Stereoselective synthesis of medium-sized cyclic compounds through the intramolecular michael-type reaction utilizing alkyne-hexacarbonyldicobalt complex formation

Article abstract of DOI:10.1246/cl.2007.474

Alkyne-hexacarbonyldicobalt complexes having silyl enol ether and electron-deficient alkene moieties on opposite ends were treated with MeAlCl₂ in the presence of 2,6-di-t-butylpyridine in CH ₂Cl₂ to give synthetically use

Full text of DOI:10.1246/cl.2007.474

474
Chemistry Letters Vol.36, No.3 (2007)
Stereoselective Synthesis of Medium-sized Cyclic Compounds through the Intramolecular
Michael-type Reaction Utilizing Alkyne–Hexacarbonyldicobalt Complex Formation
Kennichi Inaba, Jun Takaya, and Nobuharu Iwasawaꢀ
Department of Chemistry, Tokyo Institute of Technology, 2-12-1-E1-2 Ookayama, Meguro-ku, Tokyo 152-8551
(Received January 15, 2007; CL-070053; E-mail: niwasawa@chem.titech.ac.jp)
Alkyne–hexacarbonyldicobalt complexes having silyl enol
Table 1. Intramolecular Michael addition reaction of alkyne–
Co2(CO)6 complex 1
ether and electron-deficient alkene moieties on opposite
ends were treated with MeAlCl2 in the presence of 2,6-di-t-
butylpyridine in CH2Cl2 to give synthetically useful medium-
sized cyclic products as a single stereoisomer in good yield.
OTBS
MeAlCl2 (2.0 equiv.)
Co(CO)3
Co(CO)3
DTBP (0.1 equiv.)
Ph
CH2Cl2, temp.
O
1
Stereoselective formation of medium-sized ring compounds
is still a formidable challenge due to the difficulty both in the me-
dium-sized ring closure and in controlling the stereochemistry of
the products.1,2 We previously reported a novel bridged-type
[4 + 2]-cycloaddition reaction of alkyne–hexacarbonyldicobalt
complexes containing siloxydiene and electron-deficient alkene
moieties, where the reaction was found to proceed stereoselec-
tively through double-Michael type reaction with formation of
medium-sized ring.3 From the synthetic point of view, it is high-
ly desirable to establish an efficient method for the stereoselec-
tive construction of medium-sized monocyclic carbon skeleton
with multi-functional groups, which would enable further useful
transformations. In this paper, we would like to report the stereo-
selective preparation of such compounds through the Michael-
type ring closure, where perfect selectivity was realized by
the geometry of the silyl enol ether moiety and the presence of
alkyne–hexacarbonyldicobalt moiety.4
When an alkyne–hexacarbonyldicobalt complex 1 contain-
ing (Z)-silyl enol ether and electron-deficient alkene moieties
was treated with 2 equiv. of MeAlCl2 in the presence of DTBP
(2,6-(di-t-butyl)pyridine)5 at ꢁ78 ꢂC in CH2Cl2, the desired
cyclized products were obtained as a mixture of silyl enol ether
26 and its hydrolyzed ketone 3 in the combined yield of 70%
(Table 1, Entry 1). Both of the products were obtained as a single
stereoisomer with the same relative stereochemistry,7 whose
structure was determined based on the X-ray crystal structure
analysis of a compound derived from 3. Longer reaction time
increased the amount of the silyl enol ether 2, while the reaction
at ꢁ40 ꢂC gave the hydrolyzed ketone 3 as the major product.8
In both cases, the products were obtained as a single cis isomer
(Table 1, Entries 2 and 3). Interestingly, when a mixture (80:20)
of (Z)- and (E)-silyl enol ether 1 was subjected to the same reac-
tion conditions, the product 2 was obtained as a diastereomeric
mixture (cis:trans = 76:24) (Table 1, Entry 4). These results
suggest that the stereoselectivity of this reaction is dependent
on the geometry of the silyl enol ether part.9
O
O
Co(CO)3
Co(CO)3
Co(CO)3
Ph
Ph
+
Co(CO)3
OTBS
O
2
3
Product 2
(cis:trans)
Product 3
(cis:trans)
Entry (Z)-1:(E)-1
Conditions
1
2
3
4
>95:5
>95:5
>95:5
ꢁ78 ꢂC, 14.5 h 33%(>95:5) 37%(>95:5)
ꢁ78 ꢂC, 43.5 h 73%(>95:5) 6%(>95:5)
ꢁ40 ꢂC, 16.5 h 8%(>95:5) 61%(>95:5)
80:20 ꢁ78 ꢂC, 24.5 h 68%(76:24)
trace
good yield but as a mixture of diastereoisomers (Scheme 1).11
As the reaction of the corresponding alkyne–hexacarbonyldico-
balt complex (Z)-1 at ꢁ40 ꢂC still gave a single stereoisomer of
products 2 and 3 (Table 1, Entry 3), there is apparent difference
of stereoselectivity between the alkyne–hexacarbonyldicobalt
complex 1 and its alkene derivative 4. Thus, it was confirmed
that the alkyne–hexacarbonyldicobalt moiety has both accelerat-
ing effect on the reaction rate and higher control over the stereo-
selectivity of the reaction. As (Z)-silyl enol ether moiety could
be easily prepared with more than 95:5 selectivity using
TBSOTf in the presence of 2,6-lutidine as a base, this protocol
would be a useful method for the stereoselective preparation
of medium-sized compounds.
