A chiral pool approach for asymmetric syntheses of (-)-antrocin, (+)-asperolide C, and (-)-trans -ozic acid

Article abstract of DOI:10.1039/c6cc06794h

Ozonolysis of aromatic abietane (+)-carnosic acid (4) is used to create an important intermediate in an enantiomerically pure form, resulting in a simple, concise, readily scalable, and asymmetric synthesis of (-)-antrocin (1). This strategy not only provides an efficient approach to (-)-antrocin (1) synthesis but can also be readily adopted for the syntheses of optically pure (+)-asperolide C (2) and (-)-trans-ozic acid (3) from the naturally abundant aromatic abietanes (+)-podocarpic acid (5) and (+)-dehydroabietic acid (6). The strategy presented here is an example of the use of naturally occurring aromatic abietanes as a chiral pool and offers an account of the asymmetric synthesis of terpenoids.

Full text of DOI:10.1039/c6cc06794h

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CONMMUNICATION
A Chiral Pool Approach for Asymmetric Syntheses of (−)-Antrocin,
+)-Asperolide C, and (−)-trans-Ozic acid
(
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
a
,a
,a
Fu-Zhuo Li, Shuang Li, Peng-Peng Zhang, Zhi-Hui Huang, Wei-Bin Zhang,* Jianxian Gong,* and
,
a,b
Zhen Yang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Ozonolysis of aromatic abietane (+)-carnosic acid (4) is used to owing to the low isolation yields of optically pure antrocin (15
1
create an important intermediate in an enantiomerically pure mg/300 g) from Antrodia camphorate.
form, resulting in a simple, concise, readily scalable, and
Gold-catalyzed tandem reaction (11 steps with 7.3% overall yield)
asymmetric synthesis of (−)-antrocin (1). This strategy not only
provides an efficient approach to (−)-antrocin (1) synthesis but can
also be readily adopted for the syntheses of optically pure (+)-
asperolide C (2) and (−)-trans-ozic acid (3) from the naturally
abundant aromatic abietanes (+)-podocarpic acid (5) and (+)-
dehydroabietic acid (6). The strategy presented here is an example
of the use of naturally occurring aromatic abietanes as a chiral
pool and offers an account of the asymmetric synthesis of
O
O
OBn
O
OH
COOH
HO
O
[(iPr)AuCl), AgSbF
BnOH
6
H
H
CH
5
2
Cl
4%
2
, rt
Me Me
Me Me
Me
Me
(
±)-antrocin (1)
Iridium-catalyzed enantioselective polyene cyclization (16 steps with 0.6% overall yield)
[(Ir(cod)Cl) , (R)-L
2
O
O
OPMB
SiMe
Zn(OTf)2
OPMB
Me
Me
terpenoids
.
ClCH CH Cl, rt
Me
2
2
3
dr = 9:1; ee = 98:2
73%
1
2
3
(
−)-Antrocin, (+)-asperolide C, and (−)-trans-ozic acid are
naturally occurring terpenoids ( in Figure 1) and have been
the subject of synthetic interest because of their biological
OH
HO
H
HOOC Me
1–3
O
(
R)-L =
P
N
(+)-asperolide C (2)
O
4
activities. Antrocin (1) has been synthesized by us as a racemic
mixture (eq. 1 in Figure 1) via a gold-catalyzed tandem
reaction of diynes as a key step to construct its drimane core;
this total synthesis was achieved in 11 steps with a 7.3%
Iridium-catalyzed enantioselective polyene cyclization (16 steps with 2.8% overall yield)
Me
OH
Me
(
R)-L
[(Ir(cod)Cl)
Zn(OTf)
Me
Me
5
6a
2
O
Me
overall yield. The total synthesis of asperolide C (
7
2
)
and
2
Me
trans-ozic acid (
3)
has been asymmetrically achieved using
6
then BF
79% (2 sreps)
99% ee
3 2
•OEt
b
HO
iridium-catalyzed asymmetric polyene cyclization as a key
step (equiv. 2 and 3 in Figure 1).
