Synthesis of 1-acetyl-2-silyoxycycloheptane derivatives via highly stereoselective formal [5+2] cycloaddition reaction

Article abstract of DOI:10.1016/j.tetlet.2013.12.102

A stereoselective [5+2] cycloaddition reaction using a new five-carbon unit, that has a dicobalt acetylene complex moiety and an enol silyl ether moiety, was developed. In the presence of a Lewis acid, the five-carbon unit reacted with an enol triisopropylsilyl ether to give a 1-acetyl-2- silyoxycycloheptane derivative, in which the three contiguous substituents on the seven-membered ring arrange cis to each other.

Full text of DOI:10.1016/j.tetlet.2013.12.102

Tetrahedron Letters 55 (2014) 1192–1195
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 1-acetyl-2-silyoxycycloheptane derivatives
via highly stereoselective formal [5+2] cycloaddition reaction
Mami Kudo a, Fumikatsu Kondo a, Hideki Maekawa a, Tadashi Shimizu b, Masaaki Miyashita a,
Keiji Tanino a,
⇑
a Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
b Department of Pharmacy, Hyogo University of Health Sciences, Minatojima Chuo-ku, Kobe 650-8530, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective [5+2] cycloaddition reaction using a new five-carbon unit, that has a dicobalt acetylene
complex moiety and an enol silyl ether moiety, was developed. In the presence of a Lewis acid, the five-
carbon unit reacted with an enol triisopropylsilyl ether to give a 1-acetyl-2-silyoxycycloheptane deriva-
tive, in which the three contiguous substituents on the seven-membered ring arrange cis to each other.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 25 November 2013
Revised 25 December 2013
Accepted 26 December 2013
Available online 3 January 2014
Keywords:
Cycloheptane
Dicobalt acetylene complex
Cycloaddition reaction
Enol silyl ether
There are a number of natural compounds containing a cyclo-
heptane ring with various kinds of substituents. The [4+3] cycload-
dition reaction1 of dienes or furan derivatives with allyl cationic
species represents an efficient method for constructing seven-
membered carbocycles, but much less attention has been paid to
the [5+2]-type reactions.2 We have developed dicobalt acetylene
complex 1 and its analogues as useful five-carbon units in the for-
mal [5+2] cycloaddition reaction with enol silyl ethers3a,b or sily-
loxyallenes3c (Scheme 1).
The reaction proceeds through intermolecular addition of cat-
ionic species A with an enol silyl ether followed by the intramolec-
ular cyclization of silyloxonium ion B to give cycloheptanone
derivative 24 in a stereoselective fashion.5 These results led us to
develop a new synthetic method for polysubstituted cycloheptane
derivatives through another type of formal [5+2] cycloaddition
reaction (Scheme 2).
Thus, the use of dicobalt acetylene complex 3 as a five-carbon
unit would afford cycloheptane derivative 4 through the stepwise
addition reaction involving cationic intermediates C and D.6 It
should be noted that cycloadduct 4 possesses the ketone moiety
as one of the three substituents on the seven-membered ring,
while the ketone moiety of the cycloadduct 2 in Scheme 1 is
incorporated in the carbocycle. Therefore, the utility of the new
[5+2]-type reaction depends on the stereoselectivity at the three
contiguous stereogenic centers in cycloadduct 4. We report herein
the highly stereoselective formal cycloaddition reaction of
five-carbon unit 3 and its analogue with enol silyl ethers.
The new five-carbon unit was synthesized in only two steps as
shown in Scheme 3. Methyl vinyl ketone was subjected to the
conjugate addition reaction with organocopper reagent 5,7 which
was prepared by successive treatment of methyl propargyl ether
with butyllithium and copper(I) thiocyanate, in the presence of
tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf). The
resulting enol silyl ether 6 was then reacted with Co2(CO)8 to
afford the desired dicobalt acetylene complex 7.8 Although both
of the enol silyl ethers 6 and 7 were found to readily undergo
TIPSO
O
OTIPS
OTIPS
R
EtAlCl2
CH2Cl2
(CO)3Co
(CO)3Co
+
(CO)3Co
(CO)3Co
R
OBz
i
1
2
(TIPS = Pr3Si)
TIPSO
TIPSO
OTIPS
R
OTIPS
(CO)3Co
(CO)3Co
(CO)3Co
(CO)3Co
R
A
B
⇑
Corresponding author.
E-mail address: ktanino@sci.hokudai.ac.jp (K. Tanino).
Scheme 1. Cycloheptanone synthesis via a formal [5+2] cycloaddition reaction of
dicobalt acetylene complex 1.
0040-4039/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.102

