Au(I)-catalyzed tandem [3,3]-sigmatropic rearrangement-cycloisomerization cascade as a route to spirocyclic furans

Article abstract of DOI:10.1016/j.tetlet.2007.05.067

Gold-catalyzed reaction of 1-(3-hydroxypropynyl)cycloalkanol derivatives was studied. The reaction profile was highly dependent on the ring size, migrating group, as well as reaction conditions. An efficient route to spirocyclic furans via tandem [3,3]-si

Full text of DOI:10.1016/j.tetlet.2007.05.067

Tetrahedron Letters 48 (2007) 4817–4820
Au(I)-catalyzed tandem [3,3]-sigmatropic rearrangement–
cycloisomerization cascade as a route to spirocyclic furans
Hyun-Suk Yeom, Suk-Jae Yoon and Seunghoon Shin*
Department of Chemistry, Hanyang University, Seoul 133-791, Republic of Korea
Received 11 April 2007; accepted 11 May 2007
Available online 17 May 2007
Abstract—Gold-catalyzed reaction of 1-(3-hydroxypropynyl)cycloalkanol derivatives was studied. The reaction profile was highly
dependent on the ring size, migrating group, as well as reaction conditions. An efficient route to spirocyclic furans via tandem
[3,3]-sigmatropic rearrangement–cycloisomerization is reported.
Ó 2007 Elsevier Ltd. All rights reserved.
Transition metal catalyzed [3,3]-sigmatropic rearrange-
ment of propargyl ester, phosphate, and sulfonate are
important transformations in organic synthesis.1 Partic-
ularly, it opens a promising venue for selective transfor-
mations by providing in situ access to O-allenes, which
are often difficult to prepare otherwise.2 Recently,
alkynophilic gold complex turned out to be an excellent
catalyst for the [3,3]-rearrangement of a range of prop-
argylic substrates, including propargyl ester, enol ether,
and vinyl silane, thus allowing various subsequent tan-
dem transformations.3,4 In this context, we recognized
that propargyl esters A is a mechanistic synthon for
the corresponding O-acetyl allenes B and initiated a pro-
gram to investigate its application under gold-catalysis
(Scheme 1).5 Mechanistically interesting aspect is the
regioselectivity of Au-catalyzed activation of O-substi-
tuted allene: While Pd-catalyzed reaction is known to
occurs via metallation on C1 (or C3) of O-substituted
allene (i.e., hydropalladation) leading to p-allyl species,6
Au-catalyst adds on the central carbon of allene leading
to oxocarbenium ion.7 The latter species are known to
participate in a variety of reactions, including nucleo-
philic attack by indol,7a 1,3-diene formation,7b Nazarov
cyclization,7d and cycloisomerization.7e
X
O
O
X
O
O
Au
O
X
R1
O
R1
R1
R2
R2
B
R2
M
[Au]
A
Pd-H
OY
Pd
H
R1
R2
Scheme 1. Au- versus Pd-catalyzed reaction of O-allenes.
to D (route A).8 On the other hand, intervention of
allenyl intermediate via [3,3]-sigmatropic rearrangement
followed by Wagner–Meerwein type 1,2-alkyl shift
would lead to E (route B),9 which would compete with
cycloisomerization into F (route C) as reported by
Gagosz.2a,7e In this Letter, we report our investigation
of the reactivity of cycloalkanol derivatives of C under
gold catalysis that strongly depend on the ring size
and the nature of the migrating group.
We were interested in the reaction of propargyl cyclo-
butanol C, where three distinct mechanistic pathways
could be envisioned (Scheme 2). Ring expansion of
alkynyl cycloalkanol as reported by Toste, would lead
In this effort, we report a novel approach for assembling
spirocyclic furans via tandem [3,3]-sigmatropic rear-
rangement–cycloisomerization sequence. Spirofurans
are direct precursor to conformationally restricted
nucleoside analogs and find useful applications as anti-
viral agents in nucleoside mimic.9 This spurred us to fur-
ther investigate a route to various ring-sized analogs of
spirofurans.
*
Corresponding author. Tel.: +82 2 2220 0948; fax: +82 2 2299
0762; e-mail: sshin@hanyang.ac.kr
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.067