H
>
Me COOH
(-)-trans-ozic acid (3)
(
−)-Antrocin (
mushroom Antrodia camphorate in Taiwan that has been used
as dietary supplement for cancer prevention and
1) can be found in an expensive medicinal
Figure 1 Previous syntheses of natural products 1–3
a
We have previously reported the first total synthesis of
5
antrocin. However, this synthesis resulted in a racemic
8
hepatoprotection. It is a potent antagonist in various cancer
cells, including breast, lung, liver, colon, and bladder cancer
mixture, which required additional steps to obtain the optically
pure product. The development of an efficient and scalable
synthesis resulting in optically pure antrocin is necessary to
make this molecule readily available for biological
investigation.
9
cells , and can affect non-small lung cancer cells through
1
0
inhibition of the JAK/STAT3 signaling pathway. Studies of
antrocin as a potential anticancer agent have been hampered
Chiral pool synthesis is one of the main approaches to
producing enantiopure organic compounds as an alternative to
asymmetric synthesis and resolution of racemates. It involves
the synthesis of complex optically active compounds from a
stockpile of readily available enantiomerically pure
compounds. The built-in chirality present in the starting
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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material is either preserved or used to generate more chiral and dehydroabietic acid (
centers using the chosen reaction methods, leading to the and (Figure 3). Here we describe the asymmetric syntheses
target molecule. Despite the presence of various other of terpenoids from the naturally occurring (+)-carnosic
methods to produce the optically active targets, the chiral pool acid ( ), (+)-podocarpic acid ( ), and (+)-dehydroabietic acid
approach is widely used wherever it is viable. Unlike other ). The developed chemistry allows for compounds to be
resources, this approach is renewable and sometimes more readily synthesized, which is predisposed for further medicinal
6), respectively, via intermediates J
K
1
1
1–3
4
5
(
6
1–3
1
2
cost-effective.
In 1954, Woodward and his co-workers used ozonolysis of
the electron-rich 1,2-dimethoxybenzene moiety in substrate
to intermediate in the first total synthesis of strychinine (eq.
in Figure 2). In 1969, Bell and Gravestock reported a highly
regio- and stereo-selective ozonolysis reaction for the
chemistry optimization or synthetic application if necessary.
O
A
O
Me
O
Me
Me
B
O
9
9
9
10
8
1
3
10
8
10
8
A
5
B
1
A
B
A
B
5
5
4
4
4
OH
H
H
H
HOOC Me
Me Me
HOOC Me
synthesis of lactone
H
from methyl podocarpate
C
(eq. 2 in
(+)-asperolide C (2)
(
-)-trans-ozic acid (3)
1
4
(-)-antrocin (1)
Figure 2) in 85% yield.
Figure 2 shows the proposed mechanism. Accordingly,
first subjected to ozonolysis, and the resultant molozonide
should preferentially undergo a breakage of its 12,13-bond to
afford the hydroperoxide , which then might proceed a
further ozonolysis of its less-hindered C8,C14-double bond
C
was
OR
1
COOR
Me
1
COOR1
ROOC
Me
D
OR2
9
9
O
9
O
1
0
8
10
8
10
8
A
B
A
4
B
A
5
B
5
5
4
4
E
H
H
H
Me Me
Me COOR
ROOC Me
1
4
I
J
K
followed by its breakage to afford lactone
H
through
G.
The
17
Me
Me
developed ozonolysis reaction later has been applied to semi-
5
syntheses of structurally diverse sesquiterpenes.
