CuLi2Cl4 catalysed cross-coupling strategy for the formal synthesis of the diterpenoid (+)-subersic acid from (?)-sclareol

Article abstract of DOI:10.3184/174751917X14967701766923

A CuLi₂Cl₄-catalysed regioselective cross-coupling is used in a key step leading to the concise synthesis of (+)-subersic acid with an overall yield of 25.7% from commercially available (-)-sclareol. The coupled product 15-(2-methoxy-5-carbomethoxy)phenyl-labda-8(9),13Ediene was obtained in 62% yield under CuLi₂Cl₄ conditions starting from 2-iodo-4-carbomethoxyanisole and 15-acetoxy-labda-8(9),13Ediene. These were derived from 4-hydroxybenzoic acid and (-)-sclareol respectively. The 15-(2-methoxy-5-carbomethoxy)phenyl-labda- 8(9),13E-diene was easily transformed into (+)-subersic acid by demethylation of the phenol ether and ester. This cross-coupling strategy showed a good functional group tolerance and various (+)-subersic acid derivatives were obtained in moderate yields.

Full text of DOI:10.3184/174751917X14967701766923

394 RESEARCH PAPER
VOL. 41 JULY, 394–397
JOURNAL OF CHEMICAL RESEARCH 2017
CuLi Cl catalysed cross-coupling strategy for the formal synthesis of the
2
4
diterpenoid (+)-subersic acid from (−)-sclareol
Qiangyong Wu , Peiqiang Wang , Bin Zhou , Sikai Hua , Jiangmeng Ren and Bu-Bing Zeng *
a
a
a
a
a
a,b
a
School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P.R. China
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
b
Shanghai 200232, P.R. China
A CuLi Cl -catalysed regioselective cross-coupling is used in a key step leading to the concise synthesis of (+)-subersic acid with an overall
2
4
yield of 25.7% from commercially available (−)-sclareol. The coupled product 15-(2-methoxy-5-carbomethoxy)phenyl-labda-8(9),13E-
diene was obtained in 62% yield under CuLi Cl conditions starting from 2-iodo-4-carbomethoxyanisole and 15-acetoxy-labda-8(9),13E-
2
4
diene. These were derived from 4-hydroxybenzoic acid and (−)-sclareol respectively. The 15-(2-methoxy-5-carbomethoxy)phenyl-labda-
(9),13E-diene was easily transformed into (+)-subersic acid by demethylation of the phenol ether and ester. This cross-coupling strategy
8
showed a good functional group tolerance and various (+)-subersic acid derivatives were obtained in moderate yields.
Keywords: CuLi Cl , cross-coupling, total synthesis, (+)-subersic acid
2
4
1
3
14
(
+)-Subersic acid, containing a diterpene fragment and an
unprotected hydroxyl or carboxyl groups can also be tolerated
in halogen–magnesium exchange in the presence of LiCl. On
this basis, we envisioned constructing the new bond between
C15 and the aromatic ring with an iodine–magnesium exchange
followed by a copper-catalysed cross-coupling starting from
aryl iodides 2 and allylic compounds 3 (Scheme 1).
aromatic unit, is a marine terpenoid and exhibits a high
biological activity as an inhibitor of MAPKAP kinase 2. It was
isolated by Andersen and co-workers in 2004 together with the
structural analogue (+)-makassaric acid (Fig. 1), which also
possessed MAPKAP kinase 2 inhibitory activity.
Beforeitsdiscoveryasanaturalproduct,thefirsttotalsynthesis
of (+)-subersic acid had been reported by Basabe’s group in
1
Results and discussion
2
003. An aromatic lithium derivative of p-hydroxybenzoic
12
First, following the literature and using i-PrMgBr as an I–Mg
acid was coupled with a diterpene allyl bromide obtained from
exchange source, the coupled product 6a was obtained in 62%
yield under CuLi Cl conditions starting from 2c and 3c .
Compound 6a can be easily transformed into (+)-subersic acid
by demethylation of the phenol ether and ester (Scheme 2).
2
(−)-sclareol in 14 steps with an overall yield of 4.3%. Recently,
4
4
2
4
our research group reported two methods for the total synthesis
of (+)-subersic acid. One involved using a Mitsunobu reaction
and a Claisen rearrangement as key transformations in six steps
4
3
with an overall yield of 8.6%. The other was accomplished
using a palladium-catalysed Heck coupling as a critical step in
seven steps with an overall yield of 7.9%. Although these two
4
HO
methods dramatically shortened the whole process, the yields
and regioselectivity need to be further improved. In the present
study, a concise and efficient protocol was developed to provide
R3
15
COOH
(
+)-subersic acid in five steps with an overall yield of 25.7%
OR1
with good regioselectivity, using CuLi Cl -catalysed cross-
2
4
I
coupling as a key step.
