Indium tribromide-promoted arene-terminated epoxy olefin cyclization

Article abstract of DOI:10.1039/b718337b

An arene-terminated epoxy olefin cyclization was promoted by a water-tolerant Lewis acid to give tri- and tetracyclic 3β-hydroxy terpenoids and steroid derivatives in 57 and 37% yields, respectively, per new formed ring up to 75%. The Royal Society of Chemistry.

Full text of DOI:10.1039/b718337b

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COMMUNICATION
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Indium tribromide-promoted arene-terminated epoxy olefin cyclizationwz
Jun-Feng Zhao, Yu-Jun Zhao and Teck-Peng Loh*
Received (in Cambridge, UK) 28th November 2007, Accepted 17th December 2007
First published as an Advance Article on the web 16th January 2008
DOI: 10.1039/b718337b
An arene-terminated epoxy olefin cyclization was promoted by a
water-tolerant Lewis acid to give tri- and tetracyclic 3b-hydroxy
terpenoids and steroid derivatives in 57 and 37% yields, respec-
tively, per new formed ring up to 75%.
good selectivities (Table 1). Among the screened solvent
systems, DCM was the solvent of choice (Table 1, entry 7).
As shown in Table 1, with a concentration of 0.1 M in DCM,
the epoxy olefin cyclization proceeded smoothly at ambient
temperature and in the open air, furnishing the target tricyclic
product, accompanied by a monocyclic alkene, an oxabicyclo-
alkane and a ketone. In terms of yield and selectivity of the
tricyclic product, indium tribromide is the most promising
Lewis acid.
The biomimetic cyclization of polyalkenes to steroids and their
precursors continue to be of both mechanistic and synthetic
interest.1 Sulfonate esters, trisubstituted olefins, allylic alco-
hols, acetals and epoxides had been used as initiating groups
for these cascade cyclizations.2 Among them, epoxide has been
one of the most popular initiators. 2,3-Oxidosqualene had
been identified as a genuine intermediate in the conversion of
squalene to lanosterol.3 Mimicking this natural transforma-
tion, Corey, van Tamelen and Goldsmith, among others, have
exploited the acid-promoted cascade cyclization of epoxy
olefins as a very useful strategy for the building of polycyclic
terpenoids.4 However, the catalysts typically employed are
sensitive to moisture, difficult to handle and the yields (about
20%)4b,6a are not satisfactory. In this Communication, we
report a mild, convenient and simple procedure for investigat-
ing water-tolerant Lewis acid-promoted epoxy olefin cycliza-
tions to prepare arene-terminated 3-hydroxy terpenoid and
steroid derivatives.
There are numerous reports5 regarding the isolation and
biological data of polycyclic compounds containing a 3-hy-
droxy group and one terminal aromatic ring. However, there
have been very few reported synthetic studies of these struc-
tures.6 As far as we know, there have been no reports on Lewis
acid-promoted epoxy olefin cyclizations in aqueous media.
Recently, we embarked upon Lewis acid-promoted polyene
cyclizations7 and the development of water-tolerant Lewis
acidic indium salt-mediated reactions leading to the formation
of various carbon–carbon bonds.8 These results prompted us
to investigate Lewis acid-mediated epoxy olefin cyclizations in
aqueous environments.
Even 0.2 equivalents of indium tribromide is efficient en-
ough to give a combined yield of up to 86%, with the tricyclic
compound as the major product (Table 1, entry 3). The yield
and selectivity can be further increased if more indium tri-
bromide is used (Table 1, entries 6 and 7).
Encouraged by the remarkable results obtained with the
above reaction conditions, and in order to show the generality
and scope of this new protocol, we explored the reaction with
various substituted aromatic terminators. The results are
summarized in Table 2. In all cases, the tricyclic products
were obtained in good yields of up to 57%, per new formed
ring up to 75% (Table 2, entry 1). According to Yamamoto’s
strategy, the monocyclic alkene can be further converted into
the tricyclic products.9 When 3-methoxybenzene was used as
the terminator, two kinds of tricyclic products were obtained
Table 1 Indium salt-promoted epoxy olefin cyclizationa
Yield (%)b
Preliminary studies focused on the cyclization of 1 using
various Lewis acids in organic solvents. The results are
summarized in Table 1. We were gratified to find that, with
the exception of indium trifluoride, indium salts do indeed
promote fast epoxy olefin cyclization in high yields and with
2
3
4
5
Entry Solvent
Catalyst/equiv.
