Diastereoselective total synthesis of 8-epigrosheimin

Article abstract of DOI:10.1016/j.tetlet.2008.12.025

The first diastereoselective total synthesis of 8-epigrosheimin was accomplished relying entirely on substrate-controlled methods. 8-Epigrosheimin, isolated as an amoebicidal and antibiotic compound from Crepis virens, is a multi-chiral-centered guaianolide with a cis-hydroazulene and a trans-annulated γ-butyrolactone ring. Our approach featured that the γ-butyrolactone unit was formed firstly before the construction of the cycloheptane ring system. The key steps of the synthesis involved (1) a stereoselective Mukaiyama aldol addition; (2) an oxidative γ-lactonization; and (3) an intramolecular aldehyde-ene cyclization.

Full text of DOI:10.1016/j.tetlet.2008.12.025

Tetrahedron Letters 50 (2009) 1110–1112
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Diastereoselective total synthesis of 8-epigrosheimin
*
Haishen Yang, Xiaoxiao Qiao, Fangyi Li, Hui Ma, Longguan Xie, Xiaohua Xu
State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The first diastereoselective total synthesis of 8-epigrosheimin was accomplished relying entirely on sub-
strate-controlled methods. 8-Epigrosheimin, isolated as an amoebicidal and antibiotic compound from
Received 7 October 2008
Revised 7 December 2008
Accepted 9 December 2008
Available online 13 December 2008
Crepis virens, is a multi-chiral-centered guaianolide with a cis-hydroazulene and a trans-annulated
butyrolactone ring. Our approach featured that the -butyrolactone unit was formed firstly before the
construction of the cycloheptane ring system. The key steps of the synthesis involved (1) a stereoselective
c-
c
Mukaiyama aldol addition; (2) an oxidative
cyclization.
c
-lactonization; and (3) an intramolecular aldehyde-ene
Ó 2008 Elsevier Ltd. All rights reserved.
Guaianolides constitute one of the largest groups of naturally
occurring sesquiterpene lactones with structural complexity and
a wide range of biological activities.1 The structure–activity rela-
tionship (SAR) of this class of natural products is currently under
intensive investigation. In addition to the functional groups in
the cyclopentane ring system, the oxygen substituent at C-8 and
the double bond at C-10, as well as the exo-methylene group in
the lithium enolate of c-butyrolactone either in the presence or ab-
sence of ZnCl2 at ꢀ78 °C, which could be explained by the Felkin–
H
1
5
R2
R1
1
5
10
6
10
6
O
8
8
O
12
O
the trans-annulated
c
-butyrolactone moiety, play an important
H
11
11
O
role in their biological activities (Fig. 1).2 Although there are some
reports in the literature on the synthesis of guaianolide-related
compounds, to the best of our knowledge, the only example of total
synthesis that could efficiently assemble the above-mentioned
functional groups was reported by Rigby et al. in 1987 on the syn-
thesis of ( )-grosheimin 1a from tropone.3 Herein, we wish to re-
O
12
O
O
R1=H, R2=OH:
Grosheimin 1a
R1=OH, R2=H:
6,12-Guaianolide
8,12-Guaianolide
8-Epigrosheimin 1b
Figure 1. Structure of guaianolide and grosheimin 1a and 8-epigroshimin 1b.
port
a
short and stereoselective approach to the first
diastereoselective total synthesis of 8-epigrosheimin 1b, which
was isolated firstly as an amoebicidal and antibiotic compound
from Crepis virens 20 years ago.4
H
H
H
H
MOMO
CHO
OH
O
A
B
As shown in Scheme 1, our strategy featured the C-ring forma-
tion before addressing the construction of the B-ring from cyclo-
C
O
O
pentyl carbaldehyde 2a.5 We envisaged that the
c-butyrolactone
O
O
1b
of C-ring could impose considerable rigidity, and the intramolecu-
lar aldehyde-ene reaction would react diastereoselectively to give
the hydroxyl group, as well as the exo-methylene group.6 The
installation of the two stereocenters at C6 and C7 could be realized
H
H
MOMO
CO Me
MOMO
CO Me
2
2
H
H
by aldol reaction of cyclopentyl carbaldehyde 2a with
tone or by Mukaiyama reaction with the trimethylsilyl enol ether
of
-butyrolactone.7
However, instead of the desired syn diastereomer 4, the unde-
c-butyrolac-
O
HO
O
OH
c
H
O
OTMS
O
sired anti diastereomer 3a (Scheme 2) was obtained almost exclu-
sively through the aldol addition of cyclopentyl aldehyde 2a with
MOMO
+
or
O
CHO
H
2a
* Corresponding author. Tel./fax: +86 22 23504282.
E-mail address: xiaohuaxu@nankai.edu.cn (X. Xu).
Scheme 1. Retrosynthetic analysis of 8-epigrosheimin.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.025

