Asymmetric synthesis of bicyclo[n.1.0]alkanes by the enantioselective 1,3-CH insertion reaction of chiral magnesium carbenoids

Article abstract of DOI:10.1016/j.tetasy.2009.12.027

Treatment of enantiomerically pure 1-chlorovinyl p-tolyl sulfoxides, derived from cyclic ketones and (R)-chloromethyl p-tolyl sulfoxide, with the lithium enolate of tert-butyl carboxylates gave adducts in quantitative yields as single diastereomers. The a

Full text of DOI:10.1016/j.tetasy.2009.12.027

Tetrahedron: Asymmetry 21 (2010) 1–5
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Asymmetric synthesis of bicyclo[n.1.0]alkanes by the enantioselective
1,3-CH insertion reaction of chiral magnesium carbenoids
*
Tsuyoshi Satoh , Takayuki Kuramoto, Shingo Ogata, Hiroyuki Watanabe, Takahito Saitou, Makoto Tadokoro
Graduate School of Chemical Sciences and Technology, Tokyo University of Science, Ichigaya-funagawara-machi 12, Shinjuku-ku, Tokyo 162-0826, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of enantiomerically pure 1-chlorovinyl p-tolyl sulfoxides, derived from cyclic ketones and
(R)-chloromethyl p-tolyl sulfoxide, with the lithium enolate of tert-butyl carboxylates gave adducts in
quantitative yields as single diastereomers. The adducts were treated with i-PrMgCl in toluene to afford
optically active bicyclo[n.1.0]alkanes bearing a tert-butyl carboxylate moiety in up to 99% enantiomeric
excess through the enantioselective 1,3-CH insertion reaction of the generated chiral magnesium carbe-
noids. This is the first example of the enantioselective 1,3-CH insertion reaction of magnesium carbenoid.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 18 November 2009
Accepted 18 December 2009
Available online 3 February 2010
1. Introduction
place with high enantioselectivity. Herein we report the asymmetric
synthesis of bicyclo[n.1.0]alkanes based on the enantioselective 1,3-
Cyclopropanes in which the cyclopropane ring is fused with an-
other ring are referred to as bicyclo[n.1.0]alkanes and they are
interesting compounds. For example, LY354740, an agonist for
the group II metabotropic glutamate receptor, bears a bicy-
clo[3.1.0]hexane core structure.1 We are also interested in the syn-
thesis of fused cyclopropanes and recently a novel method for their
synthesis based on the 1,3-carbon–hydrogen insertion (1,3-CH
insertion) reaction2 of magnesium carbenoids (Scheme 1) was re-
ported.3 Thus, the reaction of 1-chlorovinyl p-tolyl sulfoxide 1,
which was derived from cyclohexanone and chloromethyl p-tolyl
sulfoxide,4 with the lithium enolates of tert-butyl carboxylates
gave adduct 2 in quantitative yield as a single diastereomer. Ad-
duct 2 was then treated with i-PrMgCl in toluene to give magne-
CH insertion reaction of chiral magnesium carbenoids.
Li
RCHCOOBu-t
R
i-PrMgCl
COOBu-t
Cl
*
*
Toluene
S(O)Tol
S(O)Tol
*
Cl
2
1
3
(single diastereomer)
R
R
1,3-CH insertion
COOBu-t
COOBu-t
*
*
*
*
MgCl
*
sium carbenoid
3
by the sulfoxide–magnesium exchange
Cl
reaction.5 Smooth 1,3-CH insertion reaction of the generated mag-
nesium carbenoid 3 took place to afford bicyclo[4.1.0]heptane
bearing a tert-butyl carboxylate moiety 4 in quantitative yield as
a single diastereomer.3
4
(single diastereomer)
Scheme 1. Synthesis of bicyclo[4.1.0]heptane 4 from 1-chlorovinyl p-tolyl sulfoxide
1 through adduct 2 with the 1,3-CH insertion reaction of magnesium carbenoid 3.
During the course of this investigation, we became aware that the
1,3-CH insertion reaction of the magnesium carbenoid 3 would pro-
ceed with high diastereoselectivity. Since the product bicy-
clo[4.1.0]heptane 4 (R = alkyl) has three stereogenic centers, if the
1,3-CH insertion reaction of the magnesium carbenoid proceeded
without diastereoselectivity, two diastereomers must be produced.
We investigated if the 1,3-CH insertion reaction of the magnesium
carbenoids proceeded enantioselectively and/or diastereoselective-
ly; indeed, the 1,3-CH insertion reaction of the magnesium carbe-
noid bearing a tert-butyl carboxylate moiety was seen to take
2. Results and discussion
At first, enantiomerically pure 1-chlorovinyl p-tolyl sulfoxide 5
was synthesized from cyclohexanone and enantiomerically pure
(R)-chloromethyl p-tolyl sulfoxide6 and it was treated with lithium
enolate of tert-butyl 4-phenylbutyrate to give adduct 6 in quantita-
tive yield as a single product.7 The absolute configuration of the
carbon bearing a 2-phenylethyl group7 and the carbon bearing a
chlorine atom8 of 6 was determined to be (R) and (S), respectively,
based on our previous studies (Scheme 2).7,8
Adduct 6 was treated with i-PrMgCl (ether solution) in toluene
at ꢀ78 °C and the temperature of the reaction mixture was slowly
* Corresponding author. Tel.: +81 3 5228 8272; fax: +81 3 5261 4631.
E-mail address: tsatoh@rs.kagu.tus.ac.jp (T. Satoh).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.12.027

