Synthesis, including asymmetric synthesis, of 3-oxabicyclo[3.1.0]hexanes and bicyclo[3.1.0]hexanes by the 1,5-CH insertion of cyclopropylmagnesium carbenoids as the key reaction

Article abstract of DOI:10.1016/j.tet.2011.11.085

The addition reactions of α,β-unsaturated carbonyl compounds with dichloromethyl p-tolyl sulfoxide in the presence of NaHMDS or LDA resulted in the formation of adducts, 1-chlorocyclopropyl p-tolyl sulfoxides bearing a carbonyl group at the 2-position, in almost quantitative yields. The carbonyl group of the adducts was transformed to various ether groups to give 1-chlorocyclopropyl p-tolyl sulfoxides bearing an ether functional group at the 2-position in short steps. Treatment of these products with i-PrMgCl at low temperature afforded cyclopropylmagnesium carbenoids via the sulfoxide-magnesium exchange reaction. 1,5-Carbon-hydrogen insertion (1,5-CH insertion) reaction of the generated magnesium carbenoid intermediates took place to give 3-oxabicyclo[3.1.0]hexanes or bicyclo[3.1.0]hexanes bearing an ether group at the 4-position in moderate to good yields. When this procedure was carried out starting with enantiopure dichloromethyl p-tolyl sulfoxide, enantiopure 3-oxabicyclo[3.1.0]hexanes were obtained in good overall yields. These procedures provide a good way for the synthesis, including asymmetric synthesis, of multisubstituted 3-oxabicyclo[3.1.0]hexanes and bicyclo[3.1.0]hexanes from α,β-unsaturated carbonyl compounds and dichloromethyl p-tolyl sulfoxide in short steps.

Full text of DOI:10.1016/j.tet.2011.11.085

Tetrahedron 68 (2012) 1071e1084
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis, including asymmetric synthesis, of 3-oxabicyclo[3.1.0]hexanes
and bicyclo[3.1.0]hexanes by the 1,5-CH insertion of cyclopropylmagnesium
carbenoids as the key reaction
*
Tsuyoshi Satoh , Takahiro Tsuru, Shotaro Ikeda, Toshifumi Miyagawa, Hitoshi Momochi, Tsutomu Kimura
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:
Received 31 October 2011
Received in revised form 25 November 2011
Accepted 26 November 2011
Available online 2 December 2011
The addition reactions of a,b-unsaturated carbonyl compounds with dichloromethyl p-tolyl sulfoxide
in the presence of NaHMDS or LDA resulted in the formation of adducts, 1-chlorocyclopropyl p-tolyl
sulfoxides bearing a carbonyl group at the 2-position, in almost quantitative yields. The carbonyl
group of the adducts was transformed to various ether groups to give 1-chlorocyclopropyl p-tolyl
sulfoxides bearing an ether functional group at the 2-position in short steps. Treatment of these
products with i-PrMgCl at low temperature afforded cyclopropylmagnesium carbenoids via the
sulfoxide-magnesium exchange reaction. 1,5-Carbonehydrogen insertion (1,5-CH insertion) reaction
of the generated magnesium carbenoid intermediates took place to give 3-oxabicyclo[3.1.0]hexanes
or bicyclo[3.1.0]hexanes bearing an ether group at the 4-position in moderate to good yields. When
this procedure was carried out starting with enantiopure dichloromethyl p-tolyl sulfoxide, enantio-
pure 3-oxabicyclo[3.1.0]hexanes were obtained in good overall yields. These procedures provide
a good way for the synthesis, including asymmetric synthesis, of multisubstituted 3-oxabicyclo[3.1.0]
Keywords:
Cyclopropane
Magnesium carbenoid
Cyclopropylmagnesium carbenoid
1,5-CH insertion
3-Oxabicyclo[3.1.0]hexane
hexanes and bicyclo[3.1.0]hexanes from
tolyl sulfoxide in short steps.
a
,
b
-unsaturated carbonyl compounds and dichloromethyl p-
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
p-tolyl sulfoxides with Grignard reagents and indeed the reaction
proceeded smoothly to give 3-oxabicyclo[3.1.0]hexanes in good
yields.7 We further investigated this chemistry and some new re-
sults were obtained.
In this paper, above-mentioned chemistry and development of
the chemistry to the asymmetric synthesis of 3-oxabicyclo[3.1.0]
The carbonehydrogen insertion (CH insertion) reaction1 is one
of the most striking reactions of carbenes and carbenoids.2 This
reaction enables the formation of a carbonecarbon bond between
non-activated carbon and the carbene (or carbenoid) carbons. Re-
cently, formation of a chemical bond to a non-activated carbon
(functionalization of inert CeH bond) has been received consider-
able attention.3
Previously, we found that the magnesium carbenoids, generated
from 1-chloroalkyl p-tolyl sulfoxides with Grignard regents via the
sulfoxide-magnesium exchange reaction,4 gave rise to 1,3-CH in-
sertion to give cyclopropanes in good to high yields.5 Highly ste-
reospecific 1,3-CH insertion was observed in the reaction and
asymmetric synthesis of bicyclo[n.1.0]alkanes with high optical
purity was also realized.6 In continuation of our interest in the CH
insertion reaction of magnesium carbenoids in organic synthesis,
we investigated the 1,5-CH insertion reaction of cyclo-
propylmagnesium carbenoids derived from 1-chlorocyclopropyl
hexanes are reported in detail (Scheme 1). Thus, the reaction of a,b-
unsaturated carbonyl compounds 1 with dichloromethyl p-tolyl
sulfoxide 28 in the presence of a base afforded adducts 3 in high to
quantitative yields as a single isomer. The carbonyl group in ad-
ducts 3 was converted into an ether group to give 4 in high overall
yields in two steps. Treatment of 4 with i-PrMgCl in THF resulted in
the formation of cyclopropylmagnesium carbenoids
5 in-
stantaneously at ꢀ78 ꢁC via the sulfoxide-magnesium exchange
reaction.4 Upon warming the temperature of the reaction mixture,
the magnesium carbenoids 5 gave rise to the 1,5-CH insertion re-
action smoothly to give 3-oxabicyclo[3.1.0]hexanes 6 in up to 89%
yield.9 Adducts 3 were easily converted into two-carbon homolo-
gated ether 7, from which bicyclo[3.1.0]hexanes bearing an alkoxy
group at the 4-position 8 were obtained in moderate yields. By
starting this procedure with enantiopure dichloromethyl p-tolyl
sulfoxide 2, an asymmetric synthesis of enantiopure 3-oxabicyclo
[3.1.0]hexanes 6 was realized.
* Corresponding author. Tel.: þ81 3 5228 8272; fax: þ81 3 5261 4631; e-mail
address: tsatoh@rs.kagu.tus.ac.jp (T. Satoh).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.085

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T. Satoh et al. / Tetrahedron 68 (2012) 1071e1084
O
H
O
TolS(O)CHCl2
R'
R1
Cl
R1
R2
R1
Cl
R3H2C
R
2
R
H
i-PrMgCl (3 equiv)
H
O
R2
R2
Base
Tol(O)S
Tol(O)S
THF
1
3
4
R'
R'
R1
H
R1
H
R3H2C
1,5-CH insertion
O
H
O
R2
Cl
R2
ClMg
R3
6
5
R'
R'
R1
H
R1
R3O
i-PrMgCl (3 equiv)
H
H
3
R2
R2
THF
Tol(O)S
Cl
R3O
7
8
Scheme 1. Synthesis of 3-oxabicyclo[3.1.0]hexanes 6 and bicyclo[3.1.0]hexanes 8 from
insertion reaction of cyclopropylmagnesium carbenoid intermediates 5.
a
,b
-unsaturated carbonyl compounds 1 and dichloromethyl p-tolyl sulfoxide 2 by the 1,5-CH
2. Results and discussion
on our experiences for the generation of cyclopropylmagnesium
carbenoids,12 1-chlorocyclopropyl p-tolyl sulfoxide 12 was treated
with 2.5 equiv of i-PrMgCl in THF at ꢀ78 ꢁC and the reaction mix-
ture was slowly allowed to warm to room temperature. Gratify-
ingly, this reaction gave the desired 3-oxabicyclo[3.1.0]hexane 14
(78%) as a single isomer along with chlorocyclopropane 15 (the
protonated product of the cyclopropylmagnesium carbenoid in-
termediate 13; 7%). After some investigation to find the best con-
ditions for these reactions, using 3 equiv of i-PrMgCl with warming
from ꢀ78 to 0 ꢁC over 2 h were proved to be the conditions of
choice and 14 was obtained in 82% yield.7 At the same time, the 1,5-
CH insertion reaction was proved to proceed at around ꢀ20 ꢁC.7
Stereochemistry of the carbon bearing a 4-methoxyphenyl group
of the product 14 was unambiguously determined as shown in
Scheme 2 from the coupling constant (J¼2.8 Hz) of the hydrogen on
the bridgehead carbon (Ha) and the hydrogen on the carbon bear-
ing the 4-methoxyphenyl group (Hb).9b
2.1. Synthesis of 3-oxabicyclo[3.1.0]hexanes from a,b-
unsaturated carbonyl compounds and dichloromethyl p-tolyl
sulfoxide by the 1,5-CH insertion reaction of
cyclopropylmagnesium carbenoids as the key reaction
We commenced our investigation with 1-chlorocyclopropyl p-
tolyl sulfoxide bearing an ether group at the 2-position 12. The
synthesis of 12 is summarized in Scheme 2. Thus, to a solution of
a mixture of ethyl methacrylate 9 and dichloromethyl p-tolyl sulf-
oxide 28 in THF was added NaHMDS at ꢀ78 ꢁC and the reaction
mixture was slowly allowed to warm to room temperature to afford
1-chlorocyclopropyl p-tolyl sulfoxide bearing an ethoxycarbonyl
group at the 2-position 10 in quantitative yield as a single isomer.10
The ethoxycarbonyl group was reduced with NaBH4 in a mixture of
THFemethanol11 to give alcohol 11 in 95% yield. Finally, the hydroxyl
group was benzylated with 4-methoxybenzyl chloride under the
conventional conditions to afford the desired ether 12 in 98% yield.
The key reactions, generation of cyclopropylmagnesium carbe-
noid and 1,5-CH insertion reaction, were investigated next. Based
Generality of this procedure was investigated next with the
substrates 16aec prepared from alcohol 11, and the results are
summarized in Table 1. As shown in entries 1 and 2, it is apparent
that the 1,5-CH insertion reaction was not affected by the presence
TolS(O)CHCl2
2
O
O
H
CH3
Cl
CH3
Cl
H3C
H
NaBH4 (2.5 equiv)
NaHMDS (1.2 equiv)
EtO
Tol(O)S
HO
OEt
THF, MeOH, reflux, 2 h, 95%
THF, -78 °C to r.t., 3 h
99%
Tol(O)S
9
10
11
4-Methoxybenzyl
chloride (2 equiv)
NaH (2 equiv)
i-PrMgCl
CH3
Cl
CH3
Cl
(3 equiv)
NaI (0.1 equiv)
O
O
THF, -78 to 0 °C
2 h
DMF, 0 °C, 98%
H3CO
Tol(O)S
12
H3CO
ClMg
13
CH3
CH3
Cl
1,5-CH insertion
O
O
+
H3CO
H
Ha
Hb
H3CO
15 (9%)
14 (82%)
Scheme 2. Synthesis of 3-oxabicyclo[3.1.0]hexane 14 from ethyl methacrylate 9 and dichloromethyl p-tolyl sulfoxide 2 via the 1,5-CH insertion reaction of cyclopropylmagnesium
carbenoid intermediate 13.

T. Satoh et al. / Tetrahedron 68 (2012) 1071e1084
1073
Table 1
conventional reactions as shown in Scheme 3. Quite interestingly,
treatment of 19 with i-PrMgCl under the conditions described
above gave chlorocyclopropane 20 (40%) and allene 21 (36%), and
no trace of the desired bicyclo[3.1.0]hexane was observed.
Synthesis of 3-oxabicyclo[3.1.0]hexanes 17 by treatement of 16 with i-PrMgCl
Based on this result, we propose a plausible mechanism for the
1,5-CH insertion reaction of cyclopropylmagnesium carbenoid in-
termediate 13 as follows (Scheme 3). Thus, as the sulfoxide-
magnesium exchange reaction is proved to take place with re-
tention of the configuration at the carbon bearing the sulfinyl
group,13 the sulfoxide-magnesium exchange reaction of 12 must
give cyclopropylmagnesium carbenoid intermediate 13. The mag-
nesium and the oxygen atom of the ether group are thought to
make strong interaction to generate five-membered intermediate
as shown in Scheme 3. In this intermediate, the hydrogen on the
benzylic carbon (Ha) is located close to the backside of the chlorine
atom of magnesium carbenoid carbon and the 1,5-CH insertion
reaction exactly took place between CeHa bond and the carbenoid
carbon to give 3-oxabicyclo[3.1.0]hexane 14. Thus, the interaction
of the oxygen atom with the magnesium is thought to be essential
to this 1,5-CH insertion reaction. As described above, the reaction of
19, which has only methylene carbon in the side chain, with i-
PrMgCl gave the cyclopropylmagnesium carbenoid intermediate;
however, no 1,5-CH insertion reaction occurred. This result is the
strong evidence for this mechanism.
We next synthesized 1-chlorocyclopropyl p-tolyl sulfoxide
bearing an acetal group as the side chain 22 staring from 2-(2-
phenylethyl)acrylic acid ethyl ester in a similar way described in
Scheme 2. Protection of the hydroxyl group of the corresponding
alcohol with chloromethyl methyl ether gave the desired 22 in good
overall yield. Somewhat disappointingly, treatment of 22 with i-
PrMgCl did not give any desired 3-oxabicyclo[3.1.0]hexane but
chlorocyclopropane 24 in 43% yield. This result is also explained as
follows. Thus, the sulfoxide-magnesium exchange reaction of 22
resulted in the formation of magnesium carbenoid intermediate 23.
The magnesium atom must interact with both oxygen atoms of the
acetal group to give the fixed conformation as depicted in Scheme
3. In this conformation, the two hydrogens on the acetal carbon are
too separated to react with the carbenoid carbon.
Entry
16
17
Yield (%)
R
1
16a
17a
78
2
3
16b
16c
17b
17c
79
89
or absence of strong electron-withdrawing group on the aromatic
ring at the para position. As shown in entry 3, 3-oxabicyclo[3.1.0]
hexane bearing an alkyl group at the 4-position 17c was obtained
from the corresponding sulfoxide 16c in high yield (89%). This re-
sult shows that the aromatic group as R is not essential for the 1,5-
CH insertion reaction. From these results, generality of the 1,5-CH
insertion reaction of the cyclopropylmagnesium carbenoids gen-
erated from 1-chlorocyclopropyl p-tolyl sulfoxides 16 was verified.
2.2. The mechanism and the role of the oxygen atom for the
1,5-CH insertion reaction
In order to clarify the mechanism and the role of the oxygen
atom for the 1,5-CH insertion reaction, we synthesized 1-
chlorocyclopropyl p-tolyl sulfoxide bearing methylene instead of
the oxygen in the side chain at the 2-position of the cyclopropane
ring (compound 19) from alcohol 11 via acetylene 18 in
CH3
Cl
CH3
Cl
CH3
1) I2, PPh3, Imidazole
H3CO
Ar
H
2 / Pd-C
HO
99%
Tol(O)S
Tol(O)S
H3CO
Tol(O)S
Li
/ CuI
2)
Cl
19
18
11
2 steps 56%
i-PrMgCl
CH3
Cl
CH3
(3 equiv)
+
THF, -78 to 0 °C
2 h
H3CO
H3CO
H
20 (40%)
21 (36%)
Hb
Ha
CH3
CH3
Cl
O
M
O
12
Ar
Ha
Hb
14
13
M = MgCl
H3CO
H
CH2CH2Ph
CH2CH2Ph
i-PrMgCl
O
H3CO
O
H3CO
O
CH2CH2Ph
Cl
(3 equiv)
H
H3C
O
M
Tol(O)S
H
THF, -78 to 0 °C
2 h, 43%
Cl
Cl
24
22
23
M = MgCl
Scheme 3. A plausible mechanism and critical role of the oxygen atom for the 1,5-CH insertion reaction of cyclopropylmagnesium carbenoid intermediate 13.

