Efficient Construction of (±)- epi -Costunolide through a Chromium(II)-Mediated Nozaki-Hiyama-Kishi Reaction

Article abstract of DOI:10.1055/s-0040-1720348

(±)- epi -Costunolide has been synthesized through a seven-step procedure starting from (E, E)-farnesol. The key step includes an intramolecular allylation of an aldehyde through a chromium(II)-mediated Nozaki-Hiyama-Kishi reaction, in which more than one equivalent of CrCl ₂has been recognized as the most effective reagent to promote the conversion. An anti-inflammatory screen showed that epi -costunolide is a moderate inhibitor of B lymphocyte proliferation.

Full text of DOI:10.1055/s-0040-1720348

SYNLETT
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 32, A–D
letter
A
en
W. Dai et al.
Letter
Synlett
Efficient Construction of (±)-epi-Costunolide through a Chromi-
um(II)-Mediated Nozaki–Hiyama–Kishi Reaction
Weichen Daia,b
Jie Zhenga
7 steps
12% total yield
IC50 = 9.7 0.78 μM against
B lymphocyte proliferation
Xinyu Yana
Wei Tangc
Lihong Hu*a
O
OH
O
(E,E)-farnesol
( )-epi-costunolid
Yinan Zhang*a
0
0
0
0-0
0
0
2
-0
3
6
2
-
1
4
7
3
Br
CrCl2, DMF
DBU, CH2Cl2
a Jiangsu Key Laboratory for Functional Substances of Chinese
Medicine, School of Pharmacy, Nanjing University of Chinese
Medicine, Nanjing, 210023, P. R. of China
O
CO2Me
simplest synthetic route to construct
germacrane sesquiterpene lactone
yinanzhang@njucm.edu.cn
lhhu@njucm.edu.cn
b Hanlin College, Nanjing University of Chinese Medicine, Taizhou
225300, P. R. of China
c Pharmaron (Ningbo) Technology Development Co., Ltd, Ningbo, 315336, P. R. of China
Corresponding Authors
Received: 07.06.2021
Accepted after revision: 25.06.2021
Published online: 13.07.2021
[2,3]-Wittig rearrangement to afford a germacrene scaffold
(Scheme 1b).6 Another synthesis by Yang et al.7 featured an
aldol addition of chiral camphorsultam derivative to an ,-
unsaturated aldehyde (Scheme 1c). Refunctionalization,
C8–C9 intramolecular alkylation, and oxidative lactoniza-
tion gave costunolide in a total of 13 reaction steps. The
most efficient synthetic strategy came from a bioinspired
cyclization of an aldehyde and allylic halide, which included
a Nozaki–Hiyama–Kishi (NHK) reaction or a Barbier reac-
tion developed by Hirotaka et al.,8 and by Corey and Reddy,9
respectively (Scheme 1d). The configuration of the anti-ad-
duct was controlled by a Zimmerman–Traxler transition
state. However, further conversions into the -lactone still
required an allylic oxidation involving highly flammable t-
BuLi and an extra esterification. Toward this end, we have
developed an efficient strategy for the construction of the
germacrene scaffold and the corresponding total synthesis
of (±)-epi-costunolide. This synthetic method sets the stage
for future in-depth structure–activity relationship studies
and mechanistic investigations of this fascinating natural
product.
Our initial intent was to utilize the lactone ring with a
preassembled ester group on the farnesol chain. Compared
with the existing strategy, our current retrosynthetic for-
mat features a tandem allylation reaction and a lactoniza-
tion to give costunolide in a one-pot procedure (Scheme 2).
The ester intermediate 1 might be obtained by an allylic SN′
substitution and a Baylis–Hillman reaction from aldehyde
3, which, in turn, could be simply obtained by direct oxida-
tion from (E,E)-farnesol.
DOI: 10.1055/s-0040-1720348; Art ID: st-2021-v0222-l
Abstract (±)-epi-Costunolide has been synthesized through a seven-
step procedure starting from (E,E)-farnesol. The key step includes an in-
tramolecular allylation of an aldehyde through a chromium(II)-mediated
Nozaki–Hiyama–Kishi reaction, in which more than one equivalent of
CrCl2 has been recognized as the most effective reagent to promote the
conversion. An anti-inflammatory screen showed that epi-costunolide is
a moderate inhibitor of B lymphocyte proliferation.
