First total synthesis of (+)-Carainterol A

Article abstract of DOI:10.1016/j.tetlet.2010.02.001

The first, stereospecific, and elegant synthesis of the natural product (+)-Carainterol A was developed by using the Robinson annulation reaction as a key step to build the eudesmane sketeton.

Full text of DOI:10.1016/j.tetlet.2010.02.001

Tetrahedron Letters 51 (2010) 1870–1872
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First total synthesis of (+)-Carainterol A
Kaiqing Ma a, Chunbo Zhang b, Mingming Liu a, Yong Chu a, Lu Zhou a, Changqi Hu a, Deyong Ye a,
*
a Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China
b Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, Yanbian University, Ministry of Education, Yanji, Jilin 133000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The first, stereospecific, and elegant synthesis of the natural product (+)-Carainterol A was developed by
using the Robinson annulation reaction as a key step to build the eudesmane skeleton.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 6 December 2009
Revised 29 January 2010
Accepted 1 February 2010
Available online 4 February 2010
Eudesmane sesquiterpenoids are a large group of compounds
that are abundant in structural diverse terpenes. These natural ses-
quiterpenoids have a number of biological activities,1 such as anti-
HIV,2 anti-inflammation, anti-Pyricularia oryzae P-2b, antibacte-
by the interaction between the
face selectivity of the introduction of the isopropyl group could re-
sult from the -bulky group at C4 of 5. The compound 5 could be
a-amino group and mCPBA. The
a
obtained from a Mannich reaction at C4 of 6, which would be de-
rived from an asymmetric Robinson annulation of the monomethy-
late of the dione 7,14 followed by reduction of the ketone at C1 and
protection of the hydroxyl. We considered that the stereocenters at
C1 and C5 could be derived from the established configuration at
the C10. Therefore, the pivotal control element in this strategy
would be the establishment of a C7 stereocenter and we sought
to develop an efficient and selective means for assembling this
moiety.
rial, antioxidant,
a
-amylase inhibitory, and anti-ulcer3 activities.
(+)-Carainterol A (1, Fig. 1) is first isolated from the Torilis japonica
fruit in 20024 and it contains three contiguous stereogenic centers
and one neighboring stereogenic center. In our previous study, its
diverse range of biological activities has been reported.5 It is dem-
onstrated that (+)-Carainterol A can increase glucose consumption
in C2C12 cells with an IC value of 10.7 lg/ml. To the best of our
knowledge, there are no reports concerning the synthesis of (+)-
Carainterol A or its enantiomer Verticillatol.2
The synthetic procedure for compound 5 is described in Scheme
2. The intermediate 8, which had been widely used in the synthesis
of terpenoids and steroids, was synthesized from the starting
material 7 by monomethylation, followed by an asymmetric pro-
Although the interesting bioactivities associated with this class
of compounds6 prompt studies on the synthesis of the eudes-
mane,7–11 the number of known successful strategies to construct
those stereocenters is limited. The elegant enantioselective total
synthesis of Dihydrojunenol (2) (Fig. 1) has been reported by Chen
and Baran12 Nevertheless, the strategies they employ are not
exploitable for access to the substituent at C1 on the decalin skel-
eton with the correct configuration. A novel approach for the con-
struction of ( ) Balanitol (3) is developed by Li and co-workers,13
but it does not allow for the assembly at C5. As described above,
a stereocontrolled construction of the eudesmane skeleton with
substituents at the various positions remains challenging. In our
present study, the first total synthesis of (+)-Carainterol A had been
accomplished. Moreover, the strategy we developed could intro-
duce different groups at C1, C4, C5, or C7 to systematically explore
the biological activities of (+)-Carainterol A and its analogues.
Our strategy for the synthesis of (+)-Carainterol A is outlined in
Scheme 1. This synthetic strategy relied on the use of tertiary
amine oxide at C4 as a masked exocyclic double bond.
cess promoted by
D
-(+)-proline14 (Scheme 2). The key Robinson
OH
OH
OH
H
H
OH
OH
Dihydrojunenol (2)
(+)-Carainterol A (1)
( ) Balanitol (3)
Figure 1. Representative eudesmane sesquiterpenoids.
OTBS
OTBS
4
OH
1
OTBS
5
14
9
10
5
2
3
8
7
7
4
6
6
13
4
We envisaged that an asymmetric epoxygenation at the olefins
C5–C6 could arise by means of the adjacent b-isopropyl group and
O
O
11
12
O
N
OH
Ph
Ph
N
15
O
1
5
4
6
* Corresponding author. Tel.: +86 021 51980125.
E-mail address: dyye@shmu.edu.cn (D. Ye).
Scheme 1. Retrosynthetic analysis of (+)-Carainterol A.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.001

