Novel skeleton transformation reaction of α-pyrone derivatives to spirobicyclo[3.1.0]hexane derivatives using dimethylsulfoxonium methylide

Article abstract of DOI:10.1021/ol302942m

By applying a skeleton transformation reaction using dimethylsulfoxonium methylide, a novel reaction was identified by which 5,6,7,8-tetrahydrocoumarin with the electron-withdrawing group at C3 was led to the spirobicyclo[3.1.0] hexane-cyclohexane derivative. Moreover, by establishing the scope of this reaction, it was confirmed that it is possible to apply this reaction to not only ring-fused α-pyrone derivatives but also alkyl-chain-substituted α-pyrone derivatives in moderate to good yields.

Full text of DOI:10.1021/ol302942m

ORGANIC
LETTERS
2012
Vol. 14, No. 23
6048–6051
Novel Skeleton Transformation Reaction
of r‑Pyrone Derivatives to
Spirobicyclo[3.1.0]hexane Derivatives
Using Dimethylsulfoxonium Methylide
Takuya Miura, Navnath Dnyanoba Yadav, Hiroki Iwasaki, Minoru Ozeki, Naoto Kojima,
and Masayuki Yamashita*
Kyoto Pharmaceutical University, 1 Misasagi-Shichono, Yamashina, Kyoto 607-8412,
Japan
yamasita@mb.kyoto-phu.ac.jp
Received October 25, 2012
ABSTRACT
By applying a skeleton transformation reaction using dimethylsulfoxonium methylide, a novel reaction was identified by which 5,6,7,8-
tetrahydrocoumarin with the electron-withdrawing group at C3 was led to the spirobicyclo[3.1.0]hexane-cyclohexane derivative. Moreover, by
establishing the scope of this reaction, it was confirmed that it is possible to apply this reaction to not only ring-fused R-pyrone derivatives but
also alkyl-chain-substituted R-pyrone derivatives in moderate to good yields.
The skeleton transformation reaction withdominoCꢀC
bond formation and cleavage to generate products posses-
sing different skeletons from a substrate is an attractive
tool in synthetic organic chemistry for the construction of
the basic skeleton in the target molecule. We previously
reported on a novel skeleton transformation reaction of
coumarin derivatives 1 having an electron-withdrawing
group at C3 to 2-substituted cyclopenta[b]benzofuran-3-ol
derivatives 2 by treatment with more than 2 equiv of di-
methylsulfoxonium methylide, which is Corey’s sulfur ylide
used in CoreyꢀChaykovsky cyclopropanation1 (Scheme 1).2
This reaction proceeds through the ring-opening reactiv-
ity derived from the strain of cyclopropane formed in the
CoreyꢀChaykovsky reaction. We accomplished the total
syntheses of natural products, namely, linderol A3 and
adunctin B,4 with the construction of their basic skeleton
by this transformation reaction.5,6
Herein, we describe a novel skeleton transformation
reaction, which affords 2-oxo-spirobicyclo[3.1.0]hexane
(4) Arimitsu, K.; Nomura, S.; Iwasaki, H.; Ozeki, M.; Yamashita, M.
Tetrahedron Lett. 2011, 52, 7046.
(5) Our group also reported the improvement of the skeleton transfor-
mation reaction using dimethylsulfoxonium methylide, which transformed
1,2a-disubstituted 1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-
ones to r-1,t-4a,t-9b-1,3-disubstituted 1,2,4a,9b-tetrahydrodibenzofuran-4-ols.
(6) For references of our synthesis study with the improved skeleton
transformation reaction, see: (a) Yamashita, M.; Inaba, T.; Shimizu, T.;
Kawasaki, I.; Ohta, S. Synlett 2004, 1897. (b) Yamashita, M.; Shimizu,
T.; Kawasaki, I.; Ohta, S. Tetrahedron: Asymmetry 2004, 15, 2315.
(c) Yamashita, M.; Shimizu, T.; Inaba, T.; Takada, A.; Takao, I.;
Kawasaki, I.; Ohta, S. Heterocycles 2005, 65, 1099. (d) Yamashita, M.;
Inaba, T.; Nagahama, M.; Shimizu, T.; Kosaka, S.; Kawasaki, I.; Ohta, S.
Org. Biomol. Chem. 2005, 3, 2296. (e) Yamashita, M.; Yadav, N. D.;
Sawaki, T.; Takao, I.; Kawasaki, I.; Sugimoto, Y.; Miyatake, A.; Murai,
K.; Takahara, A.; Kurume, A.; Ohta, S. J. Org. Chem. 2007, 72, 5697. (f)
Yamashita, M.; Yadav, N. D.; Sumida, Y.; Kawasaki, I.; Kurume, A.;
Ohta, S. Tetrahedron Lett. 2007, 48, 5619. (g) Yadav, N. D.; Yamashita,
M.; Nagahama, M.; Inaba, T.; Sawaki, T.; Kawasaki, I.; Kurume, A.;
Ohta, S. Tetrahedron Lett. 2008, 49, 1627. (h) Nomura, S.; Arimitsu, K.;
Yamaguchi, S.; Kosuga, Y.; Kakimoto, Y.; Komai, T.; Hasegawa, K.;
Nakanishi, A.; Miyoshi, T.; Iwasaki, H.; Ozeki, M.; Kawasaki, I.;
Kurume, A.; Ohta, S.; Yamashita, M. Chem. Pharm. Bull. 2012, 60, 94.
(1) (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1962, 84, 867.
(b) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
(2) (a) Yamashita, M.; Okuyama, K.; Kawasaki, I.; Ohta, S. Tetra-
hedron Lett. 1995, 36, 5603. (b) Yamashita, M.; Okuyama, K.; Kawajiri,
T.; Takada, A.; Inagaki, Y.; Nakano, H.; Tomiyama, M.; Ohnaka, A.;
Terayama, I.; Kawasaki, I.; Ohta, S. Tetrahedron 2002, 58, 1497.
(3) (a) Yamashita, M.; Ohta, N.; Kawasaki, I.; Ohta, S. Org. Lett.
2001, 3, 1359. (b) Yamashita, M.; Ohta, N.; Shimizu, T.; Matsumoto,
K.; Mastuura, Y.; Kawasaki, I.; Tanaka, T.; Maezaki, N.; Ohta, S.
J. Org. Chem. 2003, 68, 1216.
r
10.1021/ol302942m
Published on Web 11/19/2012
2012 American Chemical Society