+
A halogen–magnesium exchange reaction is usually used
to prepare reactive intermediates that undergo cross-coupling
reaction to generate multifunctional compounds from Grignard
reagents. This method has been widely used in the synthesis
of multifunctional aryl compounds in the presence of sensitive
functional groups, such as methyl or ethyl esters. Even
H
H
COOR2
2
2
a R1 = H, R2 = H
3a
3b R3 = I
3c = OAc
3
R = Br
5
–12
(
+)-Subersic acid
b R
1
= H, R
2
= Me
= Me
2c R
1
= Me, R
2
R
3
Scheme 1 Retrosynthetic analysis.
HO
MeO
COOH
COOMe
COOH
OMe
I
1
) i-PrMgBr, THF
) CuLi2Cl4, 3c, THF
2% over 2 steps
ref. 4
(+)-subersic acid
H
57% over
steps
OH
2
2
6
H
H
COOMe
H
(+)-subersic acid
(+)-makassaric acid
2c
6a E:Z = 4:1
Fig. 1 Structures of (+)-subersic acid and (+)-makassaric acid.
Scheme 2 Synthesis of (+)-subersic acid.
*
Correspondent. E-mail: zengbb@ecust.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2017 395
Table 1 Synthesis of (+)-subersic acid derivatives.
OH
MeI(1 equiv.)/K
CO
2
3
OH
2
b
c
R
I /KI/H O
I
75% two steps from 4
2
2
H O
2
MeI(2 equiv.)/K CO3
2
2
7
9% two steps from 4
COOH
COOH
4
2a
1
) i-PrMgBr, THF
ref.2
R-I
3a
2) CuLi Cl
2
4
, 3c, THF
H
7
6
3
b
HO
ref.15
a
c
d
Entry
R
Product
6b
6c
6d
6e
6f
6g
6h
6i
Yield (%) E:Z
1
2
3
4
5
6
7
8
9
4-(Methoxycarbonyl)phenyl
4-Fluorophenyl
3-Fluorophenyl
2-Fluorophenyl
4-Chlorophenyl
4-Bromophenyl
3-Bromophenyl
2-Bromophenyl
4-Biphenyl
2-Methylphenyl
4-Ethylphenyl
4-Methoxyphenyl
2,4-Difluorophenyl
Phenyl
50
24
44
65
42
61
54
51
44
50
29
66
NR
NR
NR
9:2
1:2
4:3
2:1
5:3
4:3
5:4
5:2
3:2
3:2
5:3
3:2
–
OH
AcO
H
OAc
PPh , I
(
-)-Sclareol
3
2
NaOAc
DMF
3
c
CH Cl
ref.16
2
2
H
5
6j
6k
Scheme 3 Preparation of aryl iodides 2 and allylic compounds 3.
1
0
1
1
6l
6m
b
1
2
To further investigate the copper-catalysed cross-coupling
between compounds 2 and 3, various reaction conditions
were explored (see ESI for details). Unfortunately, the results
indicated that when using i-PrMgCl·LiCl as an I–Mg exchange
source, no product was detected under copper catalysts such as
1
3
6n
6o
6p
1
4
–
–
15
2-Methoxyphenyl
a
Reaction conditons: (1) aryl iodide (1.5 mmol), i-PrMgBr (4.5 mmol), THF (6 mL), −40 °C,
1 h; (2) 3c (1.0 mmol), CuLi Cl (0.1 mmol), THF (6 mL), −40 °C, 2 h, then the reaction was
15
16
CuCN and CuLi Cl with 2b, 2c and 3a, 3b and 3c (Scheme
2
4
2
4
warmed to r.t. and stirred overnight.
The first step was carried out at r.t.
Isolated yields.
3
).
b
Based on CuLi Cl -catalysed cross-coupling conditions,
2
4
c
further examples of (+)-subersic acid derivatives were obtained
in moderate yields using the diterpene fragment 3c and aryl
iodides (Table 1). Aryl iodides bearing electron-withdrawing
substituents such as fluoro, chloro and bromo esters afforded
the corresponding products in moderate yields (Table 1, entries
d
The E/Z ratios were determined by comparing the spectra with that of an authentic
4
sample of 6a as determined in our previous work .
NR = no reaction.
was freshly prepared by reacting copper (II) chloride (0.5 mmol) and
lithium chloride (1.0 mmol) in anhydrous THF (10 mL). The solutions
of isopropylmagnesium chloride/bromide were freshly prepared by
reaction of Mg (56.2 mmol) with 2-chloropropane/2-bromopropane
1
–8).