1074
T. Satoh et al. / Tetrahedron 68 (2012) 1071e1084
2.3. Synthesis of multisubstituted 3-oxabicyclo[3.1.0]hexanes
Treatment of 25a and 25b with i-PrMgCl gave the desired 1,4,6-
trisubstituted 3-oxabicyclo[3.1.0]hexanes 26a and 26b in moderate
to good yields (entries 1 and 2 in Table 2). From these results, it was
anticipated that the substituents R1 and R2 on the cyclopropane
ring have some effects on the 1,5-CH insertion reaction. On the
contrary, the yield of 26c was significantly diminished by the
presence of a substituent R3 (in this case ethyl group) on the side
chain (entry 3). Quite interestingly, structurally complicated tri-
cyclic compound 26d was obtained from 1-cyclohexene-1-
carboxylic acid benzyl ester in only four steps via 25d without
formation of diastereomers in good overall yield (entry 4).
In order to extend this procedure to the synthesis of more
substituted 3-oxabicyclo[3.1.0]hexanes 26, 1-chlorocyclopropyl p-
tolyl sulfoxides 25 were synthesized from
a,b-disubstituted a,b-
unsaturated carbonyl compounds in a similar way described in
Scheme 2,10 and the results are summarized in Table 2. Thus, 25a
was synthesized from tiglic acid ethyl ester, and 25b was from (E)-
4-methyl-2-(2-phenylethyl)pent-2-enoic acid ethyl ester. Synthesis
of 25c was commenced with (E)-4,6-dimethylhept-4-en-3-one and
the adduct was reacted with NaBH414 followed by benzyl bromide.
Sulfoxide 25d was synthesized from 1-cyclohexene-1-carboxylic
acid benzyl ester in the same way as described for the synthesis
of 25a and 25b.
2.4. Investigation for the 1,4-, 1,5-, 1,6-, and 1,7-CH insertion
reactions: synthesis of bicyclo[3.1.0]hexanes bearing an
alkoxy group at the 4-position
Table 2
Synthesis of 3-oxabicyclo[3.1.0]hexanes 26 by treatment of 25 with i-PrMgCl
As described in the introduction, CH insertion reaction is very
interesting and important reaction because it enables the forma-
tion of a carbonecarbon bond between non-activated carbon and
a carbenoid carbon. In the course of our investigation reported
above, we thought that there is a possibility for 1,n-CH insertion
reaction of cyclopropylmagnesium carbenoids. We investigated
this possibility by using 1-chlorocyclopropyl p-tolyl sulfoxides
bearing a one-carbon homologated ether chain at the 2-position
(compound 30 in Scheme 4; compare with compound 12 in
Scheme 2) and two-carbon homologated compound (compound 36
in Scheme 5). Synthesis of these substrates and the reactions with
i-PrMgCl are described hereinafter.
Entry 25
26
Yield (%)
R1
R2
R3
H
1
2
25aa CH3
CH3
26a 78
26b 48
25bb
i-Pr
H
Compound 30 was synthesized from adduct 10 (Scheme 4).
Thus, the ethyl ester 10 was reduced with LDBBA15 in THF to give
aldehyde 27 in good yield. Wittig olefination followed by
hydroborationeoxidation of the aldehyde group of 27 gave alco-
hol 29 via olefin 28. The hydroxyl group of 29 was benzylated
with benzyl bromide (BnBr) to give the desired one-carbon ho-
mologated ether 30. In expectation of producing 1,4-CH insertion
product 32 or 1,6-CH insertion product 33, 1-chlorocyclopropyl p-
tolyl sulfoxide 30 was treated with i-PrMgCl under the conditions
described above; however, disappointingly, only allene 31 (rear-
rangement product of the cyclopropylmagnesium carbenoid in-
termediate) was obtained in 37% yield. No cyclized product was
obtained at all.
3
4
25cc CH3
C2H5 26c 44
25dd
26d 71e
a
b
c
Prepared from tiglic acid ethyl ester.
Prepared from (E)-4-methyl-2-(2-phenylethyl) pent-2-enoic acid ethyl ester.
Prepared from (E)-4-methyl-7-phenylhept-4-en-3-one.
Prepared from 1-cyclohexene-1-carboxylic acid benzyl ester.
i-PrMgCl (5 equiv) was used.
d
e
Two-carbon homologated compound 36 was synthesized from
aldehyde 27 (Scheme 5). Thus, the HornereWadswortheEmmons
reaction of aldehyde 27 gave
a
,
b
-unsaturated ester 34 in high
O
O
Ph3PCH3I (3.5 equiv)
NaH (3 equiv)
CH3
Cl
CH3
Cl
CH3
LDBBA (3 equiv)
EtO
Tol(O)S
H
THF, 0 °C, 10 min
84%
CH2Cl2, 0 °C to r.t., overnight
Tol(O)S
27
Tol(O)S
28
Cl
86%
10
BnBr (2 equiv)
NaH (2 equiv)
NaI (0.1 equiv)
BH3 ' THF (3 equiv)
H2O2 / NaOH
CH3
Cl
CH3
Cl
HO
Tol(O)S
Ph
O
THF, 0 °C, 30 min
76%
DMF, 0 °C, 30 min
96%
Tol(O)S
29
30
CH3
H
CH3
i-PrMgCl (3 equiv)
Ph
O
CH3
O
THF, -78 to 0 °C, 2 h
PhH2CO
H
Ph
33
32
(1,4-CH)
31 (37%)
(1,6-CH)
Scheme 4.

T. Satoh et al. / Tetrahedron 68 (2012) 1071e1084
1075
O
O
(EtO)2P(O)CH2CO2Et (3.5 equiv)
NaH (3 equiv)
CH3
Cl
CH3
Cl
NaBH4 (5 equiv)
H
EtO
THF-MeOH, reflux, 3.5 h
98%
THF, 0° C to r.t., overnight
91%
Tol(O)S
Tol(O)S
27
34
BnBr (2 equiv)
NaH (2 equiv)
NaI (0.1 equiv)
CH3
Cl
CH3
i-PrMgCl (5 equiv)
HO
Ph
O
DMF, 0 °C, 30 min
95%
THF, -78 to 0 °C, 2 h
Tol(O)S
Tol(O)S
Cl
35
Hb
O
36
CH3
CH3
CH3
Ha
CH3
Cl
CH3
BnO
+
+
BnO
Ha
Mg
Cl
Ph
O
Cl
H
H
BnO Hb
H
Ph
41
40
38 (43%)
39 (40%)
37
(1,7-CH)
(1,5-CH)
Scheme 5.
Table 3
Synthesis of bicyclo[3.1.0]hexanes 43 by treatment of 42 with i-PrMgCl
yield. The reaction of the a,b-unsaturated ester moiety with ex-
cess NaBH4 resulted in the reduction of both the double bond and
the ester group to afford saturated alcohol 35 in quantitative
yield. Finally, the hydroxyl group of 35 was benzylated to give the
desired two-carbon homologated ether 36. In expectation of
producing 1,5-CH insertion product 38 or 1,7-CH insertion prod-
uct 41, 1-chlorocyclopropyl p-tolyl sulfoxide 36 was treated with
5 equiv of i-PrMgCl under the conditions described above. This
reaction gave the desired bicyclo[3.1.0]hexane bearing an alkoxy
group at the 4-position 38 (43%) via the 1,5-CH insertion reaction
along with allene 39 (40%) and chlorocyclopropane 40 (trace).
The product from the 1,7-CH insertion reaction 41 was not ob-
served at all.
Intermediate of this reaction is thought to be 37 as shown in
Scheme 5. In this intermediate 37, the magnesium interacts with
the oxygen of the ether to give seven-membered ring, in which the
benzylic hydrogen Ha is located close to the magnesium carbenoid
carbon to give bicyclo[3.1.0]hexane bearing a benzyloxy group at
the 4-position 38. Stereochemistry of the carbon bearing a benzy-
loxy group of the product 38 was again unambiguously determined
from the coupling constant (J¼4.4 Hz) of the hydrogen on the
bridgehead carbon (Ha) and the hydrogen on the carbon bearing
the benzyloxy group (Hb).9b
Entry
R
43
44
Yield (%)
40
Yield (%)
1
2
43a
43b
44a
44b
36
43
45
43
3
43c
44c
49
4
5
TBDPS 42d
Tr 42e
0
0
44d
44e
34
36
Generality of this 1,5-CH insertion reaction giving bicyclo
[3.1.0]hexanes was investigated using 42 as the substrates and
the results are summarized in Table 3. 1-Chlorocyclopropyl p-
tolyl sulfoxides 42 were synthesized from alcohol 35 with alkyl
halides, TBDPSCl, and trityl chloride in conventional conditions.
The reaction of 42aec with 5 equiv of i-PrMgCl gave the desired
bicyclo[3.1.0]hexanes 43aec in up to 45% yield along with sig-
nificant amount of allenes 44aec. Interestingly, TBDPS ether 42d
and trityl ether 42e did not give the desired bicyclo[3.1.0]hex-
anes. This results imply that the 1,5-CH insertion reaction is
hampered considerably by the steric hindrance of the ether
group.
oxabicyclo[3.1.0]hexanes starting from
compounds with enantiopure dichloromethyl p-tolyl sulfoxide
(R)-2.
a,b-unsaturated carbonyl
At first, to a solution of ethyl methacrylate 9 and enantiopure
(R)-2 in THF at ꢀ85 ꢁC was added a solution of LDA and the tem-
perature of the reaction mixture was slowly allowed to warm to
room temperature (Scheme 6).14,17 This reaction gave the desired
(1S,2R,Rs)-1-chloro-2-ethoxycarbonyl-2-methylcyclopropyl p-tolyl
sulfoxide 45 in quantitative yield and, as expected, the optical pu-
rity was proved to be 98% by HPLC with chiral stationary column.
The absolute stereochemistry of 45 was determined on the basis of
our previous work.10 Ethyl ester group of 45 was reduced with
NaBH4, and the resultant hydroxyl group was benzylated with
benzyl bromide to afford optically active ether 46 in 75% overall
yield. Finally, treatment of 46 with i-PrMgCl under the conditions
described above resulted in the formation of (1S,4S,5R)-1-methyl-
4-phenyl-3-oxabicyclo[3.1.0]hexane 48 in 79% yield. Optical purity
of the product 48 was proved to be over 99% by HPLC with chiral
stationary column.
2.5. Asymmetric synthesis of enantiopure 3-oxabicyclo[3.1.0]
hexanes
We recently reported the preparation of enantiopure aryl
dichloromethyl sulfoxides16 and application of these compounds
to the asymmetric synthesis of enantiopure allenes.14 As a further
application of enantiopure aryl dichloromethyl sulfoxides in or-
ganic synthesis, we planed the asymmetric synthesis of 3-

