Rapid and stereoselective synthesis of spirocyclic ethers via the intramolecular Piancatelli rearrangement

Article abstract of DOI:10.1021/ol303263q

The first example of a Piancatelli rearrangement of alcohols is demonstrated utilizing dysprosium(III) triflate as a catalyst to access oxaspirocycles in a highly diastereoselective manner. The cascade reaction constructs the spirocyclic ether ring system and the tertiary stereocenter in a single operation and is experimentally easy to perform.

Full text of DOI:10.1021/ol303263q

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Rapid and Stereoselective Synthesis of
Spirocyclic Ethers via the Intramolecular
Piancatelli Rearrangement
Leoni I. Palmer and Javier Read de Alaniz*
Department of Chemistry & Biochemistry, University of California, Santa Barbara,
California 93106-9510, United States
javier@chem.ucsb.edu
Received November 27, 2012
ABSTRACT
The first example of a Piancatelli rearrangement of alcohols is demonstrated utilizing dysprosium(III) triflate as a catalyst to access
oxaspirocycles in a highly diastereoselective manner. The cascade reaction constructs the spirocyclic ether ring system and the tertiary
stereocenter in a single operation and is experimentally easy to perform.
Oxabicycles represent an important class of compounds
in organic synthesis, and they have served as key inter-
mediates in the total synthesis of numerous biologically
active molecules (Figure 1), such as grindelic acid (1),1
heliespirones B (2) and C (3),2 ophiobolin A (4),3 and
sieboldine A (5).4 Within the oxabicycle family, spirocyclic
ethers (6) represent one of the most challenging structural
motifs to access. To overcome synthetic challenges asso-
ciated with their synthesis a number of strategies have been
developed.5 Generally, the routes rely on a two-step pro-
cess where the tertiary carbon center and the spirocycle
are formed in separate, discrete steps. An especially direct
way to construct this motif would be to combine the
construction of the ether and the formation of the spir-
ocyclic ring system in a single operation using a cascade
reaction. Despite the potential, this strategy remains large-
ly unexplored.
Recently, we developed an intramolecular cascade re-
arrangement of 2-furylcarbinols to provide direct access to
azaspirocycles, based on the aza-Piancatelli reaction (eq 1).6
We recognized that the ability to employ alcohols in the
intramolecular rearrangement of 2-furylcarbinols would
provide an attractive alternative to stepwise spirocyclic
ether synthesis. In addition, it would provide a platform
to further expand the synthetic utility of the Piancatelli
rearrangement, since there are no examples with alcohol
(5) For select examples, see: (a) Ireland, R. E.; Maienfisch, P. J. Org.
Chem. 1988, 53, 640. (b) Middleton, D. S.; Simpkins, N. S.; Begley, M. J.;
Terrett, N. K. Tetrahedron 1990, 46, 545. (c) Negri, J. T.; Paquette, L. A.
J. Am. Chem. Soc. 1992, 114, 8835. (d) Paquette, L. A.; Tae, J. J. Org.
Chem. 1996, 61, 7860. (e) Haddad, N.; Rukhman, I.; Abramovich, Z.
J. Org. Chem. 1997, 62, 7629. (f) Young, J.-J.; Jung, L.-J.; Cheng, K.-M.
Tetrahedron Lett. 2000, 41, 3415. (g) Jones, K.; Toutounji, T. Tetra-
hedron 2001, 57, 2427. (h) Teng, X.; Cefalo, D. R.; Schrock, R. R.;
Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 10779. (i) Alonso, F.;
Melendez, J.; Yus, M. Russ. Chem. Bull. 2003, 52, 2628. (j) Noguchi, N.;
Nakada, M. Org. Lett. 2006, 8, 2039. (k) Adrien, A.; Gais, H. J.; Kohler,
F.; Runsink, J.; Raabe, G. Org. Lett. 2007, 9, 2155. (l) Zhang, Q.-W.;
Fan, C.-A.; Zhang, H.-J.; Tu, Y.-Q.; Zhao, Y.-M.; Gu, P.; Chen, Z.-M.
Angew. Chem., Int. Ed. 2009, 48, 8572.
(1) (a) Panizzi, L.; Mangoni, L.; Belardini, M. Tetrahedron Lett.
1961, 2, 376. (b) Paquette, L. A.; Wang, H.-L. Tetrahedron Lett. 1995,
36, 6005.
(2) (a) Macias, F. A.; Galindo, J. L. G.; Varela, R. M.; Torres, A.;
Molinillo, J. M. G.; Fronczek, F. R. Org. Lett. 2006, 8, 4513. (b) Jiao,
Z.-W.; Zhang, S.-Y.; He, C.; Tu, Y.-Q.; Wang, S.-H.; Zhang, F.-M.;
Zhang, Y.-Q.; Li, H. Angew. Chem., Int. Ed. 2012, 51, 8811.
(3) (a) Ishibashi, K.; Nakamura, R. J . Agric. Chem. Soc. Jpn. 1958,
32, 739. (b) Kobayashi, S.; Kinoshita, T.; Kawamoto, T.; Wada, M.;
Kuroda, H.; Masuyama, A.; Ryu, I. J. Org. Chem. 2011, 76, 7096.
(4) (a) Hirasawa, Y.; Morita, H.; Shiro, M.; Kobayashi, J. I. Org.
Lett. 2003, 5, 3991. (b) Canham, S. M.; France, D. J.; Overman, L. E.
J. Am. Chem. Soc. 2010, 132, 7876.
(6) Palmer, L. I.; Read de Alaniz, J. Angew. Chem., Int. Ed. 2011, 50,
7167.
(7) (a) Piancatelli, G.; Scettri, A.; Barbadoro, S. Tetrahedron Lett.
1976, 17, 3555. (b) Piancatelli, G.; Dauria, M.; Donofrio, F. Synthesis
1994, 867.
r
10.1021/ol303263q
XXXX American Chemical Society