derivatives from R-pyrone-3-carboxylate derivatives, using
dimethylsulfoxonium methylide. The development of this
method for the synthesis of spirocyclic cyclopropane is an
interesting challenge in synthetic and medicinal chemistry
owing to the characteristic structure and reactivity of this
cyclopropane.7 Additionally, because of the highly confor-
mationally constrained effect of cyclopropane, bicyclo[3.1.0]-
hexane is also a useful structure for medicinal chemistry.8,9 To
the best of our knowledge, the methodology for the synthesis
of such a ring system has been limited to date.8,10
dimethylsulfoxonium methylide from 2.4 equiv of trimethyl-
sulfoxonium iodide and 2.0 equiv of NaH in DMSO,12 we
obtained the novel product with 35% yield.
Scheme 3. Derivatization of 6a for Structure Determination
Scheme 1. Skeleton Transformation Reaction of Coumarin
Derivative (Our Previous Work)
The molecular formula of the product was found to be
C13H16O4 by HRMS, but it was difficult to determine the
structure of the product from 1H and 13C NMR spectral
data because they were very complex for analysis. We as-
sumed that this complexity of NMR data was due to the
equilibrium of ketoꢀenol tautomers derived from the
β-ketoester moiety of the product. Therefore, to simplify
the NMR data, the methoxymethyl (MOM) group was
introduced to the enol moiety of the product (Scheme 3).
The resulting protection of the enol moiety by the MOM
group enabled us to determine the products of the skeleton
transformation reaction as ketoꢀenol tautomers of 6a and
6a0, which are spirocyclic cyclopropane derivatives with
the bicyclo[3.1.0]hexane structure, by analysis of the spec-
Scheme 2. Transformation Reaction of 5,6,7,8-Tetrahydrocou-
marin Derivative (This Work)a
1
tral data of 7 from H NMR, 13C NMR, HMQC, and
HMBC (Figure 1). Finally, the structure and stereochem-
istry of 6a and 6a0 were confirmed as methyl (1R*,10R*,5S*)-
2,20-dioxospiro[bicyclo[3.1.0]hexane-6,10-cyclohexane]-
3-carboxylate and its enol tautomer by X-ray crystallographic
analysis of the p-bromobenzyl derivative 8 (Figure 2).
This outcome encouraged us to study this unique reaction
in detail.
a Prepared using Me3S(O)I (2.4 equiv) and NaH (2.0 equiv).
We were interested in the reactivity of dimethylsulfox-
onium methylide against 5,6,7,8-tetrahydrocoumarin 5a
possessing the methyl ester moiety as the electron-with-
drawing group at C3 (Scheme 2). The starting material 5a
was easily prepared as described in the literature,11 that
is, condensation and cyclization reaction between cyclo-
hexanone and dimethyl methoxymethylenemalonate with
LDA in THF. By treating 5a with the in situ prepared
(7) Takasu, K.; Nagamoto, Y.; Takemoto, Y. Chem, Eur. J. 2010, 16,
8427.
Figure 1. Selected HMBC in 7.
(8) Boatman, P. D.; Schrader, T. O.; Kasem, M.; Johnson, B. R.;
Skinner, P. J.; Jung, J. K.; Xu, J.; Cherrier, M. C.; Webb, P. J.; Semple,
G.; Sage, C. R.; Knudsen, J.; Chen, R.; Taggart, A. K.; Carballo-Jane,
E.; Richman, J. G. Bioorg. Med. Chem. Lett. 2010, 20, 2797.
(9) Monn, J. A.; Massey, S. M.; Valli, M. J.; Henry, S. S.; Stephenson,
G. A.; Bures, M.; Herin, M.; Catlow, J.; Giera, D.; Wright, R. A.;
Johson, B. G.; Andis, S. L.; Kingston, A.; Schoepp, D. D. J. Med. Chem.
2007, 50, 233.
First, we started to explore the optimal conditions. The
conditions were optimized by modifying the amounts of
(12) Procedure for in situ preparation of dimethylsulfoxonium methy-
lide: Trimethylsulfoxonium iodide was added in one portion to a
suspension of NaH (60% in mineral oil) in DMSO at rt, and the mixture
was stirred for 30 min under N2.
(10) Vash, D.; Hung, H. H.; Bhunia, S.; Gawade, S. A.; Das, A.; Liu,
R. S. Angew. Chem., Int. Ed. 2011, 50, 6911.
(11) Boger, D. L.; Mullican, M. D. J. Org. Chem. 1984, 49, 4033.
Org. Lett., Vol. 14, No. 23, 2012
6049

