Synthetic studies towards Chlorahololides A: practical synthesis of a lindenane-type sesquiterpenoid core framework with a 5,6-double bond

Article abstract of DOI:10.1016/j.tetlet.2009.12.133

Towards Chlorahololides A: a lindenane-type sesquiterpenoid framework that contains a 5,6-double bond was synthesized from simple starting materials. The reductive cyclization of a 1,6-enyne and an unusual endo-type intramolecular Heck reaction was used as key steps for ring closure.

Full text of DOI:10.1016/j.tetlet.2009.12.133

Tetrahedron Letters 51 (2010) 1374–1376
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthetic studies towards Chlorahololides A: practical synthesis
of a lindenane-type sesquiterpenoid core framework with a 5,6-double bond
*
Yong Liu, Fa-Jun Nan
The National Center for Drugs Screening, State Key laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Towards Chlorahololides A: a lindenane-type sesquiterpenoid framework that contains a 5,6-double
bond was synthesized from simple starting materials. The reductive cyclization of a 1,6-enyne and an
unusual endo-type intramolecular Heck reaction was used as key steps for ring closure.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 2 November 2009
Revised 22 December 2009
Accepted 29 December 2009
Available online 7 January 2010
Keywords:
Chlorahololides A
Lindenane-type sesquiterpenoid core
framework
Synthesis
Chlorahololides A (Fig. 1) is a sesquiterpenoid dimer isolated
from South China Chloranthus holostegius by Yue and co-workers
in 2007.1 It exhibits potent and selective inhibition of the delayed
Alder-type dimerization, and is especially useful for the synthesis
of the natural product Chlorahololides A as proposed here.
Intrigued by the interesting biological activity and intricate
structure of Chlorahololides A, we decided to study and develop
a practical synthesis route for lindenane-type sesquiterpenoids
with a 5,6-double bond, which can be used not only as a key step
for total synthesis of Chlorahololides A, but is also applicable to the
synthesis of other lindenane-type sesquiterpenoid dimers.
rectifier (IK) K+ current with an IC50 of 10.9
lM, and is 96 times as
potent as the positive control, tetraethylammonium chloride, a
classical blocker of the delayed rectifier (IK) K+ current. Potassium
(K+) channels play vital roles in the regulation of a variety of phys-
iological processes, in association with many severe human
diseases.
Herein, we report
a practical route starting from simple
According to the biogenetic hypothesis proposed by Yue et al.
(Scheme 1) for this complex natural product, Chlorahololides A
might be formed through an enzymatic Diels–Alder cycloaddition
of two molecular lindenane-type sesquiterpenoids (components
A and B).1 So far, more than 20 oligomers of lindenane-type ses-
quiterpenoids have been isolated.2–13 Most of them are dimers that
were formed through a ‘Diels–Alder-type connection’ of lindenane-
type sesquiterpenoids. Some of them have demonstrated interest-
ing bioactivities.14
materials to synthesize lindenane-type sesquiterpenoid frame-
works with a 5,6-double bond by the use of a reductive cyclization
of a 1,6-enyne and unusual endo-type intramolecular Heck reac-
tion as the key steps for ring closure.
We envisaged that the precursors of the Diels–Alder cycloaddi-
tion, components A and B could all be reached from compound 1
under base and acid conditions, respectively. Compound 1 would
be accessed from compound 2 in view of the chemical reactivity
of the butenolide22,23 (Scheme 2).
Lindenane-type sesquiterpenoids have been isolated for more
than 40 years15–19 (Fig. 2 shows the carbon skeleton of linden-
ane-type sesquiterpenoids), and some of them have displayed
meaningful bioactivity.18,20 However, until now, synthetic studies
on this type of sesquiterpenoid have been rare.21 No reports are
available on the synthesis of lindenane-type sesquiterpenoid
frameworks that contain a 5,6-double bond (Scheme 1 component
A), which actually serves as an important intermediate of Diels–
MeO2C
O
O
O
H
O
O
OH
Chlorahololides A
* Corresponding author. Tel./fax: +86 21 50800954.
E-mail address: fjnan@mail.shcnc.ac.cn (F.-J. Nan).
Figure 1. Chlorahololides A.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.133