Figure 2. Proposed mechanism of the intramolecular Piancatelli
rearrangement. LA = Lewis acid, conr. = conrotatory.
derivatives are known to ring open in the opposite direc-
tion in the presence of an acid catalyst, forming oxocarbe-
nium ion D (eq 3). For example, in the presence of catalytic
amounts of acid (p-TsOH or ZnCl2), alcohols react with 8
via D to give furan derivative 10.11 Similar conditions,
ZnCl2 in aqueous 1,2-dimethoxyethane, are reported to
convert 8 into oxabicyclic cyclopentenones (11).12 Water
was found to be critical for this transformation, and it is
believed that oxocarbenium ion D is intercepted by water.
Presumably from this proposed intermediate the reaction
proceeds analogously to the Piancatelli rearrangement
followed by formation of the more stable cyclopentenone
product. We sought to develop a new strategy that would
selectively proceed through oxocarbenium ion A.
Figure 1. Natural products that contain spirocyclic ether motifs.
nucleophiles.7 Herein, we report our studies leading to the
development of a general protocol for the synthesis of
spirocyclic ethers (eq 2). This reaction is highly diastereose-
lective, constructs the spirocyclic ether ring system and the
tertiary stereocenter in a single operation, and is the first
example of a Piancatelli rearrangement with alcohols.
As shown in Figure 2, we envisioned a mechanistic
scenario that would proceed analogous to the intramo-
lecular aza-Piancatelli rearrangement.6 We hypothesized
that the critical step for the proposed rearrangement was
the fate of spiroketal enol ether 8. We envisioned using
a Lewis acid to mediate the ring opening of 8 into oxocar-
benium ion A by coordination to O-1. Once A is formed
the desired process would rely on the same principles
as the aza-Piancatelli reaction to govern the generation
of spirocyclic cyclopentenone 9 through a Nazarov-type
electrocyclization.8
Initially, a series of Lewis acid salts were tested for their
ability to promote spirocyclic ether formation in acetoni-
trile (Table 1, entries 1À3). Unfortunately, we observed
decomposition using Dy(OTf)3 and ZnCl2. Copper sulfate
pentahydrate led exclusively to the formation of spiroketal
enol ether 13. A 16% yield of oxabicyclic cyclopentenone
15 was obtained when water was added to the reaction
mixture catalyzed by ZnCl2 (entry 4). Attempts to use
other Brønsted or rare earth Lewis acids (CSA, HCl, TFA,
AcOH, H2SO4, PMMA, PTSA, Sc(OTf)3, DyCl3) were
also unsuccessful at catalyzing the transformation of 12
into 14. However, spiroketal enol ether 13 could be formed
under a variety of conditions, including heating in toluene
in the absence of catalyst (entry 5). Upon closer analysis of
Wu et al. have extensively studied the chemistry of
spiroketal enol ether derivatives (8), but to our knowledge
conditions that facilitate the formation of oxocarbenium
ion A have never been reported.9,10 Spiroketal enol ether
(8) For reviews on the Nazarov reaction, see: (a) Tius, M. A. Eur. J.
Org. Chem. 2005, 2193. (b) Pellissier, H. Tetrahedron 2005, 61, 6479. (c)
Frontier, A. J.; Collison, C. Tetrahedron 2005, 61, 7577.
(9) For a review on spiroketal enol ethers, see: Perron, F.; Albizati,
K. F. Chem. Rev. 1989, 89, 1617.
(11) Yin, B.-L.; Wu, W.-M.; Hu, T.-S.; Wu, Y.-L. Eur. J. Org. Chem.
2003, 4016.
(12) (a) Yin, B. L.; Wu, Y. K.; Wu, Y. L. J. Chem. Soc., Perkin Trans.
1 2002, 1746. (b) Yin, B. L.; Wu, Y. L.; Lai, J. Q. Eur. J. Org. Chem. 2009,
2695.
(10) For select studies, see: (a) Gao, Y.; Wu, W.-L.; Ye, B.; Zhou, R.;
Wu, Y.-L. Tetrahedron Lett. 1996, 37, 893. (b) Yin, B.-L.; Yang, Z.-M.;
Hu, T.-S.; Wu, Y.-L. Synthesis 2003, 1995. (c) Chen, L.; Xu, H.-H.; Yin,
B.-L.; Xiao, C.; Hu, T.-S.; Wu, Y.-L. J. Agric. Food. Chem. 2004, 52,
6719 and references therein.
B
Org. Lett., Vol. XX, No. XX, XXXX