M. Kudo et al. / Tetrahedron Letters 55 (2014) 1192–1195
1193
Table 1
Stereoselective synthesis of cycloheptane derivatives by formal [5+2] cycloaddition
reactionsa,b
Entry
1
Enol silyl ether
Product
Yield (%)
69
2
3
4
5
6
77
70
76
86
78
Scheme 2. Formal [5+2] cycloaddition reaction of a new five-carbon unit leading to
substituted cycloheptanes.
Scheme 3. Preparation of the new five-carbon unit 7.
autooxidation of the allylic methylene group, addition of a small
amount of 2,6-di-tert-butyl-4-methylphenol (BHT) effectively
reduced the side reaction.
The reactions of dicobalt acetylene complex 7 and enol silyl
ethers derived from the corresponding aldehydes were examined
under the influence of ethylaluminum dichloride (Table 1).9
Gratifyingly, the formal [5+2] cycloaddition reaction proceeded at
0 °C in good yield, and the desired products were obtained in a
highly stereoselective manner. The stereochemistry of the cyclo-
heptane derivative was determined by 1H NMR spectra. Thus, the
a
The general procedure is described in Ref. 9.
Minor diastereomers were not detected by proton NMR spectra.
b
very small vicinal coupling constants10 between the
a-protons of
the three substituents indicated that these substituents are all cis
to each other (entries 1–5). The reaction of 7 with the enol silyl
ether derived from isobutyraldehyde also occurred smoothly to af-
ford a cycloheptane derivative 4f having a quaternary carbon atom
as a single diastereomer (entry 6).
The stereochemical outcome of the cycloaddition reaction can
be rationalized by the transition state models which correspond
to the intramolecular cyclization step of the silyloxonium ion inter-
mediate D in Scheme 2. Taking into account the rigidity as well as
the bulkiness of the cobalt complex moiety,11 transition state mod-
els in which the R group occupies an equatorial position can be de-
picted (Fig. 1). In these models, D-2 would suffer from the serious
steric repulsion between the two bulky silyl groups, while D-3 hav-
ing the enol silyl ether at the pseudo axial position would also be
disfavored. Therefore, the diastereomer with all-cis substituents
is formed through transition state D-1.
As was reported previously, the cyclic dicobalt acetylene com-
plexes can be transformed into useful compounds in one step
(Scheme 4). For example, cycloaddition product 4b underwent
Figure 1. Suggested transition state models for the cyclization step.