OTBS
O
MeAlCl2 (2.0 equiv.)
DTBP (0.1 equiv.)
CH2Cl2, -40 °C, 26 h
Ph
Ph
SiEt3
SiEt3
O
O
4
5
84% (cis:trans = 81:19)
Scheme 1. Intramolecular Michael addition reaction of olefinic
substrate 4.
We next examined the generality of this stereoselective
preparation of medium-sized alkyne–hexacarbonyldicobalt
complex. As summarized in Table 2, this reaction showed good
generality and not only ꢀ-methyl-substituted derivative, but also
ꢀ-ethyl-substituted and ꢁ-methyl-substituted derivatives 6a and
6b gave the corresponding products in good yield stereoselec-
tively (Entries 1 and 2).12 Furthermore, the silyl enol ether 6c de-
rived from isopropyl ketone could also be applied to this reaction
without problem (Entry 3).12 Related 7 and 9-membered prod-
To confirm the role of the alkyne–hexacarbonyldicobalt
moiety for this reaction, the reaction of a corresponding olefinic
substrate was examined. The substrate (Z)-1 was transformed
into its silylated alkene derivative (Z)-4 according to the Isobe’s
protocol for this purpose.10 Although the reaction of the alkene
derivative (Z)-4 did not proceed to an appreciable amount
at ꢁ78 ꢂC (2 equiv. MeAlCl2, 0.1 equiv. DTBP, CH2Cl2), the
reaction at ꢁ40 ꢂC proceeded to give the cyclized product 5 in
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.3 (2007)
475
Table 2. Generality of the reaction
This research was partly supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology of Japan. We are grateful to
Tosoh Finechem Corporation for a generous gift of MeAlCl2.
OTBS
MeAlCl2 (2.0 equiv.)
DTBP (0.1 equiv.)
(
)
n Co(CO)3
R
CH2Cl2, –78 °C, time
R"
Co(CO)3
R'
O
References and Notes
6
O
R
O
(
)
( )
nCo(CO)3
Co(CO)3
n Co(CO)3
Co(CO)3
1
For a review on medium-sized ring formation, see: a) L. Yet,
Chem. Rev. 2000, 100, 2963. b) G. Mehta, V. Singh, Chem.
Rev. 1999, 99, 881. c) L. Yet, Tetrahedron 1999, 55, 9349.
There are only a few reports on the intramolecular Michael
reaction, in particular, endo-mode of cyclization, to give
medium-sized products. See for examples: a) G. Berthiaume,
R
+
R"
R'
R"
O
R'
OTBS
2
7
8
Substrate 6
R0 R00
Product 7 Product 8
Yield/% Yield/%
Entry
1
Time/h
R
n
´
J.-F. Lavallee, P. Deslongchamps, Tetrahedron Lett. 1986,
27, 5451. b) J. Christoffers, H. Oertling, Tetrahedron 2000,
56, 1339. c) T. J. Greshock, R. L. Funk, J. Am. Chem. Soc.
2002, 124, 754. d) T. J. Greshock, R. L. Funk, Tetrahedron
Lett. 2006, 47, 5437.
N. Iwasawa, K. Inaba, S. Nakayama, M. Aoki, Angew.
Chem., Int. Ed. 2005, 44, 7447; See also, N. Iwasawa, F.