OH Me
OH
1
12 15
HO
20
Me
Me
11
13
14
HOOC
16
Me
1
9
6
2
3
10
8
7
5
oxidative
clevage
4
oxidative
clevage
oxidative
clevage
Ozonolysis of substituted 1,2-dimethoybenzene (A) to dimethyl hexa-2,4-dienedioate (B)
in the first total synthesis of strychinine by Woodward
H
H
H
HOOC Me
Me Me
Me COOH
1
9
18
Ts
Ts
N
N
(+)-carnosic acid (4)
(+)-podocarpic acid (5) (+)-dehydroabietic acid (6)
COOEt
COOEt
Figure 3 Retrosynthetic analysis
ozonolysis
OMe
N
N
COOMe
COOMe
Ac
Ac
We began with the asymmetric synthesis of antrocin (1). In
OMe
,2-dimethoybenzene (A)
1
dimethyl hexa-2,4-dienedioate (B)
our retrosynthetic analysis (Figure 3), we expected that the
methylene moiety in could be appended late in the
synthesis, revealing intermediate as a potential precursor. In
Synthesis of lactone H from C via Ozonolysis by Bell and Gravestock
1
O
O
I
OH
1
2
HO
COOH
O
OOH
OMe
addition, it would not be necessary to define its
stereochemistry at C8 because this chiral center would be
1
1
1
3
O
12
3
1
3
Me
H
Me
CH
MeOH
2
Cl
2
Me
14
1
4
9
2
10
8
7
eliminated at the final stage of the synthesis. Intermediate
I
3
5
MeOH
6
would be made from carnosic acid (4) through sequential
H
H
Me
COOMe
Me COOMe
Me COOMe
ozonolysis and reduction, although the ozonolysis-based
oxidative degradation of aromatic abietanes bearing a C10
carboxylic acid as a substrate has not been reported.
C
D
E
OH
O
COOH
OOH
OMe
O
Me
Me
Me
14
O
8
The synthesis results are summarized in Scheme 1. Carnosic
+
-
O
O
O
OOH
acid (
4) was subjected to ozonolysis in a mixed solvent of
O
O
MeOH and CH Cl at −78 °C, and the resultant mixture was
2
H
H
H
2
Me COOMe
Me COOMe
Me COOMe
reduced with NaBH to produce optically pure lactone
7
in 58%
yield. Next, we synthesized optically pure hydroxyl lactone
To establish a concise synthesis of antrocin ( ), we used direct
conversion of lactone to its corresponding hydroxyl lactone
. The cis-configurated tereogenic centers on C9 and C10 were
4
H
G
F
9.
1
Figure 2 Ozonolysis reactions of phenols and phenol derivatives
7
9
In our search towards a concise asymmetric synthesis of
antrocin ( ), we decided to employ the above mentioned chiral
pool approach, and used the naturally abundant carnosic acid
, $1.1/g, Nanjing Chemlin, China) as a starting material. We
chose this because of the built-in chirality on C5 and C10 in
antrocin ( ), which is also present in , which can undergo the
ozonolysis to generate intermediate (Figure 3).
We also predicted that (+)-asperolide C (
) and (−)-trans-ozic
acid ( ) could be synthesized starting from podocarpic acid (5)
16
tested under various reduction conditions and we found that
17
1
reduction of lactone
7
with Na in liquid NH3 yielded the
was treated with Na
desired product 9. In this event, lactone
7
(
4
in liquid NH at −78 °C and the resultant mixture, without
3
purification, was treated with PTSA in toluene catalyzing an
intramolecular lactonization. This resulted in the formation of
1
4
I
hydroxyl lactone
9
in 56% yield along with its isomer
8 in 28%
2
yield. Further treatment of
9
with I in the presence of Ph P
2
3
3
and imidazol produced iodide 10, which was then treated with
2
| J. Name., 2012, 00, 1-3
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DBU to produce antrocin (
1
) in 50% yield. The asymmetric
Synthesis of (+)-asperolide C (
2) began with the preparation
synthesis of antrocin was accomplished with 16.1% overall of ketoacid 11 (Scheme 2), which was obtained via sequential
yield in five steps.
ozonolysis and Zn/AcOH reduction of podocarpic acid (5,
1
5a
$
518/g, Adrich), developed by Oishi.