1194
M. Kudo et al. / Tetrahedron Letters 55 (2014) 1192–1195
formation of the product as a mixture of four diastereomers. The
reaction under the previous conditions using ethylaluminum
dichloride at 0 °C (Method A) gave the desired bicyclic ketone 12
in moderate yield along with by-product 13 which arose from desi-
lylation of the silyloxonium ion intermediate. We found, however,
that the reaction under the influence of titanium(IV) chloride pro-
ceeds even at À78 °C (Method B), giving rise to the desired product
12 in 93% yield as a single diastereomer. The reaction of six-mem-
bered substrate 11 by adopting Method B resulted in the formation
of bicyclic ketone 14 in good yield. Judging from the coupling
constants in the 1H NMR spectra, compound 12 possessed a
cis-fused 5–7 skeleton, and the configuration of the 6–7 bicyclic
system of 14 was suggested to be trans. Although the origin of
the different stereochemical outcome depending on the ring size
of the substrates is not clear, the present cycloaddition reaction
shows promise for constructing highly substituted bicyclic systems
in short steps.
Scheme 4. Transformation of the cyclic dicobalt acetylene complex.
In summary, we have developed an efficient method for the
synthesis of substituted cycloheptane derivatives on the basis of
a formal [5+2] cycloaddition reaction. The five-carbon unit 7, a
dicobalt acetylene complex possessing a leaving group and an enol
silyl ether moiety, was prepared from commercially available com-
pounds in only two steps. Under the influence of a Lewis acid, the
cobalt complex reacted with enol triisopropylsilyl ethers to afford
cycloheptane derivatives having three substituents as a single dia-
stereomer. The formal [5+2] cycloaddition reaction was applied to
construct bicyclic skeleton, and applications in total synthesis of
polycyclic natural compounds are under investigation.
Acknowledgments
This work was partially supported by the Grant-in-Aid for
Scientific Research on Innovative Areas (Project No. 2105: Organic
Synthesis Based on Reaction Integration) from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
References and notes
1. For reviews on [4+3] cycloaddition strategy, see: (a) Rigby, J. H.; Pigge, F. C. In
Organic Reactions; Paquette, L. A., Ed.; ; John Wiley & Sons: New York, 1997; 51,
pp 351–476; (b) Harmata, M. Chem. Commun. 2010, 8886–8903; (c) Harmata,
M. Chem. Commun. 2010, 8904–8922.
2. For a recent review on [5+2] cycloaddition strategy: Pellissier, H. Adv. Synth.
Catal. 2011, 353, 189–218.
3. The authors reported another type of [5+2] cycloaddition strategy: (a) Tanino,
K.; Shimizu, T.; Miyama, M.; Kuwajima, I. J. Am. Chem. Soc. 2000, 124, 6116–
6117; (b) Tanino, K.; Kondo, F.; Shimizu, T.; Miyashita, M. Org. Lett. 2002, 4,
2217–2219; (c) Mitachi, K.; Yamamoto, T.; Kondo, F.; Shimizu, T.; Miyashita,
M.; Tanino, K. Chem. Lett. 2010, 39, 630–632.
4. For a review on seven-membered dicobalt acetylene complexes, see: Green, J.
R. Synlett 2012, 1271–1282.
5. This type of transformation is classified as ‘time and space integration of
reactions’ where all reaction components are mixed at once to perform a
sequence of reactions in one-pot Yoshida, J.; Saito, K.; Nokami, T.; Nagaki, A.
Synlett 2011, 1189–1194.
Scheme 5. Synthesis and reactions of dicobalt acetylene complexes with a cyclic
enol silyl ether moiety.
6. Since the silyloxonium ion intermediate D should survive without desilylation
during the stepwise reaction, enol silyl ethers with a bulky TIPS group were
employed as the two-carbon units. In contrast, the R3Si group of five-carbon
unit 3 should be smoothly removed after the cyclization step, which led us to
use a TBS group for preparing the five-carbon unit.
reductive decomplexation12 by refluxing with tributyltin hydride
in benzene to afford the corresponding cycloheptene 8. On the
other hand, oxidation of 4b with cerium(IV) ammonium nitrate re-
sulted in the formation of maleic anhydride 9 in high yield.3,13
Next, the formal [5+2] cycloaddition reaction was applied to the
synthesis of bicyclic compounds. New five-carbon units 10 and 11
having a cyclic enol silyl ether moiety were prepared from the cor-
responding 2-cycloalken-1-ones through a similar method for the
synthesis of 7 (Scheme 5).7
In these cases, the use of 2,6-lutidine instead of BHT was found
to give better results, because the enol silyl ethers tend to undergo
hydrolysis rather than autooxidation.
The enol silyl ether derived from isobutyraldehyde was chosen
as the coupling partner with cobalt complex 10, so as to avoid the
7. Similar conjugate addition reactions using a zinc acetylide were reported: Kim,
S.; Lee, J. M. Tetrahedron Lett. 1990, 31, 7627–7630.
8. Preparation of five-carbon unit 7: To a solution of methyl propargyl ether
(2.55 mL, 30.0 mmol) in THF (80 mL) was added n-BuLi (11.0 mL, 30 mmol,
2.77 M solution in hexane) at À78 °C. After being stirred for 10 min at room
temperature, the solution of lithium acetylide was added via cannula to a
suspension of CuSCN (3.65 g, 30.0 mmol) in ether (80 mL) at À78 °C. After
being stirred for 2 h, the resulting heterogeneous mixture was added via
cannula to a solution of tert-butyldimethylsilyl triflate (5.0 mL, 22.0 mmol) and
methyl vinyl ketone (1.63 mL, 20.0 mmol) in ether (80.0 mL) at À78 °C. The
reaction mixture was stirred at the same temperature for 2 h, and to this was
added 28% aqueous NH3 solution. The mixture was separated, and the aqueous
layer was extracted three times with ether. The combined organic layer was
washed with brine and dried over MgSO4. Concentration under reduced

