Concise total synthesis of (-)-8-epigrosheimin

Article abstract of DOI:10.1021/ol201322w

A highly efficient route was developed to synthesize (-)-8-epigrosheimin in four steps from aldehyde 2 based on a substrate-controlled method. The key steps of the synthesis included (1) a stereo- and regioselective allylation addition, (2) an intramolecular translactonization, and (3) an aldehyde-ene cyclization.

Full text of DOI:10.1021/ol201322w

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3670–3673
Concise Total Synthesis of (ꢀ)-8-
Epigrosheimin
Haishen Yang, Yuzhe Gao, Xiaoxiao Qiao, Longguan Xie, and Xiaohua Xu*
State Key Laboratory of Elemento-organic Chemistry, Nankai University,
Tianjin 300071, China
xiaohuaxu@nankai.edu.cn
Received May 17, 2011
ABSTRACT
A highly efficient route was developed to synthesize (ꢀ)-8-epigrosheimin in four steps from aldehyde 2 based on a substrate-controlled method.
The key steps of the synthesis included (1) a stereo- and regioselective allylation addition, (2) an intramolecular translactonization, and (3) an
aldehyde-ene cyclization.
Guaianolides, mostly with a cis-fused hydroazulene core
and a trans-annulated γ-butyrolactone motif in the 5, 7,
5-tricyclic carbon skeleton (Figure 1),1 represent a large
subgroup of naturally occurring sesquiterpene lactones.2
Many of them display a broad biological profile including
strong antitumor, antihelmitic, contraceptive, plant growth-
regulatory, antiinflammatory, and cytostatic properties,3
whichmakestheminterestingleadstructuresfornewdrugs.
While many synthetic approaches have therefore been
developed,4 there are still some challenges in synthesizing
this kind of natural lactone. One of them is the efficient
assembly of the trans-fused γ-butyrolactone ring. Even
though there are a variety of methodologies available for
the synthesis of substituted γ-butyrolactones,5 most of the
reported methods independently introduce the methyl or
methylene group on the lactone unit at a later stage.
In a previous paper, we described a novel strategy for
the total synthesis of (ꢀ)-8-epigrosheimin (1),6 whose en-
antiomer was initially isolated as an amoebicidal and anti-
biotic compound from Crepis virens 20 years ago.7 Recently,
we found that the (ꢀ)-1 displayed promising antitumor
activities (HepG2: IC50 = 6.22 μg/mL; MCF-7: IC50
=
(1) Devreese, A. A.; De Clercq, P. J.; Vandewalle, M. Tetrahedron
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Yoshimura, H. J. Nat. Prod. 1994, 57, 433–445.
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S. M.; Veselovskii, V. V. Russ. Chem. Rev. 1995, 64, 187–200 and
ꢀ
references cited therein. (b) Carret, S.; Depres, J. P. Angew. Chem.,
Int. Ed. 2007, 46, 6870–6873 and references cited therein. (c) Schall, A.;
Reiser, O. Eur. J. Org. Chem. 2008, 2353–2364 and references cited
therein. (d) Hirose, T.; Miyakoshi, N.; Mukai, C. J. Org. Chem. 2008, 73,
1061–1066. (e) Reboul, I.; Boddaert, T.; Coquerel, Y.; Rodriguez, J. Eur.
J. Org. Chem. 2008, 2008, 5379–5382. Gone, J. R.; Wallock, N. J.;
Lindeman, S.; Donaldson, W. A. Tetrahedron Lett. 2009, 50, 1023–1025.
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(h) Navickas, V.; Ushakov, D. B.; Maier, M. E.; Strobele, M.; Meyer,
H. J. Org. Lett. 2010, 12, 3418–3421. For semisynthetic method, see: (i)
Banerjee, A. K.; Vera, W. J.; Gonzalez, N. C. Tetrahedron 1993, 49,
4761–4788 and references cited therein. (j) Yuuya, S.; Hagiwara, H.;
Suzuki, T.; Ando, M.; Yamada, A.; Suda, K.; Kataoka, T.; Nagai, K.
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V.; Blay, G.; Cardona, L.; Garcia, B.; Pedro, J. R. J. Nat. Prod. 2002, 65,
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Czech. Chem. Commun. 1979, 44, 3123–3127.
(8) Unpublished results.
(9) The natural enantiomer, (þ)-8-epigrosheimin ([R]20 þ 32.4 (c
D
1.0, CHCl3, lit.7 [R]20D þ 31.5 ( 1 (c 0.1, CHCl3)), was also synthesized,
and its biological activity is under investigation.
r
10.1021/ol201322w
Published on Web 06/15/2011
2011 American Chemical Society

