A stereoselective synthetic route to 1,6-dioxaspiro[4.4]non-3-en-2-ones from cyclopropyl alkyl ketones and α-ketoesters

Article abstract of DOI:10.1021/ol060415a

The SnCl₄-mediated reactions of cyclopropyl alkyl ketones with α-ketoesters afford a novel method for the synthesis of 1,6-dioxaspiro[4.4]non-3-en-2-ones with high stereoselectivities in moderate to good yields. This process is a sequential reaction involving a nucleophilic ring-opening reaction of the cyclopropane by H₂O, an aldol-type reaction, and a cyclic transesterification mediated by Lewis acid.

Full text of DOI:10.1021/ol060415a

ORGANIC
LETTERS
2006
Vol. 8, No. 8
1709-1712
A Stereoselective Synthetic Route to
1,6-Dioxaspiro[4.4]non-3-en-2-ones from
Cyclopropyl Alkyl Ketones and
r
-Ketoesters
Yong-Hua Yang and Min Shi*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
mshi@mail.sioc.ac.cn
Received February 16, 2006
ABSTRACT
The SnCl4-mediated reactions of cyclopropyl alkyl ketones with
r-ketoesters afford a novel method for the synthesis of 1,6-dioxaspiro[4.4]-
non-3-en-2-ones with high stereoselectivities in moderate to good yields. This process is a sequential reaction involving a nucleophilic ring-
opening reaction of the cyclopropane by H2O, an aldol-type reaction, and a cyclic transesterification mediated by Lewis acid.
Cyclopropane-containing compounds, as versatile building
blocks in organic synthesis, have been well understood.1 The
ring-opening reactions of cyclopropyl ketones are syntheti-
cally useful reactions that have been studied extensively.
Previously, Ranfaing and Pittman independently reported the
rearrangement reactions of simple cyclopropyl ketones 1 in
concentrated sulfuric acid to produce oxolan-2-ylium ions
2, γ-hydroxyketones 3, and 2,3-dihydrofurans 4 as hydro-
lyzed products (Scheme 1).2 Later, Nakai reported a conve-
nient synthetic route to 1,4-dicarbonyl compounds based on
the rearrangement of protonated cyclopropyl ketones.3 Re-
cently, we found that this promising rearrangement reaction
could also be promoted by Lewis acids and subsequently
developed mild synthetic methods for the preparation of 2-(2-
hydroxyethyl)-1,3-diarylpropenones and 5,6-dihydropyran-
2-ones from the reaction of cyclopropyl aryl ketones with
arylaldehydes and R-ketoesters, respectively.4 We envisioned
that these two processes involve formation of γ-hydroxyke-
tone 3 as a ring-opened product of the corresponding
cyclopropane via nucleophilic attack by ambient H2O in the
Scheme 1. Rearrangement of Cyclopropyl Ketones in
(1) (a) Reissig, H.-U.; Zimmer, R. Chem. ReV. 2003, 103, 1151. (b)
Paquette, L. A. Chem. ReV. 1986, 86, 733. (c) Wong, H. N. C.; Hon, M.-
Y.; Tse, C.-W.; Yip, Y.-C.; Tanko, J.; Hudlicky, T. Chem. ReV. 1989, 89,
165. (d) de Meijere, A.; Wessjohann, L. Synlett 1990, 20. (e) Kulinkovich,
O. G. Russ. Chem. ReV. 1993, 62, 839. (f) Kulinkovich, O. G. Polish J.
Chem. 1997, 849. (g) Wenkert, E. Acc. Chem. Res. 1980, 13, 27. (h)
Wenkert, E. Heterocycles 1980, 14, 1703. (i) Seebach, D. Angew. Chem.
1979, 91, 259; Angew. Chem., Int. Ed. Engl. 1979, 18, 239. (j) Gnad, F.;
Reiser, O. Chem. ReV. 2003, 103, 1603.
Concentrated Sulfuric Acid
(2) (a) Ranfaing, P. J.; Combaut, G.; Giral, L. Bull. Soc. Chim. Fr. 1974,
1048. (b) Pittman, C. U., Jr.; McManus, S. P. J. Am. Chem. Soc. 1969, 91,
5915.
(3) Nakai, T.; Wada, E.; Okawara, M. Tetrahedron Lett. 1975, 16, 1531.
10.1021/ol060415a CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/21/2006