1
2
3
4
5
6
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
InF3/0.2
InCl3/0.2
InBr3/0.2
InI3/0.2
In(OTf)3/0.2
InBr3/0.5
InBr3/2
Trace Trace Trace Trace
45
50
35
28
54
57
54
40
8
11
8
27
11
10
9
12
17
9
4
8
14
12
9
Trace
8
Trace
8
18
19
17
20
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University, 1
Nanyang Walk, Block 5 Level 3, Singapore 639798. E-mail:
teckpeng@ntu.edu.sg; Fax: +65 6791 1961; Tel: +65 6316 8899
w This paper is dedicated to Professor E. J. Corey on the occasion of
his 80th birthday.
8
9
10
11
12
a
CH3NO2 InBr3/2
Toluene InBr3/2
CH3CN InBr3/2
CHCl3
Et2O
7
Trace 12
52 11
Trace 12
Trace Trace
21
Trace 14
InBr3/2
InBr3/2
5
z Electronic supplementary information (ESI) available: Detailed
All reactions were performed with 1 (0.1 mmol) and Lewis acid in
b
1 ml of solvent at room temperature for 1 h. Isolated yield.
1
experimental procedures, H and 13C NMR data, and analytical data
for all compounds. See DOI: 10.1039/b718337b
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Table 2 Indium tribromide-promoted epoxy olefin cyclization for the
preparation of polycyclic compoundsa
in a combined yield of 77% (Table 2, entry 5). However, only
one tricyclic product was formed when 3-methoxy was re-
placed by 3-methyl (Table 2, entry 3). This may be due to
strong steric hindrance between the 3-methyl and angular
methyl groups, which prohibits one of the two cyclization
pathways.
To demonstrate the applicability and versatility of this
synthetic strategy, we further extended this method to the
preparation of tetracyclic compounds (Table 2, entries 8, 9 and
10). The indium tribromide-catalyzed epoxy olefin cyclization
afforded the tetracyclic products in yields of up to 35%, per
new formed ring up to 70% (Table 2, entry 8).
Entry
1
Epoxy olefin
Product
Yield (%)b
57
(40c)
Furan-terminated polycyclic compounds have been used as
important intermediates in the synthesis of terpenes.10 Both in
tri- and tetracyclizations, furyl terminators are much reactive
than phenyl terminators as the furyl group is more electron
rich. In the presence of 0.2 equivalents of indium tribromide,
furan-terminated epoxide olefin cyclization proceeded
smoothly to give tri- and tetracyclic products in 52 and 37%
yields, respectively (Table 2, entries 7 and 10).
2
3
4
54
51
(30c)
51
To mimic the mild reaction conditions of the biosynthesis of
steroids and terpenoids, we tested this cyclization in aqueous
media with the water-tolerant Lewis acid indium tribromide as
the catalyst. To our delight, the cyclization proceeded well in
aqueous media, albeit in decreased yields (Table 2, entries 1, 3
and 6).