2
T. Satoh et al. / Tetrahedron: Asymmetry 21 (2010) 1–5
O
S
Tol
ClH2C
O
S
(R)-chloromethyl
p-tolyl sulfoxide
H
(S)
Cl
S(O)Tol
Ph(CH2)3COOBu-t
Tol
(R)
(R)
O
3 steps
LDA, THF
-78 ºC, 5 min
Cl
COOBu-t
5
CH2CH2Ph
99%
6
H
Cl
Ha
Hb
MgCl
i-PrMgCl (in Et2O)
1,3-CH insertion
89%
oily product
[α]D28 = -41.5 (c 0.22, EtOH)
Toluene
-78 ~ 0 ºC, 2 h
COOBu-t
98%ee
CH2CH2Ph
7
CH2CH2Ph
(S)
(S)
COOBu-t
(R)
(R)
(R)
COOBu-t
CH2CH2Ph
(R)
8
9
CH-insertion between Ha
CH-insertion between Hb
Scheme 2. 1,3-CH insertion reaction of chiral magnesium carbenoid 7 derived from adduct 6 with i-PrMgCl to give optically active bicyclo[4.1.0]heptane derivative 8 or 9.
allowed to warm to 0 °C for 2 h. From this reaction was cleanly
obtained bicyclo[4.1.0]heptane bearing a tert-butyl carboxylate 8
or 9 as a single diastereomer as an oily material in 89% yield. Obvi-
ously, the intermediate of this reaction was magnesium carbenoid
7, derived from 6 by the sulfoxide–magnesium exchange reaction.
In addition, the 1,3-CH insertion reaction of magnesium carbenoid
7 took place diastereoselectively. If the 1,3-CH insertion reaction
takes place between the carbenoid carbon and Ha, 8 is the product
and when the reaction proceeds between the carbenoid carbon and
Hb, 9 is the product. Products 8 and 9 are diastereomers of each
other. The enantiomeric excess (ee) of the product was determined
to be over 98% by HPLC using the chiral stationary column (CHI-
RALCEL OD, hexane/i-PrOH = 500:1).
In order to determine the absolute configuration of the product,
we planned to derive the product to a crystalline compound. Thus,
the ester group of the product 8 or 9 was reduced with DIBAL-H to
an alcohol and then converted to 3,5-dinitrobenzoyl ester 10 with
3,5-dinitrobenzoyl chloride.9 As shown in Scheme 3, X-ray crystal-
lographic analysis revealed that ester 10 has a (1R,6R)-bicy-
clo[4.1.0]heptane core structure.10 From this result, the product
of the reaction of 6 with i-PrMgCl was proven to be 9. The mecha-
nism of this selectivity will be discussed later (vide infra).
The generality of this reaction was investigated and the results
are summarized in Scheme 4. Thus, optically active 1-chlorovinyl
p-tolyl sulfoxides 11 and 14 were synthesized from cycloheptanone
and cyclooctanone, and then treated with the lithium enolate of tert-
butyl 4-phenylbutyrate to give adducts 12 and 15, respectively, as
single products. In the case of the reaction of 14, the starting material
was recovered in 33% yield. The sulfoxide–magnesium exchange
reaction of adducts 12 and 15 with i-PrMgCl was conducted via the
same method as described above and bicyclo[5.1.0]octane 13 and
bicyclo[6.1.0]nonane 16, respectively, were cleanly obtained in
about 85% yield. The HPLC analysis of these products showed that
they were enantiomerically pure. The absolute configuration of the
products 13 and 16 was deduced from their specific rotation. From
these results, the generality of the reaction was verified.
Since we do not have a clear-cut conclusion, the reaction of
magnesium carbenoid which has a stereogenic center next to the
ester group such as 7 proceeds enantioselectively, we next at-
tempted this reaction with tert-butyl acetate and the result is
shown in Scheme 5.
At first, enantiomerically pure 1-chlorovinyl p-tolyl sulfoxide 5
was treated with the lithium enolate of tert-butyl acetate. This
reaction again gave adduct 17 in quantitative yield; however, this
CH2CH2Ph
NO2
1) DIBAL-H / Toluene
CH2O
(R)
(R)
(R)
8
9
or
O
2) 3,5-dinitrobenzoyl
chloride
NO2
10
crystalline product
[α]D27 = -4.6 (c 1.20, THF)
98%ee
Scheme 3. Derivatisation of bicyclo[4.1.0]heptane 8 or 9 to 3,5-dinitrobenzoate 10 and the crystal structure of 10.