H. Yang et al. / Tetrahedron Letters 50 (2009) 1110–1112
1111
OTMS
O
H
H
H
b
a
a
3a
+
4
2a
+
MOMO
MOMO
MOMO
H
O
O
H
3a/4 = 26:74
H
HO
O
2a
3a
H
H
H
c
CO2Me
MOMO
MOMO
CO2Me
MOMO
H
H
H
H
O
O
O
O
HO
b
H
H
O
O
MOMO
8
OH
9
H
or c
HO
O
H
H
H
5
4
d
e
CH2OH
CO2H
MOMO
Scheme 2. Reagents and conditions: (a)
2.5 h, 87%; (b) TMSOTf, CH2Cl2, 2,6-lutidine, 0 °C, 1 h; then HF, rt, 1.5 h, 61%; (c)
concd HCl, i-PrOH, 50 °C, 2.5 h, 67%.
c
-butyrolactone, THF, LDA, ZnCl2, ꢀ78 °C,
H
O
O
O
O
10
11
H
H
H
H
H
f
g
a
OH
MOMO
MOMO
OH
THPO
THPO
H
O
O
H
H
H
O
O
i
H
HO
O
O
O
12
13
2b
3b
H
H
b
h
OH
HO
1b
H
H
H
O
c
d
BzO
H
HO
3a
H
O
O
O
14
H
HO
O
HO
O
Scheme 4. Reagents and conditions: (a) BF3ꢁEt2O, CH2Cl2, ꢀ78 °C, 1.5 h, 92%; (b)
KOH, H2O, THF, rt, 4 h; HCl, pH 1, rt; CH2N2, 94%; (c) TEMPO, CH2Cl2, H2O, TBAC,
NCS, rt, 7 h, 89%;(d) NaOH, H2O, THF, rt, 80 min; then HCl, 95%; (e) (COCl)2, DMF,
CH2Cl2, 0 °C, 1 h; then NaBH4, DMF, THF, ꢀ78 to ꢀ18 °C, 7 h, 68%; (f) (1) Swern
oxidation; (2) (i-PrO)2TiCl2, CH2Cl2, ꢀ15 °C, 5 h, 85%, two steps; (g) LDA, THF,
ꢀ78 °C, Eshenmoser’s salt, 4.5 h; m-CBPA, 0 °C, 20 min, 72%; (h) i-PrOH, TsOH, 24 h,
reflux, 95%; (i) IBX, DMSO, 1.5 h, rt, 96%.
7
6
Scheme 3. Reagents and conditions: (a)
2.5 h, 72%; (b) MeOH, TsOH, rt, 6 h, 67%; (c) Py, CH2Cl2, BzCl, 0 °C, 3 h, 73%; (d)
MOMCl, CH2Cl2, DIPEA, rt, 3.5 h, 71%.
c-butyrolactone, THF, LDA, ZnCl2, ꢀ78 °C,
Anh transition state.8 Conversion of C7-(S) isomer 3a to C7-(R) iso-
mer 4 by treatment with trimethylsilyl triflate (TMSOTf) in the
presence of 2,6-lutidine at 0 °C for about 1.5 h followed by desily-
lation with HF in a similar method of Hanessian failed,7d and an
intramolecular cyclization product 5 was obtained in 61% yield
along with some unidentified by-products. In fact, the same prod-
uct 5 was yielded when lactone 3a was subjected to the acid-cata-
lyzed deprotection of MOM group conditions (HCl/i-PrOH, TMSCl/
TBAB, etc.).
In order to identify the configuration of 3a (Scheme 3), the diol
6 was prepared smoothly via the aldol addition of aldehyde 2b
with lithium enolate of c-butyrolactone in the presence of ZnCl2
at –78 °C, followed by deprotection of THP group of 3b with TsOH
in methanol at room temperature. The benzoate 7 was obtained by
selective acylation with benzoxyl chloride from diol 6, whose hy-
droxyl group at C3 was protected selectively by treatment with
methoxylmethyl chloride to yield the lactone 3a. The structure of
3a was determined as an anti diastereomer based on the X-ray
crystallographic analysis of 7.9
were isolated readily by silica gel chromatography method. Hydro-
lysis of 4 with potassium hydroxide in THF and H2O followed by
careful acidification to pH 1 with HCl and final esterification with
CH2N2 furnished the diol methyl ester 8 in 94% yield. Diol 8 was
oxidized to lactone 9 in 89% yield using Einhorn’s method.11 The
direct transformation of lactone methyl ester 9 to lactone alcohol
11 or aldehyde failed because the lactone carbonyl is more reactive
than the methyl ester carbonyl under the reduction conditions.
Fortunately, the lactone alcohol 11 was achieved in moderate yield
by activation of the carboxyl group of the lactone carboxylic acid
10 with Vilsmeier reagent, followed by reduction with sodium
borohydride in DMF.12 The unstable aldehyde was provided by
Swern oxidation of alcohol 11, which gave the intramolecular
ene cyclization product 12 in 85% yield exclusively under the catal-
ysis of (i-PrO)2TiCl2 over two steps. The structure of guaianolide 12
was determined unambiguously by X-ray crystallography.13 Meth-
ylenation of 12 with Eshenmoser’s salt furnished 13 in moderate
yield (72%),14 and subsequent deprotection of the MOM group of
13 afforded diol 14 in 95% yield. The final selective oxidation of diol
14 with 2-iodoxybenzoic acid (IBX) in DMSO15 afforded (ꢀ)-8-epi-
A survey of Lewis acid (ZnI2, ZnBr2, MgBr2, (i-PrO)TiCl3, (i-PrO)2-
TiCl2, BF3ꢁEt2O) catalysts for the Mukaiyama reaction of the alde-
hyde 2a with trimethylsilyl enol ether of
c-butyrolactone at
grosheimin 1b, ½a D20
ꢂ
ꢀ34.4 (c, 1.18, CHCl3) [lit.4a (+)-1b: ½a D20
ꢂ
different temperature (ꢀ78 °C to 0ꢀC to rt) revealed that either
+31.5 1 (c, 0.1, CHCl3)] (Scheme 4).
decomposition or no reaction was observed except in the case of
In conclusion, a new approach has been developed to synthesize
C8-oxygenated guaianolide, and this led to the success of the first
total synthesis of (ꢀ)-8-epigrosheimin 1b. Studies on the biological
activities of 1b and its enantiomer and their analogs are currently
underway. This novel synthetic route could be applied to the syn-
thesis of similar guaianolides efficiently for biological studies.
BF3ꢁEt2O. Treatment of 2a with trimethysilyl enol ether of
c-buty-
rolactone in the presence of BF3ꢁEt2O at ꢀ78 °C in methylene chlo-
ride afforded the desired 4 as the major product, and 3a in 92%
total yield (74:26, 4/3a). The structure of 4 was established unam-
biguously by X-ray crystallography.10 The two isomers 3a and 4