unpurified ketoacid was protected as a dibenzyl ester, which
was then reacted with the Wittig reagent (MePPh Br)
The resultant
oxidative
OH Me
clevage
HO
O
3
Me
a. O
NaBH
8%
[24 g scale]
O
O
HOOC
HOOC
HOOC
b. Na/NH
-78 o
3
producing olefin 12 in 61% yield over three steps. To complete
the synthesis, olefin 12 was reacted with mCPBA and epoxide
3
then
9
9
C
9
10
8
4
10
5
8
10
5
8
5
5
then
PTSA
13 was obtained as a major isomer in 80% yield along with its
H
H
H
Me Me
Me Me
[9 g scale] Me Me
diastereoisomer in 11% yield. When we carried out
hydrogenative debenzylation by treating epoxide 13 with Pd/C
as a catalyst, the resultant epoxide acid underwent an efficient
lactonization via selective epoxide opening during the
(
+)-carnosic acid (4)
7
8 (28%)
+
O
O
O
O
O
I
O
OH
c. Ph
3
P, I
2
chromatography on silica gel and the final product
2 was
9
d. DBU
10
8
9
imid.
9
1
0
5
10
5
8
8
5
obtained in 90% yield. As a result, the asymmetric synthesis of
(
50%)
(99%)
[1 g scale]
[
2 g scale]
(+)-asperolide C (
yield.
2
) was achieved in five steps with 44% overall
H
H
H
Me Me
Me Me
Me Me
(
-)-antrocin (1)
10
9
(56%)
[
20 g prepared]
Scheme 1 Synthesis of (−)-antrocin (4) from (+)-carnosic acid (1). Reagents and
conditions: (a) O , CH Cl / MeOH (3/1), −78 °C, 1.5 h, then NaBH (6.0 equiv), −78 °C to
rt, 1 h (58%); (b) Na (15.0 equiv.), NH , −78 °C, then EtOH (5.0 equiv), 2 h; (c) PTSA (0.3
equiv.), toluene, 60 °C, 1 h (28% for 8, 56% for 9 in two steps); (d) Ph P (1.3 equiv.), I
1.5 equiv.), imid. (1.5 equiv.), THF, 0 °C to rt, 1 h (99%); (e) DBU (10.0 equiv.), toluene,
0 °C, overnight (50%).
oxidative clevage
Me
OH Me
12
3
2
2
4
13
12
1
0
Me
10
COOH
O
3
13
14
Me
Me
14
a. MeI, K
2
CO
(86%)
3
Me
Me
3
2
9
6
9
1
0
8
7
9
1
0
8
10
(
5
8
5
4
b. phthaloyl
peroxide (D)
(76%)
4
c. O3
Zn/AcOH
5
8
4
H
H
H
Me COOH
Me COOMe
Me COOMe
(
+)-dehydroabietic
O
14
15
Next, we performed the asymmetric synthesis of (+)-
asperolide C ( ) using the proposed chiral pool approach
Scheme 2).
acid (6)
O
O
D =
d. EtSH, EDCI
DMAP
e. Pd/C
2
Et SiH
3
O
(
67%
(95%)
(
Me
Me
Me
in 2 steps)
O
CHO
HO oxidative clevage
1
2
Me
Me
O
Me
HOOC
Me
1
1
13
COOBn
f.PPh
3
g.PPh3 CH2
O
a. O
CH
3
Cl
b. BnBr, K
2
CO
3
CHO
Me
Me
H
10
5
14
(75% in
2 steps)
2
2
O
9
9
4
h. LiOH•H
2
O
(71%)
10
8
MeOH
8
KOH, MeOH
(83%
H
H
H
then
Zn-AcOH
c. MePPh
tBuOK
Br
3
Me COOH
Me COOMe
Me COOMe
H
H
in 2 steps)
HOOC Me
+)-podocarpic acid (5)
HOOC Me
BnOOC Me
(-)-trans-ozic
acid (3)
17
16
(82%)
(
11
12
d. mCPBA (80%)
Scheme 3 Synthesis of Synthesis of (−)-trans-ozic acid (3) from (+)-dehydroabietic acid
(6) Reagents and conditions: (a) MeI (3.0 equiv.), K CO (2.5 equiv.), acetone, rt,
overnight (86%); (b) phthaloyl peroxide (1.3 equiv.), HFIP, rt to 40 °C, 6 h, then sat.