Key words costunolide, germacrenes, Nozaki–Hiyama–Kishi reac-
tion, total synthesis, medicinal chemistry, sesquiterpenoid lactones
Costunolide is a germacrene sesquiterpene lactone iso-
lated from the herbal preparation radix aucklandiae, ob-
tained from the roots of Saussurea costus (formerly Auck-
landia lappa Decne), that shows a wide variety of pharma-
cological
activities
including
antiinflammatory,1
antibacterial,2 and antitumor properties.3 Costunolide has a
ten-membered-ring skeleton fused to a trans -methylene
-lactone at the C6 and C7 positions. Owing to its simple
structure and unique activities, costunolide has received
much attention from the synthetic and medicinal commu-
nities. Although its structural modifications and structure–
activity relationship have been extensively studied,4 only a
few synthetic approaches have focused on the construction
of the germacrene scaffold. The challenges mostly lie in (1)
the formation of a medium-sized ring, (2) stereochemical
control, and (3) structurally sensitivity to both acidic and
basic conditions.
Since the key step is the tandem allylation and lacton-
ization, we attempted a template reaction between 3-meth-
ylcrotonaldehyde (5) and the Baylis–Hillman ester 6. First,
we screened the general conditions previously studied for
either the Barbier or the NHK reaction (Table 1). To our de-
light, more than one equivalent of CrCl2 in DMF gave the
The first total synthesis was carried out by Grieco and
Nishizawa,5 who employed -santonin as the starting mate-
rial and a Cope sigmatropic rearrangement to expand to the
ten-membered ring (Scheme 1a). In contrast, Takahashi et
al. contracted a 13-membered cyclic ether ring through a
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
W. Dai et al.
Letter
Synlett
a) Ring-expansion reaction:
1
9
2
3
8
7
10
5
Δ
13
O
4
6
H
11
12
O
O
O
O
O
O
O
O
dehydrosaussurea lactone
costunolide
α-santonin
b) Ring-contraction reaction:
t-BuLi
t-BuLi
[2,3]-Wittig
OPG
B(OMe)3
H2O2
O
OH
Br
MnO2
c) Aldol addition and C8–C9 intramolecular alkylation:
Br
O[Si]
N
SO2Ph
S
O
O
+
O
HO
O
O
HO
O
O[Si]
d) Barbier or Nozaki–Hiyama–Kishi reaction:
In or Cr(II)
t-BuLi
B(OMe)3
H2O2
OPG
OH
O
Br
(E,E)-farnesol
Scheme 1 Reported syntheses of costunolide
syn-product 7 in 82% yield (Table 1, entry 1). However, none
of the corresponding product was detected when chromi-
um(II) was generated in situ with LiAlH4 (entry 2). Note
that a catalytic amount of CrCl2 with Mn(0)10 also gave the
desired product, albeit in a low yield (entry 3). Since the
NHK reaction did not directly give the anti-lactone product,
we next tried several standard conditions for the Barbier re-
action. Zero-valent metals such as In,11 Zn,12 or Zn–Cu12 af-
forded the syn-lactone product 8 in good to moderate yields
(entries 4–6). Unfortunately, an extensive search of condi-
tions showed that no metal exclusively gave the desired
anti-lactone product 9 in a satisfactory yield (entries 7 and
8). Other conditions with various Sn salts failed to give the
desired product (entry 9).13
vated ester undergoes coordination to the acrylate 5. The
(Z)-allyl intermediate that produces the syn-product adopts
a chair transition state, whereas the formation of the (E)-al-
lyl intermediate requires a boat transition state, which hin-
ders the production of the anti-product. Tin could have pro-
duced a mixture of syn- and anti-products as a result of in-
stability of the allyltin toward Z–E isomerization.14
MeOOC
M
H
O
OH COOMe
Br
(Z)-allyl intermediate
syn-product
[M]
CHO
+
H
CO2Me
M
5
6
O
MeOOC
A plausible mechanism for the metal-mediated carbonyl
allylation is proposed in Figure 1. Initially, a metal–halogen
exchange activates the Baylis–Hillman ester 6, and the acti-
OH COOMe
(E)-allyl intermediate
anti-product
Figure 1 A plausible mechanism for the carbonyl allylation.
allylic
substitution
allylation and
lactonization
Br
With the optimal conditions for the allylation in hand,
we made a further attempt at a total synthesis (Scheme 3)
starting with TBDPS protection and epoxidation of (E,E)-
farnesol on a gram scale (49% overall yield). Periodate oxi-
dation of 4 afforded the desired aldehyde 3 in an excellent
yield. Note that a TBS protective group was not stable to
periodate oxidation, whereas TBDPS survived this. Use of
the standard Baylis–Hillman conditions successfully added
the acrylate moiety to the scaffold, which was converted
into the allylic bromide 10 in the presence of PPh3 and CBr4.
