR (400 MHz,
CDCl3) δ 6.14 (dt, J = 16.8 Hz, 10.0 Hz, 1H), 5.06-4.99 (m, 2H), 4.39
(t, J = 8.8 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 4.00-3.86 (m, 3H), 3.82-
3.69 (m, 2H), 3.00 (br s, 1H), 2.84 (dd, J = 15.6 Hz, 4.4 Hz,1H), 2.52
(dd, J = 15.6 Hz, 8.0 Hz,1H), 2.29-2.28 (m, 2H), 1.69-1.57 (m, 4H),
1.33 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H), 1.12 (s, 3H), 0.85 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 172.5, 137.2, 117.3, 111.2, 92.1, 80.2, 78.5,
65.0, 63.9, 61.4, 60.9, 57.5, 56.2, 42.5, 40.9, 34.3, 30.7, 22.8, 22.3,
14.1, 11.2; HRMS (ESI) m/z: [M - H]- calcd for C21H31O6 379.2121,
found 379.2129.
To a solution of above mentioned crude product in anhydrous
THF (10 mL) was cooled to –78 °C under Ar, then LiAlH(Ot-Bu)3 (1.0
mL, 1.1 M in THF, 1.1 mmol, 1.1 eq.) was added dropwise. After 5
min, sat. NH4Cl (3 mL) was added and the mixture was extracted
with EtOAc (2 × 10 mL). The combined organic layers were washed
with brine (3 × 10 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
FCC (PE/EtOAc = 4:1) to afford α-hydroxy lactone 45 (274 mg, 89%
1
for 2 steps) as a white solid. mp: 155-156 °C; H NMR (400 MHz,
CDCl3) δ 6.10 (dt, J = 16.8 Hz, 9.6 Hz, 1H), 5.07 (dd, J = 10.0 Hz, 2.4
Hz, 1H), 5.00 (dd, J = 16.8 Hz, 2.0 Hz, 1H), 4.79 (d, J = 9.2 Hz, 1H),
4.00-3.90 (m, 2H), 3.86-3.74 (m, 2H), 2.65 (d, J = 9.6 Hz, 1H), 2.39
(br s, 1H), 2.11 (d, J = 9.6 Hz, 1H), 1.74-1.62 (m, 3H), 1.56 (s, 3H),
1.32 (m, 1H), 1.07 (s, 3H), 0.92 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
177.0, 135.3, 118.4, 110.3, 94.3, 70.7, 65.1, 64.1, 59.8, 56.6, 52.9,
42.8, 34.0, 30.7, 23.2, 19.9, 11.0; HRMS (ESI) m/z: [M - H]- calcd for
C17H23O5 307.1545, found 307.1557.
Compound 49. A solution of α-hydroxy lactone 45 (100 mg, 0.325
mmol, 1.0 eq.) and (Triphenyl phosphoranylidene) ketene (192 mg,
0.65 mmol, 2.0 eq.) in m-xylene (65 mL) was heated to 195 °C in a
dried sealed tube and kept stirring for 35 min. Upon completion,
the reaction mixture was concentrated under reduced pressure.
The residue was purified by FCC (PE/EtOAc = 5:1) to afford lactone
49 (89.5 mg, 83%) as a white solid. mp: 194-195 °C; 1H NMR (400
MHz, CDCl3) δ 6.07 (dt, J = 16.8 Hz, 10.0 Hz, 1H), 5.33 (d, J = 8.8 Hz,
1H), 5.05 (d, J = 10.0 Hz, 1.6 Hz, 1H), 4.95-4.91 (m, 2H), 4.00-3.91
(m, 2H), 3.86-3.75 (m, 2H), 2.61 (d, J = 8.8 Hz, 1H), 2.08 (d, J = 10.0
Hz, 1H), 1.71 (m, 1H), 1.67 (s, 3H), 1.63-1.59 (m, 2H),1.32 (m, 1H),
0.97 (s, 3H), 0.90 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 184.4, 175.5,
135.0, 118.7, 112.9, 110.0, 84.4, 81.9, 65.2, 64.2, 60.7, 58.1, 53.5,
42.3, 33.5, 30.8, 21.7, 20.3, 11.3; HRMS (ESI) m/z: [M + H] + calcd for
C19H25O5 333.1702, found 333.1711.
Crystallographic data for 45 has been deposited with the Cambridge
Crystallographic Data Center, accession number CCDC 1916444.