However, when 2,4-difluoroiodobenzene was used as
starting material, the reaction barely occurred. Aryl iodides
bearing substituents such as methyl, ethyl and phenyl were
also tolerated under the reaction conditions (Table 1, entries
(
46.8 mmol) in anhydrous THF (30.0 mL). Nuclear magnetic
1
13
resonance ( H NMR at 400 MHz, C NMR at 100 MHz) spectra were
determined on a Bruker AV-400 instrument unless otherwise noted.
Chemical shifts are reported in parts per million (ppm) downfield
9
–11). When 4-iodoanisole was used as a substrate, halogen–
magnesium exchange took place at room temperature and the
desired product was obtained in 66% yield (Table 1, entry 12).
It was notable that when iodobenzene and 2-iodoanisole were
used as substrates, halogen–magnesium exchange did not occur
from tetramethylsilane (δ) as the internal standard (CDCl : 7.26
3
1
13
ppm for H NMR, 77.0 ppm for C NMR) and coupling constants
are given in hertz (Hz). Melting points were measured in a capillary
tube on a SGW X-4 melting point apparatus without correction. High-
resolution mass spectra (HRMS) were obtained with a Finigann
MAT-95 instrument (EI) and Thermo Fisher Scientific LTQ FT Ultra
(NSI). Optical rotations were measured on an Autopol III automatic
polarimeter. Infrared spectra were recorded on a Bio-Rad FTS 165
FTIR spectrometer.
(
Table 1, entries 14 and 15).
Conclusions
In summary, a concise and convenient CuLi Cl -catalysed
2
4
cross-coupling has been developed leading to the regioselective
synthesis of (+)-subersic acid with an overall yield of 25.7% and
involving five steps starting from (−)-sclareol. In particular,
various derivatives of (+)-subersic acid have been synthesised
smoothly for further biological activity testing.
17
Methyl 4-hydroxy-3-iodobenzoate (2b)
A stirred solution of 4-hydroxybenzoic acid (5.0 g, 36 mmol) in
ammonia (200 mL) was treated with iodine (9.2 g, 36 mmol) and
KI (29.4 g, 180 mmol) in water (100 mL) dropwise at r.t. After the
addition, the mixture was stirred overnight at the same temperature.
Experimental
All reactions were carried out with magnetic stirring, and if moisture
or air sensitive, in oven-dried glassware under nitrogen or argon using
standard Schlenk techniques. Tetrahydrofuran (THF) was distilled
over sodium and benzophenone before use. Reagents were commercial
grade and used without further purification unless otherwise specified.
Commercial copper (II) chloride and lithium chloride were used after
drying under reduced pressure at room temperature CuLi Cl solution
−1
Then, hydrochloric acid (2.0 mol L ) was added to adjust the pH of
the mixture to pH 2.0 and a white solid precipitated. After filtration,
the filter cake was washed with water. The white solid was dried and
then dissolved in DMF (100 mL). Next, K CO (5.0 g, 18 mmol) was
2
3
added to the mixture, and it was stirred for 1 h at r.t. Then MeI (2.5 mL,
36 mmol) was added and the mixture was stirred overnight. The
2
4

396 JOURNAL OF CHEMICAL RESEARCH 2017
mixture was diluted with water and extracted with ethyl acetate (2 ×
20 mL). The organic layer was washed with water and then dried with
solvent gave a crude product, which was purified on silica gel to give
the final products.
1
anhydrous sodium sulfate. After concentration under reduced pressure,
the crude product was purified by column chromatography to give
compound 2b as: White solid ; yield 7.5 g (75%); H NMR (400 MHz,
15-(4-Methoxycarbonyl)phenyl-labda-8(9),13E-diene (6b): Colourless
2
2
1
oil; yield 203 mg (50%); aꢀ = +35.6° (c = 0.5, CHCl ); H NMR (CDCl ,
3
3
17
1
400 MHz): δ 7.95 (d, J = 8.1 Hz, 2H), 7.26–7.24 (m, 2H), 5.33 (t, J = 7.2 Hz,
1H), 3.90 (s, 3H), 3.40 (d, J = 7.2 Hz, 2H), 2.15–1.80 (m, 7H), 1.75–1.64 (m,
4H), 1.57 (s, 3H), 1.50–1.37 (m, 3H), 1.27–1.10 (m, 4H), 0.94 (s, 3H), 0.88
DMSO-d ): δ 11.30 (s, 1H), 8.23 (d, J = 2.1 Hz, 1H), 7.82 (dd, J = 8.5,
6
13
2
.1 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H), 3.80 (s, 3H); C NMR (100 MHz,
+
DMSO-d ): δ 164.8, 161.1, 140.2, 131.1, 122.2, 114.6, 84.4, 51.9.
(s, 3H), 0.83 (s, 3H). HRMS (NSI) m/z calcd for C H O [M + H] :
6
28 41
2
4
09.3101; found: 409.3098.