Sakurada, M. Iwamoto, Org. Lett. 2000, 2, 871.
For recent examples on utilization of alkyne–Co2(CO)6 com-
plexes for medium-sized ring formation, see: a) N. Iwasawa,
H. Satoh, J. Am. Chem. Soc. 1999, 121, 7951. b) K. Tanino,
F. Kondo, T. Shimizu, M. Miyashita, Org. Lett. 2002, 4,
2217. c) D. G. J. Young, J. A. Burlison, U. Peters, J. Org.
Chem. 2003, 68, 3494. d) T. Baba, S. Takai, N. Sawada,
M. Isobe, Synlett 2004, 603. e) N. Ortega, T. Martin, V. S.
Martin, Org. Lett. 2006, 8, 871. f) J. DiMartino, J. R. Green,
Tetrahedron 2006, 62, 1402, references cited therein.
P. V. Bonnesen, C. L. Puckett, R. V. Honeychuck, W. H.
Hersh, J. Am. Chem. Soc. 1989, 111, 6070.
6a Ph
H
Et
H
1
1
35.3
11.5
7a
7b
7c
7d
7e
69
41
61
30
29
8a
8b
8c
8d
8e
10
0
0
43
47
2a 6b Ph Me
3
6c i-Pr
4a 6d Ph
6e Ph
H
H
H
Me 1 48
Me 0 44
Me 2 16.5
3
4
5
aThis reaction was carried out at ꢁ40 ꢂC.
ucts were obtained in good yield as a single diastereoisomer12
(Entries 4 and 5). It should be noted that 9-membered ring prod-
uct, which belongs to the most difficult ring size to prepare,
could be obtained in good yield stereoselectively by this method.
Finally, the demetallation reaction of the cyclized product 3
was examined. Although the reaction was not fully optimized,
treatment of the product 3 with Et3SiH (10 equiv. Et3SiH, 5
equiv. bis(trimethylsilyl)acetylene, 65 ꢂC, ClCH2CH2Cl)10 gave
the silylated cyclooctenone derivative 5, while simple heating of
3 in toluene–H2O3 gave the cyclooctenone derivative 9 in rea-
sonable yield (Scheme 2). Thus, this cyclization–demetallation
reaction would be a useful method for the stereoselective synthe-
sis of these medium-sized cyclic compounds.
5
6
Geometry of the silyl enol ether part was determined to be
(E) by the NOE experiment.
Mild acid treatment of 2 gave 3 in good yield.
7
8
It is likely that the aluminum enolate produced by the
Michael addition was slowly silylated at ꢁ78 ꢂC, but we
are not certain why the hydrolyzed ketone 3 was obtained
as the major product at ꢁ40 ꢂC.
O
O
Et3SiH
Co(CO)3
Co(CO)3
TMS
TMS
Ph
Ph
DCE, 65 °C, 19 h
SiEt3
O
O
3-cis
5-cis
9
In the Lewis acid promoted intermolecular Michael addition
reaction of silyl enol ethers, both (E)- and (Z)-isomers
usually give the same syn isomer through open-transition
structure.
53%
O
O
Co(CO)3
Co(CO)3
Ph
Ph
10 S. Takai, P. Ploypradith, A. Hamajima, K. Kira, M. Isobe,
Synlett 2002, 588.
11 These compounds coincided with those derived from 3 by
the Isobe’s protocol.10
H2O/toluene
reflux, 1.5 h
O
O
3-cis
9
57%
12 All the products obtained here are single diastereoisomers.
Stereochemistry of 8e was determined to be cis based on
X-ray analysis of a compound derived from 8e. 7e was
hydrolyzed to give 8e. Although obvious determination has
not yet been achieved, 8-membered ring products 7a, 7c
and 8a, 8c were thought to have the same cis stereochemistry
as 2 and 3. The stereochemistry of the 7-membered ring
products 7d and 8d has not yet been determined.
Scheme 2. Demetallation reactions of cycloadduct 3.
In conclusion, we have developed a concise method for
the stereoselective preparation of the medium-sized cyclic
compounds utilizing alkyne–hexacarbonyldicobalt complex
formation. Synthetically useful medium-sized ring skeletons
with multiple functionalities could be prepared stereoselectively
by this procedure.
Published on the web (Advance View) February 24, 2007; doi:10.1246/cl.2007.474