Compound 46. To a solution of 45 (154 mg, 0.50 mmol, 1.0 eq.) in
anhydrous THF (5 mL) was cooled to –40 °C under Ar, then DIBAL-H
(0.75 mL, 1.0 M in THF, 0.75 mmol, 1.5 eq.) was added dropwise.
After 10 h, sat. NH4Cl (2 mL) was added and the mixture was
warmed to 25 °C and stirred for another 20 min. The mixture was
extracted with EtOAc (2 × 10 mL) and the combined organic layers
were washed with brine (3 × 5 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
FCC (PE/EtOAc = 5:1) to afford lactol 46 (82 mg, 53%) as a white
Compound 35. To a solution of lactone 39 (248 mg, 1.0 mmol, 1.0
eq.) in anhydrous THF (10 mL) at –78 °C under Ar was added LiHMDS
(3.0 mL, 1.0 M in THF, 3.0 mmol, 3.0 eq.) and the mixture was kept
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Chin. J. Chem. 2021, 39, XXX－XXX

Running title
Chin. J. Chem.
stirring for 30 min at this temperature. Davis’ oxaziridine 43 (574
mg, 2.2 mmol, 2.2 eq.) in THF (1.5 mL) was added dropwise and the
reaction mixture was stirred for additional 1 h. Upon completion,
sat. NH4Cl (2 mL) was added and the mixture was extracted by
EtOAc (2 × 10 mL). The combined organic layers were washed with
brine (2 × 10 mL), dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was passed through a short
column of silica gel to provide the corresponding alcohol as a white
solid.
To a solution of crude alcohol in DCM (10 mL) was added DMP
(636 mg, 1.5 mmol, 1.5 eq.) at 25 °C and the reaction was kept
stirring until TLC indicated complete consumption of the substrate.
Then sat. Na2SO3 (5 mL) was added and the mixture was extracted
with DCM (2 × 10 mL). The combined organic layers were washed
mL, 3.0 M in Toluene, 1.6 mmol, 16 eq.) was added dropwise and
the mixture was maintained at this temperature for 30 min. Then
the reaction mixture was cooled to –78 °C, and 2-butanol (0.150 mL,
1.6 mmol, 16 eq.) was added dropwise followed by lactone 49 (33.2
mg, 0.10 mmol, 1.0 eq.) in THF (1 mL). The mixture was warmed to
–20 °C gradually and kept stirring for 1 h at this temperature. Upon
completion, 2 M HCl solution (5 mL) was added and the mixture was
stirred for another 30 min. The mixture was extracted with EtOAc
(2 × 15 mL). The combined organic layers were washed with brine
(3 × 15 mL), dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by FCC (PE/EtOAc = 2:1)
to afford lactone 14 (26.4 mg, 91% for 2 steps) as a white solid. mp:
164-165 °C; [α]D25 +140.13 (c 0.06, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 5.35 (dt, J = 16.0, 10.0 Hz, 1H), 5.19 (s, 1H), 5.15 (d, J = 8.8 Hz, 1H)
with Na2SO3 (2 × 5 mL), brine (3 × 10 mL), dried over Na2SO4, filtered, 5.09 (dd, J = 6.4, 2.4 Hz, 1H), 4.60 (s, 1H), 2.69-2.68 (m, 2H), 2.58-
and concentrated under reduced pressure. The residue was passed
through a short column of silica gel to provide the corresponding
triketone as a white solid.
2.56 (m, 2H), 2.41 (dd, J = 9.6, 6.0 Hz, 2H), 1.86 (m, 1H), 1.76 (m,
1H), 1.29 (s, 3H), 1.23 (s, 3H), 0.97 (s, 3H);13C NMR (100 MHz, CDCl3)
δ 211.9, 174.9, 132.1, 121.2, 92.6, 87.6, 63.2, 62.4, 60.4, 44.4, 36.2,
35.6, 34.3, 29.7, 21.8, 19.3, 12.5; HRMS (ESI) m/z: [M + H] + calcd for
C17H23O4 291.1596, found 291.1588.
Crystallographic data for 14 has been deposited with the Cambridge
Crystallographic Data Center, accession number CCDC 1916457.