4
2
-Iodo-4-carbomethoxyanisole (2c)
1
5-(4-Fluoro)phenyl-labda-8(9),13E-diene (6c): Colourless oil;
The above procedure was repeated with K CO (20.0 g, 72 mmol) and
22
1
2
3
yield 89.6 mg (24%); aꢀ = +31.4° (c = 0.5, CHCl ); H NMR (CDCl ,
3
3
MeI (10.0 mL, 144 mmol) to give compound 2c as: White solid; m.p.
4
00 MHz): δ 7.15–7.11 (m, 2H), 6.99–6.94 (m, 2H), 5.34–5.24 (m, 1H),
3.35–3.31 (m, 2H), 2.17–1.82 (m, 7H), 1.79–1.74 (m, 3H), 1.62–1.58 (m,
H), 1.61–1.58 (m, 5H), 1.50–1.39 (m, 3H), 1.26–1.11 (m, 4H), 0.95 (s,
1
9
4.7–95.2 °C; yield 8.4 g (79%); H NMR (400 MHz, CDCl ): δ 8.45
3
(
1
d, J = 2.0 Hz, 1H), 8.01 (dd, J = 8.6, 2.0 Hz, 1H), 6.83 (d, J = 8.6 Hz,
3
13
H), 3.94 (s, 3H), 3.88 (s, 3H); C NMR (100 MHz, CDCl ): δ 165.1,
13
3
3H), 0.89 (s, 3H), 0.84 (s, 3H); C NMR (100 MHz, CDCl ): δ 160.8
3
161.2, 140.1, 131.2, 123.9, 109.5, 84.9, 56.1, 51.7. HRMS (EI) m/z calcd
(
d, JC–F = 244.3 Hz), 139.9, 136.9, 129.1 (d, JC–F = 7.6 Hz), 125.6, 122.5,
121.8, 114.6 (d, JC–F = 21.1 Hz), 51.43, 41.36, 39.97, 38.61, 36.62, 33.23,
for C H O I: 291.9596; found: 291.9594.
9
9
3
4
32.89, 32.38, 26.75, 26.23, 22.93, 21.27, 19.75, 19.17, 18.66, 15.80.
1
5-Acetoxy-labda-8(9),13E-diene (3c)
+
HRMS (NSI) m/z calcd for C H F [M + H] : 369.2952; found:
2
6
38
A solution of PPh (6.3 g, 24 mmol) in CH Cl (50 mL) was treated
with iodine (6.1 g, 24 mmol) and the mixture was stirred at r.t. for
min. Then, a solution of 5 (9.4 g, 24 mmol) in CH Cl (50 mL) was
added and the mixture was stirred for a further 8 h. DMF (100 mL) was
then added to the mixture, followed by sodium acetate (24.6 g,
2 mmol). The mixture was stirred at r.t. overnight. The solution was
diluted with CH Cl (200 mL), washed with Na S O and brine, and
dried over Na SO . Evaporation of the organic solvent gave a crude
product, which was purified on silica gel to give compound 3c as:
Yellowish liquid; yield 6.0 g (75%); a = +68° (c = 0.78, CHCl );
3
2
2
369.2951.
1
5-(3-Fluoro)phenyl-labda-8(9),13E-diene (6d): Colourless oil;
5
2
2
22
1
yield 160 mg (44%); aꢀ = +29.2° (c = 0.5, CHCl ); H NMR (CDCl ,
3
3
4
(
1
3
00 MHz): δ 7.24–7.20 (m, 3H), 6.96 (d, J = 7.65 Hz, 2H), 6.90–6.85
m, 2H), 5.35–5.25 (m, 1H), 3.38–3.35 (m, 2H), 2.17–1.82 (m, 7H),
.80–1.74 (m, 3H), 1.61–1.58 (m, 5H), 1.51–1.38 (m, 3H), 1.26–1.11 (m,
7
2
2
2
2
3
13
H), 0.95 (s, 3H), 0.89 (s, 3H), 0.84 (s, 3H); C NMR (100 MHz,
2
4
CDCl ): δ 163.0 (d, J = 245.1 Hz), 144.4 (d, JC–F = 7.0 Hz), 140.4,
3
C–F
137.9 (d, JC–F = 17.4 Hz), 129.7, 126.4 (d, JC–F = 26.9 Hz), 123.9, 121.8 (d,
2
2
ꢀ
3
JC–F = 93.2 Hz), 115.1 (d, JC–F = 21.0 Hz), 112.5 (d, JC–F = 21.2 Hz), 51.8
1
H NMR (400 MHz, CDCl ): δ 5.37 (t, J = 7.0 Hz, 1H), 4.60 (d, J = 7.0
Hz, 2H), 2.07 (s, 3H), 2.03–1.91 (m, 4H), 1.83 (d, J = 12.0 Hz, 2H), 1.74
s, 3H), 1.70–1.63 (m, 2H), 1.58 (s, 3H), 1.53–1.37 (m, 4H), 1.20–1.11
m, 3H), 0.95 (s, 3H), 0.89 (s, 3H), 0.84 (s, 3H).