starting material on this transformation reaction (Table 2).
However, no improvement was observed in the case of
ethyl, tert-butyl, and benzyl ester derivatives 5bꢀd, as
compared with the case of the methyl ester derivative 5a.
Regarding the reaction of 5d, a benzyl ester derivative, the
product yield was the lowest and it took a longer time
to complete the reaction than in the case of other ester
derivatives. This finding revealed that the larger the ester
moiety at C3 is, the lower the yield of the product is. It was
considered that a small and electron-poor substituent
would be suitable for this reaction as an electron-with-
drawing group at C3.
Figure 2. ORTEP drawing of 8.
Table 3. Application to R-Pyrone Derivative
Table 1. Optimization of Reaction Conditions
entry
Me3S(O)I (equiv)
NaH (equiv)
yielda
1
2
3
4
5
2.4
3.0
3.8
4.8
5.0
2.0
2.5
3.2
4.0
4.0
35%
44%
73%
61%
34%
a Isolated yield of a mixture of ketoꢀenol tautomers.
Table 2. Effect of Ester Moiety on Transformation Reaction
entry
R, 5
time (h)
yield in 6a
1
2
3
4
Me, 5a
4
4
6a, 73%
6b, 59%
6c, 43%
6d, 34%
Et, 5b
tert-Bu, 5c
benzyl, 5d
4
24
a Structures were determined by transformation to the correspond-
ing MOM-protected enol derivatives.13 Isolated yield of a mixture of
ketoꢀenol tautomers.
reagents, both trimethylsulfoxonium iodide and NaH, as
shown in Table 1. Under the conditions of entry 3, dimethyl-
sulfoxonium methylide was prepared from 3.8 equiv of
trimethylsulfoxonium iodide and 3.2 equiv of NaH; the
yield of the ketoꢀenol tautomers of 6a was improved from
35% to 73%, as compared with the yield of entry 1.
a Structures were determined by transformation to the correspond-
ing MOM-protected enol derivatives.13 b Isolated yield of a mixture of
ketoꢀenol tautomers.
Next, under the optimized conditions (Table 1, entry 3),
we examined the effect of the ester moiety at C3 of the
6050
Org. Lett., Vol. 14, No. 23, 2012