OH
PG = TBDPS
O
O
1
CO2Me
OPG CO2Me
2
O
costunolid
Baylis–Hillman
reaction
oxidation
cleavage
O
(E,E)-farnesol
O
OPG
4
OPG
3
Scheme 2 Retrosynthetic analysis of costunolide synthesis
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–D

C
W. Dai et al.
Letter
Synlett
Table 1 Optimization of a Template Carbonyl Allylationa
deliver the desired lactone product directly under the opti-
mal reaction conditions (Table 2). Finally, an intramolecular
cyclization was carried out with DBU to give (±)-epi-cos-
tunolide 12, the relative configuration of which was re-
vealed by NOE spectroscopy (see the Supporting Informa-
tion). Note also that Massanet’s group previously obtained
epi-costunolide by a semi-synthesis from natural costuno-
lide;16 however, our method is based on an ab initio syn-
thetic route.
Br
CHO
+
O
O
OH
CO2Me
CO2Me
6
O
O
5
7
8
9
En-
try
Condi-
tions
Equi Sol-
Temp
(℃)
Time
(h)
Prod- Yieldb
uct
v
vent
DMF
DMF
(%)
1
2
CrCl2
7
rt
rt
5
5
7
82
c
CrCl3/Li-
AlH4
8/4
–
–
Table 2 Completion of the (±)-epi-Costunolide (12) Synthesisa
3
CrCl2/Mn
0.1/
2
DMF
rt
8
7
8
DBU
Br
CH2Cl2
4
5
6
7
In
2
6
6
DMF
THF
THF
THF
rt
4
8
56
51
79
67%
O
CO2Me
Zn
65
rt
10
1
8
CO2Me
OH
11
Equiv Sol-
O
O
Zn–Cu
SnCl2/KI
8
12, ( )-epi-costunolid
1
1.5/
1.5
rt
18
8, 9
16, 25d
En-
try
Condi-
tions
Temp
(℃)
Time
(h)
Yieldb (%) of
11
vent
DMF
DMF
THF
THF
8
Sn
2
THF–
aq
NH4Cl
(2:1)
60
12
7, 8,
9
20, 7,
13d
1
2
3
4
CrCl2
In
7
2
6
6
rt
3
76
c
rt
5
–
c
Zn
65
rt
10
10
–
e
9
Sn-
Cl4/TBAI
2/6
CH2Cl2 rt
48
–
–
c
Zn–Cu
–
a All reactions were conducted under an argon atmosphere. 3-Methylcro-
tonaldehyde (5) reacted with the Baylis–Hillman ester 6 in a ratio of 1:2;
see the Supporting Information for details.
a All reactions were conducted under an argon atmosphere; see the Sup-
porting Information for details.
b Isolated yield.
b Isolated yield unless specified.
c Decomposition of compound 1.
c Decomposition of the starting material.
d 8 and 9 were inseparable by silica gel chromatography, and their yields
were determined by 1H NMR spectroscopy of the mixture.
e No product was detected.
Biological studies showed that the epimer (IC50: 9.7 ±
0.78 M) had a weaker antiinflammatory effect than natu-
ral costunolide (IC50: 1.2 ± 0.19 M) in inhibiting B lympho-
cyte proliferation.
The precursor 1 was obtained by Dess–Martin oxidation af-
ter removal of the TBDPS group in a HF/pyridine medium.
The overall yield of this five-step conversion was, remark-
ably, as high as 24%.
By using our optimized conditions, precursor 1 was
treated with CrCl2 in DMF to give the homoallylic alcohol
syn-product 11 in a comparable yield to that of the NHK
template reaction.15 However, zero-valent metals under
Barbier conditions decomposed compound 1 and failed to
In summary, a robust and effective route including a key
intramolecular cyclization reaction with CrCl2 readily af-
forded (±)-epi-costunolide. Starting from (E,E)-farnesol, this
is the simplest synthetic route to date for constructing a
germacrane sesquiterpene lactone, requiring only seven
steps and giving a 12% total yield. Considering its high ste-
reoselectivity, the chromium(II)-mediated NHK reaction
has proven to be a convenient method for the synthesis of
further analogues of use in a medicinal perspective; these
are under development in our laboratory and will be re-
ported in due course.
a
c
b
O
O
OTBDPS
4
OH
OTBDPS
3
Br
Br
Conflict of Interest
e
OH
d
The authors declare no conflict of interest.