3
(d, JC–F = 6.6 Hz), 41.8, 40.4, 39.0, 37.0, 33.9, 33.6, 33.3, 32.8, 27.2, 26.6,
2
3.4, 21.7, 20.2, 20.1, 19.6, 19.5, 19.1, 16.3. HRMS (NSI) m/z calcd for
(
(
+
C H F [M + H] : 369.2952; found: 369.2951.
2
6
38
1
5-(2-Fluoro)phenyl-labda-8(9),13E-diene (6e): Colourless oil;
2
2
1
1
5-(2-Methoxyl-5-carbomethoxy)phenyl-labda-8(9),13E-diene (6a)
yield 240 mg (65%); aꢀ = +58° (c = 0.5, CHCl ); H NMR (CDCl ,
3
3
4
3
00 MHz); δ 7.22–7.13 (m, 2H), 7.08–6.98 (m, 2H), 5.33–5.24 (m, 1H),
i-PrMgBr (1.05 mmol, 1.56 M in THF) was added to a solution of the
aromatic iodide 2c (103 mg, 0.35 mmol) in THF (1.0 mL) at −40 °C and
then stirred for 2 h at this temperature. The solution was then
transferred over 2 min via a syringe to a round-bottom flask containing
.40–3.36 (m, 2H), 2.16–1.85 (m, 7H), 1.79–1.75 (m, 3H), 1.62–1.58
(m, 5H), 1.49–1.39 (m, 3H), 1.27–1.10 (m, 3H), 0.94 (s, 3H), 0.89 (s,
13
3H), 0.83 (s, 3H); C NMR (100 MHz, CDCl ): δ 161.0 (d,
3
−1
JC–F = 245.0 Hz), 140.4, 138.0, 137.8, 130.2 (d, JC–F = 4.7 Hz), 127.3,
25.8, 123.9, 121.4, 120.7, 115.2 (d, JC–F = 22.1 Hz), 77.3, 77.0, 76.8,
1.9, 41.8, 40.4, 39.0, 37.0, 33.6, 33.3, 32.8, 27.1, 26.6, 23.4, 21.7, 20.1,
CuLi Cl (0.023 mmol, 0.05 mol L ) and the acetate 3c (79 mg, 0.23
2
4
1
5
mmol) in anhydrous THF (1.0 mL) at −40 °C. The reaction was stirred
for 1 h at −40 °C before being warmed to r.t. and stirred overnight. The
+
19.5, 19.1, 16.2. HRMS (NSI) m/z calcd for C H F [M + H] :
reaction was quenched with saturated NH Cl solution, diluted with
26 38
4
369.2952; found: 369.2948.
water and extracted with ethyl acetate. The combined organic extracts
were washed with brine and dried over Na SO . Evaporation of the
1
5-(4-Chloro)phenyl-labda-8(9),13E-diene (6f): Colourless oil;
2
4
2
2
1
yield 160 mg (42%); aꢀ = +47.4° (c = 0.5, CHCl ); H NMR (CDCl ,
400 MHz): δ 7.25 (dd, J = 8.4, 2.0 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H),
5.33–5.23 (m, 1H), 3.35–3.31 (m, 2H), 2.14–1.91 (m, 6H), 1.84–1.74
organic solvent gave a crude product, which was purified on silica gel
3
3
2
2
to give compound 6a as: Colourless liquid; yield 62.5 mg (62%); a
=
ꢀ
1
+
42.4° (c = 0.5, CHCl ); H NMR (400 MHz, CDCl ): δ 7.89 (dd,
3
3
(m, 4H), 1.57 (s, 3H), 1.61–1.58 (m, 5H), 1.50–1.39 (m, 3H), 1.27–1.11
J = 8.8, 2.2 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H),
.31 (t, J = 7.2 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.33 (d, J = 8 Hz, 2H),
.16–1.76 (m, 8H), 1.73 (s, 3H), 1.72–1.61 (m, 2H), 1.58 (s, 3H),
.50–1.34 (m, 4H), 1.30–1.10 (m, 4H), 0.94 (s, 3H), 0.88 (s, 3H), 0.83
13
(m, 3H), 0.95 (s, 3H), 0.89 (s, 3H), 0.84 (s, 3H); C NMR (100 MHz,
5
2
CDCl ): δ 139.8, 137.4, 129.2, 128.0, 125.7, 125.4, 122.1, 121.3, 51.5,
3
4
1.40, 40.0, 38.6, 36.6, 33.2, 33.1, 32.9, 26.7, 26.2, 22.9, 21.3, 19.7, 19.1,
1
+
18.7, 15.8. HRMS (NSI) m/z: calcd for C H Cl [M + H] : 385.2668;
26 38
13
(s, 3H); C NMR (100 MHz, CDCl ): δ 166.7, 160.7, 140.1, 137.3,
3
found: 385.2654.