Y. Liu, F.-J. Nan / Tetrahedron Letters 51 (2010) 1374–1376
1375
MeO2C
O
MeO2C
O
O
MeO2C
O
O
O
H
O
OAc
O
H
O
OAc
Oxidation and
rearrangement
H
endo Diels-Alder
cycloaddition
OAc
H
OH
H
H
H
Component A
Component B
Scheme 1. Biogenetic pathway proposed for Chlorahololides A.
Intermediate 1
Chlorahololides A
12
9
14
figuration a,b-unsaturated ester 6 was produced in 77% yield based
8
11
13
1
7
on 56% conversion without Z-product. The unsaturated ester 6
obtained was then converted to alkynol 9 by deprotection, fol-
lowed by Swern oxidation and further ethynylation in excellent
yield (Scheme 3). Diastereomers were produced in the ethynyla-
tion reaction, which could be easily separated by silica-gel column
chromatography. The ratio of diastereomers was 8:5. However,
they could both be converted to the same compound 20 after oxi-
dation of the hydroxyl group through our next reaction route;
therefore, the mixture was used in the next step without further
separation.
10
4
5
6
2
3
15
Figure 2. Carbon skeleton of lindenane-type sesquiterpenoids.
MeO2C
O
O
H
O
O
O
O
With alkynol 9 in hand, we next sought to investigate cycliza-
tion of the 1,6-enyne.25 After hydroxyl group protection, desilyla-
O
tion, reduction of the
a,b-unsaturated ester and protection of
Component A
OAc
primary alcohol 13, reductive cyclization was accomplished to pro-
vide the exomethylene product 14 (Scheme 4), using the method of
Trost,26 in 97% yield, and no other diastereomer, although it was
confirmed that the configuration of the chiral methyl group of 14
is unexpected by NOE analysis of tetracyclic ketone 21 at a later
stage (Fig. 3).
H
1
2
Component B
Scheme 2. Retrosynthetic analysis of the key intermediate.
After desilylation of 14, Swern oxidation of primary alcohol 15
led to aldehyde 16 in excellent yield. Then aldehyde 16 was treated
with Grignard reagent 1727 to afford butenolide diastereomers 18a
and 18b (diastereomer ratio >10:1) that could be separated by sil-
ica-gel column chromatography. The butenolide 18a was con-
verted to the precursor of the intramolecular Heck reaction
through deprotection and Swern oxidation. Although an exo-type
intramolecular Heck reaction is impossible for this substrate,28
the endo-type ring closure was still problematic. No desired prod-
uct was detected under Overman’s conditions.29 After many reac-
tion condition screenings, tetracyclic ketone 21 was produced in
a 40% yield based on 50% conversion under ligand-free conditions.
We started from the racemic bicyclic lactone 3, which was pre-
pared from copper-catalyzed intramolecular cyclopropanation of
the allylic diazoacetate, as reported previously.24 By controlling
the addition speed of methyllithium solution in ether and the reac-
tion temperature, alcohol 4 was obtained without any overmethy-
lation product, and then the resulting primary hydroxyl group was
protected by tert-butyldimethylsilyl (TBS) to afford ketone 5 in
good yield from two steps. The HWE reaction of ketone 5 and
triethyl phosphonoacetate was problematic because of the steric
effect and tendency to be racemized under harsh base conditions.
We accomplished the reaction after many trials using sodium
hydride as base in toluene at reflux temperature for 4 h. The E-con-
H
H
OTHP
TBAF
DHP
EtO
9
H
H
H
H
H
H
1.2 eq
TBSCl
THF/H2O
quant
CH Li
PPTs
quant
3
OTBS
OH
O
O
TMS
THF/Et O
Imidazole
73% two steps
2
O
O
O
10
H
º
-78 C
(¡À)3
4
5
H
H
H
H
H
H
H
H
H
OTHP
OTHP
OTBS
(EtO)2POCH2COOEt
NaH, Tol.
OH
1%HCl
TBSCl
DIBAL-H
To l.
EtOH
EtO
EtO
H
Imidazole
quant EtO
º
110 C, 4hrs, 77%
(56%, BORSM)
O
OH
91% two steps
O
O
H
11
12
6
7
OTHP
H
H
OTHP
OH
O
Pd(dba)2
Li
TMS
EtO
Swern Ox.
EtO
91%
99%
Et3SiH, BBEDA, HOAc
97%
OTBS
13
O
OTBS
14
O
TMS
8
9
Scheme 3. Synthesis of intermediate 9.
Scheme 4. Synthesis of first ring-closing intermediate 14.