4818
H.-S. Yeom et al. / Tetrahedron Letters 48 (2007) 4817–4820
O
Initially we were interested in gold-catalyzed ring expan-
sion (route B, Scheme 2) and tested reaction of BnO-
allene-substituted cyclobutanol (Eq. 1).10 Under
5 mol % of Au(PPh3)OTf in 1,2-dichloroethane at rt, 1
was smoothly converted into a-vinylated cyclopenta-
none 2 in good yield.11
X
O
O
X
OH
O
HO
n
route C
O
n
OCOX
C
n
F
route B
O
route A
O
5 mol%
Au(PPh3)OTf
OH
OBn
O
O
ð1Þ
DCE, rt, 3 h
O
X
OCOX
OBn
OCOX
HO
n
2
85%
1
n
D
E
n
[Au]
Encouraged by the result, we prepared a series of prop-
argylic ester derivatives 3–5 according to Scheme 3 and
investigated their reactions. For the preparation of
Scheme 2. Evolution of propargyl ester C under Au-catalysis.
Scheme 3. Preparation of substrates 3a–d, 4a–d, and 5a–d. Reagents and conditions: (a) (1) n-BuLi, THF, then cyclobutanone, 0 °C, (2) TsOHÆH2O,
MeOH, (3) (Boc)2O, DMAP, Et3N, THF; (b) cyclopentaone (or cyclohexanone), CeCl3, THF, 0 °C; (c) Ac2O, Py; (d) PivCl, Py; (e) (Boc)2O, DMAP,
Et3N; (f) BzCl, Py.
Table 1. Reactions of 3–5 under Au(I)-catalysis
O
O
HO
OR
O
OR
+
+
OR
OR
n
n
n
n
6/9/12
7/10/13
8/11/14
Entry
Substrate
Conditiona
Product, yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
3a R = Ac
3b R = Piv
3b R = Piv
3c R = Boc
3c R = Boc
3d R = Bz
4a R = Ac
4a R = Ac
4a R = Ac
4a R = Ac
4b R = Piv
4c R = Boc
4d R = Bz
5a R = Ac
5b R = Piv
5c R = Boc
5d R = Bz
A
A
B
A
B
A
A
B
C
D
B
B
B
B
B
B
B
6a (96)c
7b (60)
7b (73)
7c (68)
7c (75)
7d (66)
10a (16), 11a (5)d
10a (61)
9a (11), 10a (2)d
10a (34)
10b (81)
10c (84)
10d (98)
13a (92)
13b (66)
13c (63)
13d (93)
a All reactions were conducted in CH2Cl2 at rt. Condition A: Au(PPh3)OTf (5 mol % formed in situ), Condition B: Au[t-Bu2P(o-biphenyl)]OTf
(5 mol %), Condition C: Au[P(C6F5)3]OTf (5 mol %), Condition D: Au[P(o-tol)3]OTf (5 mol %).
b Isolated yield after chromatography.
c 1 mol % of catalyst was used in this case.
d Other byproducts could not be identified.