130.3, 129.7, 128.9, 128.6, 127.3, 125.3, 121.7, 120.6, 109.1, 55.1, 51.5,
1
5-(4-Bromo)phenyl-labda-8(9),13E-diene (6g): Colourless oil;
5
1.3, 41.4, 40.1, 38.6, 36.6, 33.2, 32.9, 27.7, 26.8, 21.3, 19.7, 19.1, 18.7,
2
2
1
+
yield 260 mg (61%); aꢀ = +35° (c = 0.5, CHCl ); H NMR (CDCl ,
15.7. HRMS (NSI) m/z calcd for C H O [M + H] : 439.3207; found:
3
3
2
9
43
3
4
5
00 MHz): δ 7.39 (dd, J = 8.36, 2.0 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H),
439.3201.
.34–5.23 (m, 1H), 3.33–3.29 (m, 2H), 2.16–1.92 (m, 6H), 1.79–1.73
Synthesis of (+)-subersic acid derivatives (6b–m); general procedure
(m, 4H), 1.61–1.56 (m, 5H), 1.50–1.39 (m, 5H), 1.26–1.11 (m, 5H),
13
i-PrMgBr (1.56 M in THF, 4.5 mmol) was added to a solution of the
aromatic iodide 2 (1.5 mmol) in THF (6.0 mL) at −40 °C and then
stirred for 2 h at this temperature. The solution was then transferred
over 2 min via a syringe to a round-bottom flask containing CuLi Cl
1.27–1.11 (m, 3H), 0.95 (s, 3H), 0.89 (s, 3H), 0.84 (s, 3H); C NMR
(100 MHz, CDCl ): δ 140.3, 139.8, 137.3, 130.9, 129.6, 125.6, 121.9,
121.2, 51.4, 41.4, 39.9, 38.6, 36.6, 33.2, 32.9, 32.4, 26.7, 26.2, 22.9, 21.3,
+
19.7, 19.2, 18.6, 15.8. HRMS (NSI) m/z calcd for C H Br [M − H] :
26 38
429.2151; found: 429.2148.
3
2
4
−1
(
0.1 mmol, 0.05 mol L ) and the acetate 3c (1.0 mmol) in anhydrous
THF (6.0 mL) at −40 °C. The reaction was stirred for 1 h at −40 °C
before being warmed to r.t. and stirred overnight. The reaction was
15-(3-Bromo)phenyl-labda-8(9),13E-diene (6h): Colourless oil; yield
2
2
1
232 mg (54%); aꢀ = +26° (c = 0.5, CHCl ); H NMR (CDCl , 400 MHz):
3
3
quenched with saturated NH Cl solution, diluted with water and
δ 7.33–7.30 (m, 2H), 7.17–7.10 (m, 2H), 5.33–5.23 (m, 1H), 3.36–3.32 (m,
2H), 2.16–1.92 (m, 6H), 1.80–1.74 (m, 3H), 1.61–1.58 (m, 4H), 1.51–1.39
(m, 4H), 1.26–1.11 (m, 4H), 1.27–1.11 (m, 3H), 0.95 (s, 3H), 0.89 (s, 3H),
4
extracted with ethyl acetate. The combined organic extracts were
washed with brine and dried over Na SO . Evaporation of the organic
2
4

JOURNAL OF CHEMICAL RESEARCH 2017 397
1
3
0
1
3
.83 (s, 3H); C NMR (100 MHz, CDCl ): δ 144.2, 140.3, 138.0, 131.4,
136.9, 136.7, 133.9, 129.2, 126.0, 125.8, 123.6, 122.8, 113.8, 77.3, 77.0,
76.7, 55.3, 51.9, 41.8, 40.4, 39.0, 37.0, 33.6, 33.3, 33.2, 32.8, 27.2, 26.7,
23.4, 21.7, 20.1, 19.5, 19.1, 16.2. HRMS (NSI) m/z calcd for C H O [M
3
29.9, 128.8, 127.0, 126.1, 122.1, 121.1, 51.8, 41.8, 40.4, 39.0, 37.0, 33.8,
3.6, 33.3, 32.8, 26.6, 23.4, 21.7, 20.2, 19.6, 19.1, 16.3. HRMS (NSI) m/z
2
7
41
+
calcd for C H Br [M − H] : 429.2151; found: 429.2150.
