Total syntheses of the proposed structures of cuevaene a

Article abstract of DOI:10.1016/j.tetlet.2010.06.133

Two proposed structures of cuevaene A were synthesized and the NMR spectra of both structures are proved to be inconsistent with those of the natural product. The structure of cuevaene A is still unclear and needs to be revised.

Full text of DOI:10.1016/j.tetlet.2010.06.133

Tetrahedron Letters 51 (2010) 4655–4657
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total syntheses of the proposed structures of cuevaene A
Yunxiu Chen a, Jianfeng Huang a, Bo Liu a,b,
*
a Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610 064, China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, 345 Lingling Road, Shanghai 200 032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Two proposed structures of cuevaene A were synthesized and the NMR spectra of both structures are
proved to be inconsistent with those of the natural product. The structure of cuevaene A is still unclear
and needs to be revised.
Received 9 May 2010
Revised 12 June 2010
Accepted 30 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Cuevaene A
Total synthesis
Natural product
Cascade
In 2000, the Gräfe group reported the isolation of cuevaenes A
and B, both of which displayed moderate antibacterial activity
against Gram-positive bacteria.1 Very interestingly, two structur-
ally related compounds, named JBIR-23 and -24, were reported
by the Takagi and Shin-ya group in 2009. JBIR-23 and -24 were
isolated from the same species, but showed highly cytotoxic ef-
fects against several malignant pleural mesothelioma (MPM) cell
lines.2 All of these natural products embrace a tricyclic core and
a polyene side chain with an enol methyl ether inside. Such type
of triene fragment is novel in natural products and has never been
reported before, to the best of our knowledge. However, the struc-
ture of cuevaene A was originally proposed as compound 1, the
Takagi and Shin-ya group suggested to revise it to compound 2
by altering the connective position of the polyene side chain to
the same site on the cyclohexane ring as that in JBIR-23 and
-24, based on the extensive NMR correlations of JBIR-23 and -24
and the possible biosynthetic relationship between them and
cuevaene A (Fig. 1). Allured by the novel but uncertain structure
of cuevaene A and to lay a foundation for the total synthesis of
JBIR-23 and -24, we were interested and involved in the total syn-
thesis and structural confirmation of cuevaene A. Herein, we
would like to present our endeavors on the total syntheses of
compounds 1 and 2.
OMe Me
O
OH
O
OH
CO2H
1 (proposed by Grafe et al)
MeO
Me
OMe Me
O
O
H
O
OH
O
H
O
H
OR
R = CH3 JBIR-23
JBIR-24
HO
2 (proposed by Takagi et al)
R = H
proposed structures of cuevaene A
Figure 1. Proposed structures of cuevaene A and JBIR-23 and -24.
OMe Me
Ph3P=CHCO2Me
O
O
O
+
(iPrO)2P
CO2Me
OH
OMe
+
2
HO
Convinced by the intimate relationship of the structure and bio-
synthesis between cuevaene A and JBIR-23 and -24, we decided to
initiate the total synthesis of compound 2. The retrosynthesis of
compound 2 is depicted in Scheme 1, following a linear strategy.
Accordingly, the triene side chain of the target molecule could be
Ph3P=CMeCO2Me
+
O
O
O
OTBS
+
4
5
OTMS
3
O
* Corresponding author. Tel./fax: +86 28 8541 3712.
E-mail address: chembliu@scu.edu.cn (B. Liu).
Scheme 1. Retrosynthetic analysis of compound 2.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.133