the reaction, we found that ketal 13 forms and decomposi-
tion was occurring from this species.
Scheme 1. Substrate Studies for Intramolecular Piancatellia
Table 1. Optimization Studies for Spirocyclic Ether Synthesis
temp
yield (%)a
entry
catalyst
solvent
MeCN
(°C)
13:14:15
1
Dy(OTf)3
ZnCl2
80
80
60
80
60
60
60
80
100
80
decomp
decomp
33:0:0
2
MeCN
3
CuSO4•5H2O
ZnCl2
MeCN
4
MeCN/H2O
PhMe
0:0:16
5
À
28:0:0b
71:0:0
6
Dy(OTf)3
Dy(OTf)3
Dy(OTf)3
Dy(OTf)3
Dy(OTf)3
MeCN,K2CO3
PhMe
7
0:89:0c
0:91:0d
0:73:0e
0:82:0
8
9
PhMe
PhMe
10
PhMe/H2O
a Yield of isolated product. b Reaction quenched after 6 d. Base-
washed glassware was used. c Reaction was complete in 20 h. 13 could be
isolated in 82% yield when the reaction was quenched after 2.5 h.
d Reaction was complete in 6 h. e Reaction was complete in 2 h.
Knowing that the formation of 13 was facile, we shifted
our focus to the reactivity of the spiroketal enol ether (13).
It has been reported that the choice of solvent can affect
oxocarbenium ion reactivity.13 We were pleased to find
that the desired transformation to 14 could be realized
using Dy(OTf)3 asthe catalystandtolueneasthesolvent. It
is critical that the reactions be run in base-washed glass-
ware, but an inert atmosphere and distilled solvents are
unnecessary.14 Pleasingly, it was found that increasing
the reaction temperature resulted in an enhanced rate of
conversion (20 to 2 h, entries 7À9) with little effect on the
isolated yield. We settled on 80 °C as the optimal tempera-
ture; however for sluggish reactions increasing the tem-
perature can be beneficial. In contrast to the reaction
mediated by ZnCl2 (entry 4), bicyclic cyclopentenone 15
was not observed when water was added to the reaction
mixture catalyzed by Dy(OTf)3 (entry 10).
With an optimized protocol in hand, we next investi-
gated the scope of this cascade rearrangement process.
Scheme 1 summarizes these studies. The reaction pro-
ceeded in moderate to excellent yields, and in all cases only
a single diastereomer of the product was generated.15
Electron-rich (18) and bulkier aromatic substituents (22
and 24) proceeded cleanly and efficiently, with a slight
drop in yield for the most challenging mesityl substrate, a
b
c
a Yield of isolated product. Reaction performed at 100 °C. An
inseparable 9:1 ratio of diastereomers was isolated in this case.
trend seen in the corresponding aza-Piancatelli rearrange-
ment.6 When the aryl group at the 2-position of the
furylcarbinol possessed a strong electron-withdrawing
group we noticed the reactions took up to 7 d for comple-
tion. To our gratification, it was found that a good yield
could be achieved in a reasonable time (16 h) with an
increase in the reaction temperature from 80 to 100 °C
(19À21). A thiophene heterocycle can also be incorporated
at the 2-position without a decrease in efficiency (23).
In contrast to the analogous aza-Piancatelli reaction
nonaryl substituents at the 2-position of the furylcarbinol
proved more challenging. Initial attempts to rearrange
substrates containing an alkyl group at this position were
unsuccessful (26 and 27). In both cases we observed
decomposition, accompanied by substitution (formation
of 10 via nucleophilic attack of the pendant alcohol) for the
isopropyl substrate (27). It was noticed that the reaction to
construct 25 proceeded more rapidly than the analogous
transformation to form 14 (2 vs 6 h, respectively). In this
case, there was no evidence of formation of the transient
ketal (8), which is easily identified (by isolation or TLC
analysis) in reactions of all the successful primary alcohol
(13) (a) Nasveschuk, C. G.; Rovis, T. J. Org. Chem. 2007, 73, 612. (b)
Marra, A.; Esnault, J.; Veyrieres, A.; Sinay, P. J. Am. Chem. Soc. 1992,
114, 6354.
(14) See Supporting Information.
(15) The diastereomeric ratio was >99:1 for all cases examined, with
the exception of 21 (see Supporting Information).
Org. Lett., Vol. XX, No. XX, XXXX
C