1076
T. Satoh et al. / Tetrahedron 68 (2012) 1071e1084
O
S
:
Tol
(
R)-2
(99% ee)
CHCl2
O
H
1) NaBH4 / THF-MeOH,
reflux
Ph
H3C
Cl
(R)
CO2Et
H3C
Cl
LDA (1.2 equiv)
H3C
H
O
OEt
(S)
O
O
THF, -85 °C to r.t., 99%
2) BnBr / NaH, DMF, 0 °C
75%
)S
S
Tol
Tol
(R
:
:
9
45 (98% ee)
46 (99% ee)
Ph
H3C (
H3C
S
)
(
O
i
-PrMgCl (3 equiv)
1,5-CH insertion
79%
O
)
S
(R)
THF, -78 to 0°C
MgCl
Cl
Ph
H
H
48 (99%ee)
47
26
[ ] D -150 (
c
0.16, acetone)
Scheme 6. Asymmetric synthesis of enantiopure (1S,4S,5R)-1-methyl-4-phenyl-3-oxabicyclo[3.1.0]hexane 48 from ethyl methacrylate and (R)-dichloromethyl p-tolyl sulfoxide (R)-2.
Further application of the procedure described above to the
asymmetric synthesis of multisubstituted 3-oxabicyclo[3.1.0]
hexanes was carried out with a,b-disubstituted a,b-unsaturated
ester 49a and ketone 49b and the results are summarized in
Scheme 7. The addition reaction of 49a with (R)-2 in the presence
Finally, in Scheme 8, we would like to report the asymmetric
synthesis of tricyclic compound bearing five stereogenic centers
from (E)-2-(3-phenylpropylidene)cyclohexanone 54. The addition
reaction of 54 with (R)-2 in the presence of LDA afforded the de-
sired spiro-cyclopropyl sulfoxide 55 in 90% yield and the ee was
found to be 99%. The ketone group was reduced with NaBH4 to
afford alcohol 56 in high yield. In order to confirm the absolute
configuration and the stereochemistry of the hydroxyl group, X-ray
crystallographic analysis of single crystal of racemic 56 was carried
out, and the result was shown in Fig. 1.
Structurally confirmed alcohol 56 was benzylated with benzyl
bromide under the conventional conditions to give ether 57. Finally,
57 was treated with 3 equiv of i-PrMgCl under the conditions de-
scribed above to give enantiopure (1S,3R,4S,5S,6R)-3-phenyl-5-(2-
phenylethyl)-2-oxatricyclo[4.4.0.04,6]decane 59 in 51% yield.
In conclusion, we have developed a method for the synthesis of
3-oxabicyclo[3.1.0]hexanes and bicyclo[3.1.0]hexanes bearing an
of
LDA
gave
(1R,2S,3R,Rs)-1-chloro-2-ethoxycarbonyl-3-
isopropyl-2-(2-phenylethyl)cyclopropyl p-tolyl sulfoxide 50a10
in quantitative yield with 98% ee. The same treatment of 49b
with (R)-2 afforded (1R,2S,3R,Rs)-1-chloro-2-methyl-3-(2-
phenylethyl)-2-propionylcyclopropyl p-tolyl sulfoxide 50b in
quantitative yield with 98% ee. The carbonyl groups in 50 were
reduced to hydroxyl group,18 which was benzylated to give 52a
and 52b both in good overall yields. Finally, 52a and 52b were
treated with 3 equiv of i-PrMgCl to give (1R,4R,5S,6S)-6-isopropyl-
4-phenyl-1-(2-phenylethyl)-3-oxabicyclo[3.1.0]hexane 53a and
(1R,2S,4R,5S,6S)-2-ethyl-1-methyl-4-phenyl-6-(2-phenylethyl)-
3-oxabicyclo[3.1.0]hexane 53b, respectively, in moderate yield
with high ee. As a result, multisubstituted 3-oxabicyclo[3.1.0]
alkoxy group at the 4-position from various
a,b-unsaturated
hexanes in high enantiomeric purity were synthesized from
disubstituted -unsaturated carbonyl compounds and enantio-
pure (R)-2 in only four steps.
a
,
b
-
carbonyl compounds and dichloromethyl p-tolyl sulfoxide 2 via
the 1,5-CH insertion of cyclopropylmagnesium carbenoid
intermediates as the key reaction in short steps. When the
a,b
Scheme 7. Asymmetric synthesis of multisubstituted 3-oxabicyclo[3.1.0]hexanes 53 from a,b-disubstituted a,b-unsaturated carbonyl compounds 49 with (R)-2.

T. Satoh et al. / Tetrahedron 68 (2012) 1071e1084
1077
Scheme 8. Asymmetric synthesis of (1S,3R,4S,5S,6R)-3-phenyl-5-(2-phenylethyl)-2-oxatricyclo[4.4.0.04,6]decane 59 from (E)-2-(3-phenylpropylidene)cyclohexanone 54 with (R)-2.
spectrometer. Electron-impact mass spectra (MS) were obtained at
70 eV by direct insertion with HITACHI M-80B mass spectrometer.
IR spectra were recorded on a PerkineElmer Spectrum One FTIR
instrument. Silica gel 60 N (KANTO CHEMICAL) containing 0.5%
fluorescence reagent 254 and a quartz column were used for col-
umn chromatography, and the products having UV absorption were
detected by UV irradiation. In experiments requiring dry solvents
and reagents, THF was distilled from diphenylketyl. Diisopropyl-
amine was distilled from CaH2. 1-Ethynyl-4-methoxybenzene was
distilled before use. All reactions involving air- or water-sensitive
compounds were routinely conducted in glassware, which was
flame-dried under a positive pressure of argon. Sulfoxides 10,10
racemic 50b,10 and racemic 5510 are known compounds.
3.1.1. [(1R*,2S*)-2-Chloro-1-methyl-2-(p-tolylsulfinyl)cyclopropyl]
methanol (11). Sodium borohydride (56.7 mg; 1.50 mmol) was
added to a solution of 10 (150 mg; 0.500 mmol) in THF (3 mL) at
room temperature, and the mixture was stirred under reflux for
5 min. Methanol (0.3 mL) was added dropwise to the resulting
Fig. 1. ORTEP drawing of rac-56 with thermal ellipsoids at the 50% probability level.
Hydrogen atoms except those attached to C2 and C4 have been omitted for clarity.
ꢀ
Selected bond lengths (A) and angles (deg): C1eC2 1.5123(19); C2eC3 1.5190(19);
C3eC1 1.5131(19); C1eC2eC3 59.89(9); C2eC3eC1 59.84(9); C3eC1eC2 60.28(9).
solution, and the mixture was stirred under reflux for 2 h. The
reaction was quenched with satd aq NH4Cl (5 mL), and the mixture
was extracted with CHCl3 (2ꢂ5 mL). The organic layer was dried
procedures were carried out starting from enantiopure 2, asym-
over MgSO4 and concentrated in vacuo. The residue was purified
by column chromatography on silica gel using hexane/AcOEt as
the eluent to give 11 (52.0 mg; 0.48 mmol; 95%) as a colorless
crystal; mp 117.0e117.5 ꢁC (hexane/AcOEt); IR (KBr) 3326, 2986,
metric synthesis of 3-oxabicyclo[3.1.0]hexanes was realized. These
procedures provide a good way for the synthesis, including
asymmetric synthesis, of multisubstituted 3-oxabicyclo[3.1.0]
hexanes from a,b-unsaturated carbonyl compounds. The chemis-
try presented here is unprecedented and would contribute to the
chemistry of magnesium carbenoids.
2901, 1499, 1096, 1031, 812 cmꢀ1
;
1H NMR
d
1.17 (d, J¼7.2 Hz, 1H),
1.47 (s, 3H), 1.96 (d, J¼7.2 Hz, 1H), 2.44 (s, 3H), 2.58e2.68 (m, 1H),
3.83 (dd, J¼7.0, 11.9 Hz, 1H), 4.08 (dd, J¼5.3, 11.9 Hz, 1H), 7.34 (d,
J¼8.1 Hz, 2H), 7.68 (d, J¼8.1 Hz, 2H); Anal. Calcd for C12H15ClO2S: C,
55.70; H, 5.84; Cl, 13.70; S, 12.39, found: C, 55.69; H, 5.78; Cl, 13.73;
S, 12.44.
3. Experimental
3.1. General
3.1.2. 1-({[(1R*,2S*)-2-Chloro-1-methyl-2-(p-tolylsulfinyl)cyclo-
propyl]methoxy}methyl)-4-methoxybenzene (12). Sodium hydride
(55% oil suspension; 26.2 mg; 0.60 mmol) was added to a solution
All melting points were measured on a Yanaco MP-S3 apparatus
and are uncorrected. 1H NMR spectra were measured in a CDCl3
solution with JEOL JNM-LA 300, 500, Bruker DPX 400, and AV 600

1078
T. Satoh et al. / Tetrahedron 68 (2012) 1071e1084
of 11 (77.7 mg; 0.300 mmol), 4-methoxybenzyl chloride (104 mg;
0.600 mmol), and sodium iodide (4.50 mg; 0.0300 mmol) in DMF
(3 mL) at 0 ꢁC, and the mixture was stirred at that temperature for
30 min. The reaction was quenched with satd aq NH4Cl (1 mL), and
the mixture was extracted with benzene (2ꢂ1 mL). The organic
layer was dried over MgSO4 and concentrated in vacuo. The residue
was purified by column chromatography on silica gel using hexane/
AcOEt as the eluent to give 12 (111 mg; 0.294 mmol; 98%) as a pale
J¼7.1 Hz, 1H), 2.42 (s, 3H), 2.72 (t, J¼7.0 Hz, 2H), 3.42e3.55 (m, 2H),
3.67 (d, J¼10.0 Hz, 1H), 3.78 (d, J¼10.0 Hz, 1H), 7.12e7.36 (m, 7H),
7.74 (d, J¼8.2 Hz, 2H); MS (EI) m/z (%) 376 (Mþ, 1), 359 (1), 119 (34),
91 (100); HRMS (EI) calcd for C21H25ClO2S: 376.1264, found:
376.1263.
3.1.8. (1R*,4R*,5S*)-4-(4-Fluorophenyl)-1-methyl-3-oxabicyclo[3.1.0]
hexane (17a). Colorless oil; IR (neat) 2958, 2845, 1608, 1510, 1221,
yellow oil; IR (neat) 2933, 2862, 1612, 1514, 1248, 1086, 813 cmꢀ1
1H NMR
;
1086, 1033, 823 cmꢀ1; 1H NMR
d
0.42 (dd, J¼4.4, 7.6 Hz, 1H), 0.68 (t,
d
1.30 (d, J¼7.2 Hz, 1H), 1.45 (s, 3H), 1.95 (d, J¼7.2 Hz, 1H),
J¼4.4 Hz, 1H), 1.31 (s, 3H), 1.49 (ddd, J¼2.9, 4.4, 7.6 Hz, 1H), 3.73 (d,
J¼8.2 Hz, 1H), 3.93 (d, J¼8.2 Hz, 1H), 5.02 (d, J¼2.9 Hz, 1H), 7.01 (t,
J¼8.6 Hz, 2H), 7.34 (dd, J¼5.5, 8.6 Hz, 2H); MS (EI) m/z (%) 192 (Mþ,
52), 191 (31), 174 (23), 163 (82), 146 (23), 135 (65), 123 (100), 109
(79), 95 (31), 68 (18), 67 (24), 53 (13); HRMS (EI) calcd for C12H13FO:
192.0950, found: 192.0950.
2.40 (s, 3H), 3.67 (d, J¼9.8 Hz, 1H), 3.82 (d, J¼9.8 Hz, 1H), 3.82 (s,
3H), 4.49 (d, J¼11.6 Hz,1H), 4.51 (d, J¼11.6 Hz,1H), 6.88 (d, J¼8.7 Hz,
2H), 7.27 (m, 4H), 7.68 (d, J¼8.7 Hz, 2H); MS (EI) m/z (%) 378 (Mþ,
0.2), 361 (8), 225 (32), 121 (100); HRMS (EI) calcd for C20H23ClO3S:
378.1056, found: 378.1055.
3.1.3. (1R*,4R*,5S*)-4-(4-Methoxyphenyl)-1-methyl-3-oxabicyclo
[3.1.0]hexane (14). A solution of isopropylmagnesium chloride in
THF (2.0 mol/L; 0.15 mL; 0.30 mmol) was added dropwise to
a solution of 12 (37.9 mg; 0.100 mmol) in THF (1 mL) at ꢀ78 ꢁC. The
mixture was allowed to warm to 0 ꢁC over 2 h. The reaction was
quenched with satd aq NH4Cl (0.5 mL), and the mixture was
extracted with CHCl3 (2ꢂ3 mL). The organic layer was dried over
MgSO4 and concentrated in vacuo. The residue was purified by
column chromatography on silica gel using hexane/AcOEt as the
eluent to give 14 (16.8 mg; 0.0822 mmol; 82%) as a colorless oil;
3.1.9. (1R*,4R*,5S*)-1-Methyl-4-phenyl-3-oxabicyclo[3.1.0]hexane
(17b). Colorless oil; IR (neat) 2926, 2854, 1733, 1455, 1093, 1032,
698 cmꢀ1; 1H NMR
d
0.41 (dd, J¼4.7, 7.7 Hz, 1H), 0.72 (t, J¼4.7 Hz,
1H), 1.31 (s, 3H), 1.52 (ddd, J¼2.9, 4.7, 7.7 Hz, 1H), 3.74 (d, J¼8.2 Hz,
1H), 3.95 (d, J¼8.2 Hz, 1H), 5.56 (d, J¼2.9 Hz, 1H), 7.24e7.44 (m,
5H); MS (EI) m/z (%) 174 (Mþ, 61), 145 (81), 117 (59), 105 (100), 91
(59), 77 (35); HRMS (EI) calcd for C12H14O: 174.1045, found:
174.1047.
3.1.10. (1R*,4S*,5S*)-1-Methyl-4-(2-phenylethyl)-3-oxabicyclo[3.1.0]
hexane (17c). Colorless oil; IR (neat) 2928, 2840, 1604, 1497,
IR (neat) 2956, 2836, 1614, 1513, 1247, 1173, 1087, 1034, 819 cmꢀ1
1H NMR
0.42 (m, 1H), 0.74 (m, 1H), 1.30 (s, 3H), 1.47 (m, 1H), 3.71
;
d
1455, 1091, 1033, 699 cmꢀ1
;
1H NMR
d
0.34 (dd, J¼4.3, 7.7 Hz,
(d, J¼8.1 Hz, 1H), 3.81 (s, 3H), 3.92 (d, J¼8.1 Hz, 1H), 5.00 (d,
J¼2.8 Hz, 1H), 6.86 (d, J¼8.8 Hz, 2H), 7.31 (d, J¼8.8 Hz, 2H); MS (EI)
m/z (%) 204 (Mþ, 48), 175 (100), 149 (36), 147 (14), 135 (53), 121
(27), 108 (17); HRMS (EI) calcd for C13H16O2: 204.1150, found:
204.1150.
1H), 0.61 (t, J¼4.3 Hz, 1H), 1.19 (ddd, J¼2.9, 4.3, 7.7 Hz, 1H), 1.23
(s, 3H), 1.66e1.80 (m, 1H), 1.80e1.95 (m, 1H), 2.60e2.79 (m, 2H),
3.53 (d, J¼8.2 Hz, 1H), 3.75 (d, J¼8.2 Hz, 1H), 3.97 (dt, J¼2.9,
6.5 Hz, 1H), 7.14e7.33 (m, 5H); MS (EI) m/z (%) 202 (Mþ, 22), 97
(81), 91 (100), 41 (37); HRMS (EI) calcd for C14H18O: 202.1358,
found: 202.1355.
3.1.4. 1-{[((1R*,2S*)-2-Chloro-1-methylcyclopropyl)methoxy]
methyl}-4-methoxybenzene (15). Colorless oil; IR (neat) 2934, 2857,
3.1.11. 1-{3-[(1R*,2R*)-2-Chloro-1-methyl-2-(p-tolylsulfinyl)cyclo-
propyl]prop-1-ynyl}-4-methoxybenzene (18). Imidazole (264 mg;
3.00 mmol) was added to a solution of 11 (389 mg; 1.50 mmol),
triphenylphosphine (788 mg; 3.00 mmol), and iodine (762 mg;
3.00 mmol) in CHCl3 (1.5 mL) at 0 ꢁC, and the mixture was stirred at
room temperature for 5 min. The reaction was quenched with satd
aq Na2SO3 (10 mL), and the mixture was extracted with CHCl3
(2ꢂ3 mL). The organic layer was dried over MgSO4 and concentrated
in vacuo. The residue was purified by column chromatography
on silica gel using hexane/AcOEt as the eluent to give 1-{[(1R*,2R*)-
1-chloro-2-(iodomethyl)-2-methylcyclopropyl]sulfinyl}-4-methylb-
enzene (504 mg) as a colorless crystal. A solution of BuLi in hexane
(1.67 mol/L; 1.88 mL; 3.1 mmol) was added to a solution of
1-ethynyl-4-methoxybenzene (415 mg; 3.14 mmol) and copper(I)
iodide (19.0 mg; 0.100 mmol) in THF (12.9 mL) at 0 ꢁC, and the
mixture was stirred at that temperature for 10 min. A solution of 1-
{[(1R*,2R*)-1-chloro-2-(iodomethyl)-2-methylcyclopropyl]sulfinyl}-
4-methylbenzene (504 mg; 1.37 mmol) in THF (0.8 mL) was added to
the resulting solution at ꢀ78 ꢁC. The mixture was allowed to warm
to room temperature over 2.5 h, and the mixture was stirred at that
temperature overnight. The reaction was quenched with satd aq
NH4Cl (7 mL), and the mixture was extracted with CHCl3 (2ꢂ7 mL).
The organic layer was dried over MgSO4 and concentrated in vacuo.
The residue was purified by column chromatography on silica gel
using hexane/AcOEt as the eluent to give 18 (343 mg; 0.920 mmol;
56% yield for two steps) as a pale yellow crystal; mp 126.5e127.0 ꢁC
(hexane/AcOEt); IR (KBr) 2964, 2926, 1509, 1245, 1059, 827,
1613, 1513, 1248, 1088, 1036, 821 cmꢀ1
;
1H NMR
d
0.60 (dd, J¼4.1,
6.2 Hz, 1H), 1.04 (dd, J¼6.2, 7.7 Hz, 1H), 1.29 (s, 3H), 3.03 (dd, J¼4.1,
7.7 Hz, 1H), 3.20 (d, J¼9.8 Hz,1H), 3.31 (d, J¼9.8 Hz,1H), 3.80 (s, 3H),
4.40 (d, J¼11.7 Hz,1H), 4.44 (d, J¼11.7 Hz,1H), 6.88 (d, J¼8.7 Hz, 2H),
7.23 (d, J¼8.7 Hz, 2H); MS (EI) m/z (%) 240 (Mþ, 7), 121 (100); HRMS
(EI) calcd for C13H17ClO2: 240.0917, found: 240.0914.
3.1.5. 1-({[(1R*,2S*)-2-Chloro-1-methyl-2-(p-tolylsulfinyl)cyclo-
propyl]methoxy}methyl)-4-fluorobenzene (16a). Yield (99%); color-
less oil; IR (neat) 2930, 2866, 1603, 1514, 1222, 1054, 813, 760 cmꢀ1
;
1H NMR
d
1.30 (d, J¼7.2 Hz, 1H), 1.47 (s, 3H), 1.97 (d, J¼7.2 Hz, 1H),
2.41 (s, 3H), 3.72 (d, J¼9.9 Hz, 1H), 3.86 (d, J¼9.9 Hz, 1H), 4.51 (d,
J¼11.6 Hz, 1H), 4.56 (d, J¼11.6 Hz, 1H), 7.04 (t, J¼8.7 Hz, 2H),
7.25e7.37 (m, 4H), 7.67 (d, J¼8.2 Hz, 2H); MS (EI) m/z (%) 366 (Mþ,
0.1), 349 (0.2), 109 (100); HRMS (EI) calcd for C19H20ClFO2S:
366.0857, found: 366.0858.
3.1. 6. 1-{[(1R*, 2S*)-2-(Benzyloxymethyl)-1-chloro-2-
methylcyclopropyl]sulfinyl}-4-methylbenzene (16b). Yield (99%);
colorless oil; IR (neat) 2930, 2863,1495,1455,1363, 1087, 812 cmꢀ1
;
1H NMR
d
1.31 (d, J¼7.1 Hz, 1H), 1.47 (s, 3H), 1.95 (d, J¼7.1 Hz, 1H),
2.40 (s, 3H), 3.71 (d, J¼10.0 Hz, 1H), 3.86 (d, J¼10.0 Hz, 1H), 4.55 (d,
J¼11.8 Hz, 1H), 4.60 (d, J¼11.8 Hz, 1H), 7.20e7.39 (m, 7H), 7.69 (d,
J¼8.2 Hz, 2H); MS (EI) m/z (%) 348 (Mþ, 0.1), 331 (0.2), 91 (100);
HRMS (EI) calcd for C19H21ClO2S: 348.0951, found: 348.0950.
3.1.7. 1-({(1R*,2S*)-1-Chloro-2-methyl-2-[(3-phenylpropoxy)methyl]
cyclopropyl}sulfinyl)-4-methylbenzene (16c). Yield (90%); colorless
oil; IR (neat) 2932, 2864, 1496, 1455, 1112, 1065, 751 cmꢀ1; 1H NMR
714 cmꢀ1
;
1H NMR
d
1.32 (d, J¼7.3 Hz, 1H), 1.55 (s, 3H), 2.03 (d,
J¼7.3 Hz, 1H), 2.41 (s, 3H), 2.93 (d, J¼17.2 Hz, 1H), 3.05 (d, J¼17.2 Hz,
1H), 3.83 (s, 3H), 6.85 (d, J¼8.9 Hz, 2H), 7.28 (d, J¼8.2 Hz, 2H), 7.37 (d,
J¼8.9 Hz, 2H), 7.71 (d, J¼8.2 Hz, 2H); MS (FABþ) m/z (%) 373 ([MþH]þ,
d
1.32 (d, J¼7.1 Hz, 1H), 1.47 (s, 3H), 1.87e2.06 (m, 2H), 1.96 (d,