M. Kudo et al. / Tetrahedron Letters 55 (2014) 1192–1195
1195
pressure followed by purification by silica gel column chromatography gave
enol silyl ether 6 (2.92 g, 11.5 mmol, 57%) as a pale yellow oil. 1H NMR
(500 MHz, CDCl3) E isomer: d 4.38 (t, J = 6.9 Hz, 1H), 3.98 (s, 2H), 3.26 (s, 3H),
2.86 (dd, J = 6.9, 1.1 Hz, 2H), 1.68 (d, J = 1.1 Hz, 3H), 0.95 (s, 9H), 0.15 (s, 6H).
With the peaks due to a small amount of Z isomer at: d 4.58 (t, J = 7.5 Hz, 1H),
4.07 (s, 2H), 3.30 (s, 3H), 2.77 (d, J = 7.5 Hz, 2H), 1.62 (s, 3H), 0.92 (s, 9H), 0.13
ether (0.50 mmol) and cobalt complex
(2.0 mL) via cannula at 0 °C. After being stirred for about 10 min at 0 °C, the
7
(270 mg, 0.50 mmol) in CH2Cl2
reaction mixture was quenched with saturated aqueous Roschell’s salt
a
solution. The mixture was stirred at room temperature vigorously for 1 h under
argon atmosphere. The mixture was separated, and the aqueous layer was
extracted with ether. The combined organic layer was washed with brine and
dried over MgSO4. Concentration under reduced pressure followed by
purification by silica gel column chromatography gave the [5+2]
(s, 6H). To
a solution of Co2(CO)8 (4.12 g, 12.1 mmol) and BHT (0.13 g,
0.57 mmol) in CH2Cl2 (37 mL) was added a solution of 6 (2.92 g, 11.5 mmol)
in CH2Cl2 (35 mL) at room temperature. After being stirred for 1 h, the mixture
was filtered through a pad of celite. Concentration under reduced pressure
followed by purification by silica gel column chromatography afforded cobalt
complex 7 (6.20 g, 11.5 mmol, 100%) as a dark brown oil. 1H NMR (500 MHz,
CDCl3) E isomer: d 4.59 (s, 2H), 4.55 (t, J = 6.9 Hz, 1H), 3.56 (d, J = 6.9 Hz, 2H),
3.50 (s, 3H), 1.80 (s, 3H), 0.91 (s, 9H), 0.16 (s, 6H). With the peaks due to a small
amount of Z isomer at: d 4.65 (s, 2H), 4.80 (t, J = 6.3 Hz, 1H), 4.59 (s, 2H), 3.50 (s,
3H), 3.49 (d, J = 6.3 Hz, 2H), 1.80 (s, 3H), 0.91 (s, 9H), 0.16 (s, 6H) With the peaks
due to a small amount of Z isomer at: d 4.65 (s, 2H), 4.80 (t, J = 6.3 Hz, 1H), 4.59
(s, 2H), 3.50 (s, 3H), 3.49 (d, J = 6.3 Hz, 2H), 1.80 (s, 3H), 0.91 (s, 9H), 0.16 (s, 6H).
9. General procedure: To a mixture of EtAlCl2 (1.04 M solution of hexane, 0.96 mL,
1.0 mmol) in CH2Cl2 (3.0 mL) was added a solution of an enol triisopropylsilyl
cycloaddition product as
a
dark brown oil. The data for 4e: 1H NMR
(500 MHz, CDCl3) d 5.10 (t, J = 7.1 Hz, 1H), 3.72 (s, 1H), 3.41 (dd, J = 16.1,
13.2 Hz, 1H), 3.15 (d, J = 16.1 Hz, 1H), 2.94 (dd, J = 15.5, 12.1 Hz, 1H), 2.90 (dd,
J = 15.5, 13.2 Hz, 1H), 2.47 (d, J = 12.1 Hz, 1H), 2.28 (m, 2H), 2.25 (s, 3H), 2.19
(m, 1H), 1.73 (s, 3H), 1.61 (s, 3H), 1.05 (m, 21H).
10. In general, the a
-methyne proton of the silyloxy group in the 1H NMR spectra
of cycloaddition products appears as a singlet. For example, see the data for 4e
in Ref. 6.
11. Cotton, F. A.; Jamerson, J. D.; Stults, B. R. J. Am. Chem. Soc. 1976, 98, 1774–1779.
12. Hosokawa, S.; Isobe, M. Tetrahedron Lett. 1998, 39, 2609–2612.
13. Mitachi, K.; Shimizu, T.; Miyashita, M.; Tanino, K. Tetrahedron Lett. 2010, 51,
3983–3986.