substrates (14, 18À24) before proceeding to the desired
products (17). This observation led us to discover that the
installation of a substituent R to the oxygen on the alkyl
chain, such as a gem dimethyl (29 and 30), provided a
solution to the use of 2-alkyl substituted furylcarbinols
in the rearrangement. It is unclear exactly why the gem
dimethyl has such a beneficial effect, but it may block
coordination to O-6 which helps drive the reaction toward
oxocarbenium ion A (Figure2). Extending the chain length
of the appended alcohol to yield 5,6-spirocycles (28 and 31)
proved more taxing. Formation of ketal (8) occurred
relatively well; however only the substrate employing a
pendant tertiary alcohol formed the desired product (31),
where other substrates led to decomposition.
Scheme 2. Substrate Studies for Intramolecular Piancatellia
Encouraged by these results, we performed an explora-
tory study to determine whether substituents on the
furan could control the torquoselectivity of the 4π electro-
cyclization event.16 The two possible conrotation modes,
clockwise or counterclockwise, lead to two different dia-
stereomers.17 Substituents were placed at three separate
positions (R, β, and γ position relative to the furan ring)
along the backbone of the appended alcohol (Scheme 2).
Surprisingly, initial experiments showed that these groups
do not greatly influence the torquoselectivity; in all cases
a moderate diastereoselectivity of 1:2 to 1:3 was observed
(34À38). However, these studies provide insight into the
steric tolerance of the overall transformation. Substituents
at the β- and γ-position are well tolerated. Substituents
at the R-position failed to afford cyclopentenones. In these
cases the spiroketal enol ether (8) was observed prior to
decomposition.
a Yield of isolated product. b Yield determined by 1H NMR spectro-
scopy using dimethyl terephthalate as the internal standard.
ether moiety in pentadienyl cation B appears to prefer an
E configuration.
In conclusion, a novel Piancatelli rearrangement with
alcohol nucleophiles has been developed. The rearrange-
ment is catalyzed by dysprosium(III) triflate under oper-
ationally simple reaction conditions.20 The spirocyclic
ethers are formed exclusively as the trans diastereomer
and the fully substituted carbon center bearing an oxygen
heteroatom, and a spirocyclic ring system is constructed in
a single operation. Current efforts are focused on extend-
ing the methodology to include an asymmetric variant and
employing it to access biologically important scaffolds.
Single-crystal X-ray analysis of the spirocyclic cyclopen-
tenone 1418 as well as 2D NMR evidence confirmed that
the rearrangement had taken place with the expected trans
selectivity, consistent with our aza-Piancatelli reaction19 and
a 4π electrocyclization of pentadienyl cation B (Figure 2).8
Further investigations are ongoing to understand why the
(16) Jefford, C. W.; Bernardinelli, G.; Wang, Y.; Spellmeyer, D. C.;
Buda, A.; Houk, K. N. J. Am. Chem. Soc. 1992, 114, 1157.
(17) Torquoselectivity has been used to control the relative and
absolute stereochemistry in the Nazarov reaction. For select examples
of torquoselectivity in the Nazarov reaction, see: (a) Jones, T. K.;
Denmark, S. E. Helv. Chim. Acta 1983, 66, 2397. (b) Denmark, S. E.;
Habermas, K. L.; Hite, G. A.; Jones, T. K. Tetrahedron 1986, 42, 2821.
(c) Denmark, S. E.; Wallace, M. A.; Walker, C. B. J. Org. Chem. 1990,
55, 5543. (d) Hu, H.; Smith, D.; Cramer, R. E.; Tius, M. A. J. Am. Chem.
Soc. 1999, 121, 9895. (e) Prandi, C.; Deagostino, A.; Venturello, P.;
Occhiato, E. G. Org. Lett. 2005, 7, 4345.
Acknowledgment. This work was supported by UCSB
and the National Science Foundation (CAREER Award
CHE-1057180). We also thank Dr. Guang Wu (UCSB) for
X-ray analysis and Dr. Hongjun Zhou (UCSB) for NMR
assistance.
Supporting Information Available. Full experimental
data. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) See Supporting Information.
(19) Veits, G. K.; Wenz, D. R.; Read de Alaniz, J. Angew. Chem., Int.
Ed. 2010, 49, 9484.
(20) For a review on dysprosium chemistry, see: Veits, G. K.; Read de
The authors declare no competing financial interest.
Alaniz, J. Tetrahedron 2012, 68, 2015.
D
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