Formation of tetrahydrofuran from homoallylic alcohol via a tandem sequence: 2-Oxonia [3,3]-sigmatropic rearrangement/cyclization catalyzed by In(OTf)3

Full text of DOI:10.1021/ja005831j

2450
J. Am. Chem. Soc. 2001, 123, 2450-2451
Table 1. Formation of Tetrahydrofuran from Homoallylic Alcohol
Catalyzed by In(OTf)3
Formation of Tetrahydrofuran from Homoallylic
Alcohol via a Tandem Sequence: 2-Oxonia
[3,3]-Sigmatropic Rearrangement/Cyclization
Catalyzed by In(OTf)3
a
Teck-Peng Loh,* Qi-Ying Hu, and Li-Ting Ma†
yieldb/
Department of Chemistry, National UniVersity of Singapore
3 Science DriVe 3, Singapore 117543, Singapore
In(OTf)3/ RCHO/ T/ time/
entry
R
equiv
equiv °C
h
% (2:3)c
1
2
3
4
5
6
7
8
9
a
a
a
a
b
b
c
PhCH2CH2
PhCH2CH2
PhCH2CH2
PhCH2CH2
Ph
0.1
0.2
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.2
0.1
0.1
0.1
0.1
1.0
0.1
1.0
0.1
1.0
0.1
0.5
1.0
25 240 54 (81:19)
25 192 70 (59:41)
ReceiVed NoVember 28, 2000
40
40
40
40
40
40
40
40
40
14 56 (70:30)
14 60 (3:97)
14 28e (72:28)
14 66 (3:97)
14 59 (75:25)
14 58 (7:93)
14 61 (81:19)
14 57 (38:62)
14 82 (27:73)d
In the past decade, indium(III) complexes have enjoyed
remarkably widespread use as efficient Lewis acid catalysts for
various carbon-carbon bond formation reactions and important
synthetic transformations.1 In accordance with the recent surge
of interest in metal triflates,2 In(OTf)3 has emerged as a promising
catalyst in the past few years. The Sn(OTf)2-catalyzed conversion
of γ-adduct homoallylic alcohol to the corresponding R-adduct
was reported by Nokami’s group recently.3 Nevertheless, unsat-
isfactory results in the case of prenyl adducts limited its
applicability in view that the prenyl moiety is featured as a key
structural fragment in terpenoids, as well as their synthetic
precursors.4 This encouraged us to explore modifications by
employing In(OTf)3, a stronger Lewis acid, instead. Herein we
describe an unexpected formation of tetrahydrofuran during the
course of exploration.
Ph
CH3(CH2)7
CH3(CH2)7
p-ClC6H4
p-ClC6H4
p-ClC6H4
c
d
d
d
10
11
a Strem Chemicals, Inc. b Combined yield based on 1. c Determined
by 1H NMR. d In addition, eliminated rearrangement product 5d′ (8%)
was isolated. e Low isolated yield due to volatile nature of 2b.
It was found that by increasing the amount of In(OTf)3 to 0.2
equiv, the conversion of 1a to 2a and 3a can be driven to
completion, albeit with a compromise in the selectivity (entry
2). As a result, efforts were directed toward improving the
selectivity of this method. It is noteworthy that either 2 or 3 can
be made the major product by simply altering the reaction
condition. When the reaction was conducted in the presence of a
catalytic amount of In(OTf)3 (0.1 equiv) and aldehyde (0.1 equiv)
at 40 °C for 14 h, 2 was formed preferentially (ratio up to 81:19,
entry 9). On the other hand, upon increasing the amount of
aldehyde to 1 equiv, 3 became the major product, with selectivity
up to 97% (entry 4). In addition, the double bond in 3 was
determined by NOESY to have an (E) geometry in all cases.
Nevertheless, no cyclization was observed with 1-alkyl-2-methyl-
3-butenols and 1-alkyl-3- butenols, wherein only the correspond-
ing R-adduct homoallylic alcohols were obtained.8
On the basis of the above observations, we postulate that the
reaction sequence involves first an In(OTf)3-promoted conversion
of the homoallylic alcohol (γ-adducts) 1 to the corresponding
R-adduct 5 via a 2-oxonia [3,3]-sigmatropic rearrangement3,7c,7d
of oxocarbenium 4A. This is followed by a rapid intramolecular
oxyindiation9 with In(OTf)3 to give the tetrahydrofuranyl-indium
species 6 (Scheme 1). Trapping 6 with a proton source would
furnish 2, while alternative nucleophilic attack at the parent
aldehyde would provide 3 through elimination. The involvement
of R-adduct 5 as an intermediate was supported by the fact that
In our initial study, a solution of homoallylic alcohol 1a5 and
the corresponding aldehyde (0.1 equiv) in dichloromethane was
stirred with a catalytic amount of In(OTf)3 (0.1 equiv) at room
temperature for 10 days (Table 1, entry 1). The crude NMR
indicated that 70% of the starting material was consumed, with
the appearance of two new sets of gem-dimethyl signals (δ 1.32,
1.23 and 1.27, 1.24), neither of which corresponds to those
expected for the desired R-adduct.3b Chromatographic separation
gave two products 2a and 3a, which were subjected to extensive
spectroscopic studies. To our surprise, both compounds were
found to possess an unexpected 2-substituted 5,5-dimethyltet-
rahydrofuran skeleton. Since this moiety is featured in a large
number of biologically important natural products,6 and the
development of synthetic methods is needed,7 the reaction was
studied in detail (Table 1).