H.-S. Yeom et al. / Tetrahedron Letters 48 (2007) 4817–4820
4819
cyclobutanol analogs, a four step sequence involving
Supplementary data
THP protection was required. However, for 5- and 6-
membered substrates, a sequence involving reaction of
dianion with cycloalkanone, followed by appropriate
protection, efficiently delivered desired substrates.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2007.05.067.
Treatment of propargyl acetate 3a with 1 mol % of
Au(PPh3)OTf pre-catalyst in dichloromethane at rt for
1 h, direct ring expansion without [3,3]-rearrangement
(route A, Scheme 2) occurred to give cyclopentanone
6a in an excellent yield (96%, Table 1, entry 1).12 Chang-
ing protecting group as in 3b–d led to faster [3,3]-rear-
rangement and completely diverted the reaction path
into rearrangement followed by cycloisomerization
(route C, Scheme 2), giving 7 in modest yields (entries
2, 4, and 6). In these cases, 6 or 8 could not be isolated
in any significant amounts. The reactivity of 3b–d shows
that the resulting O-acyl-allenyl intermediate cycloiso-
merize faster than ring-expansion, which is in contrast
to BnO-allenyl derivative 1 (Eq. 1) and this could be
rationalized by the lack of electron-donation of ester
oxygen to bring about activation of allene. Interestingly,
changing ligand into Au[t-Bu2P(o-biphenyl)]OTf further
increased the yield of 7 (entries 3 and 5).13 In an attempt
to decrease the rate of cycloisomerization, 3d was con-
verted into TMS ether and was subject to the condition
A in the presence of 2 equiv of isopropanol. Unsuccess-
fully, the reaction gave cycloisomerized 7d in 62% yield
in a much slower reaction.
References and notes
1. (a) Oelberg, D. G.; Schiavelli, M. D. J. Org. Chem. 1977,
42, 1804; (b) Schlossarczyk, H.; Sieber, W.; Hesse, M.;
Hanson, H. J.; Schmid, H. Helv. Chim. Acta 1973, 56,
875.
2. For examples of 1,3-acyl shift: (a) Marion, N.; Nolan, S.
P. Angew. Chem., Int. Ed. 2007, 46, 2750; (b) Shigemasa,
Y.; Yasui, M.; Ohrai, S.-I.; Sasaki, M.; Sashiwa, H.;
Saimoto, H. J. Org. Chem. 1991, 56, 910; (c) Ma, S.; Gao,
W. J. Org. Chem. 2002, 67, 6104; (d) Kim, S.; Kim, Y. G.
Synlett 1991, 869; (e) Shigemasa, Y.; Oikawa, H.; Sashiwa,
H.; Saimoto, H. Bull. Chem. Soc. Jpn. 1992, 65, 2594; (f)
Trost, B. M.; Oi, S. J. Am. Chem. Soc. 2001, 123, 1230; (g)
Grissom, J. W.; Klingberg, D.; Huang, D.; Slattery, B. J.
J. Org. Chem. 1997, 62, 603.
3. For recent reviews on gold-catalysis, see: (a) Hashmi, A. S.
K.; Hutchings, G. J. Angew. Chem., Int. Ed. 2006, 45,
7896; (b) Hoffmann-Ro¨der, A.; Krause, N. Org. Biomol.
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´
Chem. 2005, 3, 387; (c) Jimenez-Nunez, E.; Echavarren, A.
˜
M. Chem. Commun. 2007, 333.
4. (a) Binder, J. T.; Kirsch, S. F. Org. Lett. 2006, 8, 2151; (b)
Suhre, M. H.; Reif, M.; Kirsch, S. F. Org. Lett. 2005, 7,
3925; (c) Engel, D. A.; Dudley, G. B. Org. Lett. 2006, 8,
4027; (d) Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc.
2004, 126, 15978; (e) Sherry, B. D.; Maus, L.; Laforteza,
B. N.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 8132; (f)
Horino, Y.; Luzung, M. R.; Toste, F. D. J. Am. Chem.
Soc. 2006, 128, 11364; (g) Zhao, J.; Hughes, C. O.; Toste,
F. D. J. Am. Chem. Soc. 2006, 128, 7436.
5. Au-catalyzed reaction of allenes are much less investigated
than those of alkynes. For example, see: (a) Morita, N.;
Krause, N. Org. Lett. 2004, 6, 4121; (b) Hoffmann-Ro¨der,
A.; Krause, N. Org. Lett. 2001, 3, 2537; (c) Morita, N.;
Krause, N. Angew. Chem., Int. Ed. 2006, 45, 1897; (d)
Kang, J.-E.; Lee, E.-S.; Park, S.-L.; Shin, S. Tetrahedron
Lett. 2005, 46, 7431.
6. (a) Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Khan, F. A.
Chem. Rev. 2000, 100, 3067; (b) Yoshida, M.; Komatsu-
zaki, Y.; Nemoto, H.; Ihara, M. Org. Biomol. Chem. 2004,
2, 3099.
7. (a) Zhang, L. J. Am. Chem. Soc. 2005, 127, 16804; (b)
Wang, S.; Zhang, L. J. Am. Chem. Soc. 2006, 128, 8414;
(c) Wang, S.; Zhang, L. Org. Lett. 2006, 8, 4585; (d)
Zhang, L.; Wang, S. J. Am. Chem. Soc. 2006, 128, 1442;
(e) Buzas, A.; Istrate, F.; Gagosz, F. Org. Lett. 2006, 8,
1957.
Reaction of 4 which is free of ring strain showed more
complex reaction profile. Using Au(PPh3)OTf
(5 mol %), small amount of ring expansion product
11a (route B, Scheme 2) was observed from the complex
reaction mixture, but most of the mass balance was
attributed to an unidentified product (entry 7). Use of
electron-deficient ligand gave a small amount of ring
expansion product 9a through route A (Scheme 2), al-
beit in low yield (entry 9). Use of Au[t-Bu2P(o-biphe-
nyl)]OTf (5 mol %) significantly improved the yield of
10a and delivered the spirocycle in 61% yield (entry 8).
Other derivatives of 4 gave more efficient conversion
into spirocycles 10 in 81–98% yield (entries 11–13).
Spirocyclization of six membered ring-substrates 5a–d
also went uneventfully giving the corresponding spiro-
cycles 13a–d in moderate to excellent yields (entries
14–17).
In summary, we reported a novel gold-catalyzed route to
conformationally biased spirocyclic furans having vari-
ous ring sizes. Our report shows the fate of 1-(3-hydroxy-
propynyl)cycloalkanol substrates is highly dependent
upon the ring size as well as migrating group. Further
effort to utilize this spirofuran skeleton in the synthesis
of nucleoside analogs is underway in our laboratory.
8. (a) Markham, J. P.; Staben, S. T.; Toste, F. D. J. Am.
Chem. Soc. 2005, 127, 9708; For Pd-catalyzed processes:
(b) Sugimoto, K.; Yoshida, M.; Ihara, M. Synlett 2006,
1923; (c) Wei, L.-M.; Wei, L.-L.; Pan, W.-B.; Wu, M.-J.
Tetrahedron Lett. 2003, 44, 595.
9. (a) Paquette, L. A.; Bibart, R. T.; Seekamp, C. K.;
Kahane, A. L. Org. Lett. 2001, 3, 4039, and references
cited therein; (b) Paquette, L. A.; Kahane, A. L.; Seek-
amp, C. K. J. Org. Chem. 2004, 69, 5555; (c) Yoshimura,
Y.; Asami, K.; Matsui, H.; Tanaka, H.; Takahata, H. Org.
Lett. 2006, 26, 6015.
10. A similar Pd-catalyzed process is reported: (a) Nemoto,
H.; Yoshida, M.; Fukumoto, K. J. Org. Chem. 1997, 62,
6450; (b) Jeong, I.-Y.; Shiro, M.; Nagao, Y. Heterocycles
Acknowledgements
This work was supported by the research fund of the
Hanyang University (HY-2005-s). Y.H.S. thanks
BK21 program for fellowship.