Scheme 1. Synthesis of Cyclopentyl Aldehyde 2
(Scheme 1).12 Reduction of THP-predeprotected 5 could
avoid some side reactions6 and improve the yield of
diol 6.13
Figure 1. Representative examples of guaianolides.
0.68 μg/mL).8,9 Encouraged by these results, a much more
efficient synthetic route for this compound was developed
bytaking advantageof a highly diastereoselective synthetic
method of R-exo-methylene-γ-butyrolactone as a crucial
step.
Scheme 2
As shown retrosynthetically in Figure 2,10 one key step
should be the introduction of an R-exo-methylene-γ-bu-
tyrolactone unit via the γ-addition of organozinc 3 to
aldehyde 2. The reason is that there are scarce studies on
the allylic addition reactions of this kind with densely
functionalized organometallic reagents.11 Furthermore,
this step was expected to form the stereocenters at C6
and C7 and introduce simultaneously the R-exo-methylene
and carbonyl groups of the 6,12-lactone moiety, and
further translactionization would assemble the R-exo-
methylene-γ-butyrolactone motif and liberate the primary
alcohol of C8 for the B-ring construction via aldehyde 4.
To our excitement, we found that mediated by zinc with
satd. aq NH4Cl in THF, 3-(bromomethyl)-2(5H)-furan-2-
one (7),14 precursor to 3, reacted smoothly with aldehyde 2
to give the anticipated lactone 8 in quantitative yield
(Scheme 2). During this process, the carbonyl group on
the cyclopentane ring remained intact. The high regio- and
stereoselectivity could be explained by the FelkinꢀAhn
transition state.15
The translactonization of lactone 8 to lactone 9 was
realized smoothly in 89% yield by the ring opening of
(10) A related approach using an organoboron reagent was reported
during the course of our study.4g
(11) Manchanayakage, R.; Handy, S. T. Tetrahedron Lett. 2007, 48,
3819–3822.
Figure 2. Retrosynthetic analysis of (ꢀ)-8-Epigrosheimin.
(12) Oliver, S. F.; Hogenauer, K.; Simic, O.; Antonello, A.; Smith,
M. D.; Ley, S. V. Angew. Chem., Int. Ed. 2003, 42, 5996–6000.
(13) Pogrebnoi, S.; Saraber, F. C. E.; Jansen, B. J. M.; Groot, A.
Tetrahedron 2006, 62, 1743–1748.
Another key step should be the intramolecular aldehyde-
ene cyclization because of the unstable precursor 4, whose
doublebondofthe exomethylenegroupispronetomigrate
into the ring and form the stable conjugation aldehyde.
The enantiomer of cyclopentyl carbaldehyde 2 was
synthesized from (S)-carvone via 5 by Ley’s protocol
(14) In addition to our study on 3-(bromomethyl)-2(5H)-furan-2-
one, see: (a) Yang, H. S.; Qiao, X. X.; Cui, Q.; Xu, X. H. Chin. Chem.
Lett. 2009, 20, 1023–1024. (b) Xu, X., Yang, H.; Qiao, X.; Xie, L. CN
101481367, 2009; Chem. Abstr. 2009, 151, 245843. (c) Cui, Q.; Wang, J.;
Yang, H. S.; Xie, L. G.; Xu, X. H. Chin. J. Org. Chem. 2010, 30, 1705–
1710. Another research group studied this bromolactone: Hodgson,
D. M.; Talbot, E. P. A.; Clark, B. P. Org. Lett. 2011, 13, 2594–2597.
(15) Roush, W. R. J. Org. Chem. 1991, 56, 4151–4157.
Org. Lett., Vol. 13, No. 14, 2011
3671