4656
Y. Chen et al. / Tetrahedron Letters 51 (2010) 4655–4657
Since the silyl protective group on phenol was cleaved under the
OTMS
OBF3
O
BF3
WHE reaction condition, reprotection was made to produce com-
pound 11. The installation of the last disubstituted alkene was
achieved via a reduction–oxidation-Wittig reaction sequence to
give ester 12. The desired stereochemistry of the triene fragment
was confirmed by NOESY and NOE difference spectrometry of com-
pound 12. The proposed structure of cuevaene A, compound 2, was
achieved by removing the TBS protection and hydrolyzing the ester
with lithium hydroxide (Scheme 3). However, to our disappoint-
ment, the NMR spectra of the synthetic compound 2 do not fit with
those of cuevaene A.6 The major difference between the 1H NMR of
cuevaene A and that of compound 2 is the space between the
chemical shifts of H5 and H7 on the spectra (0.26 ppm vs
0.07 ppm). Thus we wondered if the structure originally proposed
by the Gräfe group be the real one of cuevaene A.
O
O
OH
O
4
5
O
OTMS
BF3
TMS
OH
OTMS
BF3
-H2O
-TMSOH
7
O
O
HO
Scheme 2. Formation of compound 7.
Then we turned our attention to the total synthesis of com-
pound 1, starting with an epoxide-opening reaction with bromide
13 and epoxide 14. After compound 157 was obtained in a quanti-
tative yield, it was oxidized to ketone 16 under Dess–Martin con-
dition. The introduction of the side chain of compound 1 began
installed by Wittig reactions and HWE reaction sequentially. Retro-
synthetically, we envisioned the 6–5–6 fused tricyclic motif arising
from a Lewis acid-promoted cascade methodology, and coupling
with enol silyl ether 4 and para-benzoquinone 5.
According to the known procedure,3 compound 4 was facilely
prepared via Michael addition of vinyl Grignard reagent with 2-
cyclohexen-1-one in the presence of copper (I) iodide, which was
followed by a cascade reaction promoted by boron trifluoride,
affording compound 7. Actually, the formation of benzofuran from
cyclohexenyloxytrimethyl-silane and para-quinone in the presence
of lithium perchlorate had been described in the literature.4 How-
ever, we found that the application of lithium perchlorate did not
facilitate the workup process for the cascade reaction in a prepara-
tive scale, while using boron trifluoride instead achieved compara-
ble yield (Scheme 2).
with the installation of an ester at a-position of the ketone, achiev-
ing compound 17.8 In the presence of boron tribromide,9 the
deprotection of methyl ether and the formation of benzofuran
were realized in one-pot in 52% yield to form compound 18, whose
free phenol was protected as TBS ether 19 in a quantitative yield.
After the remaining construction of the triene fragment on the side
chain by following the same sequence as in Scheme 3, compound 1
was achieved. It is worth noting that two isomers (21a/21b) were
obtained in a ratio of 1:2.5 when compound 20 reacted with the re-
agent W1. The relative configurations of the double bonds of 21
and 22 were confirmed through NOE difference spectrometry or
NOESY. The final transformation with lithium hydroxide afforded
compound 1 (Scheme 4). Unfortunately, the NMR spectra of the
synthetic compound 1 are closely similar to those of the synthetic
compound 2, and still inconsistent with those of the natural cuev-
aene A.
After the protection of the free phenol of compound 7, the ter-
minal alkene was transformed to an aldehyde via Johnson–Lemi-
eux oxidation (OsO4/NaIO4), which was subjected to Wittig
condition to give compound 9 as the sole detected stereoisomer.
After following the routine reduction–oxidation transformation,
aldehyde 10 was obtained from ester 9. Then the second trisubsti-
tuted alkene fragment was constructed as the only detected ste-
reoisomer through coupling of aldehyde 10 with reagent W1.5
In summary, we have completed the syntheses of two proposed
structures of cuevaene A and both are proved incorrect. The correct
structure needs to be further probed.
OTMS
1) CuI, THF, -78 o
C
O
p-benzoquinone
OH
OTBS
BF3 OEt2, THF
TBSCl, imid.
2) TMSCl, HMPA,
+
MgBr
-10 oC, 2 h
Et3N, -78 oC to rt
DCM, rt, 2 h
86%
38% from 6
O
O
6
one-pot
4
8
7
O
EtO
H3C
H
O
1) OsO4/NaIO4, rt,
THF/H2O (1:1), 10 h
1) LiBH4, THF
0 oC-rt, 6 h
W1
, KHMDS, 18-C-6,
OTBS
OTBS
THF, 0 oC, 8 h;
H3C
2) Ph3P=CMeCO2Et
PhMe, rt, 18 h
78% in two steps
2) MnO2, DCM,
rt, 10 h
then TBSCl, imid.,
DCM, rt, 2 h. 56% from 9
O
O
10
9
CO2Me
MeO
MeO
O
1) LiBH4, THF, 0 oC-rt, 12 h
2) MnO2, DCM, rt, 10 h
H3CO
H3C
LiOH, rt, 7 h
OTBS
OTBS
2
H3C
3) Ph3P=CHCO2Me, DCM,
rt, 5 h. 56% for three steps
dioxane/H2O
(1/1). 60%
O
(iPrO)2P
CO2Me
O
11
O
12
nOe
W1 OMe
Scheme 3. Total synthesis of compound 2.