NaHCO , MeOH, 40 °C (76%); (c) O , CH Cl / MeOH (3/1), −78 °C, 1.5 h, then Zn (20.0
eqiuv.), AcOH, RT, 2.5h; (d) EtSH (3.5 equiv.), EDCI (2.5 equiv.), DMAP (0.4 equiv.),
CH Cl , 0 °C to RT, overnight (67% in 2 steps); (e) Pd/C (0.1 equiv.), Et SiH (5.0 equiv.),
THF, rt, overnight. (95%); (f) Wittig reagent (2.0 equiv.), toluene, 110 °C, 24 h, (71%); (g)
O
COOBn
2
3
Me
e. Pd/C, H
then SiO
Me
2
O
2
3
3
2
2
O
(90%)
OH
H
H
2
2
3
HOOC Me
BnOOC Me
(
+)-asperolide C (2)
Scheme 2 Synthesis of (+)-asperolide C (2) from podocarpic acid (5) Reagents and
conditions: (a) O , CH Cl
/ MeOH (3/1), −78 °C, 40 min, then Zn (20.0 eqiuv.), AcOH, rt,
.5 h; (b) BnBr (8.0 equiv.), K CO (7.0 equiv.), DMF, rt, overnight (75% in 2 steps); (c)
PBr (3.5 eqiuv.), BuOK (3.0 eqiuv.), THF, 0 °C to rt, 3 h (82%); (d) mCPBA (1.5
Cl , Pd/C (0.1 equiv), MeOH, rt, 5 h, then silica
, −10 °C, 12 h (80%); (e) H
gel, 5 h (90%).
13
t
MePPh
3
Br (6.0 equiv.), BuOK (5.0 equiv.), THF, 0 °C to RT, 3 h; (h) LiOH•H
2
O (8.0
equiv.), KOH (10.0 equiv.), MeOH/H
2
O (5/1), reflux, 24 h, (83% in two steps).
3
2
2
2
2
3
t
MePh
3
Finally, we carried out the asymmetric synthesis of (−)-
trans-ozic acid ( ) from (+)-dehydroabietic acid ( ). From a
synthetic perspective, ( )-trans-ozic acid ( ) can be derived
eqiuv.), CH
2
2
2
3
6
−
3
7
from ketoaldehyde 16 using a sequential Wittig reaction and
hydrolysis. Ketoaldehyde 16 would be made from ketoacid 15
using Fukuyama’s reductive de-sulfuration reaction of the
Retrosynthetically, we expected that (+)-asperolide C (2)
could be generated from the epoxide 13 via a trifluoroacetic
6
acid-mediated epoxide opening reaction. Epoxide 13, in turn,
1
7
thioester, which can be made from ketoacid 15 by a
1
8
was expected to be derived from olefin 12 by a mCPBA-
mediated stereoselective epoxidation, because mCPBA would
approach the double bond from the less-hindered side (the
bottom face). Our retrosynthetic analysis would trace back to
the ketoacid 11, which could be made from podocarpic acid
condensation with EtSH in the presence of EDCI and DMAP.
We also expected that ketoacid 15 could be prepared from 18-
1
9
methylesterferruginol (14
)
via ozonolysis, although this
transformation has not been reported. Because 14 is not
commercially available, we decided to prepare it from the
naturally abundant and commercially available (+)-dehydro-
(5), as mentioned above.
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2
0
abietic acid (
phthaloyl peroxide-mediated oxidation developed by Siegel.
Scheme 3 illustrates the synthesis of (−)-trans-ozic acid (
). In
the first step, (+)-dehydroabietic acid ( ) was reacted with MeI
in the presence of K CO in acetone, and the resultant methyl
6
, $85/kg, Nanjing Chemlin, China ) using
5
6
H. Shi, L. Fang, C. Tan, L. Shi, W. Zhang, C. Li, T. Luo and Z.
Yang, J. Am. Chem. Soc. 2011, 133, 14944.
(a) O. F. Jeker, A. G. Kravina and E. M. Carreira, Angew. Chem.
Int. Ed. 2013, 52, 12166; (b) M. A. Schafroth, D. Sarlah, S.
Krautwald and E. M. Carreira, J. Am. Chem. Soc. 2012, 134,
20276.