the lactone with NaOH, followed by careful acidifica-
tion to pH 1 with HCl (Scheme 3). However, subsequent
Swern oxidation of alcohol 9 gave rise to aldehyde 10 in
62% yield, in which the exo-methylene double bond
had concurrently migrated into conjugation with the
aldehyde and lactone carbonyl groups. A series of
oxidation reagents and conditions (PCC, IBX, DMP)
was attempted. It was found that the reaction was clean
with DMP as the oxidation reagent and pyridine as the
cosolvent. The obtained crude aldehyde 4 underwent
ene cyclization to give the desired (ꢀ)-8-epigrosheimin
via the pyrolytic elimination of the sulfoxide 14, which was
obtained readily by oxidizing thioether 13a with NaIO4 in
ethanol at room temperature.
Moreover, when the lactone 8 was treated with K2CO3
in methanol, not only translactonization but also Michael
addition occurred to give the methyl ether 11b in 86% yield
(Scheme 5). Swern oxidation and aldehyde-ene reaction
gave the cyclized 13b in 83% yield in two steps. The
β-elimination of 13b with DBU in refluxing toluene af-
forded 1 in 61% yield.
(1) in 85% yield under catalysis with BF3 OEt2 at rt in
3
3 h.
Scheme 5
Scheme 3
In summary, a highly diastereoselective and efficient
total synthesis of (ꢀ)-8-epigrosheimin (1) was achieved
from commercially available (S)-carvone in 11 steps with
45% overall yield. This synthesis featured an efficient in-
stallation of the trans-fused R-exo-methylene-γ-butyrolac-
tone unit via a highly regio- and diastereoselective Barbier
reaction. The key assembly of the framework of the natu-
ral product was the sequential allylation, intramolecular
translactonization, and intramolecular aldehyde-ene cycli-
zation. This sequence could serve as a general total syn-
thetic route for guaianolides,16 especially for 8-oxygenated
guaianolides,17 which could not be hydroxylated easily
from R-santonin18 or C8-deoxygenated guaianolide.
Furthermore, total synthesis of the closely related pseudo-
guaianolides2 could utilize this approach as an alternative
Alternatively, the double bond of the R-exomethylene
butyrolactone of 9 could be protected first by thiophenol
via Michael addition to produce thiother 11a in 71% yield
(Scheme 4). Following a similar procedure developed by
us,14 Swern oxidation of the primary alcohols 11a and
intramolecularaldehyde-ene cyclization under (i-PrO)2TiCl2
catalysis generated guaianolides 13a in 81% in two steps.
The absolute configuration of 13a was confirmed unam-
biguously by X-ray crystallographic analysis. The target
molecule 1 was produced from thioether 13a in 92% yield
Scheme 4
(16) The hydroxyl group at C8 could be eliminated readily; see:
Kalidindi, S.; Jeong, W. B.; Schall, A.; Bandichhor, R.; Nosse, B.;
Reiser, O. Angew. Chem., Int. Ed. 2007, 46, 6361–6363.
(17) This subgroup of guaianolide family attracted intensive atten-
tion for the synthetic community; see: (a) Rigby, J. H.; Senanayake, C.
J. Am. Chem. Soc. 1987, 109, 3147–3149. (b) Rigby, J. H.; Wilson,
J. A. Z. J. Org. Chem. 1987, 52, 34–44. (c) Oliver, S. F.; Hogenauer, K.;
Simic, O.; Antonello, A.; Smith, M. D.; Ley, S. V. Angew. Chem., Int. Ed.
2003, 42, 5996–6000. (d) Ley, S. V.; Antonello, A.; Balskus, E. P.; Booth,
D. T.; Christensen, S. B.; Cleator, E.; Gold, H.; Hogenauer, K.; Hunger,
U.; Myers, R. M.; Oliver, S. F.; Simic, O.; Smith, M. D.; Sohoel, H.;
Woolford, A. J. A. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12073–
12078. (e) Andrews, S. P.; Ball, M.; Wierschem, F.; Cleator, E.; Oliver,
S.; Hogenauer, K.; Simic, O.; Antonello, A.; Hunger, U.; Smith, M. D.;
ꢀ
Ley, S. V. Chem.;Eur. J. 2007, 13, 5688–5712. (f) Carret, S.; Depres,
J. P. Angew. Chem., Int. Ed. 2007, 46, 6870–6873.
(18) (a) Blay, G.; Luz Cardona, M.; Garcia, B.; Pedro, J. R. J. Org.
Chem. 1991, 56, 6172–6175. Ramachandran, P. V.; Garner, G.; Pratihar,
D. Org. Lett. 2007, 9, 4753–4756.
3672
Org. Lett., Vol. 13, No. 14, 2011

protocol. Studies along these lines are ongoing in this
laboratory.
Supporting Information Available. Experimental pro-
cedures; spectroscopic data of compounds 2, 4, 8ꢀ10,
11a, 11b, 13a, and 13b; and crystallographic informa-
tion file (CIF) for compound 13a. This material is
available free of charge via the Internet at http://pubs.
acs.org.
Acknowledgment. We thank the National Science
Foundation of China (Grant Nos. 20572055 and
20421202) for financial support.
Org. Lett., Vol. 13, No. 14, 2011
3673