Y. Chen et al. / Tetrahedron Letters 51 (2010) 4655–4657
4657
OMe
OMe
OMe
OMe
nBuLi, BF3 OEt2
Br
Dess-Martin [O]
NaH, CO(OMe)2
+
O
THF, -78 oC, 1.5 h
quant.
reflux, 2 h, quant.
DCM, rt, 3.5 h
78%
OH
O
CH3
O
O
CH3
16
15
13
14
OMe
1) LiBH4, THF, 30 oC,4 h;
2) Dess-Martin [O], DCM, rt, 1.5 h;
MeO2C
MeO2C
BBr3, -10 oC-rt
TBSCl, imid.
O
O
DCM, 15 min
52%
DCM, rt, 2.5 h
quant.
3) Ph3P=CMeCO2Et, PhMe,
rt, 10 h. 85% in 3 steps
MeO2C
O
O
CH3
17
19
18
OH
OTBS
5
5
1) LiBH4, THF, 30 oC, 4 h, 93%
3
3
2) Dess-Martin [O], DCM, rt, 2 h
EtO2C
1
4
4
2
+
Me
O
MeO
MeO2C
O
O
3) W1, LDA, THF, 0 oC, 3h
2
CO2Me
OMe
1
20
OTBS
OTBS
OTBS
(2Z, 4E)-21b; 57%
(2E, 4E)-21a; 23%
1) LiBH4, THF, 0-30 oC, 4 h;
2) Dess-Martin [O], DCM, 2 h;
LiOH, rt, 8 h
1
(
)
2Z, 4E -21b
O
THF/H2O (1/1)
72%
3) Ph3P=CHCO2Me, DCM,
rt, 10 h. 73% from 21b
MeO2C
OMe
nOe
Scheme 4. Total synthesis of compound 1.
22
OTBS
3. (a) Clive, D. L. J.; Russell, C. G.; Suri, S. C. J. Org. Chem. 1982, 47, 1632–1641; (b)
Jones, T. K.; Denmark, S. E. J. Org. Chem. 1985, 50, 4037–4045; (c) Kerdesky, F. A.
J.; Schmidt, S. P.; Holms, J. H.; Dyer, R. D.; Carter, G. W.; Brooks, D. W. J. Med.
Chem. 1987, 30, 1177–1186.
4. Saraswathy, V. G.; Sankararaman, S. J. Org. Chem. 1995, 60, 5024–5028.
5. Scheidt, K. A.; Bannister, T. D.; Tasaka, A.; Wendt, M. D.; Savall, B. M.; Fegley, G.
J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 6981–6990.
Acknowledgments
We appreciate the financial support from NSFC (20702032,
20872098), the Ministry of Education of China (IRT0846), and
National Basic Research Program of China (973 Program,
2010CB833200). We also thank the Analytical & Testing Center of
Sichuan University for the NMR recording.
6. See Supplementary data for the details please.
7. (a) Alexakis, A.; Vrancken, E.; Mangeney, P. Synlett 1998, 11, 1165–1167; (b)
Wagner, J. M.; McElhinny, C. J., Jr.; Lewin, A. H.; Carroll, F. I. Tetrahedron:
Asymmetry 2003, 14, 2119–2125.
Supplementary data
8. Direct introducing a formyl group seems straightforward, making the synthesis
more concise; however, the formation of the benzofuran proved problematic
only in 14% yield.
Supplementary data (experimental procedures, characteriza-
tion data for new compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2010.06.133.
OMe
OMe
BBr3, 0 oC-rt
Na, EtOH
HCO2Et
OH
ether, rt, 81%
14%
DCM,
O
16
O
CH3
O
References and notes
OHC
O O
OHC
9. Srikrishna, A.; Ravikumar, P. C. Tetrahedron Lett. 2005, 46, 6105–6109.
CH3
1. Schlegel, B.; Groth, I.; Gräfe, U. J. Antibiot. 2000, 53, 415–417.
2. Motohashi, K.; Hwang, J.-H.; Sekido, Y.; Takagi, M.; Shin-ya, K. Org. Lett. 2009, 11,
285–288.