A stirred solution of triketone above mentioned in anhydrous THF
(10 mL) was cooled to –78 °C under Ar, then LiAlH(Ot-Bu)3 (1.0 mL,
1.1 M in THF, 1.1 mmol, 1.1 eq.) was added dropwise. After 5 min,
sat. NH4Cl (3 mL) was added and the mixture was extracted with
EtOAc (2 × 10 mL). The combined organic layers were washed with
brine (3 × 10 mL), dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by FCC (PE/EtOAc
= 3:1) to afford α-hydroxy lactone 35 (230 mg, 87% for 3 steps) as a
white solid. mp: 148-149 °C; [α]D25 +110.00 (c 0.50, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 5.35 (dt, J = 16.4, 10.0 Hz, 1H), 5.23 (d, J = 9.6
Hz, 1H), 5.16 (d, J = 16.4, 1H), 4.90 (m, 1H), 2.92 (d, J = 9.2 Hz, 1H),
2.52 (dd, J = 18.4, 7.2 Hz, 1H), 2.45 (d, J = 9.6 Hz, 1H), 2.36 (dt, J =
18.4, 10.0 Hz, 1H), 1.81-1.68 (m, 2H), 1.35 (s, 3H), 1.24 (s, 3H), 1.05
(s, 3H);13C NMR (100 MHz, CDCl3) δ 210.1, 176.2, 131.6, 122.0, 91.7,
70.3, 64.2, 60.3, 53.8, 44.2, 35.7, 35.4, 22.5, 18.4, 11.8; HRMS (ESI)
m/z: [M - H]- calcd for C15H19O4 263.1283, found 263.1287.
Compound 51. To a solution of tetracyclic lactone 14 (232 mg, 0.80
mmol, 1.0 eq.) in AcOH (8 mL) was added Py·HBr3 (312 mg, 0.88
mmol, 1.1 eq.) at 25 °C and the reaction was stirred for 10 min.
Upon completion, sat. NaHCO3 (4 mL) was added and the mixture
was extracted with EtOAc (2 × 10 mL). The combined organic layers
were washed with brine (3× 10 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
FCC (PE/EtOAc = 2:1) to afford α-bromide ketone 51 (236 mg, 80%)
as a white solid. mp: 197-198 °C; [α]D25 +104.62 (c 0.065, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 5.32-5.16 (m, 3H), 5.11 (dd, J = 6.8, 3.2 Hz,
1H), 4.71 (dd, J = 11.2, 9.6 Hz, 1H), 4.61 (m, 1H), 2.70-2.69 (m, 2H),
2.64 (d, J = 6.8 Hz, 1H), 2.55 (d, J =7.2 Hz, 1H), 2.47 (m, 1H), 2.30 (dd,
J = 14.0, 11.6 Hz, 1H), 1.29 (s, 3H), 1.26 (s, 3H), 1.05 (s, 3H);13C NMR
(100 MHz, CDCl3) δ 202.5, 174.5, 131.1, 122.3, 92.4, 87.1, 77.2, 64.2,
61.5, 60.9, 50.6, 49.3, 46.6, 34.2, 21.0, 19.5, 13.1; HRMS (ESI) m/z:
[M + H]+ calcd for C17H22BrO4 369.0701, found 369.0699.
Compound 50. A solution of α-hydroxy lactone 35 (21.0 mg, 0.080
mmol, 1.0 eq.) and (Triphenyl phosphoranylidene) ketene (48.0 mg,
0.16 mmol, 2.0 eq.) in m-xylene (16 mL) was heated to 160 oC from
145 oC in a dried sealed tube and kept stirring for 35 min. Upon
completion, the reaction mixture was concentrated under reduced
Crystallographic data for compound 51 has been deposited with the
Cambridge Crystallographic Data Center, accession number CCDC
1916445.
pressure. The residue was purified by FCC (PE/EtOAc = 5:1) to afford
25
lactone 50 (14 mg, 61%) as a white solid. mp: 185-186 °C; [α]D
–
10.00 (c 0.08, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.39-5.22 (m, 2H),
5.23 (d, J = 10.0 Hz, 1H), 5.12 (d, J = 16.0 Hz, 1H), 5.04 (s, 1H), 2.88
(d, J = 8.8 Hz, 1H), 2.51 (dd, J = 18.4, 6.4 Hz, 1H), 2.40-2.30 (m, 2H),
1.81-1.68 (m, 2H), 1.46 (s, 3H), 1.11 (s, 3H), 1.07 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 209.1, 183.5, 174.8, 131.3, 122.1, 109.3, 85.3,
81.2, 65.4, 61.1, 54.4, 43.8, 35.5, 35.0, 20.9, 18.8, 12.2. HRMS (ESI)
m/z: [M + H] + calcd for C17H21O4 289.1440, found 289.1444.