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H.-S. Yeom et al. / Tetrahedron Letters 48 (2007) 4817–4820
2000, 52, 85; (c) Trost, B. M.; Xie, J. J. Am. Chem. Soc.
2006, 128, 6044.
(s, 2H), 3.19 (br t, J = 7.7 Hz, 2H), 2.89 (br t, J = 7.7 Hz,
2H), 2.23–2.10 (m, 2H), 2.18 (s, 3H). 13C (100 MHz,
CDCl3): d 192.4, 170.6, 170.3, 116.8, 68.3, 35.1, 33.2, 20.8,
18.2.
11. To the best of knowledge, gold-catalyzed Wagner–
Meerwein shift of allenyl cyclobutanol of type 1 is
not known. However, at this point, the possible
involvement of Brønsted-acid catalysis cannot be
excluded: Stone, G. B.; Liebeskind, L. S. J. Org. Chem.
1990, 55, 4614.
13. A representative procedure for cycloisomerization of 3b:
Au[t-Bu2P(o-biphenyl)]Cl (10.0 mg, 0.019 mmol) and
AgOTf (4.9 mg, 0.019 mmol) was weighed in a test tube.
Starting propargyl pivalate 3b (80.0 mg, 0.38 mmol) in
dichloromethane (1.0 mL) was added and the resulting
mixture was stirred 3 h. To the mixture was added three
drops of triethylamine and the resulting mixture was
filtered through a short pad of silica gel. The eluent was
evaporated to dryness and the resulting oil was purified by
flash chromatography (EtOAc–hex = 1:10) to give 58.5 mg
(73%) of 7b as colorless oil. 1H NMR (400 MHz, CDCl3): d
5.78 (br s, 1H), 4.63 (d, J = 1.5 Hz, 2H), 2.48–2.22 (m, 4H),
1.82–1.60 (m, 2H), 1.31 (s, 9H). 13C (100 MHz, CDCl3): d
175.6, 148.4, 104.9, 86.4, 72.3, 39.7, 35.3, 37.3, 12.2.
12. A representative procedure for ring expansion of 3a: To a
solution of Au(PPh3)Cl (2.4 mg, 0.0048 mmol) and AgOTf
(1.2 mg, 0.0048 mmol) in dichloromethane (1 mL) was
added a solution of 3a (80.0 mg, 0.475 mmol) dichloro-
methane (2 mL). The mixture was stirred 2 h at rt and
three drops of triethylamine was added. The mixture was
filtered through a short pad of silica gel and evaporated to
dryness. The resulting oil was purified by flash chroma-
1
tography to get 76.6 mg (96%) of 6a as colorless oil. H
NMR (400 MHz, CDCl3): d 6.00 (t, J = 1.9 Hz, H), 4.69