T. Satoh et al. / Tetrahedron 68 (2012) 1071e1084
1079
11), 233 (21), 135 (100); HRMS (FABþ) calcd for C21H22ClO2S:
373.1029, found: 373.1031.
([MþH]þ, 43), 255 (6), 231 (7), 198 (3), 154 (2), 139 (22), 91 (100), 77
(3); HRMS (FABþ) calcd for C20H24ClO2S: 363.1187, found: 363.1189.
3.1.12. 1-{3-[(1R*,2R*)-2-Chloro-1-methyl-2-(p-tolylsulfinyl)cyclo-
propyl]propyl}-4-methoxybenzene (19). Pd/C (20% wt; 28.0 mmg;
0.053 mmol) was added to a solution of 18 (112 mg; 0.300 mmol) in
THF (0.75 mL) at room temperature, and the mixture was stirred at
that temperature under H2 atmosphere (1 atm; balloon) overnight.
The mixture was passed through a pad of CeliteÒ545, and the
filtrate was concentrated in vacuo. The residue was purified by
column chromatography on silica gel using hexane/AcOEt as the
eluent to give 19 (112 mg; 0.297 mmol; 99%) as a colorless crystal;
mp 64.0e64.5 ꢁC (hexane/AcOEt); IR (KBr) 2935, 2917, 1610, 1513,
3.1.18. 1-{[(1R*,2S*,3R*)-2-(Benzyloxymethyl)-1-chloro-3-isopropyl-
2-(2-phenylethyl)cyclopropyl]sulfinyl}-4-methylbenzene (25b). Yield
(99%); colorless oil; IR (neat) 2964, 2869, 1601, 1454, 1090, 1064,
699 cmꢀ1; 1H NMR
d
0.49 (d, J¼6.5 Hz, 3H), 0.97 (d, J¼6.5 Hz, 3H),
1.34 (d, J¼10.5 Hz, 1H), 1.56e1.73 (m, 2H), 2.22 (ddd, J¼6.5, 11.3,
14.0 Hz, 1H), 2.42 (s, 3H), 2.64e2.83 (m, 2H), 3.77 (d, J¼10.0 Hz, 1H),
4.04 (d, J¼10.0 Hz, 1H), 4.58 (d, J¼12.2 Hz, 1H), 4.65 (d, J¼12.2 Hz,
1H), 7.13e7.26 (m, 4H), 7.27e7.47 (m, 8H), 7.56 (d, J¼8.2 Hz, 2H); MS
(FABþ) m/z (%) 481 ([MþH]þ, 31), 233 (10),139 (14), 91 (100); HRMS
(FABþ) calcd for C29H34ClO2S: 481.1968, found: 481.1968.
1250, 1055, 805 cmꢀ1; 1H NMR
d
1.21 (d, J¼6.9 Hz, 1H), 1.31 (s, 3H),
1.69e1.92 (m, 5H), 2.43 (s, 3H), 2.62 (t, J¼6.9 Hz, 2H), 3.80 (s, 3H),
6.85 (d, J¼8.6 Hz, 2H), 7.11 (d, J¼8.6 Hz, 2H), 7.32 (d, J¼8.2 Hz, 2H),
7.53 (d, J¼8.2 Hz, 2H); MS (FABþ) m/z (%) 377 ([MþH]þ, 80), 201
(18), 147 (16), 121 (100), 93 (20); HRMS (FABþ) calcd for
C21H26ClO2S: 377.1342, found: 377.1343.
3.1.19. 1-({(1R*,2S*,3R*)-2-[(S*)-1-(Benzyloxy)propyl]-1-chloro-2-
methyl-3-(2-phenylethyl)cyclopropyl}sulfinyl)-4-methylbenzene
(25c). Yield (99%); colorless crystal; mp 142.5e143.0 ꢁC (hexane/
AcOEt); IR (KBr) 2967, 2932, 1599, 1495, 1455, 1087, 1059,
747 cmꢀ1
;
1H NMR
d
1.05 (t, J¼7.4 Hz, 3H), 1.21 (t, J¼6.9 Hz, 1H),
1.25 (s, 3H), 1.39e1.57 (m, 2H), 1.63e1.94 (m, 2H), 2.12 (ddd, J¼6.1,
10.4, 14.0 Hz, 1H), 2.35 (ddd, J¼5.7, 10.4, 14.0 Hz, 1H), 2.42 (s, 3H),
3.61 (dd, J¼4.1, 9.0 Hz, 1H), 4.61 (d, J¼11.4 Hz, 1H), 4.79 (d,
J¼11.4 Hz, 1H), 7.09 (d, J¼7.2 Hz, 2H), 7.15e7.25 (m, 2H), 7.26e7.38
(m, 6H), 7.48 (d, J¼7.2 Hz, 2H), 7.55 (d, J¼8.2 Hz, 2H); 13C NMR
3.1.13. 1-[3-((1R*,2R*)-2-Chloro-1-methylcyclopropyl)propyl]-4-
methoxybenzene (20). Colorless oil; IR (neat) 2933, 2856, 1612,
1513, 1461, 1301, 1246, 1177, 1036, 830 cmꢀ1 1H NMR
; d 0.52 (dd,
J¼4.0, 6.1 Hz, 1H), 0.83 (dd, J¼6.1, 7.5 Hz, 1H), 1.18e1.30 (m, 5H), 1.67
(quint, J¼7.9 Hz, 2H), 2.48e2.56 (m, 2H), 2.84 (dd, J¼4.0, 7.5 Hz,1H),
3.79 (s, 3H), 6.82 (d, J¼8.7 Hz, 2H), 7.07 (d, J¼8.7 Hz, 2H); MS (EI) m/
z (%) 238 (Mþ, 19), 176 (16), 147 (51), 134 (22), 121 (100), 91 (10);
HRMS (EI) calcd for C14H19ClO: 238.1124, found: 238.1123.
d
10.4, 11.3, 21.6, 25.4, 26.4, 27.6, 34.3, 37.5, 71.6, 73.3, 82.0, 125.8,
126.2, 127.4, 127.9, 128.1, 128.2, 128.5, 129.5, 137.9, 138.8, 140.1,
142.3; MS (FABþ) m/z (%) 481 ([MþH]þ, 13), 373 (9), 233 (17), 139
(42), 91 (100); HRMS (FABþ) calcd for C29H34ClO2S: 481.1968,
found: 481.1967.
3.1.14. 1-Methoxy-4-(4-methylhexa-4,5-dienyl)benzene
(21). Colorless oil; IR (neat) 2935, 2857, 1959, 1612, 1513, 1442,
3.1.20. (1R*,6S*,7S*)-1-(Benzyloxymethyl)-7-chloro-7-(p-tol-
1300, 1246, 1177, 1039, 844 cmꢀ1
;
1H NMR
d
1.65e1.78 (m, 5H),
ylsulfinyl)bicyclo[4.1.0]heptane (25d). Yield (78%); colorless oil; IR
1.89e2.00 (m, 2H), 2.57 (t, J¼7.6 Hz, 2H), 3.78 (s, 3H), 4.60 (sextet,
J¼3.2 Hz, 2H), 6.82 (d, J¼8.7 Hz, 2H), 7.10 (d, J¼8.7 Hz, 2H); MS (EI)
m/z (%) 202 (Mþ, 21), 134 (100), 121 (33); HRMS (EI) calcd for
C14H18O: 202.1358, found: 202.1355.
(neat) 2942, 2857, 1494, 1454, 1091, 1064, 698 cmꢀ1 1H NMR
;
d
1.19e1.52 (m, 5H), 1.74 (dd, J¼1.6, 8.5 Hz, 1H), 1.76e1.99 (m, 2H),
2.04e2.21 (m, 1H), 2.41 (s, 3H), 3.79 (d, J¼10.0 Hz, 1H), 3.84 (d,
J¼10.0 Hz, 1H), 4.58 (d, J¼12.2 Hz, 1H), 4.62 (d, J¼12.2 Hz, 1H),
7.28e7.44 (m, 7H), 7.51 (d, J¼8.2 Hz, 2H); MS (FABþ) m/z (%) 389
([MþH]þ, 100), 281 (9), 185 (10), 154 (14), 139 (17), 136 (11), 123 (5),
107 (6), 91 (53), 77 (5); HRMS (FABþ) calcd for C22H26ClO2S:
389.1342, found: 389.1340.
3.1.15. 1-({(1R*,2S*)-1-Chloro-2-[(methoxymethoxy)methyl]-2-(2-
phenylethyl)cyclopropyl}sulfinyl)-4-methylbenzene
(71%); colorless oil; IR (neat) 2928, 1496, 1455, 1092, 1040,
700 cmꢀ1; 1H NMR
(22). Yield
d
1.36 (d, J¼7.3 Hz, 1H), 1.94e2.08 (m, 2H), 2.14
(ddd, J¼6.8, 10.9, 14.1 Hz, 1H), 2.43 (s, 3H), 2.62e2.82 (m, 2H), 3.44
(s, 3H), 3.88 (d, J¼10.6 Hz, 1H), 4.03 (d, J¼10.6 Hz, 1H), 4.71 (s, 2H),
7.10e7.39 (m, 5H), 7.34 (d, J¼8.2 Hz, 2H), 7.68 (d, J¼8.2 Hz, 2H); MS
(EI) m/z (%) 392 (Mþ, 0.3), 295 (15), 184 (26), 139 (25), 91 (74), 45
(100); HRMS (EI) calcd for C21H25ClO3S: 392.1213, found:
392.1212.
3.1.21. (1R*,4R*,5S*,6S*)-1,6-Dimethyl-4-phenyl-3-oxabicyclo[3.1.0]
hexane (26a). Colorless oil; IR (neat) 2954, 2842, 1451, 1055, 1021,
698 cmꢀ1; 1H NMR
d
0.94e1.05 (m, 4H), 1.16 (t, J¼3.1 Hz,1H), 1.26 (s,
3H), 3.74 (d, J¼8.2 Hz, 1H), 3.90 (d, J¼8.2 Hz, 1H), 5.03 (d, J¼2.9 Hz,
1H), 7.21e7.42 (m, 5H); MS (EI) m/z (%) 188 (Mþ, 50), 173 (35), 131
(83), 120 (63), 105 (100), 91 (61), 82 (62), 77 (46), 67 (83), 41 (35);
HRMS (EI) calcd for C13H16O: 188.1201, found: 188.1202.
3.1.16. (2-{(1R*,2S*)-2-Chloro-1-[(methoxymethoxy)methyl]cyclo-
propyl}ethyl)benzene (24). Colorless oil; IR (neat) 2930, 1454, 1150,
3.1.22. (1R*,4R*,5S*,6S*)-6-Isopropyl-1-(2-phenylethyl)-4-phenyl-3-
1108, 1047, 699 cmꢀ1
;
1H NMR
d
0.67 (dd, J¼4.2, 6.3 Hz, 1H), 1.07
oxabicyclo[3.1.0]hexane (26b). Colorless oil; IR (neat) 2956, 2864,
(dd, J¼6.3, 7.6 Hz, 1H), 1.86e2.04 (m, 2H), 2.73 (ddd, J¼7.1, 10.0,
17.2 Hz, 1H), 2.87 (ddd, J¼6.8, 10.0, 17.2 Hz, 1H), 3.13 (dd, J¼4.2,
7.6 Hz, 1H), 3.38 (s, 3H), 3.38 (d, J¼10.4 Hz, 1H), 3.50 (d, J¼10.4 Hz,
1H), 4.60 (d, J¼7.2 Hz, 1H), 4.62 (d, J¼7.2 Hz, 1H), 7.12e7.34 (m, 5H);
MS (FABþ) m/z (%) 277 ([MþNa]þ, 7), 193 (14), 157 (49), 129 (31), 91
(100), 45 (53); HRMS (FABþ) calcd for C14H19ClNaO2: 277.0971,
found: 277.0972.
1604, 1454, 1052, 698 cmꢀ1 1H NMR
; d 0.74e0.84 (m, 4H), 0.99 (d,
J¼6.6 Hz, 3H), 1.15e1.31 (m, 2H), 1.86e2.05 (m, 2H), 2.68 (ddd,
J¼7.2, 10.3, 16.8 Hz, 1H), 2.87 (ddd, J¼6.8, 10.3, 16.8 Hz, 1H), 3.90 (d,
J¼8.2 Hz, 1H), 3.94 (d, J¼8.2 Hz, 1H), 4.95 (d, J¼2.8 Hz, 1H),
7.17e7.25 (m, 4H), 7.26e7.40 (m, 6H); MS (EI) m/z (%) 306 (Mþ, 60),
263 (39), 249 (31), 159 (38), 129 (20), 117 (22), 105 (67), 91 (100);
HRMS (EI) calcd for C22H26O: 306.1984, found: 306.1979.
3.1.17. 1-{[(1R*,2S*,3R*)-2-(Benzyloxymethyl)-1-chloro-2,3-
3.1.23. (1R*,2S*,4R*,5S*,6S*)-2-Ethyl-1-methyl-6-(2-phenylethyl)-4-
dimethylcyclopropyl]sulfinyl}-4-methylbenzene (25a). Yield (97%);
phenyl-3-oxabicyclo[3.1.0]hexane (26c). Colorless oil; IR (neat)
colorless oil; IR (neat) 2931, 2864,1496, 1455, 1086, 1059, 813 cmꢀ1
;
2929, 2875, 1604, 1495, 1453, 1099, 698 cmꢀ1; 1H NMR
d 0.94e1.07
1H NMR
d
1.18 (d, J¼6.4 Hz, 3H), 1.27 (s, 3H), 2.01 (q, J¼6.4 Hz, 1H),
(m, 4H), 1.17 (s, 3H), 1.25 (t, J¼3.3 Hz, 1H), 1.43e1.73 (m, 4H),
2.40 (s, 3H), 3.70 (d, J¼9.8 Hz, 1H), 3.83 (d, J¼9.8 Hz, 1H), 4.53 (d,
J¼11.8 Hz, 1H), 4.60 (d, J¼11.8 Hz, 1H), 7.23 (d, J¼8.2 Hz, 2H),
7.28e7.41 (m, 5H), 7.67 (d, J¼8.2 Hz, 2H); MS (FABþ) m/z (%) 363
2.41e2.62 (m, 2H), 3.81 (dd, J¼3.4, 9.8 Hz, 1H), 5.05 (d, J¼2.7 Hz,
1H), 6.96e7.04 (m, 2H), 7.09e7.41 (m, 8H); 13C NMR
d 10.6, 10.7,
22.8, 25.1, 30.3, 30.9, 35.2, 36.0, 78.0, 85.8, 125.7, 126.4, 127.1, 128.1,