T. Satoh et al. / Tetrahedron: Asymmetry 21 (2010) 1–5
3
O
S
H
Cl
S(O)Tol
CH2CH2Ph
COOBu-t
Tol
Ph(CH2)3COOBu-t
i-PrMgCl (in Et2O)
LDA, THF
-78 ~ -60 ºC, 30 min
Toluene
-78 ~ 0 ºC, 2 h
Cl
COOBu-t
CH2CH2Ph
12
11
13
86%
99%
[α]D30 = -26.2 (c 0.27, EtOH)
99% ee
O
S
CH2CH2Ph
H
Cl
S(O)Tol
COOBu-t
Tol
Ph(CH2)3COOBu-t
i-PrMgCl (in Et2O)
LDA, THF
-78 ~ -60 °C, 30 min
Toluene
-78 ~ 0 ºC, 2 h
COOBu-t
CH2CH2Ph
15
Cl
16
14
66%
82%
[α]D22 = -18.7 (c 0.98, EtOH)
99% ee
Scheme 4. Asymmetric synthesis of bicyclo[5.1.0]octane and bicyclo[6.1.0]nonane derivative 13 and 16 from optically active 1-chlorovinyl p-tolyl sulfoxides 11 and 14,
respectively.
O
H
(S)
H
(S)
Cl
S(O)Tol
Cl
MgCl
S
Tol CH3COOBu-t
i-PrMgCl (in Et2O)
(R)
Toluene
-78 ~ 0 ºC, 2 h
LDA, THF
-78 ºC, 5 min
CH2COOBu-t
17
CH2COOBu-t
18
Cl
5
99%
74%
Br
CH2COOBu-t
CH2CH2OTs
1) DIBAL-H
CH2CH
2N
3,6-dibromocarbazole
(S)
2) TsCl,Et3N,
DMAP, 88%
KOH, DMSO
85%
(R)
21
19
20
Br
[α]D30 = +1.7 (c 0.69, acetone)
crystalline product
30
[α]D = -18.5 (c 0.42, acetone)
92%ee
21
Scheme 5. Asymmetric synthesis of bicyclo[4.1.0]heptane derivative 19 and the crystal structure of 3,6-dibromocarbazole derivative 21, derived from 19.
time about 7% yield of a diastereomer was observed. The main ad-
duct was treated with i-PrMgCl to afford optically active bicy-
clo[4.1.0]heptane bearing a tert-butyl acetate moiety 19 in 74%
yield. The absolute stereochemistry and enantiomeric excess were
determined from 3,6-dibromocarbazole derivative 21. Thus, 19
was reduced with DIBAL-H and the resultant alcohol was tosylated
to give tosylate 20 in 88% overall yield. Tosylate 20 was treated
with 3,6-dibromocarbazole in the presence of KOH in DMSO11 to
give crystalline 21 in 85% yield. The enantiomeric excess was mea-
sured by HPLC with chiral stationary column (CHIRALPAK AD, hex-
ane/i-PrOH = 50:1) and it was found to be 92%. The absolute
stereochemistry of 21 was determined from X-ray crystallographic
analysis10 and again 21 has a (1S,6R)-bicyclo[4.1.0]heptane core
structure. From these results, we concluded that the 1,3-CH inser-
tion reaction of chiral magnesium carbenoid bearing a tert-butyl
carboxylate 18 proceeds with high enantioselectivity.
The asymmetric synthesis of bicyclo[n.1.0]alkanes bearing a
tert-butyl acetate moiety 24 starting from 1-chlorovinyl p-tolyl
sulfoxide derived from cyclopentanone 22, 11, and 14 are summa-
rized in Table 1. The enantiomeric excess of the products 24 was
again obtained from their 3,6-dibromocarbazole derivatives 26 de-
rived from 24 through tosylates 25. Table 1 shows that the enantio-
meric excess of 26 is very high, and it also indicates that the
enantiomeric excess of 24 is also very high.