2
1
3
6
2
3
ester was converted to the optically active compound 14 by
7
8
9
J. Deng, S. Zhou, W. Zhang, J. Li, R. Li and A. Li, J. Am. Chem.
Soc. 2014, 136, 8185.
M. Geethangili and Y.-M. Tzeng, Evid. Based. Complement.
Alternat. Med. 2011, 212641.
K.-Y. Chiu, C.-C. Wu, C.-H. Chia, S.-L. Hsu and Y.-M. Tzeng,
Cancer Lett. 2016, 373, 174; and recent study indicates.
oxidation with phthaloyl peroxide in hexafluoro-isopropanol
(
HFIP). Following the protocol reported by Oishi and co-
15a
workers, phenol 14 underwent a typical ozonolysis followed
by a reduction with Zn/AcOH. A condensation with EtSH in the
presence of EDCI and DMAP was carried out with the resultant 10 C.-T. Yeh, W.-C. Huang, Y. K. Rao, M. Ye, M. W.-H. Lee, L.-S.
Wang, D. T. W. Tzeng, C.-H. Wu, Y.-S. Shieh, C.-Y. F. Huang,
ketoacid 14 to give a thioester in 67% yield in two steps. Using
Y.-J. Chen, M. Hsiao, A. T. H. Wu, Z. Yang and Y.-M. Tzeng,
Carcinogenesis 2013, 34, 2918.
3
Fukuyama’s reductive de-sulfuration reactions (Pd/C/Et SiH),
the thioester was converted to aldehyde 16 in 95% yield. After
sequential treatment of aldehyde 16 with two Wittig reagents,
followed by hydrolysis, the asymmetric synthesis of (−)-trans-
1
1 (a) S. Hanessian, Total Synthesis of Natural Products: The
‘Chiron’ Approach; J. E. Baldwin, Ed.; Pergamon: Oxford, UK,
1983. (b) W. A. Nugent, T. V. Rajanbabu and M. J. Burk,
Science 1993, 259, 479.
ozic acid (
3) from (+)-dehydroabietic acid (6) was achieved in
1
1
2 M. S. Taylor and E. N. Jacobsen, Proc. Natl. Acad. Sci. U.S.A.
eight steps with 24% yield.
1
2
3 R. B. Woodward, M. P. Cava, W. D. Ollis, A. Hunger, H. U.
004, 101, 5368.
13
The H-NMR and C-NMR spectra and optical rotations of
the synthesized terpenoids are in agreement with the
1
–
3
Daeniker and K. Schenker, J. Am. Chem. Soc. 1954, 76, 4749.
14 R. A. Bell and M. B. Gravestock, Canad. J. Chem. 1970, 48,
105.
1
-3
published data of the naturally occurring compounds.
1
1
5 (a) H. Akita and T. Oishi, Tetrahedron Lett. 1978, 39, 3733; (b)
H. Akita and T. Oishi, Chem. Pharm. Bull. 1981, 29, 1580; (c) R.
C. Cambie, G. R. Clark, M. E. Goeth, C. E. F. Rickard, P. S.
Rutledge, G. R. Ryan and P. D. Woodgate, Aust. J. Chem.
Conclusions
In summary, we have developed a unified strategy for the
asymmetric syntheses of terpenoids based on a chiral pool
strategy from naturally occurring aromatic abietanes using
ozonolysis as a key step. This strategy not only achieves the
1
989, 42, 497; (d) R. C. Cambie, A. C. Grimsdafe, P. S.
Rutfedge and P. D. Woodgate, Aust. J. Chem. 1990, 43, 485;
e) J. G. Bendall, R. C. Cambie, A. C. Grimsdale, P. S. Rutledge
and P. D. Woodgate, Aust. J. Chem. 1992, 45, 1063.
1), (+)-asperolide C (2
), and (−)- 16 Several reduction conditions have been profiled, see
(
syntheses of (−)-antrocin (
trans-ozic acid ( ) but also provides an efficient approach to
Supporting Information for details.
7 P. R. LePlae, N. Umezawa, H.-S. Lee and S. H. Gellman, J. Org.
Chem. 2001, 66, 5629.