1080
T. Satoh et al. / Tetrahedron 68 (2012) 1071e1084
128.2, 128.5, 141.2, 142.3; MS (EI) m/z (%) 306 (Mþ, 25), 277 (23), 117
(35), 91 (100), 77 (13), 57 (13); HRMS (EI) calcd for C22H26O:
306.1984, found: 306.1988.
H2O2 (3.7 mL), and the mixture was extracted CHCl3 (2ꢂ10 mL).
The organic layer was dried over MgSO4 and concentrated in
vacuo. The residue was purified by column chromatography on
silica gel using hexane/AcOEt as the eluent to give 29 (332 mg;
3.1.24. (1R*,4R*,5S*,6S*)-4-Phenyl-3-oxatricyclo[4.4.0.01,5]decane
1.22 mmol; 76%) as a colorless crystal; mp 100.0e100.5 C (hex-
ane/AcOEt); IR (KBr) 3391, 2865, 1429, 1173, 1048, 808 cmꢀ1 1H
NMR
ꢁ
(26d). i-PrMgCl (5 equiv) was used. Colorless oil; IR (neat) 2926,
;
2850, 1450, 1061, 1028, 698 cmꢀ1
;
1H NMR
d
1.05e1.12 (m, 1H),
d
1.16 (d, J¼7.0 Hz, 1H), 1.39 (s, 3H), 1.74e1.84 (m, 1H), 1.96
1.16e1.32 (m, 3H), 1.36e1.50 (m, 3H), 1.66e1.97 (m, 3H), 3.75 (d,
J¼8.1 Hz,1H), 3.92 (d, J¼8.1 Hz,1H), 5.02 (d, J¼3.0 Hz,1H), 7.21e7.41
(d, J¼7.0 Hz, 1H), 2.10 (td, J¼6.4, 13.7 Hz, 1H), 2.20 (td, J¼6.4,
13.7 Hz, 1H), 2.43 (s, 3H), 3.87 (q, J¼6.4 Hz, 2H), 7.33 (d, J¼8.2 Hz,
2H), 7.60 (d, J¼8.2 Hz, 2H); MS (FABþ) m/z (%) 273 ([MþH]þ, 100),
141 (17); HRMS (FABþ) calcd for C13H18ClO2S: 273.0716, found:
273.0715.
(m, 5H); 13C NMR
d 15.7, 22.1, 22.5, 23.0, 23.2, 28.3, 33.1, 74.9, 81.4,
126.4, 127.2, 128.1, 140.9; MS (EI) m/z (%) 214 (Mþ, 89), 171 (21), 157
(42), 120 (59), 105 (100), 91 (57), 77 (48); HRMS (EI) calcd for
C15H18O: 214.1358, found: 214.1360.
3.1.28. 1-({(1R*,2R*)-2-[2-(Benzyloxy)ethyl]-1-chloro-2-
methylcyclopropyl}sulfinyl)-4-methylbenzene (30). Colorless crys-
tal; mp 33.8e34.3 ꢁC (hexane/AcOEt); IR (KBr) 2925, 2864, 1597,
3.1.25. (1R*,2S*)-2-Chloro-1-methyl-2-(p-tolylsulfinyl)cyclo-
propanecarbaldehyde (27). Lithium diisobutyl-tert-butoxyaluminum
hydride (LDBBA) was prepared according to the procedure described
in the literature.15 A solution of BuLi in hexane (1.67 mol/L; 1.31 mL;
2.2 mmol) was added to a solution of tert-butyl alcohol (163 mg,
2.20 mmol) in THF (1 mL) at 0 ꢁC, and the mixture was stirred at
room temperature for 1 h. A solution of DIBALH in hexane (1.03 mol/
L; 1.94 mL; 2.0 mmol) was then added dropwise to the resulting
solution at 0 ꢁC, and the mixture was stirred at room temperature for
2 h. The resulting solution containing LDBBA was added dropwise to
a solution of 10 (60.2 mg; 0.200 mmol) in THF (2 mL) at 0 ꢁC, and the
mixture was stirred at that temperature for 10 min. The reaction was
quenched with 10% hydrochloric acid (0.5 mL), and the mixture was
extracted with Et2O (2ꢂ5 mL). The organic layer was dried over
MgSO4 and concentrated in vacuo. The residue was purified by col-
umn chromatography on silica gel using hexane/AcOEt as the eluent
to give 27 (43.3 mg; 0.169 mmol; 84%) as a colorless crystal; mp
92.0e92.5 ꢁC (hexane/AcOEt); IR (KBr) 3068, 2981, 2842, 1711, 1454,
1494, 1454, 1085, 1062 cmꢀ1; 1H NMR
d
1.22 (d, J¼7.0 Hz, 1H), 1.35
(s, 3H), 2.00 (d, J¼7.0 Hz, 1H), 2.15 (td, J¼6.6, 13.9 Hz, 1H), 2.21 (td,
J¼6.0, 13.9 Hz, 1H), 2.42 (s, 3H), 3.68 (m, 2H), 4.55 (s, 2H), 7.30e7.36
(m, 3H), 7.36e7.39 (m, 4H), 7.56 (d, J¼8.1 Hz, 2H); MS (FABþ) m/z (%)
363 ([MþH]þ, 100), 91 (68); HRMS (EI) calcd for C20H24ClO2S:
363.1186, found: 363.1185.
3.1.29. [(3-Methylpenta-3,4-dienyloxy)methyl]benzene
(31). Colorless oil; IR (neat) 2981, 2858, 1961, 1454, 1364, 1103, 849,
736, 697 cmꢀ1
;
1H NMR
d
1.71 (t, J¼3.2 Hz, 3H), 2.27 (tt, J¼3.2,
6.9 Hz, 2H), 3.58 (t, J¼6.9 Hz, 2H), 4.52 (s, 2H), 4.60 (sextet, J¼3.2 Hz,
2H), 7.26e7.39 (m, 5H); MS (EI) m/z (%) 188 (Mþ, 4), 91 (100); HRMS
(EI) calcd for C13H16O: 188.1201, found: 188.1197.
3.1.30. (E)-Ethyl 3-[(1R*,2S*)-2-chloro-1-methyl-2-(p-tolylsulfinyl)cy-
clopropyl]acrylate (34). Sodium hydride (55% oil suspension;
65.5 mg; 1.50 mmol) was added to a solution of triethyl phos-
phonoacetate (392 mg; 1.75 mmol) in THF (1.5 mL) at 0 ꢁC, and the
mixture was stirred at room temperature for 1 h. A solution of 27
(129 mg; 0.502 mmol) in THF (1 mL) was then added to the
resulting solution at 0 ꢁC, and the mixture was stirred at room
temperature overnight. The reaction was quenched with satd aq
NH4Cl (1 mL), and the mixture was extracted with CHCl3 (2ꢂ5 mL).
The organic layer was dried over MgSO4 and concentrated in
vacuo. The residue was purified by column chromatography on
silica gel using hexane/AcOEt as the eluent to give 34 (149 mg;
0.456 mmol; 91%) as a colorless crystal; mp 112.0e112.5 ꢁC (hex-
ane/AcOEt); IR (KBr) 2982, 2935, 1715, 1645, 1239, 1096, 1050,
1056, 805 cmꢀ1; 1H NMR
d
1.47 (s, 3H), 1.73 (d, J¼7.6 Hz, 1H), 2.43 (s,
3H), 2.75 (d, J¼7.6 Hz, 1H), 7.34 (d, J¼8.2 Hz, 2H), 7.49 (d, J¼8.2 Hz,
2H), 9.61 (s, 1H); MS (FABþ) m/z (%) 257 ([MþH]þ, 100), 185 (18), 154
(28), 139 (16), 137 (28), 93 (37); HRMS (FABþ) calcd for C12H14ClO2S:
257.0403, found: 257.0403.
3.1.26. 1-[((1R*,2S*)-1-Chloro-2-methyl-2-vinylcyclopropyl)sulfinyl]-
4-methylbenzene (28). Sodium hydride (55% oil suspension;
26.2 mg; 0.60 mmol) was added to a solution of methyl-
triphenylphosphonium iodide (283 mg; 0.700 mmol) in THF
(1.5 mL) at 0 ꢁC, and the mixture was stirred at room temper-
ature for 1 h. A solution of 27 (51.4 mg; 0.200 mmol) in THF
(0.5 mL) was added to the resulting solution at 0 ꢁC, and the
mixture was stirred at room temperature overnight. The re-
action was quenched with satd aq NH4Cl (10 mL), and the
mixture was extracted with CHCl3 (2ꢂ7 mL). The organic layer
was dried over MgSO4 and concentrated in vacuo. The residue
was purified by column chromatography on silica gel using
hexane/AcOEt as the eluent to give 28 (43.9 mg; 0.172 mmol;
86%) as a colorless crystal; mp 103.0e103.3 ꢁC (hexane/AcOEt);
812 cmꢀ1
;
1H NMR
d
1.33 (t, J¼7.2 Hz, 3H), 1.48 (s, 3H), 1.72 (d,
J¼7.4 Hz, 1H), 2.37 (d, J¼7.4 Hz, 1H), 2.42 (s, 3H), 4.26 (q, J¼7.2 Hz,
2H), 6.02 (d, J¼15.7 Hz, 1H), 7.10 (d, J¼15.7 Hz, 1H), 7.30 (d,
J¼8.2 Hz, 2H), 7.98 (d, J¼8.2 Hz, 2H); Anal. Calcd for C16H19ClO3S: C,
58.80; H, 5.86; Cl, 10.85; S, 9.81, found: C, 58.75; H, 5.79; Cl, 10.78;
S, 9.79.
3.1.31. 3-[(1R*,2R*)-2-Chloro-1-methyl-2-(p-tolylsulfinyl)cyclo-
propyl]propan-1-ol (35). NaBH4 (5 equiv) was used. Colorless crys-
tal; mp 57.5e58.0 ꢁC (hexane/AcOEt); IR (KBr) 3419, 2931, 2870,
IR (KBr) 3070, 2988, 1635, 1621, 1081, 1054, 517 cmꢀ1 1H NMR
;
d
1.45 (s, 3H), 1.61 (d, J¼7.2 Hz, 1H), 2.23 (d, J¼7.2 Hz, 1H), 2.42
(s, 3H), 5.34 (dd, J¼0.4, 17.2 Hz, 1H), 5.36 (dd, J¼0.4, 10.6 Hz, 1H),
6.02 (dd, J¼10.6, 17.2 Hz, 1H), 7.30 (d, J¼8.2 Hz, 2H), 7.55 (d,
J¼8.2 Hz, 2H); MS (FABþ) m/z (%) 255 ([MþH]þ, 100), 115 (26),
79 (12); HRMS (FABþ) calcd for C13H16ClOS: 255.0610, found:
255.0613.
1456, 1085, 1059, 810, 755 cmꢀ1; 1H NMR
d
1.19 (d, J¼7.0 Hz,1H),1.36
(s, 3H), 1.70e2.09 (m, 6H), 2.43 (s, 3H), 3.64e3.80 (m, 2H), 7.33 (d,
J¼8.1 Hz, 2H), 7.58 (d, J¼8.1 Hz, 2H); MS (EI) m/z (%) 286 (Mþ, 0.7),
269 (7), 201 (24), 140 (100), 123 (10), 92 (35), 85 (19), 77 (16), 65 (8);
HRMS (EI) calcd for C14H19ClO2S: 286.0794, found: 286.0796.
3.1.27. 2-[(1R*,2R*)-2-Chloro-1-methyl-2-(p-tolylsulfinyl)cyclo-
propyl]ethanol (29). A solution of boraneetetrahydrofuran com-
plex in THF (0.95 mmol/L; 4.5 mL; 4.3 mmol) was added dropwise
to a solution of 28 (410 mg; 1.61 mmol) in THF (8 mL) at 0 ꢁC, and
the mixture was stirred at that temperature for 1 h. The reaction
mixture was quenched with aq NaOH (3 mol/L; 4.1 mL) and 35%
3.1.32. 1-({(1R*,2R*)-2-[3-(benzyloxy)propyl]-1-chloro-2-
methylcyclopropyl}sulfinyl)-4-methylbenzene (36). Colorless oil; IR
(neat) 2930, 2861, 1455, 1095, 1063, 739 cmꢀ1 1H NMR
; d 1.23 (d,
J¼6.9 Hz, 1H), 1.32 (s, 3H), 1.72e1.97 (m, 5H), 2.43 (s, 3H), 3.48e3.56
(m, 2H), 4.53 (s, 2H), 7.27e7.41 (m, 7H), 7.55 (d, J¼8.2 Hz, 2H); MS
(FABþ) m/z (%) 377 ([MþH]þ, 100), 269 (8), 231 (9), 201 (4), 154 (2),