5
77d
According to the Stork–Eschenmoser hypothesis,2e–g the
pre-organized chair–chair–chair conformation is important
to the diastereoselectivity. Lewis acid-promoted epoxide ring
opening initiated the cascade antiparallel addition of the
olefins, furnishing the trans,trans-tetracyclized products with
excellent regio- and diastereoselectivity. Five chiral centers are
created in a single operational step, and only 2 out of 32
possible isomers are formed (Scheme 1). The relative stereo-
chemical configurations of the products were determined by
detailed 1D- and 2D-NMR, and by X-ray analysis.12 The
stereochemistry of the 3-OH group (b-face) was further as-
6
58
(31c)
7
8
52e
35
signed from the coupling constant between 3-CHa and 2-
CH2(b,c) (3JH
3
E 11 Hz, JH
E 5 Hz). The
axial–Hequatorial
axial–Haxial
physical and spectroscopic properties of 2a, 2f, 2g and 2h,
obtained in our conversions, were identical with those
reported previously.6a,11
9
31
In conclusion, we have reported the first indium tribromide-
promoted epoxide ring opening-initiated and arene-terminated
polyene cyclization. This procedure offers several advantages,
10
37e
a
All reactions were performed with 1 (0.1 mmol) and 2 equivalents of
InBr3 in 1 ml of solvent at room temperature for 1 h unless otherwise
b
stated. Isolated yield. Reactions were carried out with 1 (0.1 mmol)
c
in 1 ml DCM/H2O (10 : 1) in the presence of 4 equivalents of
d
InBr3. The combined yield of 2ea and 2eb; the ratio of 2ea : 2eb
e
was 37 : 40. 0.2 equivalents of InBr3 were used.
Scheme 1 X-Ray crystallographic structure of 2i; 50% probability
was chosen for the ellipsoids.12
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including easy handling, mild conditions, high selectivity and
improved yields, which make it a useful and attractive strategy
for the synthesis of steroid and terpenoid derivatives. In
addition, this reaction can be carried out in aqueous media.
Further work to design a better catalyst to effect the reaction
in aqueous environments is in progress.
(c) E. E. van Tamelen, J. Willet, M. Schwartz and R. Nadeau, J.
Am. Chem. Soc., 1966, 88, 59372; (d) E. E. van Tamelen and T. M.
Leiden, J. Am. Chem. Soc., 1982, 104, 2061; (e) E. J. Corey and M.
Sodeoka, Tetrahedron Lett., 1991, 32, 7005; (f) E. J. Corey and D.
D. Staas, J. Am. Chem. Soc., 1998, 120, 3562; (g) E. J. Corey and S.
Lin, J. Am. Chem. Soc., 1996, 118, 8765; (h) E. J. Corey, H. M.
Cheng, C. H. Baker, S. P. T. Matsuda, D. Li and X. L. Song, J.
Am. Chem. Soc., 1997, 119, 1277; (i) M. Bogenstatter, A. Limberg,
L. E. Overman and A. L. Tomasi, J. Am. Chem. Soc., 1999, 121,
12206.
5 (a) Y. Orihara, J. W. Yang, N. Komiya, K. Koge and T.
Yoshikawa, Phytochemistry, 2002, 59, 385; (b) I. Ara, B. S.
Siddiqui, S. Faizi and S. Siddiqui, J. Nat. Prod., 1990, 53, 816;
(c) Y. Takaishi, N. Wariishi, H. Tateishi, K. Kawazoe, K. Miyagi,
K. Li and H. Duan, Phytochemistry, 1997, 45, 979; (d) R. Fujita,
H. Duan and Y. Takaishi, Phytochemistry, 2000, 53, 715; (e)
Antioxidant: H. Haragushi, H. Ishikawa and I. Kubo, Planta
Med., 1997, 63, 213; (f) Cathartic and emetic: G. Appendino, E.
Belloro, G. C. Tron, J. Jakupovic and M. Ballero, Fitoterapia,
2000, 71, 134.
6 (a) V. Rosales, J. Zambrano and M. Demuth, Eur. J. Org.
Chem., 2004, 1798; (b) M. Ralph and R. Peter, Helv. Chim.
Acta, 2003, 86, 439; (c) J. F. Lavallee, T. W. Doyle, E. Rioux,
L. Belec, D. Rabouin and X. Billot, US Pat. 2005032802,
2005.
7 Y. J. Zhao, S. S. Chng and T. P. Loh, J. Am. Chem. Soc., 2007,
129, 492.
8 (a) T. P. Loh and G. L. Chua, Chem. Commun., 2006, 2739; (b) M.