presence of a Lewis acid. During our ongoing investigations
of this Lewis acid mediated reaction, we found that when
using cyclopropyl alkyl ketones (R1 ) alkyl group, R2 )
H) as the substrate, the reaction produced an interesting spiro-
γ-lactone along with other products. Herein, we report a
novel method for the synthesis of 1,6-dioxaspiro[4.4]non-
3-en-2-ones with high stereoselectivities by reaction of
cyclopropyl alkyl ketones with R-ketoesters in the presence
of the Lewis acid SnCl4.
Figure 1. Important compounds bearing a spiro-γ-lactone moiety.
Initially we attempted to examine the reaction of cyclo-
propyl hexyl ketone with methyl benzoylformate (5a) in the
presence of the Lewis acid TMSOTf (1.0 equiv). Surprisingly
the reaction not only afforded the expected product 5,6-
dihydropyran-2-one 6a in 21% yield, but also gave the three
additional products 9-hexylidene-1,9-dihydro-2H-3-oxafluo-
ren-4-one (7a), 5-hexylidene-4-(2-hydroxyethyl)-3-phenyl-
5H-furan-2-one (9a), and spiro-γ-lactone compound 8a in
15%, 45%, and 16% yields, respectively (Scheme 2).5
four of the products are formed via the same intermediate
3a, which is a hydrolyzed product produced from cyclopropyl
hexyl ketone and ambient H2O in the presence of Lewis acid.
Scheme 3. Proposed Mechanism for the Reaction of
Cyclopropyl Hexyl Ketone 1a with R-Ketoester 5a
Scheme 2. Reaction of Cyclopropyl Hexyl Ketone 1a with
R-Ketoester 5a in the Presence of TMSOTf (1.0 equiv)
Spiro-γ-lactones constitute an important class of oxygen-
containing heterocyclic compounds, and such groups can be
found in many biologically active natural products. For
example, the most widely studied spiro-γ-lactone compound,
(+)-Pyrenolide D, exhibits significant cytotoxic activity
toward HL-60 cells,6 and Massarinoline A shows biological
activity against Bacillus subtilis (ATCC 6051) and Staphy-
lococcus aureus (ATCC 29213), affording zones of inhibition
of 17 and 10 mm, respectively (Figure 1). The biological
profiles of these compounds, in combination with their
special structure have spawned many efforts to develop
synthetic methods for the synthesis of spiro-γ-lactones.
Therefore, our above findings encouraged us to explore a
selective synthetic method for the spiro-γ-lactone from
readily available cyclopropyl alkyl ketone and R-ketoester.
During our previous studies on the reaction of cyclopropyl
aryl ketones with R-ketoesters,4b it was determined that all
(4) (a) Shi, M.; Yang, Y.-H.; Xu, B. Tetrahedron 2005, 61, 1893. (b)
Yang, Y.-H.; Shi, M. J. Org. Chem. 2005, 70, 10082-10085.
(5) The structures of all the products were determined by NMR
spectroscopic data, microanalyses, and HRMS. The geometrical configu-
ration of 7a and 9a was determined by NOESY (see the Supporting
Information).
(6) (a) Nukina, M.; Hirota, H. Biosci. Biotechnol. Biochem. 1992, 56,
1158. (b) Ackland, M. J.; Hanson, J. R.; Hitchcock, P. B.; Ratcliffe, A. H.
J. Chem. Soc., Perkin Trans. 1 1985, 843. (3) Engstrom, K. M.; Mendoza,
M. R.; Navarro-Villalobos, M.; Gin, D. Y. Angew. Chem., Int. Ed. 2001,
40, 1128.
As shown in Scheme 3, if an aldol-type reaction occurs
at the C-3 position (Path a), intermediate A could be formed
as a mixture of E- and Z-isomers. Thus, product 6a can be
formed after an intramolecular transesterification process via
intermediate E-A.4b The highly conjugated product Z-7a can
be formed by dehydration of intermediate B, which itself
can be derived from a Bradsher-type cyclization reaction (or
1710
Org. Lett., Vol. 8, No. 8, 2006