1112
H. Yang et al. / Tetrahedron Letters 50 (2009) 1110–1112
Chem. 1985, 50, 4166; (b) Page, P. C. B.; Gambera, G.; Hayman, C. M.; Edgar, M.
Acknowledgment
Synlett 2006, 3411.
7. For parts of references concerning the Mukaiyama aldol additions of the
We thank the National Science Foundation of China (Grant Nos.
20572055 and 20421202) for financial support.
trimethylsilyl enol ether of c-butyrolactone with aldehydes, see: (a) Evans, D.
A.; Murry, J. A.; Kozlowski, M. C. J. Am. Chem. Soc. 1996, 118, 5814; (b) Chen, C.
T.; Chao, S. D.; Yen, K. C. Synlett 1998, 924; (c) Chen, C. T.; Hon, S. W.; Weng, S. S.
Synlett 1999, 816; (d) Hanessian, S.; Hou, Y.; Bayrakdarian, M.; Tintelnot-
Blomley, M. J. Org. Chem. 2005, 70, 6735; (e) Evans, D. A.; Kozlowski, M. C.;
Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem.
Soc. 1999, 121, 669.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.12.025.
8. Roush, W. R. J. Org. Chem. 1991, 56, 4151.
9. Crystallographic data for
7 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication CCDC 704510.
Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
References and notes
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3. Rigby, J. H.; Senanayake, C. J. Am. Chem. Soc. 1987, 109, 3147.
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1979, 44, 3123; (b) Kisiel, W.; Zielin´ ska, K.; Joshi, S. P. Phytochemistry 2000, 54,
763.
5. This synthon was obtained from (S)-carvone in the similar procedure, see: (a)
Lee, E.; Yoon, C. H. J. Chem. Soc., Chem. Commun. 1994, 479; (b) Pogrebnoi, S.;
Saraber, F. C. E.; Jansen, B. J. M.; Groot, A. Tetrahdron 2006, 62, 1743.
6. The aldehyde-ene-cyclization products were obtained without practical
stereoselectivity by Ley and co-workers in the course of construction of the
seven-ring system of guaianolide catalyzed by Me2AlCl, see: Ley, S. V.;
Antonello, A.; Balskus, E. P.; Booth, D. T.; Christensen, S. B.; Cleator, E.; Gold,
H.; Högenauer, K.; Hünger, U.; Myers, R. M.; Oliver, S. F.; Simic, O.; Smith, M. D.;
Søhoel, H.; Woolford, A. J. A. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12073; For the
other references concerning the intramolecular ene reaction to construct the
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10. Crystallographic data for
4 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication CCDC 704509.
Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
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13. Crystallographic data for 12 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication CCDC 704511.
Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
14. About 13% of 1,4-addition by-product of 13 with diisopropylamine was
obtained through the typical procedure developed by Danishefsky, see:
Danishefsky, S.; Kitahara, T.; McKee, R.; Schuda, P. F. J. Am. Soc. Chem. 1976,
98, 6715. We found that the
a-methylene group on the lactone unit could be
liberated smoothly via the N-oxide from the tertiary amine.
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