+
26
38
+ H] : 381.3152; found: 381.3149.
1
5-(2-Bromo)phenyl-labda-8(9),13E-diene (6i): Colourless oil;
yield 220 mg (51%); a2 = +38° (c = 0.5, CHCl ); H NMR (CDCl ,
00 MHz): δ 7.55–7.53 (m, 1H), 7.24–7.23 (m, 2H), 7.08–7.04 (m, 1H),
.33–5.27 (m, 1H), 3.49–3.45 (m, 2H), 2.18–1.92 (m, 6H), 1.82–1.72
m, 4H), 1.68–1.56 (m, 5H), 1.51–1.36 (m, 3H), 1.23–1.11 (m, 3H), 0.96
s, 3H), 0.89 (s, 3H), 0.84 (s, 3H); C NMR (100 MHz, CDCl ): δ
41.0, 140.4, 138.3, 132.6, 130.0, 127.4, 125.9, 124.7, 121.2, 120.6, 51.9,
1.8, 40.5, 39.1, 37.0, 34.6, 33.7, 33.4, 33.0, 27.2, 26.6, 23.4, 21.7, 20.2,
9.6, 19.1, 16.4. HRMS (NSI) m/z calcd for C H Br [M + H] :
2
1
ꢀ
3
3
Acknowledgements
4
5
(
(
1
ThisworkwasfinanciallysupportedbyNationalNaturalScience
Foundation of China (21302053), Science and Technology
Commission of Shanghai Municipality (14DZ1900102) and
the Fundamental Research Funds for the Central University
(WY1113007).
13
3
4
1
+
26 38
Electronic Supplementary Information
429.2151; found: 429.2147.
1
5-(1,4-Biphenyl)-labda-8(9),13E-diene (6j): Colourless oil; yield
The ESI is available through:
stl.publisher.ingentaconnect.com/content/stl/jcr/supp-data
22
1
1
87 mg (44%); a = +38.2° (c = 0.5, CHCl ); H NMR (CDCl , 400
MHz): δ 7.59–7.57 (m, 2H), 7.51 (dd, J = 8.1, 2.9 Hz, 2H), 7.44–7.40
m, 2H), 7.34–7.30 (m, 1H), 7.28–7.25 (m, 2H), 5.41–5.31 (m, 1H),
.43–3.39 (m, 2H), 2.21–1.86 (m, 7H), 1.81–1.77 (m, 3H), 1.63–1.59 (m,
H), 1.51–1.37 (m, 3H), 1.30–1.11 (m, 4H), 0.95 (s, 3H), 0.88 (s, 3H),
.83 (s, 3H); C NMR (100 MHz, CDCl ): δ 141.2, 141.0, 138.7, 137.5,
28.8, 127.1, 127.0 (2C), 125.9, 122.2, 77.3, 77.0, 76.8, 51.9, 41.9, 40.5,
9.1, 37.0, 33.9, 33.7, 33.4, 32.9, 27.2, 26.7, 23.5, 21.7, 20.1, 19.6, 16.3.
HRMS (NSI) m/z calcd for C H [M + H] : 427.3359; found:
ꢀ
3
3
(
Received 13 April 2017; accepted 22 May 2017
Paper 1704702
https://doi.org/10.3184/174751917X14967701766923
Published online: 26 June 2017
3
4
0
1
3
13
3
+
References
32
43
4
27.3355.
1
2
3
4
5
6
D.E. Williams, J.-B. Telliez, J. Liu, A. Tahir, R.v. Soest and R.J. Andersen, J.
Nat. Prod., 2004, 67, 2127.
P. Basabe, A. Diego, S. Delgado, D. Díez, I.S. Marcos and J.G. Urones,
Tetrahedron, 2003, 59, 9173.
15-(2-Methyl)phenyl-labda-8(9),13E-diene (6k): Colourless oil;
2
2
1
yield 180 mg (50%); a = +49.5° (c = 0.5, CHCl ); H NMR (CDCl ,
4
2
ꢀ
3
3
00 MHz): δ 7.18–1.11 (m, 4H), 5.29–5.21 (m, 1H), 3.36–3.32 (m, 1H),
.30 (s, 3H), 2.20–1.85 (m, 7H), 1.80–1.76 (m, 3H), 1.63–1.58 (m, 5H),
P.-Q. Wang, J. Li, C.-L. Yu, X. Xiao, P.-Y. Wu and B.-B. Zeng, Tetrahedron,
2
015, 71, 4647.
J. Wang, P.-Q Wang, J. Li, P.-Y. Wu, J.-M. Ren and B.-B. Zeng, Chin. J. Chem.,
015, 33, 679.