Compound 52. IBX oxidation of 14 for preparation of 52. To a
solution of lactone 14 (116 mg, 0.4 mmol, 1.0 eq.) in anhydrous
DMSO (4.0 mL) was added IBX (4.0 g, 14.3 mmol, 35.7 eq.) at 85 °C.
After 14 h, sat. NaHCO3 (5 mL) was slowly added and the mixture
was extracted with EtOAc (2 × 10 mL). The combined organic layers
were washed with NaHCO3 (3 × 10 mL), brine (3 × 10 mL), dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by FCC (PE/EtOAc = 4:1 to 1.5:1) to afford
unsaturated ketone 52 (46.1 mg, 40%) as a white solid. mp: 175-
176 °C; [α]D +24.62 (c 0.13, CHCl3); H NMR (400 MHz, CDCl3) δ
6.68 (dd, J = 9.6, 2.4 Hz, 1H), 5.89 (d, J = 9.6 Hz, 1H), 5.54 (dt, J =
17.2, 9.6 Hz, 1H), 5.22-5.16 (m, 2H), 4.97 (dd, J = 6.4, 2.8 Hz, 1H),
4.71 (d, J = 3.2 Hz, 1H), 2.78 (dd, J = 9.2, 2.0 Hz, 1H), 2.71-2.68 (m,
2H), 2.51 (d, J = 6.4 Hz, 1H), 1.39 (s, 3H), 1.12 (s, 3H), 1.04 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 201.1, 174.8, 156.8, 132.1, 126.9, 121.7,
93.6, 85.1, 79.3, 63.9, 62.5, 60.6, 46.8, 34.7, 21.9, 19.4, 12.6; HRMS
(ESI) m/z: [M + H] + calcd for C17H21O4 289.1440, found 289.1447.
Preparation of 14 from 50. A suspension of CuI (153 mg, 0.80 mmol,
8.0 eq.) in THF (4 mL) was cooled to –10 °C under Ar. Red-Al (0.533
mL, 3.0 M in Toluene, 1.6 mmol, 16 eq.) was added dropwise and
the mixture was maintained at this temperature for 30 min. Then
the reaction mixture was cooled to –78 °C, and 2-butanol (0.150 mL,
1.6 mmol, 16 eq.) was added dropwise followed by lactone 50 (28.8
mg, 0.10 mmol, 1.0 eq.) in THF (1 mL). The mixture was warmed to
–20 °C gradually and kept stirring for 1 h at this temperature. Upon
completion, sat. NH4Cl (2 mL) was added and the mixture was
extracted with EtOAc (2 × 10 mL). The combined organic layers were
washed with brine (3 × 10 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
FCC (PE/EtOAc = 2:1) to afford lactone 14 (27 mg, 94%) as a white
solid.
25
1
Pd-catalyzed dehydrobromination for preparation of 52 and 53. To
a stirred solution of the α-bromide ketone 51 (36.8 mg, 0.10 mmol,
1.0 eq.) in anhydrous DMSO (10 mL) was added PPh3 (31.4 mg, 0.12
mmol, 1.2 eq.) and Et3N (69.7 μL, 0.50 mmol, 5.0 eq.) under Ar. After
discharging oxygen with argon for 5 min, Pd(OAc)2 (13.4 mg, 0.060
mmol, 0.60 eq.) was added under Ar and the mixture was stirred
Preparation of 14 from 49. A suspension of CuI (153 mg, 0.80 mmol,
8.0 eq.) in THF (4 mL) was cooled to –10 °C under Ar. Red-Al (0.533
Chin. J. Chem. 2021, 39, XXX－XXX
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
www.cjc.wiley-vch.de

Zhang et al.
Report
overnight at 25 °C. The reaction mixture was diluted with EtOAc (10
mL), washed with brine (5 × 5 mL), dried over anhydrous Na2SO4
and filtered. The filtrate was evaporated under reduced pressure
and the residue was purified by PTLC (PE/EtOAc = 1:1) to give
unsaturated ketone 52 (12 mg, 41%) and Heck-type product 53 (11
mg, 38%) as white solid.