Table 1. Optimization of the Reaction Conditions of
Cyclopropyl Alkyl Ketone 1b with Methyl Benzoylformate 5aa
Lewis acid
(equiv)
yield/%b
entry
time/h
8b
1
2
3
4
5
6
TMSOTf (1.0)
TfOH (1.0)
TiCl4 (1.0)
Sn(OTf)2 (1.0)
SnCl4 (1.0)
SnCl4 (0.5)
10
10
24
24
10
24
60
66
trace
trace
72
34
Figure 2. ORTEP drawing of 8b.7
a Reactions were carried out in parallel with 0.4 mmol of 1b and 0.2
mmol of 5a at 40 °C in DCE, please see the Supporting Information for
details. b Isolated yields.
Table 1, the corresponding spiro-γ-lactone compound can
be obtained in 60% yield in the presence of 1.0 equiv of
TfOH in 1,2-dichloroethane (DCE) at 40 °C (Table 1, entry
2). On the other hand, TiCl4 and Sn(OTf)2 showed low
catalytic abilities in this reaction and led to the recovery of
most starting materials (Table 1, entries 3 and 4). Other metal
triflates, such as Zn(OTf)2, Cu(OTf)2, Ln(OTf)2, and Yb-
(OTf)3, did not promote this reaction under the standard
conditions. However, SnCl4 showed high catalytic ability for
the reaction and afforded 8b in 72% within 10 h (Table 1,
entrie 5). When the amount of SnCl4 employed was
decreased to 0.5 equiv, the yield of 8b decreased to 34%
yield (Table 1, entry 6). Therefore, 1.0 equiv of SnCl4 is
necessary for this reaction to give 8b in good yield.
Next, the scope of this new and efficient synthetic protocol
for the construction of 1,6-dioxaspiro[4.4]non-3-en-2-ones
was investigated by employing a variety of cyclopropyl alkyl
ketones and R-ketoesters under the optimized reaction
conditions. As shown in Table 2, starting from 1-(1-
phenylcyclopropyl)pentan-1-one 1b and various R-ketoesters,
the corresponding 1,6-dioxaspiro[4.4]non-3-en-2-ones 8a-g
were obtained in moderate to good yields (Table 2, entries
1-6). In the reactions of 1b with various aryl R-ketoesters,
an electronic effect was clearly observed. In general, aryl
R-ketoesters having an electron-withdrawing group on the
aromatic ring were more reactive and afforded the corre-
sponding products 8 in higher yields (Table 2, entries 2 and
3). For aryl R-ketoesters 5d and 5e bearing an electron-
donating substituent (methyl or methoxyl group) on the
aromatic ring, the corresponding products 8e and 8f were
obtained in lower yields under the standard conditions (Table
2, entries 4 and 5). This reactivity of R-ketoesters is also
consistent with the role of the aldol acceptors in the reactions.
a Friedel-Crafts reaction) of 6a. On the other hand, product
Z-9a can be formed from Z-A via dehydration of intermediate
C′, which itself can be produced via an intramolecular
cyclization of intermediate B′ derived from hydrolysis of
Z-A. Alternatively, if the aldol-type reaction takes place at
the C-5 position in γ-hydroxyketone 3a, another intermediate,
C, would be formed along with regeneration of an equivalent
of H2O, which can react with 1a to initiate the next reaction
cycle. Intramolecular nucleophilic attack by the terminal
hydroxyl group at the ketone group can take place, leading
to the corresponding cyclic intermediate D containing a
hemiacetal hydroxyl group. From intermediate D, the cor-
responding product 1,6-dioxaspiro[4.4]non-3-en-2-one 8a can
be formed via an intramolecular transesterification. Overall,
the formation of spiro-γ-lactone product 8a is a cascade
reaction involving a nucleophilic ring-opening reaction of
the cyclopropane group by H2O, an aldol type reaction, and
an intramolecular transesterification. Moreover, ambient
water is only required to initiate the process since the
following necessary H2O in the reaction is regenerated in
situ during the aldol-type reaction.
On the basis of the above mechanistic analysis, we
envisioned that the spiro-γ-lactone product 8 would be the
predominant product obtained if a substituent is introduced
at the position of cyclopropane adjacent to the carbonyl group
in substrate 1 because it could give the corresponding
intermediate 3 containing a substituent at C-3 position. This
would prevent the reaction shown in Path a because the
release of H2O is prohibited. Therefore, we chose substrate
1b, with a substituent phenyl group at the R-position of the
carbonyl group, for study. As expected, the compound 3,9-
diphenyl-4-propyl-1,6-dioxaspiro[4.4]non-3-en-2-one (8b)
was obtained as a sole product with trans-configuration in
60% yield in the presence of 1.0 equiv of TMSOTf (Table
1, entry 1). The structure and the configuration of the 8b
were confirmed by X-ray crystallographic analysis (Figure
2).7 Moreover, we also examined the effect of Brønsted acid
and other Lewis acids on the reaction. As can be seen from
(7) The crystal data of 8b have been deposited in the CCDC, number
287396. Empirical formula C22H22O3; formula weight 334.40; crystal size
0.503 × 0.361 × 0.160; crystal color colorless; habit prismatic; crystal
system monoclinic; lattice type primitive; lattice parameters a ) 15.4115-
(17) Å, b ) 15.2733(17) Å, c ) 15.5755(18) Å, R ) 90°, â ) 101.178-
(2)°, γ ) 90°, V ) 3596.7(7) Å3; space group C2/c; Z ) 8; Dcalc ) 1.235
g/cm3; F000 ) 1424; R1 ) 0.0526, wR2 ) 0.1355; diffractometer Rigaku
AFC7R.
Org. Lett., Vol. 8, No. 8, 2006
1711