T. Satoh et al. / Tetrahedron 68 (2012) 1071e1084
1081
123 (11), 91 (80), 77 (3); HRMS (FABþ) calcd for C21H26ClO2S:
377.1342, found: 377.1343.
and the mixture was extracted with benzene (2ꢂ3 mL). The or-
ganic layer was dried over MgSO4 and concentrated in vacuo. The
residue was purified by column chromatography on silica gel us-
ing hexane/AcOEt as the eluent to give 42d (246 mg; 0.468 mmol;
78%) as a colorless oil; IR (neat) 2931, 2858, 1428, 1111, 1063,
3.1.33. (1R*,4R*,5S*)-4-(Benzyloxy)-1-methylbicyclo[3.1.0]hexane
(38). i-PrMgCl (5 equiv) was used. Colorless oil; IR (neat) 2926,
2862, 1454, 1096, 1075, 697 cmꢀ1; 1H NMR
d
0.31 (dd, J¼5.0, 7.8 Hz,
703 cmꢀ1; 1H NMR
d
1.07 (s, 9H), 1.24 (d, J¼7.1 Hz, 1H), 1.29 (s, 3H),
1H), 0.80 (t, J¼5.0 Hz, 1H), 1.62 (s, 3H), 1.20e1.29 (m, 2H), 1.55 (dt,
J¼8.2, 12.6 Hz, 1H), 1.75 (dd, J¼8.2, 12.6 Hz, 1H), 1.89 (td, J¼8.2,
12.6 Hz, 1H), 4.28 (dt, J¼4.4, 8.2 Hz, 1H), 4.49 (d, J¼11.9 Hz, 1H), 4.58
(d, J¼11.9 Hz, 1H), 7.22e7.39 (m, 5H); MS (EI) m/z (%) 202 (Mþ, 1),
158 (19), 111 (17), 91 (100), 79 (13), 65 (11), 55 (12); HRMS (EI) calcd
for C14H18O: 202.1358, found: 202.1359.
1.60e1.96 (m, 5H), 2.43 (s, 3H), 3.72 (t, J¼6.0 Hz, 2H), 7.28e7.48
(m, 8H), 7.52 (d, J¼8.2 Hz, 2H), 7.60 (dd, J¼1.4, 7.5 Hz, 4H); MS
(FABþ) m/z (%) 525 ([MþH]þ, 23), 467 (35), 447 (75), 199 (51), 135
(93), 93 (100), 77 (27); HRMS (FABþ) calcd for C30H38ClO2SSi:
525.2050, found: 525.2051.
3.1.40. ({3-[(1R*,2R*)-2-Chloro-1-methyl-2-(p-tolylsulfinyl)cyclopropyl]
propoxy}methanetriyl)tribenzene (42e). 4-Dimethylaminopyridine
(2.4 mg; 0.020 mmol) and triethylamine (60.7 mmg; 0.600 mmol)
were added to a solution of trityl chloride (167 mg; 0.600 mmol)
and 35 (57.4 mg; 0.200 mmol) in CHCl3 (0.4 mL) at room tem-
perature, and the mixture was stirred at that temperature over-
night. The reaction was quenched with satd aq NH4Cl (0.5 mL),
and the mixture was extracted with CHCl3 (2ꢂ3 mL). The organic
layer was dried over MgSO4 and concentrated in vacuo. The resi-
due was purified by column chromatography on silica gel using
hexane/AcOEt as the eluent to give 42e (87.6 mmg; 0.166 mmol;
83%) as a colorless crystal; mp 106.0e106.5 ꢁC (hexane/AcOEt); IR
3.1. 34. [(4-Methylhexa-4, 5-dienyloxy)methyl]benzene
(39). Colorless oil; IR (neat) 2939, 2855, 1960, 1454, 1104, 847,
735 cmꢀ1
;
1H NMR
d
1.68 (t, J¼3.1 Hz, 3H), 1.72e1.81 (m, 2H),
1.98e2.06 (m, 2H), 3.50 (t, J¼6.5 Hz, 2H), 4.50 (s, 2H), 4.58 (sextet,
J¼3.1 Hz, 2H), 7.26e7.36 (m, 5H); MS (EI) m/z (%) 202 (Mþ, 5), 111
(23), 105 (30), 91 (100), 79 (17), 77 (22), 65 (12), 55 (11), 43 (11);
HRMS (EI) calcd for C14H18O: 202.1358, found: 202.1356.
3.1.35. {[3-((1R*,2R*)-2-Chloro-1-methylcyclopropyl)propoxy]
methyl}benzene (40). Colorless oil; IR (neat) 2941, 2855, 1455, 1102,
1029, 697 cmꢀ1
;
1H NMR
d
0.53 (dd, J¼4.0, 6.0 Hz, 1H), 0.86 (t,
J¼6.0 Hz, 1H), 1.21 (s, 3H), 1.26e1.38 (m, 2H), 1.64 (quint, J¼6.4 Hz,
2H), 2.88 (dd, J¼4.0, 7.6 Hz, 1H), 3.45 (t, J¼6.4 Hz, 2H), 4.89 (s, 2H),
7.26e7.36 (m, 5H); MS (ESIþ) m/z (%) 263 (35), 261 ([MþNa]þ 100),
225 ([MꢀHClþNa]þ 32); HRMS (ESIþ) calcd for C14H19ClONa:
261.1022, found: 261.1017.
(KBr) 3058, 2930, 1491, 1449, 1063, 756 cmꢀ1 1H NMR
; d 1.19 (d,
J¼6.9 Hz, 1H), 1.29 (s, 3H), 1.68e1.96 (m, 5H), 2.42 (s, 3H),
3.08e3.22 (m, 2H), 7.20e7.26 (m, 3H), 7.26e7.34 (m, 8H),
7.38e7.50 (m, 6H), 7.54 (d, J¼8.2 Hz, 2H); MS (FABþ) m/z (%) 551
([MþNa]þ, 100), 243 (73), 165 (24); HRMS (FABþ) calcd for
C33H33ClO2SNa: 551.1787, found: 551.1788.
3.1.36. 1-({3-[(1R*,2R*)-2-Chloro-1-methyl-2-(p-tolylsulfinyl)cyclo-
propyl]propoxy}methyl)-4-fluorobenzene (42a). Yield (95%); color-
3.1.41. (1R*,4R*,5S*)-4-(4-Fluorobenzyloxy)-1-methylbicyclo[3.1.0]
hexane (43a). Colorless oil; IR (neat) 2927, 2863, 1510, 1223, 1102,
less oil; IR (neat) 2930, 2863, 1509, 1221, 1091, 1062, 810 cmꢀ1
;
1H NMR
d
1.22 (d, J¼6.9 Hz, 1H), 1.33 (s, 3H), 1.72e1.98 (m, 5H),
1087, 824 cmꢀ1
;
1H NMR
d
0.31 (dd, J¼4.8, 7.7 Hz, 1H), 0.79 (t,
2.43 (s, 3H), 3.52 (m, 2H), 4.83 (s, 2H), 7.03 (t, J¼8.6 Hz, 2H),
7.28e7.36 (m, 4H), 7.55 (d, J¼8.2 Hz, 2H); MS (FABþ) m/z (%) 395
([MþH]þ, 100), 269 (6), 185 (16), 154 (17), 137 (19), 109 (90), 93
(28); HRMS (EI) calcd for C21H25FO2S: 395.1248, found:
395.1247.
J¼4.8 Hz, 1H), 1.17 (s, 3H), 1.18e1.31 (m, 2H), 1.49e1.62 (m, 1H), 1.76
(dd, J¼8.3, 12.9 Hz, 1H), 1.89 (td, J¼8.0, 12.9 Hz, 1H), 4.27 (dt, J¼4.4,
8.0 Hz, 1H), 4.44 (d, J¼11.6 Hz, 1H), 4.54 (d, J¼11.6 Hz, 1H), 7.01 (t,
J¼8.8 Hz, 2H), 7.32 (dd, J¼5.6, 8.8 Hz, 2H); MS (EI) m/z (%) 220 (Mþ,
0.6), 202 (1), 109 (100), 93 (7); HRMS (EI) calcd for C14H17FO:
220.1263, found: 220.1262.
3.1.37. 1-({3-[(1R*,2R*)-2-Chloro-1-methyl-2-(p-tolylsulfinyl)cyclo-
propyl]propoxy}methyl)-4-methoxybenzene (42b). Yield (96%); col-
orless oil; IR (neat) 2933, 2861, 1612, 1513, 1247, 1091, 1035,
3.1.42. (1R*,4R*,5S*)-4-(4-Methoxybenzyloxy)-1-methylbicyclo[3.1.0]
hexane (43b). Colorless oil; IR (neat) 2955, 2861, 1613, 1514, 1248,
811 cmꢀ1; 1H NMR
d
1.23 (d, J¼6.9 Hz, 1H), 1.31 (s, 3H), 1.70e1.96 (m,
1087, 820 cmꢀ1
;
1H NMR
d
0.30 (dd, J¼4.5, 7.8 Hz, 1H), 0.79 (t,
5H), 2.43 (s, 3H), 3.45e3.53 (m, 2H), 3.80 (s, 3H), 4.45 (s, 2H), 6.88 (d,
J¼8.3 Hz, 2H), 7.29 (d, J¼8.2 Hz, 2H), 7.32 (d, J¼8.3 Hz, 2H), 7.55 (d,
J¼8.2 Hz, 2H); MS (FABþ) m/z (%) 407 ([MþH]þ, 17), 121 (100); HRMS
(FABþ) calcd for C22H28ClO3S: 407.1448, found: 407.1449.
J¼4.5 Hz, 1H), 1.16 (s, 3H), 1.19e1.29 (m, 2H), 1.54 (dt, J¼8.0, 12.5 Hz,
1H),1.75 (dd, J¼8.2,12.5 Hz,1H), 1.87 (td, J¼8.0,12.5 Hz,1H), 3.78 (s,
3H), 4.26 (dt, J¼4.4, 8.0 Hz, 1H), 4.42 (d, J¼11.4 Hz, 1H), 4.51 (d,
J¼11.4 Hz, 1H), 6.87 (d, J¼8.6 Hz, 2H), 7.28 (d, J¼8.6 Hz, 2H); MS (EI)
m/z (%) 232 (Mþ, 13), 147 (11), 121 (100); HRMS (EI) calcd for
C15H20O2: 232.1463, found: 232.1463.
3.1.38. 1-({(1R*,2R*)-1-Chloro-2-methyl-2-[3-(3-phenylpropoxy)pro-
pyl]cyclopropyl}sulfinyl)-4-methylbenzene (42c). Yield (87%); color-
less oil; IR (neat) 2933, 2861, 1495, 1455, 1116, 1063, 701 cmꢀ1
;
1H
3.1.43. (1R*,4R*,5S*)-1-Methyl-4-(3-phenylpropoxy)bicyclo[3.1.0]
NMR
d
1.25 (d, J¼6.9 Hz, 1H), 1.34 (s, 3H), 1.70e1.98 (m, 7H), 2.42 (s,
hexane (43c). Colorless oil; IR (neat) 2942, 2860, 1454, 1342, 1106,
3H), 2.70 (t, J¼7.7 Hz, 2H), 3.44 (t, J¼6.4 Hz, 2H), 3.46 (t, J¼6.3 Hz,
2H), 7.16e7.22 (m, 3H), 7.26e7.30 (m, 2H), 7.32 (d, J¼8.2 Hz, 2H),
7.57 (d, J¼8.2 Hz, 2H); MS (FABþ) m/z (%) 405 ([MþH]þ, 100), 269
(10), 119 (20), 91 (59); HRMS (FABþ) calcd for C23H30ClO2S:
405.1655, found: 405.1650.
1073, 699 cmꢀ1
;
1H NMR
d
0.29 (dd, J¼4.6, 7.7 Hz, 1H), 0.76 (t,
J¼4.6 Hz, 1H), 1.09e1.27 (m, 5H), 1.48e1.61 (m, 1H), 1.75 (dd, J¼8.3,
12.5 Hz,1H),1.81e1.96 (m, 3H), 2.69 (t, J¼7.7 Hz, 2H), 3.38 (td, J¼6.5,
9.3 Hz, 1H), 3.50 (td, J¼6.6, 9.3 Hz, 1H), 4.17 (dt, J¼4.4, 8.0 Hz, 1H),
7.13e7.31 (m, 5H); MS (EI) m/z (%) 230 (Mþ, 1), 215 (1), 135 (12), 118
(54), 91 (100); HRMS (EI) calcd for C16H22O: 230.1671, found:
230.1666.
3.1.39. tert-Butyl{3-[(1R*,2R*)-2-chloro-1-methyl-2-(p-tolylsulfinyl)
cyclopropyl]propoxy}diphenylsilane (42d). A solution of 35
(172 mg; 0.600 mmol) in DMF (0.5 mL) was added to a solution of
imidazole (61.2 mmg; 0.900 mmol) and tert-butyl-
chlorodiphenylsilane (247 mmg; 0.900 mmol) in DMF (0.7 mL) at
room temperature, and the mixture was stirred at that tempera-
ture for 4 h. The reaction was quenched with satd aq NH4Cl (1 mL),
3.1.44. 1-Fluoro-4-[(4-methylhexa-4,5-dienyloxy)methyl]benzene
(44a). Colorless oil; IR (neat) 2940, 2858, 1960, 1604, 1509, 1223,
1093, 824 cmꢀ1; 1H NMR
1.95e2.06 (m, 2H), 3.49 (t, J¼6.5 Hz, 2H), 4.46 (s, 2H), 4.58 (sextet,
J¼3.2 Hz, 2H), 7.02 (t, J¼8.8 Hz, 2H), 7.30 (dd, J¼5.5, 8.8 Hz, 2H); MS
d
1.68 (t, J¼3.2 Hz, 3H), 1.70e1.81 (m, 2H),