4
T. Satoh et al. / Tetrahedron: Asymmetry 21 (2010) 1–5
Table 1
Asymmetric synthesis of bicyclo[n.1.0]alkane derivatives 24 and transformation of them to 3,6-dibromocarbazole derivatives 26
O
H
(S)
Cl
CH3COOBu-t
S(O)Tol
i-PrMgCl (in Et2O)
CH2COOBu-t
(S)
S
Tol
(R)
(R)
m
LDA, THF
Toluene
CH2COOBu-t
23
m
Cl
m
24
11
m = 3
Br
Br
14 m = 4
22
m = 1
1) DIBAL-H
CH2CH2OTs
3,6-dibromocarbazole
KOH, DMSO
CH2CH2N
2) TsCl, Et3N
DMAP
m
m
25
26
Entry
1-Chlorovinyl p-tolyl sulfoxide
23
Bicyclo[n.1.0]alkane 24
26
Yield (%)
Yield (%)
74
[
a
]
(in acetone)
ee (%)
96
[
a
]
(in acetone)
D
D
S(O)Tol
½
a 2D9
ꢁ
¼ ꢀ4:9 (c 0.39)
½
a 2D8
ꢁ
¼ ꢀ22:2 (c 0.33)
1
2
85
99
Cl
22
S(O)Tol
Cl
½
a 3D0
ꢁ
¼ ꢀ56:6 (c 0.52)
¼ ꢀ86:8 (c 0.45)
½
a 3D0
ꢁ
¼ ꢀ20:1 (c 0.44)
¼ ꢀ24:2 (c 0.42)
77
84
99
99
11
S(O)Tol
½
a 3D1
ꢁ
½
a 3D0
ꢁ
3
99
Cl
14
Hb
H
cally to the carbon–chlorine bond, the 1,3-CH insertion reaction
hardly takes place and ent-19 is rarely produced.
t-BuO
(R)
(S)
Mg
Cl
H
3. Conclusion
O
Ha
Cl
In conclusion, the asymmetric synthesis of bicyclo[n.1.0]alkanes
bearing a tert-butyl carboxylate moiety was realized based on the
enantioselective 1,3-CH insertion reaction of chiral magnesium
carbenoids. This is the first example of the enantioselective 1,3-
CH insertion reaction of magnesium carbenoid. The procedure pre-
sented herein will contribute greatly to the synthesis of optically
active bicyclo[n.1.0]alkanes and the asymmetric synthesis by using
chiral sulfoxides.
COOBu-t
18
19
Hb
H
t-BuO
(R)
(S)
Mg
H
O
Ha
Cl
COOBu-t
ent-19
Cl
Acknowledgements
18
This work was supported by a Grant-in-Aid for Scientific Re-
search No. 19590018 from the Ministry of Education, Culture,
Sports, Science and Technology, Japan, and TUS Grant for Research
Promotion from Tokyo University of Science, which are gratefully
acknowledged.
Figure 1.
Finally, a plausible mechanism for this enantioselective magne-
sium carbenoid 1,3-CH insertion reaction is proposed as shown in
Figure 1. Since the sulfoxide–magnesium exchange reaction is
known to take place with retention of configuration of the carbon
bearing a sulfinyl group,12 treatment of 17 with i-PrMgCl gives
magnesium carbenoid with an (S)-configuration 18. The magne-
sium and carbonyl oxygen atom of the tert-butyl ester group make
six-membered intermediate. The carbon–hydrogen(Hb) bond of
the methylene attacks the carbenoid carbon from backside of the
carbon–chlorine bond to give 19.13 On the other hand, as the car-
bon–hydrogen(Ha) bond of the methylene is placed almost verti-
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