bicyclo[3.1.0]hexane 6k having the 1-pentanone substitu-
ent and n-propyl tether at C6.
Scheme 4. Plausible Reaction Mechanism
The plausible mechanism of this reaction is illustrated in
Scheme 4. After cyclopropane intermediate 9 was formed
via the CoreyꢀChaykovsky reaction, the cyclopropane
ring would be opened by the attack of the additional
CH2dS(O)Me2 to give the ring-opening intermediate 10
similarly to the skeleton transformation reaction against
coumarin derivatives.2b Migration of the acidic proton
occurs, followed by the addition of the produced sulfur
ylide portion to the β-carbon in the R,β-unsaturated
carbonyl moiety. The attack of the obtained R-carbanion
and elimination of DMSO would immediately lead to the
bicyclo[3.1.0]hexane product without formation of the
enol intermediate 12 because of the lack of the conjugated
ring system as in the coumarin derivatives.2b,16 The stereo-
chemistry at the spirocenter of 6 would be controlled by
steric hindrance between the carbonyl group on the left
side and the cyclopentane ring during formation of the
spirobicyclichexane moiety as shown in 6.
In summary, we have described a novel skeleton trans-
formation reaction from R-pyrone derivatives possessing
an ester group as the electron-withdrawing group at C3 to
bicyclo[3.1.0]hexane compounds with good to moderate
yields. This reaction is interesting from the viewpoint of
obtaining products containing potentially reactive cyclo-
propane moieties, which indicates that such products
would become useful intermediates for organic synthesis.
Details about the research and further applications of this
reaction will be reported in due course.
We proposed that this unique transformation reaction
would be applied to not only 5,6,7,8-tetrahydrocoumarin
5a, which is a six-membered ring-fused R-pyrone deriva-
tive, but also other substituted R-pyrone derivatives. Under
the optimal conditions established, the scope of this trans-
formation reaction was explored against various ring-fused
R-pyrone derivatives and alkyl-chain-substituted R-pyrone
derivatives possessing an electron-withdrawing group at
C3 (Table 3). For all cases, the structures of products were
determined from the spectral data of compounds that
were prepared by introducing the MOM group to the
β-ketoester moiety on the right side of the isolated products
in order to suppress the ketoꢀenol tautomerism, and the
stereochemistry of the products was speculated from 6a.13
As expected, with the transformation reaction, five-,
seven-, and eight-membered ring-fused R-pyrone deriva-
tives 5eꢀg14 were successfully converted to correspond-
ing spirobicyclo[3.1.0]hexane products 6eꢀg in relatively
good yields, namely, 75%, 76%, and 62%, respectively
(entries 2ꢀ4). Moreover, the application to macrocyclic
ring-fused R-pyrone derivative 5h gave the corresponding
product 6h with a moderate yield (entry 5). In entries 6
and 7, heterocycle fused compounds 5i,14 j were trans-
formed to the spiro[bicyclo[3.1.0]hexane-piperidine] deri-
vative 6i and spiro[bicyclo[3.1.0]hexane-chroman] deriva-
tive 6j with moderate yields. Furthermore, in the case of a
ring-unfused substrate, an R-pyrone derivative 5k sub-
stituted with alkyl chains, an n-propyl group at C5, and
an n-butyl group at C6,15 the reaction proceeded to give
Acknowledgment. This research was supported in part
by a Strategic Research Foundation Grant-Aided Project
for Private Universities from the Ministry of Educa-
tion, Culture, Sports, Science, and Technology of Japan
(MEXT), a Grant-in-Aid for Scientific Research (C)
(22590023) from Japan Society for the Promotion of
Science (JSPS), and the Kyoto Pharmaceutical University
Fund for the Promotion of the Scientific Research. We
are very grateful to Ms. S. Fujioka in our laboratory for
assistance in synthesis.
Supporting Information Available. Experimental pro-
1
cedures, spectral data and copies of H and 13C NMR
spectra for all new compounds, and crystal information
files (CIF) for 8. This material is available free of charge
via the Internet at http://pubs.acs.org.
(13) The spectral data of MOM-protected enol derivatives are shown
in the Supporting Information.
(14) Schotten, T.; Janowski, F.; Schmidt, A.; Hinrichsen, K.;
Ammenn, J. Synthesis 2003, 2027.
(15) Ceglia, S. S.; Kress, M. H.; Nelson, T. D.; McNamara, J. M.
(16) In the case of entries 5 and 8 in Table 3, products correspond-
ing to 13 were obtained with 19% yield from 5h and a trace amount
from 5k.
Tetrahedron Lett. 2005, 46, 1731.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 23, 2012
6051