CO2Me
CO2Me
O
CO2Me
TBDPSO
TBDPSO
1
10
2
Funding Information
Scheme 3 Synthesis of precursor 1. Reagents and conditions: (a) (i) TB-
DPSCl, imidazole, CH2Cl2; (ii) NBS, THF–H2O (3:1); (iii) K2CO3, MeOH;
49% for three steps; (b) H5IO6, NaIO4, THF–H2O (4:1), 95%; (c) methyl
acrylate, DABCO, MeOH, 81%; (d) CBr4, Ph3P, DIPEA, CH2Cl2, 86%; (e) (i)
HF–pyridine, THF, 84%; (ii) Dess–Martin periodinane, CH2Cl2, 87%.
This work was supported by the National Natural Science Foundation
of China (grants: 21877062, YZ; 81803342, LH), the key research proj-
ects of Jiangsu Higher Education (No. 18KJA360010, YZ), and the Nat-
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–D

D
W. Dai et al.
Letter
Synlett
ural Science Foundation of the Jiangsu Higher Education Institutions
(5) Grieco, P. A.; Nishizawa, M. J. Org. Chem. 1977, 42, 1717.
of China (grant: 18KJD360001).
N
aturalScienceFo
u
n
d
atio
n
o
f
theJiangsu
H
igher
E
d
u
cationInsituti
o
ns(1
8
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3
6
0
0
0
1)K
e
y
ResearchProjects
o
f
theJia
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gsu
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i
gher
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d
ucationInstiuttions(1
8
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JA
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1
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, YZ)Natural
S
cience
F
o
u
n
datio
n
o
f
theJia
n
gsu
H
ig
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ucatio
n
(1
8
K
JD
3
6
0
0
0
1)
(6) Takahashi, T.; Nemoto, H.; Kanda, Y.; Tsuji, J.; Fujise, Y. J. Org.
Chem. 1986, 51, 4315.
(7) Yang, Z.-J.; Ge, W.-Z.; Li, Q.-Y.; Lu, Y.; Gong, J.-M.; Kuang, B.-J.; Xi,
X.; Wu, H.; Zhang, Q.; Chen, Y. J. Med. Chem 2015, 58, 7007.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1720348. Su
p
p
ortingInformatio
n
S
u
p
p
ortingI
n
formatio
n
References and Notes
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(15) Intramolecular Allylation of Compound 1
A solution of the aldehyde 1 (94 mg, 0.273 mmol) in anhyd DMF
(2.5 mL) was added to a solution of CrCl2 (235 mg, 1.9 mmol) in
anhyd DMF (12 mL) at rt under Ar. The mixture was stirred for 3
h and then the reaction was quenched with H2O (8 mL). The
mixture was extracted with EtOAc, and the combined organic
layers were washed with brine, dried (Na2SO4), and concen-
trated under a reduced pressure. The residue was purified by
column chromatography (silica gel, 5% EtOAc–hexane) to give
11 as a colorless oil; yield: 54.5 mg (0.208 mmol, 76%).
1H NMR (500 MHz, CDCl3):  = 6.36–6.29 (m, 1 H), 5.78–5.74 (m,
1 H), 5.13–4.98 (m, 2 H), 4.41–4.40 (m, 1 H), 3.80 (s, 3 H), 2.76–
2.52 (m, 2 H), 2.43–2.33 (m, 2 H), 2.22–2.19 (m, 1 H), 2.13 (d, J =
9.3 Hz, 3 H), 2.02–1.84 (m, 1 H), 1.78–1.69 (m, 2 H), 1.59 (s, 3 H),
1.44–1.40 (m, 1 H). 13C NMR (125 MHz, CDCl3):  = 168.7, 142.7,
138.7, 137.4, 126.7, 124.3, 122.1, 70.3, 52.2, 44.3, 40.0, 37.3,
34.9, 25.6, 21.0, 17.0. HRMS (ESI-TOF): m/z [M + Na]+ calcd for
C16H24NaO3: 287.1623; found: 287.1618
(16) Azarken, R.; Guerra, F. M.; Moreno-Dorado, F. J.; Jorge, Z. D.;
Massanet, G. M. Tetrahedron 2008, 64, 10896.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–D