mg, 0.016 mmol) in CH2Cl2 (2 mL) was irradiated by UV lamp (254
nm, 8W) at 25 °C for 20 h. The solution was evaporated under re-
duced pressure and the residue was purified by FCC (PE/EtOAc = 4:1)
to afford pallambin A (5) (3.3 mg, 65%) as a white solid. mp: 162-
163 °C; [α]D25 –240.2 (c 0.102, MeOH); 1H NMR (600 MHz, CDCl3) δ
6.67 (q, J = 7.3 Hz, 1H), 4.93 (dd, J = 7.1 Hz, 3.5 Hz, 1H), 4.73 (d, J =
3.5 Hz, 1H), 2.47 (br s, 1H), 2.46 (br s, 1H), 2.43 (d, J = 7.1 Hz, 1H),
2.25 (d, J = 7.3 Hz, 3H), 1.42-1.37 (m, 2H), 1.32 (s, 3H), 1.16 (s, 3H),
25
1
Compound 53: mp: 156-157 °C; [α]D +122.7 (c 0.16, CHCl3); H
NMR (400 MHz, CDCl3) δ 4.99 (s, 1H), 4.93 (s, 1H), 4.91 (dd, J = 5.6
Hz, 2.4 Hz, 1H ), 4.63 (t, J = 2.8 Hz 1H), 2.84 (d, J = 4.4 Hz, 1H), 2.75
(s, 1H), 2.68 (s, 1H), 2.67 (d, J = 3.2 Hz, 1H), 2.54 (d, J = 6.0 Hz, 1H),
1.75 (dd, J = 13.2, 4.8 Hz, 1H), 1.51 (d, J = 13.2 Hz, 1H), 1.33 (s, 3H),
1.28 (s, 3H), 1.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 212.2, 174.9,
148.1, 106.1, 94.4, 86.5, 78.4, 66.7, 65.1, 63.1, 56.2, 45.6, 40.9, 35.4,
1.09 (s, 3H), 0.88-0.85 (m, 1H), 0.54 (dd, J = 14.0 Hz, 7.7 Hz, 1H); 13
C
NMR (150 MHz, CDCl3) δ 214.4, 168.4, 144.9, 126.0, 89.8, 84.7, 80.1,
67.0, 60.8, 58.0, 54.9, 44.6, 21.5, 19.5, 15.0, 14.5, 14.2, 12.0, 7.3;
+
HRMS (ESI) m/z: [M + H] calcd for C19H23O4 315.1596, found
315.1593.
+
23.4, 23.2, 14.2; HRMS (ESI) m/z: [M + H] calcd for C17H21O4
Synthesis of pallambin B (6). A stirred solution of pallambin D (4)
(5 mg, 0.016 mmol) in CH2Cl2 (2 mL) was irradiated by UV lamp (254
nm, 8W) at 25 °C for 20 h. The solution was evaporated under re-
duced pressure and the residue was purified by FCC (PE/EtOAc = 5:1)
to afford pallambin B (6) (3.5 mg, 70%) as a white solid. mp: 182-
289.1440, found 289.1431.
Crystallographic data for compound 53 has been deposited with the
Cambridge Crystallographic Data Center, accession number CCDC
1917634.
25
1
183 °C; [α]D –315.0 (c 0.10, MeOH); H NMR (600 MHz, CDCl3) δ
7.01 (qd, J = 7.2 Hz, 1.0 Hz, 1H), 4.98-4.95 (m, 2H), 2.48 (br s, 1H),
2.46 (d, J = 7.0 Hz, 1H), 2.40 (br s, 1H), 2.02 (d, J = 7.2 Hz, 3H), 1.41-
1.36 (m, 2H), 1.32 (s, 3H), 1.15 (s, 3H), 1.11 (s, 3H), 0.88-0.85 (m,
1H), 0.54 (dd, J = 14.0 Hz, 7.7 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ
214.4, 169.5, 142.0, 127.5, 90.2, 85.4, 75.7, 67.0, 60.6, 58.1, 54.9,
44.6, 21.6, 19.5, 16.0, 15.0, 14.2, 12.0, 7.2; HRMS (ESI) m/z: [M + H]
+ calcd for C19H23O4 315.1596, found 315.1600.
Pallambin C (3) and pallambin D (4). To a stirred solution of
unsaturated ketone 52 (15.0 mg, 0.052 mmol, 1.0 eq.) in THF (3 mL)
at –78 °C under Ar. LiHMDS (0.10 mL, 1.0 M in THF, 0.10 mmol, 2.0
eq.) was added. After stirring at the same temperature for 30 min,
CH3CHO (15 μL, 0.26 mmol, 5.0 eq.) was added dropwise. The
reaction mixture was kept strring for 2 h at the same temperature.
Upon completion, sat. NH4Cl (1 mL) was added and the mixture was
extracted with EtOAc (3 × 5 mL). The combined organic layers were
washed with brine (3 × 5 mL), dried over Na2SO4, filtered and
concentrated under reduced pressure to give a crude product,
which was immediately used in the next step without further
purification.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2021xxxxx.