1082
T. Satoh et al. / Tetrahedron 68 (2012) 1071e1084
(EI) m/z (%) 220 (Mþ, 2), 123 (9), 109 (100); HRMS (EI) calcd for
C14H17FO: 220.1263, found: 220.1261.
rate¼0.50 mL/min, detection at 254 nm, retention time¼16.8 min
(minor), 19.5 min (major), 98% ee.
3.1.45. 1-Methoxy-4-[(4-methylhexa-4,5-dienyloxy)methyl]benzene
3.1.53. [(1S,2R,3R)-2-Chloro-1-methyl-3-(2-phenylethyl)-2-((RS)-p-
(44b). Colorless oil; IR (neat) 2937, 2856, 1960, 1514, 1248, 1100,
tolylsulfinyl)cyclopropyl]-propan-1-one (50b). Colorless crystal; mp
847 cmꢀ1; 1H NMR
d
1.68 (t, J¼2.9 Hz, 3H),1.74 (quint, J¼6.8 Hz, 2H),
72.5e73.0 ꢁC (hexane/AcOEt); ½a 2D8
ꢀ11.1 (c 0.42, acetone); HPLC:
ꢃ
1.96e2.05 (m, 2H), 3.46 (t, J¼6.8 Hz, 2H), 3.80 (s, 3H), 4.43 (s, 2H),
4.58 (sextet, J¼2.9 Hz, 2H), 6.67 (d, J¼8.5 Hz, 2H), 7.26 (d, J¼8.5 Hz,
2H); MS (EI) m/z (%) 232 (Mþ, 0.7), 135 (22), 121 (100); HRMS (EI)
calcd for C15H20O2: 232.1463, found: 232.1466.
DAICEL CHIRALCEL OD (
f
0.46 cmꢂ25 cm), 2-propanol/hexane¼1/
9, flow rate¼0.50 mL/min, detection at 254 nm, retention
time¼26.7 min (minor), 29.7 min (major), 98% ee.
3.1.54. [(1S,2R,3R)-2-Chloro-3-isopropyl-1-(2-phenylethyl)-2-((RS)-
p-tolylsulfinyl)cyclopropyl]methanol (51a). Colorless crystal; mp
162.0e162.5 ꢁC (hexane/AcOEt); IR (KBr) 3380, 2961, 1602, 1494,
1455, 1425, 1085, 1065, 1036, 1014, 813, 762, 739, 702, 513 cmꢀ1; 1H
3.1.46. [3-(4-Methylhexa-4,5-dienyloxy)propyl]benzene
(44c). Colorless oil; IR (neat) 2941, 2858, 1960, 1604, 1455, 1116,
699 cmꢀ1 1H NMR
; d 1.65e1.78 (m, 5H), 1.82e1.96 (m, 2H),
1.96e2.07 (m, 2H), 2.69 (t, J¼7.7 Hz, 2H), 3.42 (t, J¼6.5 Hz, 2H), 3.43
(t, J¼6.6 Hz, 2H), 4.60 (sextet, J¼3.2 Hz, 2H), 7.16e7.31 (m, 5H); MS
(EI) m/z (%) 230 (Mþ, 1), 118 (63), 112 (20), 91 (100), 79 (16).
NMR
d
0.68 (d, J¼6.5 Hz, 3H), 1.00 (d, J¼6.6 Hz, 3H), 1.49 (d,
J¼10.5 Hz, 1H), 1.55e1.72 (m, 1H), 1.85e2.07 (m, 2H), 2.43 (s, 3H),
2.77 (dd, J¼4.8, 8.6 Hz, 1H), 2.80e2.91 (m, 2H), 4.03 (dd, J¼4.8,
12.7 Hz, 1H), 4.16 (dd, J¼8.6, 12.7 Hz, 1H), 7.14e7.30 (m, 5H), 7.34 (d,
J¼8.1 Hz, 2H), 7.58 (d, J¼8.2 Hz, 2H); Anal. Calcd for C22H27ClO2S: C,
67.59; H, 6.96; Cl, 9.07; S, 8.20, found: C, 67.42; H, 6.98; Cl, 9.04; S,
3.1.47. tert-Butyl(4-methylhexa-4,5-dienyloxy)diphenylsilane
(44d). Colorless oil; IR (neat) 2932, 2858, 1960, 1428, 1112,
702 cmꢀ1; 1H NMR
d
1.04 (s, 9H), 1.63e1.76 (m, 5H), 1.97e2.07 (m,
8.15; ½a 2D9
ꢃ
ꢀ50.1 (c 0.47, acetone); HPLC: DAICEL CHIRALCEL OD (
f
2H), 3.68 (t, J¼6.4 Hz, 2H), 4.55 (sextet, J¼3.2 Hz, 2H), 7.32e7.46 (m,
6H), 7.67 (dd, J¼1.7, 7.7 Hz, 4H); MS (EI) m/z (%) 350 (Mþ, 0.1), 293
(77), 281 (13), 215 (46), 199 (100), 183 (18), 123 (13); HRMS (EI)
calcd for C23H30OSi: 350.2066, found: 350.2064.
0.46 cmꢂ25 cm), 2-propanol/hexane¼1/9, flow rate¼0.50 mL/min,
detection at 254 nm, retention time¼26.8 min (major), 42.2 min
(minor), 99% ee (after recrystallization).
3.1.55. (S)-1-[(1S,2R,3R)-2-Chloro-1-methyl-3-(2-phenylethyl)-2-
((RS)-p-tolylsulfinyl)cyclopropyl]propan-1-ol (51b). Sodium borohy-
dride (136 mg; 3.60 mmol) was added to a solution of 50b (475 mg;
1.22 mmol) in ethanol (12 mL) at 0 ꢁC, and the mixture was stirred
at that temperature for 30 min. The reaction was quenched with
satd aq NH4Cl (7 mL), and the mixture was extracted with CHCl3
(2ꢂ10 mL). The organic layer was dried over MgSO4 and concen-
trated in vacuo. The residue was purified by column chromatog-
raphy on silica gel using hexane/AcOEt as the eluent to give 51b
(471 mg; 1.20 mmol; 99%) as a colorless crystal; mp 168.5e169.0 ꢁC
(hexane/AcOEt); IR (KBr) 3454, 2925, 2879, 1599, 1496, 1452, 1321,
3.1.48. [(4-Methylhexa-4,5-dienyloxy)methanetriyl]tribenzene
(44e). Colorless oil; IR (neat) 2939, 2870, 1959, 1490, 1448, 1072,
706 cmꢀ1
;
1H NMR
d
1.66 (t, J¼3.2 Hz, 3H), 1.76 (quint, J¼6.8 Hz,
2H), 1.95e2.06 (m, 2H), 3.08 (t, J¼6.8 Hz, 2H), 4.53 (sextet,
J¼3.2 Hz, 2H), 7.21e7.25 (m, 3H), 7.25e7.31 (m, 6H), 7.41e7.44 (m,
6H); MS (EI) m/z (%) 354 (Mþ, 0.5), 243 (100), 183 (6), 165 (23), 105
(9), 77 (3), 67 (2); HRMS (EI) calcd for C26H26O: 354.1984, found:
354.1980.
3.1.49. (1R,2S)-Ethyl 2-chloro-1-methyl-2-((RS)-p-tolylsulfinyl)cyclo-
propanecarboxylate (45). Colorless oil; ½a D27
ꢃ
þ3.6 (c 0.38, acetone);
1114, 1084, 1031, 814, 746, 700 cmꢀ1
;
1H NMR
d
1.02 (t, J¼7.5 Hz,
HPLC: DAICEL CHIRALCEL AD (
f
0.46 cmꢂ25 cm), 2-propanol/
3H), 1.27 (s, 3H), 1.48e1.65 (m, 2H), 1.65e1.86 (m, 3H), 2.36e2.59
(m, 2H), 2.43 (s, 3H), 3.04e3.08 (m, 1H), 3.82e3.90 (m, 1H), 7.11 (d,
J¼7.7 Hz, 2H), 7.17e7.32 (m, 3H), 7.34 (d, J¼8.2 Hz, 2H), 7.46 (d,
J¼8.2 Hz, 2H); MS (FABþ) m/z (%) 391 ([MþH]þ, 100), 233 (55), 154
(28), 139 (87), 91 (58), 57 (34); HRMS (FABþ) calcd for C22H28ClO2S:
hexane¼1/9, flow rate¼0.50 mL/min, detection at 254 nm, re-
tention time¼26.7 min (major), 31.0 min (minor), 98% ee.
3.1.50. 1-{(RS)-[(1S,2R)-2-(Benzyloxymethyl)-1-chloro-2-
methylcyclopropyl]sulfinyl}-4-methylbenzene (46). Colorless oil;
391.1499, found: 391.1498; ½a D27
þ22.9 (c 0.38, acetone); HPLC:
ꢃ
½
a 2D8
ꢃ
þ38.9 (c 0.26, acetone); HPLC: DAICEL CHIRALCEL AD (
f
DAICEL CHIRALCEL OD (
f
0.46 cmꢂ25 cm), 2-propanol/hexane¼1/
0.46 cmꢂ25 cm), 2-propanol/hexane¼1/9, flow rate¼0.50 mL/min,
detection at 254 nm, retention time¼24.6 min (major), 26.4 min
(minor), 99% ee.
9, flow rate¼0.50 mL/min, detection at 254 nm, retention
time¼23.2 min (minor), 26.6 min (major), 99% ee (after
recrystallization).
3.1.51. (1S,4S,5R)-1-Methyl-4-phenyl-3-oxabicyclo[3.1.0]hexane
3.1.56. 1-{(RS)-[(1R,2S,3R)-2-(Benzyloxymethyl)-1-chloro-3-
(48). Colorless oil; ½a D26
ꢃ
ꢀ150 (c 0.16, acetone); HPLC: DAICEL
isopropyl-2-(2-phenylethyl)cyclopropyl]sulfinyl}-4-methylbenzene
CHIRALCEL IA (
f
0.46 cmꢂ25 cm), 2-propanol/hexane¼1/200, flow
(52a). Colorless oil; ½a D29
ꢀ31.8 (c 0.27, acetone); HPLC: DAICEL
ꢃ
rate¼0.25 mL/min, detection at 254 nm, retention time¼23.4 min
CHIRALCEL OD (
f
0.46 cmꢂ25 cm), 2-propanol/hexane¼1/10, flow
(minor), 24.5 min (major), 99% ee.
rate¼0.30 mL/min, detection at 254 nm, retention time¼47.4 min
(major), 50.4 min (minor), 99% ee.
3.1.52. (1S,2R,3R)-Ethyl 2-chloro-3-isopropyl-1-(2-phenylethyl)-2-
((RS)-p-tolylsulfinyl)cyclopropanecarboxylate (50a). Colorless oil; IR
(neat) 2967, 2934, 1727, 1597, 1495, 1454, 1367, 1265, 1246, 1191,
3.1.57. 1-((RS)-{(1R,2S,3R)-2-[(S)-1-(Benzyloxy)propyl]-1-chloro-2-
methyl-3-(2-phenylethyl)cyclopropyl}sulfinyl)-4-methylbenzene
1092, 1067, 1038, 811, 752, 734 cmꢀ1
;
1H NMR
d
0.43 (d, J¼6.6 Hz,
(52b). Colorless crystal; mp 62.5e63.0 ꢁC (hexane/AcOEt); ½a 2D9
ꢃ
3H), 1.05 (d, J¼6.6 Hz, 3H), 1.40 (t, J¼7.1 Hz, 3H), 1.57e1.67 (m, 1H),
1.94 (d, J¼10.5 Hz,1H),1.97e2.09 (m,1H), 2.13e2.25 (m,1H), 2.40 (s,
3H), 2.85 (t, J¼8.6 Hz, 2H), 4.35 (q, J¼7.1 Hz, 1H), 4.37 (q, J¼7.1 Hz,
1H), 7.15e7.33 (m, 7H), 7.60 (d, J¼8.2 Hz, 2H); MS (EI) m/z (%) 432
(Mþ, 0.3), 416 (0.2), 387 (0.2), 325 (0.2), 293 (45), 265 (15), 149 (24),
91 (100); HRMS (EI) calcd for C24H29ClO3S: 432.1526, found:
þ14.9 (c 0.27, acetone); HPLC: DAICEL CHIRALCEL OD
(f
0.46 cmꢂ25 cm), 2-propanol/hexane¼1/9, flow rate¼0.50 mL/min,
detection at 254 nm, retention time¼21.0 min (major), 31.8 min
(minor), 99% ee (after recrystallization).
3.1.58. (1R,4R,5S,6S)-6-Isopropyl-1-(2-phenylethyl)-4-phenyl-3-
432.1529; ½a 2D9
ꢃ
ꢀ54.4 (c 0.41, acetone); HPLC: DAICEL CHIRALCEL
oxabicyclo[3.1.0]hexane (53a). Colorless oil; ½a D27
þ72.5 (c 0.30,
ꢃ
OD
(f
0.46 cmꢂ25 cm), 2-propanol/hexane¼1/9, flow
acetone); HPLC: DAICEL CHIRALCEL IA (
f
0.46 cmꢂ25 cm), 2-