3
1
1
1
2
access analogs of these biologically active terpenoids.
8 T. Fukuyama, S. C. Lin and L. P. Li, J. Am. Chem. Soc. 1990
,
1
22, 7050.
9 W. S. Lee, J.-R. Kim, J.-M. Han, K. C. Jang, D.-E. Sok and T.-S.
Acknowledgements
Jenog, J. Agric. Food Chem. 2006, 54, 5369.
0 The purchase order of (+)-dehydroabietic acid (6) from
Nanjing Chemlin of China is provided as Supporting Material
in this submission.
We thank the National Science Foundation of China (Grant
Nos. 21372016, 21572009 and 21402002.), Guangdong Natural
Science Foundation (Grant Nos. 2014A030312004 and
2
016A030306011), NSFC-Shandong Joint Fund for Marine 21 (a) C. Yuan, Y. Liang, T, Hernandez, A. Berriochoa, K. N. Houk
and D. Siegel, Nature 2013, 499, 192; (b) C. Yuan, A. M.
Eliasen, A.M. Camelio and D. Siegel. Nature protocols 2014, 9,
624.
Science Research Centers (Grant No. U1406402), and
Shenzhen Basic Research Program (Grant Nos.
JSGG20140717102922014,
JCYJ20160226105337556 and
2
ZDSYS20140509094114168,
JCYJ20150629144231017,
JCYJ20160330095629781) for financial support.
Notes and references
1
2
3
4
H.-C. Chiang, D.-P. Wu, I. W. Cherng and C. H. Ueng,
Phytochemistry 1995, 39, 613.
H.-F. Sun, X.-M. Li, L. Meng, C.-M. Cui, S.-S. Gao, C.-S. Li, C.-G.
Huang and B.-G. Wang, J. Nat. Prod. 2012, 75, 148.
R. D. Stipanovic, D. H. O'Brien, C. E. Rogers and T. E.
Thompson, J. Agric. Food Chem. 1979, 27, 459.
Selective reviews for bioactive studies of drimane-type and
labdane-type terpenes: (a) B. J. M. Jansen and A. de Groot,
Nat. Prod. Rep. 1991, 8, 309; (b) B. J. M. Jansen and A. de
Groot, Nat. Prod. Rep. 2004, 21, 449; (c) I. Chinou, Curr. Med.
Chem. 2005, 12, 1295; (d) L. M. T. Frija, R. F. M. Frade and C.
A. M. Afonso, Chem. Rev. 2011, 111, 4418.
4
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DOI: 10.1039/C6CC06794H
TOC
O
O
1
Me
10
O
Me
Me
O
9
9
9
8
10
8
A
4
B
0
8
A
4
A
4
B
B
5
5
5
OH
H
H
H
HOOC Me
Me Me
HOOC Me
(+)-asperolide C (2)
(
-)-trans-ozic acid (3)
(
-)-antrocin (1)
OR1
COOR1
COOR1
O
ROOC
9
Me
10
Me
10
OR2
O
9
9
10
8
8
8
A
B
A
4
B
A
4
B
5
5
5
4
H
H
H
Me Me
Me COOR
ROOC Me
A
B
C
Me
OH
Me17
OH
12
15
HO
Me
20
13
Me
Me
H
1
1
16
Me
HOOC
1
2
9
14
10
8
oxidative
clevage
3
5
7
6
oxidative
clevage
oxidative
clevage
4
H
H
HOOC Me
Me Me
Me COOH
19
18
(
+)-carnosic acid (4)
(+)-podocarpic acid (5)
(+)-dehydroabietic acid (6)
Ozonolysis of aromatic abietanes (4-6) is used to create important intermediates in an enantiomerically
pure form, resulting in a simple, concise, readily scalable, and asymmetric semi-syntheses of (−)-antrocin (1),
(
+)-asperolide C (2) and (−)-trans-ozic acid (3). The strategy presented here is an example of the use of naturally
occurring aromatic abietanes as a chiral pool and offers an account of the asymmetric synthesis of terpenoids.