J. Lin and T. P. Loh, J. Am. Chem. Soc., 2003, 125, 13042; (c) F.
Liu and T. P. Loh, Org. Lett., 2007, 9, 2063; (d) T.-P. Loh and L.-
L. Wei, Tetrahedron Lett., 1998, 39, 323.
We thank Dr Yong-Xin Li for undertaking the X-ray
analysis. We gratefully acknowledge the Nanyang Technolo-
gical University and a Singapore MOE grant for funding this
research.
Notes and references
1 (a) I. Abe, M. Rohmer and G. D. Prestwich, Chem. Rev., 1993, 93,
2189; (b) G. D. Brown, Nat. Prod. Rep., 1998, 15, 653; (c) C.
Jenson and W. S. Johnson, J. Am. Chem. Soc., 1997, 119, 10846;
(d) K. Ishihara, S. Nakamura and H. Yamamoto, J. Am. Chem.
Soc., 1999, 121, 4906; (e) A. Sakakura, A. Ukai and K. Ishihara,
Nature, 2007, 445, 900.
2 For reviews, see: (a) R. A. Yoder and J. N. Johnston, Chem. Rev.,
2005, 105, 4730; (b) K. U. Wendt, G. E. Schulz, E. J. Corey and D.
R. Liu, Angew. Chem., Int. Ed., 2000, 39, 2812; (c) E. E. van
Tamelen, Acc. Chem. Res., 1968, 1, 111; (d) W. S. Johnson, Acc.
Chem. Res., 1968, 1, 1; (e) A. Eschenmoser and D. Arigoni, Helv.
Chim. Acta, 2005, 88, 3011; (f) A. Eschenmoser, L. Ruzicka, O.
Jeger and D. Arigoni, Helv. Chim. Acta, 1955, 38, 1890; (g) G.
Stork and A. W. Burgstaher, J. Am. Chem. Soc., 1955, 77, 5068.
3 (a) R. G. Langdon and K. Bloch, J. Am. Chem. Soc., 1952, 74,
1869; (b) R. B. Woodward and K. Bloch, J. Am. Chem. Soc., 1953,
75, 2023; (c) R. G. Langdon and K. Bloch, J. Biol. Chem., 1953,
200, 135; (d) M. B. Jarstfer, B. S. J. Blagg, D. H. Rogers and C. D.
Poulter, J. Am. Chem. Soc., 1996, 118, 13089; (e) E. J. Corey, H.
Cheng, C. H. Baker, S. P. T. Matsuda, D. Li and X. Song, J. Am.
Chem. Soc., 1997, 119, 1289; (f) E. J. Corey, H. Cheng, C. H.
Baker, S. P. T. Matsuda, D. Li and X. Song, J. Am. Chem. Soc.,
1997, 119, 1277; (g) R. Thoma, T. S. Gasch, B. D’Arcy, J. Benz, J.
Aebi, H. Dehmlow, M. Hennig, M. Stihle and A. Ruf, Nature,
2004, 432, 118.
9 (a) K. Ishihara, H. Ishibashi and H. Yamamoto, J. Am. Chem.
Soc., 2002, 124, 3647; (b) H. Ishibashi, K. Ishihara and H.
Yamamoto, J. Am. Chem. Soc., 2004, 126, 11122.
10 (a) S. P. Tanis and P. M. Herrinton, J. Org. Chem., 1983, 48, 4572;
(b) S. P. Tanis, J. Org. Chem., 1988, 53, 4929.
11 (a) S. Ghosh, A. K. Ghosh and U. R. Ghatak, Synth. Commun.,
1992, 22, 553; (b) Previously reported X-ray data for 2h: J. Y.
Lallemand, M. Julia and D. Mansuy, Tetrahedron Lett., 1973, 45,
4461.
12 CCDC 669258 and 669259 contain the supplementary crystallo-
graphic data of 2h and 2i. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b718337b.
4 (a) D. J. Goldsmith, J. Am. Chem. Soc., 1962, 84, 3913; (b) D. J.
Goldsmith and C. F. Phillips, J. Am. Chem. Soc., 1969, 91, 5862;
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Chem. Commun., 2008, 1353–1355 | 1355