† Current address: Lynk Biotechnologies Pte Ltd, 41 Science Park Road,
The Gemini #01-21/22, Singapore Science Park 2, Singapore 117610,
Singapore.
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(8) These results will be published elsewhere in due time.
(9) The term “oxyindiation” refers to the additive incorporation of an oxygen
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10.1021/ja005831j CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/16/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 10, 2001 2451
Scheme 1. Postulated Reaction Pathway
Scheme 2. Application to Synthesis of the Steroid Side Chain
route. Explorations were conducted on homoallylic sterol 8,12 and
an optimized procedure (8 1.0 equiv, parent aldehyde13 0.1 equiv,
In(OTf)3 0.15 equiv, 40 °C, 48 h) was adopted to give 9 in 51%
yield (Scheme 2), together with 21% of undesired 3 (R ) Std).
The stereochemistry of C-22 was determined to be the desired
(R)-configuration by single-crystal X-ray diffraction analysis.14
This provided strong support for the involvement of a 2-oxonia
[3,3]-sigmatropic rearrangement as proposed in Scheme 1. In
addition, the reaction displays excellent functionality tolerance
toward the A ring enone. With this, we established the potential
applicability of the method to natural product synthesis.
In summary, a tandem 2-oxonia [3,3]-sigmatropic rearrange-
ment/cyclization sequence catalyzed by In(OTf)3 was discovered
in our laboratory, and subsequently developed as an efficient
method for the selective formation of tetrahydrofuran 2 or 3 in a
stereospecific fashion, from the corresponding γ-adduct homoal-
lylic alcohol. The formation of 3 suggested the involvement of a
tetrahydrofuranyl-indium species, plausibly formed via an in-
tramolecular oxyindiation of the intermediate R-adduct 5 generated
in situ. This method opens up a new avenue for the stereospecific
synthesis of cyclic ethers, and has been demonstrated in the
construction of the tetrahydrofuran moiety present in the shidas-
terone side chain.
Figure 1. Structure of shidasterone.
4-methyl-1-phenylpent-3-en-1-ol3b (5b) gave the same product 3b
when subjected to the conditions of entry 6. In addition, the
isolation of byproduct 5d′ in entry 11 provided further evidence
for this.
Acknowledgment. We gratefully acknowledge the National Univer-
sity of Singapore for generous financial support. We thank Dr. Jagadese
J. Vittal and Ms. Tan Geok Kheng of the X-ray Diffraction Laboratory,
National University of Singapore, for determining the crystal structure
of 9. We also wish to thank Madam Han Yan-Hui for high-field NMR
(500 MHz) assistance.
Shidasterone (7), an ecdysteroid first isolated in 1969,6b has
attracted renewed synthetic interest due to recent reports of its
antitumor activity,10 in addition to its role as an insect molting
hormone. The structure of shidasterone features a 5,5-dimeth-
yltetrahydrofuran-2-yl fragment attached at C-22 in an anti-Cram11
manner (Figure 1).
According to our postulated reaction pathway, its side chain
can be derived stereospecifically from the corresponding Cram
γ-adduct homoallylic sterol, thus furnishing an efficient synthetic
Supporting Information Available: Complete experimental details,
including characterization data for all new compounds, and copies of
COSY, NOESY, HMQC, and HMBC NMR spectra of compound 3a
(PDF); X-ray crystal data for 9 (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
JA005831J
(12) Loh, T.-P.; Hu, Q.-Y.; Vittal, J. J. Synlett 2000, 523.
(13) 4-Pregnene-20â-carboxaldehyde-3-one was purchased from Sigma
Chemical Co.
(14) X-ray data for 9: C27H42O2; fw ) 398.61; orthorhombic; space group
P212121; a ) 6.0506(6) Å, b ) 17.507(2) Å, c ) 22.199(2) Å; V ) 2351.4(4)
Å 3; Z ) 4; R1 ) 0.0721, wR2 ) 0.1474, GOF ) 0.981 for 6804 observations
with I > 2(I).
(10) (a) Roussel, P. G.; Turner, N. J.; Dinan, L. N. J. Chem. Soc., Chem.
Commun. 1995, 933. (b) Roussel, P. G.; Sik, V.; Turner, N. J.; Dinan, L. N.
J. Chem. Soc., Perkin Trans. 1 1997, 2237. (c) Baltayev, U. A.; Galiautdinov,
I. V.; Odinokov, V. N. MendeleeV Commun. 1999, 122.
(11) Yamamoto, Y.; Nishii, S.; Yamada, J. I. J. Am. Chem. Soc. 1986,
108, 8, 7116.