1
3
1
3
.52–1.40 (m, 3H), 1.27–1.11 (m, 3H), 0.96 (s, 3H), 0.90 (s, 3H), 0.85 (s,
H); C NMR (100 MHz, CDCl ): δ 140.4, 140.0, 137.1, 136.1, 130.0,
28.6, 128.5, 125.9, 122.4, 121.7, 51.9, 41.8, 40.4, 19.1, 37.0, 33.7, 33.3,
2.9, 32.1, 31.9, 26.6, 23.4, 21.7, 20.2, 19.5, 19.1, 16.3. HRMS (NSI) m/z
13
3
2
W. Dohle, N. Gommermann, F.F. Kneisel, F. Kopp, T. Korn, I. Sapountzis, V.A.
Vu and P. Knochel, Angew. Chem. Int. Ed., 2003, 42, 4302.
M. Rottländer, L. Boymond, L. Bérillon, A. Leprêtre, G. Varchi, S. Avolio, H.
Laaziri, G. Quéguiner, A. Ricci, G. Cahiez and P. Knochel, Chem. Eur. J., 2000,
6, 767.
+
calcd for C H [M + H] : 365.3203; found: 365.3203.
2
7
41
15-(4-Ethyl)phenyl-labda-8(9),13E-diene (6l): Colourless oil; yield
2
2
1
111 mg (29%); a = +57.8° (c = 0.5, CHCl ); H NMR (CDCl , 400
ꢀ
3
3
MHz): δ 7.13 (s, 4H), 5.39–5.28 (m, 1H), 3.36 (t, J = 7.1 Hz, 2H),
7
A.E. Jensen, W. Dohle, I. Sapountzis, D.M. Lindsay, V.A. Vu and P. Knochel,
Synthesis, 2002, 565.
2
3
0
1
2
.66–2.61 (m, 1H), 2.21–1.84 (m, 7H), 1.80–1.7 (m, 3H), 1.65–1.60 (m,
8
9
H. Ila, O. Baron, A.J. Wagner and P. Knochel, Chem. Commun., 2006, 6, 583.
A. Krasovskiy and P. Knochel, Angew. Chem. Int. Ed., 2004, 43, 3333.
A. Krasovskiy, B.F. Straub and P. Knochel, Angew. Chem. Int. Ed., 2006, 1, 159.
J.E. Zakarian, Y. El-Azizi and S.K. Collins, Org. Lett., 2008, 10, 2927.
J.-E. Bäckvall, M. Sellén and B. Grant, J. Am. Chem. Soc., 1990, 112, 6615.
F. Kopp, A. Krasovskiy and P. Knochel, Chem. Commun., 2004, 2288.
F. Kopp, S. Wunderlich and P. Knochel, Chem. Commun., 2007, 2075.
H), 1.52–1.41 (m, 3H), 1.28–1.12 (m, 7H), 0.97 (s, 3H), 0.91 (s, 3H),
.86 (s, 3H); C NMR (100 MHz, CDCl ): δ 144.2, 140.0, 138.6, 136.3,
27.9, 127.4, 125.6, 123.1, 51.5, 41.4, 40.0, 38.6, 36.6, 33.3, 32.9, 32.4,
1
3
3
1
0
1
1
8.0, 26.8, 26.3, 23.0, 21.3, 19.8, 19.2, 18.7, 15.8, 15.3. HRMS (NSI)
1
2
+
m/z calcd for C H [M + H] : 379.3359; found: 379.3356.
2
8
42
1
3
15-(4-Methoxy)phenyl-labda-8(9),13E-diene (6m): Colourless oil;
1
4
2
2
1
yield 250 mg (66%); a = +37.2° (c = 0.5, CHCl ); H NMR (CDCl ,
4
ꢀ
3
3
15 E.J. Alvarez-Manzaneda, R. Chahboun, E. Cabrera Torres, E. Alvarez, R.
00 MHz): δ 7.11–7.09 (m, 2H), 6.84–6.82 (m, 2H), 5.35–5.24 (m, 1H),
Alvarez-Manzaneda, A. Haidour and J.M. Ramos López, Tetrahedron Lett.,
3.79 (s, 1H), 3.32–3.29 (m, 2H), 2.17–1.90 (m, 6H), 1.78–1.74 (m, 2H),
2005, 46, 3755.
1
.62–1.57 (m, 5H), 1.50–1.37 (m, 3H), 1.29–1.10 (m, 4H), 0.94 (s, 3H),
16 Y. Arima, M. Kinoshita and H. Akita, Tetrahedron: Asymmetry, 2007, 18, 1701.
17 A. A. Vasil’ev and L. Engman, J. Org. Chem., 1998, 63, 3911.
13
0.88 (s, 3H), 0.83 (s, 3H); C NMR (100 MHz, CDCl ): δ 157.7, 140.5,
3