K. Ma et al. / Tetrahedron Letters 51 (2010) 1870–1872
1871
O
O
12 by using i-PrMgCl/CeCl3 at À30 °C with moderate diastereose-
lectivity (4:1) by HPLC (Scheme 4).
OR
a, b
c
With 12 in hand, we started to explore the feasibility of the C–O
bond cleavage at C7. Originally we assumed that 13 could be ac-
cessed with esterification of the hydroxyl at C7, followed by reduc-
tion with LiAlH4. However, the esterification of the tertiary alcohol
failed to afford the desired product presumably due to the steric
hindrance of the adjacent isopropyl group at C7. The reported
reduction23–25 from tertiary alcohol to alkane with ZnI2–NaCNBH3
prompted us to investigate similar reaction with 12. Nevertheless,
several conditions provided intractable mixtures with no desired
product. This result might be attributed to the formation of the
B–N complex. Fortunately, 13 was achieved upon treatment of 12
with AlCl3–LiAlH4 at 0 °C with no isomerized by-product being
formed.
O
O
O
7
8
9
9 R=H
d
6 R=TBS
OTBS
OTBS
f
e
O
O
Ph
N
5
10
We have now advanced to the stage for the completion of the
total synthesis of (+)-Carainterol A. To this end, the directed epox-
ygenation of 13 was accomplished by using mCPBA to afford the
epoxide 4 with diastereoselectivity (9:1 by GC) accompanied by
the tertiary amine group being simultaneously converted to the
N-oxide.26 The N-oxide group of 4 was used as a handle on the
introduction of the exocyclic double bond. Subsequent elimination
of the N-oxide of 4 to form the exocyclic double bond was per-
formed in a mild condition without opening of the epoxy ring.
The configuration of C7 at 14 was confirmed by means of NOESY
experiments, which indicated a strong cross-peak connecting the
C10 methyl group with the C7 isopropyl group. The signal for H-
6 in the epoxide 14 was a singlet. Molecular models we established
indicated that the dihedral angle of H-6 and H-7 was near to 90°.
Scheme 2. Synthesis of 5. Reagent and conditions: (a) NaOH, MeI, 10 h, 60%; (b)
MVK, -(+)-Proline, DMSO, 24 h, 65%; (c) NaBH4, EtOH, 95%; (d) TBSCl, imidazole,
DMF, 80%; (e) TsOH, CH(OEt)3, THF, 95%; and (f) N-methylaniline, 40% CH2O, EtOAc,
D
70%.
annulation allowed us to build a decalin skeleton with desired C10
quaternary stereocenter.
The angular methyl group at C10 of 8 offered a considerable ste-
ric hindrance from the b-face of the decalin. This inherent bias in-
flicted the facial selectivity, allowing for the reduction at the a-face
of the ketone. Thus the reduction of 8 smoothly afforded 9 with the
desired b configuration of hydroxyl.15 We envisioned that the
introduction of a bulky protective group at the b-hydroxyl could
govern the attack of cationic carbon from the opposite face in the
Mannich reaction. The protection of the hydroxyl at C1 of 9 was
achieved by using a large excess of TBSCl and imidazole without
elimination of the hydroxyl.16
At the next stage of the synthesis, conversion of enone 6 to die-
nol 10 paved the way for the introduction of a Mannich base at C4.
After the substantial experimentations, it was subsequently found
that the Mannich reaction could be best performed at 0 °C to pro-
vide 5 with 3:1 diastereoselectivity.17,18
Therefore, the epoxy group was in the a-face.
Upon treatment with TBAF, 14 was easily transformed into its
free alcohol. The opening of the epoxide with the cleavage of the
C–O bond at the less hindered secondary carbon led to the target
molecule 1. All the spectral data of the synthetic (+)-Carainterol
A
were identical to those of the authentic isolated natural
product.4,5
In summary, an efficient route to synthesize (+)-Carainterol A
had been established in 12 steps with an overall yield of 4.5%.
The approach reported herein also could be adapted for the enan-
tioselective synthesis of Verticillatol, the enantiomer of (+)-Carain-
terol.2 Due to the flexibility of our approach, the synthesis of
additional eudesmanes from the intermediates reported in our
synthetic route could be achieved.
The angular a-hydroxyl at C5 of 11 was derived from the olefins
C5–C6 through epoxygenation, followed by reduction with organo-
selenium reagent phenylselenide anion (PhSeÀ)19 (Scheme 3). With
the route to 11 having been secured, efforts were then directed to-
ward the introduction of the C7 isopropyl group. At the onset of
this synthetic endeavor, it was perceivable that the Wittig reaction
should serve as an effective means for the construction of a C–C
double bond at C7, followed by the catalytic hydrogenation. Unfor-
tunately, it failed to undergo the Wittig reaction without the prob-
lematic elimination. Moreover, every attempt to protect the
angular hydroxyl at C5 with various groups was troublesome.
For this transformation,20,21 our studies were enlightened by
those of de Groot and Wijnberg,22 who employed CeCl3 as a Lewis
acid catalyst to introduce an isopropyl group, as well as the estab-
lishment of the C7 stereocenter with the desired configuration. We
reasoned that the favored equatorial conformation might account
for the facial selectivity. Therefore, the introduction of the isopro-
pyl group to 5 at C7 was satisfactorily accomplished in 70% yield of
OTBS
O
OTBS
OTBS
a
c
O
R
Ph
Ph
Ph
N
N
5
N
O
12
4
12 R = OH
13 R = H
b
OH
OR
f
d
OTBS
OTBS
OTBS
OH
O
OH
1
a, b
O
O
14
OH
11
Ph
Ph
Ph
14 R= TBS
e
N
N
N
15 R= H
5
Scheme 4. Synthesis of (+)-Carainterol A. Reagent and conditions: (a) i-PrMgCl,
CeCl3, THF, 70%; (b) AlCl3, LiAlH4, THF, 88%; (c) mCPBA, CH2Cl2, 75%; (d) 10% NaOH,
H2O, 78%; (e) TBAF, THF, 90%; and (f) LiAlH4, THF, 70%.
Scheme 3. Synthesis of 11. Reagent and conditions: (a) 50% H2O2, NaOH, EtOH and
(b). NaBH4, (PhSe)2, EtOH.

1872
K. Ma et al. / Tetrahedron Letters 51 (2010) 1870–1872
9. Mehta, G.; Kumaran, R. S. Tetrahedron Lett. 2003, 44, 7055–7059.
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This research is supported by National Science Foundation of
China (30672511).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.02.001.
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