The above crude alcohol was dissolved in dry CH2Cl2 (3 mL) and
treated with Et3N (0.22 mL, 1.6 mmol, 30 eq.), DMAP (1.22 mg,
0.010 mmol, 0.20 eq.), and MsCl (20 μL, 0.26 mmol, 5.0 eq.). The
mixture was then stirred at 0 °C for 10 min. Then sat. NaHCO3 (1mL)
was added and stirred for another 10 min, the mixture was
extracted with EtOAc (3 × 5 mL) and the combined organic layers
were washed with brine (3 × 5 mL), dried over Na2SO4, filtered and
concentrated under reduced pressure. The residue was purified by
PTLC (PE/EtOAc = 3:1, developed by ten times) to afford synthetic
pallambin C (3) (colorless oil, 4.9 mg, 30% for two steps) and
pallambin D (4) (white soild, 8.3 mg, 51% for two steps).
Acknowledgement
This research was supported by the National Natural Science
Foundation of China (Nos. 21925101 and 21572008).
References
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25
Pallambin C (3): [α]D –151.0 (c 0.08, MeOH); 1H NMR (400 MHz,
CDCl3) δ 6.71-6.66 (m, 2H), 5.89 (d, J = 9.6 Hz, 1H), 5.54 (dt, J = 17.0
Hz, 10.0 Hz, 1H), 5.12-5.15 (m, 2H), 4.87 (dd, J = 6.7 Hz, 3.2 Hz, 1H),
4.84 (d, J = 3.2 Hz, 1H), 2.83 (dd, J = 9.6 Hz, 1.9 Hz, 1H), 2.53 (d, J =
6.6 Hz, 1H), 2.25 (d, J = 7.3 Hz, 3H), 1.42 (s, 3H), 1.14 (s, 3H), 1.04 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 201.4,168.2, 157.0, 144.7, 132.2,
126.8, 125.9, 121.6, 94.0, 83.0, 82.2, 63.8, 62.6, 60.6, 46.8, 22.4,
+
19.7, 14.6, 12.9; HRMS (ESI) m/z: [M + H] calcd for C19H23O4
315.1596, found 315.1583.
Pallambin D (4): mp: 145-146 °C; [α]D25 –160.2 (c 0.10, MeOH); 1H
NMR (600 MHz, CDCl3) δ 7.00 (q, J = 7.1 Hz, 1H), 6.68 (dd, J = 9.6 Hz,
2.1 Hz, 1H), 5.89 (d, J = 9.6 Hz, 1H ), 5.53 (dt, J = 16.9 Hz, 9.8 Hz, 1H),
5.19-5.15 (m, 2H), 5.09 (d, J = 3.2 Hz, 1H), 4.90 (dd, J = 7.0 Hz, 3.5
Hz, 1H), 2.76 (dd, J = 9.5 Hz, 1.7 Hz, 1H), 2.56 (d, J = 7.0 Hz, 1H), 2.04
(d, J = 7.2 Hz, 3H), 1.42 (s, 3H), 1.16 (s, 3H), 1.01 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 201.4,169.4, 157.0, 141.7, 132.2, 127.5, 126.8,
121.6, 94.3, 83.6, 77.6, 63.9, 62.6, 60.5, 46.9, 22.3, 19.6, 16.0, 12.7;
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www.cjc.wiley-vch.de
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Manuscript received: XXXX, 2021
Manuscript revised: XXXX, 2021
Manuscript accepted: XXXX, 2021
Accepted manuscript online: XXXX, 2021
Version of record online: XXXX, 2021
www.cjc.wiley-vch.de
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
Chin. J. Chem. 2021, 39, XXX－XXX

Running title
Chin. J. Chem.
Entry for the Table of Contents
Protecting-Group-Free Total Synthesis of (–)-Pallambins A-D
Xiwu Zhang,‡ Yuan Wang,‡ Peng Chen, Xinxian Cai, and Yanxing Jia*
Chin. J. Chem. 2021, 39, XXX—XXX. DOI: 10.1002/cjoc.202100XXX
Protecting-group-free synthesis
H
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Me
C:
D:
Z
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A:
B:
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E
)
pallambin
pallambin
(
(
)
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pallambin
pallambin
(
(
The first enantioselective total synthesis of (–)-pallambins A-D have been achieved. The described synthesis avoids protecting-group manipulations by
designing highly chemo- and stereoselective transformations.
Chin. J. Chem. 2021, 39, XXX－XXX
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
www.cjc.wiley-vch.de