Scheme 4. Reaction of 1b with 5a Mediated by SnCl4 in the
Table 2. Reactions of Cyclopropyl Ketones 1b-e with
Various R-Ketoesters under These Optimized Conditions
Presence of 4 Å MS (60 mg)
yield/%a
entry
R1/R2
R3/R4
8
product 8b abruptly decreased to 39% under identical
conditions. Therefore we believe that additional H2O in this
system does not favor the reaction. The best result was
obtained with commercially available DCE solvent without
any additional water.
Exclusive formation of products 8 with trans-configuration
in the reaction can be rationalized by the proposed mecha-
nism shown in Scheme 2. Because the terminal hydroxyl
group in intermediate C would presumably prefer to attack
from the opposite side of the R2 functional group to avoid
the steric interactions, this would lead exclusively to trans-
configuration in the cyclization process (Scheme 5).
1
2
3
4
5
6
7
8
9
1b, C3H7/C6H5
1b, C3H7/C6H5
1b, C3H7/C6H5
1b, C3H7/C6H5
1b, C3H7/C6H5
1b, C3H7/C6H5
1b, C3H7/C6H5
1b, C3H7/C6H5
1b, C3H7/C6H5
1c, C3H7/CH3
1d, H/C6H5
5a, C6H5/Me
5b, p-ClC6H4/Et
5c, p-FC6H4/Et
5d, p-MeC6H4/Me
5e, p-MeOC6H4/Et
5f, EtOOC/Et
5g, Me/Et
10, Me/H
11, C6H5/H
5a, C6H5/Me
5a, C6H5/Me
5a, C6H5/Me
8b, 72
8c, 85
8d, 77
8e, 66
8f, 41
8g, 74
8h, trace
8h, 55
8b, 55
8i, 63
10
11
12
8j, 67
8k, 72
1e, C6H5/C6H5
a Isolated yields.
Scheme 5. Configuration in the Formation of Spiro-γ-lactone
On the other hand, diethyl ketomalonate 5f showed high
reactivity in this reaction and afforded the product 8g in 74%
yield due to the high electrophilicity of the carbonyl group
in 5f (Table 2, entry 6). As for aliphatic R-ketoesters, the
reaction of ethyl pyruvate 5g, an enolizable compound, with
1a only afforded a trace amount of product 8h (Table 2,
entry 7). However, when pyrivic acid (10) was subjected to
the reaction instead of 5g, the yield of the product 8h
increased to 55% (Table 3, entrie 8). The reaction of
oxophenylacetic acid (11) with 1b also afforded the product
8b in moderate yield (Table 2, entry 9). Furthermore, we
examined the reaction of a variety of cyclopropyl alkyl
ketones with methyl benzoylformate 5a using the standard
conditions (Table 2, entries 10-12). A series of 3-phenyl-
1,6-dioxaspiro[4.4]non-3-en-2-ones 8i-k were prepared in
moderate to good yields. In summary, the reaction was found
to be quite general for a variety of substrate with trans-
configuration selectivity in which R1, R2, and R3 could be
aromatic and aliphatic groups.
To further understand the role of H2O in the reaction, the
control experiment shown in Scheme 4 was performed, where
60 mg of 4 Å molecular sieves was introduced to a 0.2 mmol
scale reaction. As a consequence, the reaction became
sluggish and gave only a trace amount of product 8b after 1
day at 40 °C, indicating that H2O does indeed play a key
role in the initiation step of the reaction. On the other hand,
we also examined the effect of the amount of H2O on the
reaction by addition of 1.0 equiv of H2O into the reaction
system. The result showed that the yield of the corresponding
Moiety
In conclusion, we have found a reaction process involving
the sequential ring-opening reaction of cyclopropyl alkyl
ketones by H2O, followed by an aldol-type reaction, and
finally a transesterification reaction mediated by Lewis acids,
which affords an efficient synthetic protocol for the prepara-
tion of 1,6-dioxaspiro[4.4]non-3-en-2-ones. Further work
directed at elucidation of the detailed mechanisms of this
process and the application of it to the synthesis of spiro-
γ-lactone containing natural products is currently in progress.
Acknowledgment. We thank the State Key Project of
Basic Research (Project 973) (No. G2000048007), Shanghai
Municipal Committee of Science and Technology, and the
National Natural Science Foundation of China for financial
support (20472096, 203900502, and 20272069).
Supporting Information Available: The spectroscopic
and analytic data, X-ray crystal data for 8b, and a detailed
description of experimental procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL060415A
1712
Org. Lett., Vol. 8, No. 8, 2006