1376
Y. Liu, F.-J. Nan / Tetrahedron Letters 51 (2010) 1374–1376
O
natural product Chlorahololides A, only the 14-methyl group is
epimeric.
In summary, we have developed a practical synthesis of the lin-
H
H
H
H3C
denane-type sesquiterpenoid framework containing a 5,6-double
bond. Although it gives an unexpected 14-epi methyl configuration
in cyclization of the 1,6-enyne, it is still valuable for the synthesis
of the lindenane-type sesquiterpenoid framework. The chiral
14-methyl configuration could be redressed in the early stage of
synthesis to construct the correct final product. Currently we are
working on this and the results will be described elsewhere.
H
O
H
O
Figure 3. NOE analysis of tetracyclic ketone 21.
MeO2C
OTHP
OTHP
BrMg
17
96%
Acknowledgement
Br
TBAF
98%
Swern
94%
Ox.
14
This work was supported by The National Natural Science Foun-
dation of China (Grants 30725049 and 30721005).
OH
O
15
16
OH
References and notes
OTHP
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Yue, J. M. Org. Lett. 2007, 9, 903.
p-TsOH
quant
Br
Br
O
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3. Kawabata, J.; Mizutani, J. Phytochemistry 1992, 31, 1293.
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5. Okamura, H.; Iwagawa, T.; Nakatani, M. Bull. Chem. Soc. Jpn. 1995, 68, 3465.
6. Kavabata, J.; Fukushi, E.; Mizutani, J. Phytochemistry 1993, 32, 1347.
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8. Zhang, C. F.; Nakamura, N.; Tewtrakul, S.; Hattori, M.; Sun, Q. s.; Wang, Z. t.;
Fujiwara, T. Chem. Pharm. Bull. 2002, 50, 1195.
O
O
O
19
18a
OTHP
9. Yang, S.-P.; Yue, J.-M. Tetrahedron Lett. 2006, 47, 1129.
10. Xu, Y. J.; Tang, C. P.; Ke, C. Q.; Zhang, J. B.; Weiss, H. C.; Gesing, E. R.; Ye, Y. J. Nat.
Prod. 2007, 70, 1987.
Br
11. Wang, X. C.; Zhang, Y. N.; Wang, L. L.; Ma, S. P.; Liu, J. H.; Hu, L. H. J. Nat. Prod.
2008, 71, 674.
12. Wu, B.; Chen, J.; Qu, H.; Cheng, Y. J. Nat. Prod. 2008, 71, 877.
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Takaishi, Y. Tetrahedron Lett. 2009, 50, 6032.
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2006, 104, 270.
15. Takeda, K. I.; Horibe, I.; Minato, H. J. Chem. Soc. (C) 1968, 569.
O
O
18b
O
O
Pd(OAc)2, Et3N
Br
O
Swern Ox.
93%
DMF, 80oC, 4hrs
16. Nozoe, S.; Uchida, M. Heterocycles 1978, 9, 139.
40%
17. Mizutani, J.; Kawabata, J. Agric. Biol. Chem. 1979, 43, 885.
18. Maia, L. F.; Epifanio, R. A.; Eve, T.; Fenical, W. J. Nat. Prod. 1999, 62, 1322.
19. Kouno, I.; Hirai, A.; Fukushige, A.; Jiang, Z. H.; Tanaka, T. J. Nat. Prod. 2001, 64,
286.
O
O
(50%, BORSM)
O
20
21
N
N
N
20. Trentin, A. P.; Santos, A. R.; Guedes, A.; Pizzolatti, M. G.; Yunes, R. A.; Calixto, J.
B. Planta Med. 1999, 65, 517.
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2003, 5, 3049.
SO2Me
N
tBu
NaHMDS
57%
O
O
23. Corey, E. J.; Roberts, B. E. J. Am. Chem. Soc. 1997, 119, 12425.
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22
Scheme 5. Synthesis of lindenane-type sesquiterpenoid framework 22.
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13095.
NOE analysis of 21 (Fig. 3) provided all relative stereochemistry
characteristics. Finally, the methylenation reaction was achieved
under modified Julia–Kocienski conditions21 in moderate yield to
give compound 22,30 which possesses a typical lindenane-type
sesquiterpenoid framework with a 5,6-double bond (Scheme 5).
Compared with the desired key intermediate for the synthesis of
30. Characterization data of compound 22: 1H NMR (CDCl3, 300 MHz): d 6.54 (s, 1H),
5.34 (s, 1H), 5.13 (s, 1H), 4.97–5.03 (m, 1H), 2.43 (dd, J = 5.1, 11.7 Hz, 1H), 1.94–
2.00 (m, 1H), 1.89 (s, 3H), 1.48–1.57 (m, 2H), 1.27 (s, 3H), 0.74–0.81 (m, 1H),
0.12–0.16 (m, 1H); 13C NMR (CDCl3, 75 MHz): d 174.9, 156.4, 154.9, 149.6,
119.5, 113.7, 107.2, 77.0, 45.6, 40.1, 28.6, 26.2, 20.5, 12.2, 8.7; HRMS (EI) m/z
[M+] calcd for C15H16N4O2: 228.1150, found: 228.1154.