T. Satoh et al. / Tetrahedron 68 (2012) 1071e1084
1083
propanol/hexane¼1/200, flow rate¼0.24 mL/min, detection at
3.2. X-ray crystallographic analysis of rac-56
254 nm, retention time¼28.2 min (major), 31.1 min (minor), 99% ee.
Single crystals of rac-56 suitable for an X-ray diffraction study
were grown by slow diffusion of hexane into the ethyl acetate so-
lution of rac-56 at room temperature. A colorless block crystal of
rac-56 having approximate dimensions of 0.26ꢂ0.33ꢂ0.35 mm was
mounted on a glass fiber. Diffraction data were collected on
a Bruker AXS SMART APEX CCD diffractometer at 173 K with
3.1.59. (1R,2S,4R,5S,6S)-2-Ethyl-1-methyl-6-(2-phenylethyl)-4-
phenyl-3-oxabicyclo[3.1.0]hexane (53b). Colorless oil; ½a D29
þ76.7 (c
ꢃ
0.21, acetone); HPLC: DAICEL CHIRALCEL IA (
f
0.46 cmꢂ25 cm),
2-propanol/hexane¼1/200, flow rate¼0.15 mL/min, detection at
254 nm, retention time¼28.1 min (minor), 34.5 min (major),
99% ee.
19
ꢀ
graphite-monochromated Mo K
a
radiation (l¼0.71073 A). The
data reduction and integration were performed using the program
SAINT.20 An empirical absorption correction was applied using the
program SADABS.21 The structure was solved by direct methods
with SHELXS-9722 and refined by full-matrix least squares tech-
niques against F2 using SHELXL-97.23 All non-hydrogen atoms were
refined anisotropically. Hydrogen atoms were placed in calculated
positions and refined using the riding model. Crystal data for rac-
56: C23H27ClO2S, M¼402.96, triclinic, space group Pꢀ1, a¼9.8624
3.1.60. (1R,2R,3S)-1-Chloro-2-(2-phenylethyl)-1-((RS)-p-tol-
ylsulfinyl)spiro[2.5]octan-4-one (55). Colorless oil; ½a D28
ꢀ52.8 (c
ꢃ
0.43, acetone). Enantiomeric excess of compound 55 could not be
determined by chiral HPLC analysis because the enantiomers were
inseparable on chiral HPLC.
3.1.61. (1R,2R,3S,4S)-1-Chloro-2-(2-phenylethyl)-1-((RS)-p-tol-
¼76.5840 (10)ꢁ,
¼86.8140
b
ꢀ
ꢀ
ꢀ
a
ylsulfinyl)spiro[2.5]octan-4-ol
(56). Colorless
crystal;
mp
(4) A, b¼9.8812 (4) A,ꢁc¼11.4540 (5) A,
3
108.5e109.0 ꢁC (hexane/AcOEt); IR (KBr) 3409, 2914, 1603, 1595,
(10)ꢁ,
g
¼70.6580 (10) , V¼1024.20 (7) A , Z¼2, Dcalcd¼1.307 g cmꢀ3
,
ꢀ
1495, 1450, 1404, 1294, 1157, 1120, 1088, 1057, 1009, 810, 767,
m(Mo K
a
)¼0.304 mmꢀ1, F(000)¼428, 4437 reflections, 246 pa-
716 cmꢀ1
;
1H NMR
d
1.14e1.31 (m, 1H), 1.40e1.49 (m, 1H),
rameters, R1¼0.0345 [I>2 (I)], Rw¼0.0911 (all data), GOF¼1.030.
s
1.49e1.59 (m, 2H), 1.59e1.70 (m, 1H), 1.71 (q, J¼3.9 Hz, 1H),
1.73e1.86 (m, 2H), 1.86e1.98 (m, 1H), 1.98e2.08 (m, 1H), 2.15 (dt,
J¼3.5, 13.5 Hz, 1H), 2.43 (s, 3H), 2.34e2.46 (m, 1H), 2.58 (ddd,
J¼5.8, 9.9, 13.6 Hz, 1H), 3.17 (t, J¼2.0 Hz, 1H), 4.10 (s, 1H), 7.12 (d,
J¼7.2 Hz, 2H), 7.18e7.31 (m, 3H), 7.35 (d, J¼8.2 Hz, 2H), 7.45 (d,
J¼8.2 Hz, 2H); MS (FABþ) m/z (%) 403 ([MþH]þ, 82), 385 (24), 245
(48), 209 (55), 154 (51), 139 (79), 91 (100); HRMS (FABþ) calcd for
Crystallographic data (excluding structure factors) for rac-56 have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 837286. Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK, [fax: þ44 (0)1223 336,033 or e-mail:
deposit@ccdc.cam.ac.Uk].
C23H28ClO2S: 403.1499, found: 403.1506; ½a D29
ꢃ
þ25.2 (c 0.28, ace-
Acknowledgements
tone); HPLC: DAICEL CHIRALCEL AD (
f
0.46 cmꢂ25 cm), 2-
propanol/hexane¼1/9, flow rate¼0.50 mL/min, detection at
254 nm, retention time¼28.6 min (major), 41.3 min (minor), 99%
ee (after recrystallization).
This work was supported by a Grant-in-Aid for Scientific Re-
search No. 19590018 and 22590021 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.
3.1.62. (1R,2R,3S,4S)-4-(Benzyloxy)-1-chloro-2-(2-phenylethyl)-1-
((RS)-p-tolylsulfinyl)spiro[2.5]octane (57). Colorless crystal; mp
142.2e142.7 ꢁC (hexane/AcOEt); IR (KBr) 2930, 2862, 1598, 1455,
1088, 1061, 696 cmꢀ1; 1H NMR
d
1.15e1.29 (m, 1H), 1.34 (dd, J¼5.9,
References and notes
7.5 Hz, 1H), 1.40e1.57 (m, 4H), 1.66e1.87 (m, 3H), 1.99e2.23 (m,
3H), 2.32 (ddd, J¼5.5, 10.1, 13.7 Hz, 1H), 2.39 (s, 3H), 3.63 (d,
J¼2.5 Hz, 1H), 4.58 (d, J¼11.4 Hz, 1H), 4.85 (d, J¼11.4 Hz, 1H),
6.97e7.08 (m, 2H), 7.15e7.40 (m, 8H), 7.48e7.54 (m, 4H); 13C NMR
1. Some reviews concerning carbonehydrogen insertion reaction: (a) Padwa, A.;
Krumpe, K. E. Tetrahedron 1992, 48, 5385; (b) Sulikowski, G. A.; Cha, K. L.; Su-
likowski, M. M. Tetrahedron: Asymmetry 1998, 9, 3145; (c) Davies, H. M. L.;
Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861; (d) Davies, H. M. L.; Loe, O. Syn-
thesis 2004, 2595; (e) Davies, H. M. L. Angew. Chem., Int. Ed. 2006, 45, 6422; (f)
Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704; (g)
Slattery, C. N.; Ford, A.; Maguire, A. R. Tetrahedron 2010, 66, 6681.
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(c) Carbene Chemistry; Bertrand, G., Ed.; Marcel Dekker: New York, NY, 2002;
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H. F., III. Acc. Chem. Res. 1979, 12, 288; (h) Wynberg, H.; Meijer, E. W. Org. React.
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J. Syn. Org. Chem. Jpn. 1986, 44, 736; (k) Oku, A. J. Synth. Org. Chem. Jpn. 1990, 48,
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Weingarten, M. D. Chem. Rev. 1996, 96, 223; (n) Zaragoza, F. Tetrahedron 1997,
53, 3425; (o) Kirmse, W. Angew. Chem., Int. Ed. 1997, 36, 1164; (p) Braun, M.
Angew. Chem., Int. Ed. 1998, 37, 430; (q) Bourissou, D.; Guerret, O.; Gabbai, F. P.;
Bertrand, G. Chem. Rev. 2000, 100, 39; (r) Boche, G.; Lohrenz, J. C. W. Chem. Rev.
2001, 101, 697; (s) Mehta, G.; Muthusamy, S. Tetrahedron 2002, 58, 9477; (t)
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d
20.0, 21.5, 24.3, 24.9, 25.5, 28.0, 29.4, 34.5, 40.1, 70.4, 72.7, 78.1,
125.7, 126.2, 127.4, 128.1, 128.2, 128.3, 128.5, 129.3, 138.4, 138.5,
141.3, 141.9; MS (FABþ) m/z (%) 493 ([MþH]þ, 38), 385 (19), 245
(32), 209 (29), 139 (41), 91 (100); HRMS (FABþ) calcd for
C30H34ClO2S: 493.1968, found: 493.1966; ½a D29
þ69.8 (c 0.31, ace-
ꢃ
tone); HPLC: DAICEL CHIRALCEL IA (
f
0.46 cmꢂ25 cm), 2-
propanol/hexane¼1/5, flow rate¼0.30 mL/min, detection at
254 nm, retention time¼33.4 min (major), 64.9 min (minor), 99%
ee (after recrystallization).
3.1.63. (1S,3R,4S,5S,6R)-3-Phenyl-5-(2-phenylethyl)-2-oxatricyclo
[4.4.0.04,6]decane (59). Colorless oil; IR (neat) 2930, 2854, 1603,
1496, 1449, 1082, 1042, 699 cmꢀ1 1H NMR
; d 0.94e1.03 (m, 1H),
1.20e1.52 (m, 5H), 1.54e1.87 (m, 5H), 1.90e2.02 (m, 1H),
2.38e2.60 (m, 2H), 3.90 (dd, J¼6.1, 10.2 Hz, 1H), 5.16 (d, J¼2.7 Hz,
1H), 6.94e7.00 (m, 2H), 7.08e7.26 (m, 3H), 7.27e7.42 (m, 5H); 13C
3. CeH Activation; Yu, J.-Q., Shi, Z., Eds.; Springer: Berlin Heidelberg, 2010.
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Wakasugi, D.; Satoh, T. Tetrahedron 2008, 64, 5711; (e) Watanabe, H.; Ogata, S.;
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NMR
d 20.9, 23.5, 25.1, 29.4, 30.8, 33.5, 33.9, 36.0, 78.3, 80.2,
125.6, 126.2, 127.1, 128.1, 128.2, 128.4, 141.0, 142.3; MS (EI) m/z (%)
318 (Mþ, 60), 227 (15), 213 (33), 117 (63), 105 (33), 91 (100);
HRMS (EI) calcd for C23H26O: 318.1984, found: 318.1979; ½a D29
ꢃ
þ77.2 (c 0.27, acetone); HPLC: DAICEL CHIRALCEL IA
(f
0.46 cmꢂ25 cm), 2-propanol/hexane¼1/100, flow rate¼0.30 mL/
min, detection at 254 nm, retention time¼16.6 min (major),
50.0 min (minor), 99% ee.
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rahedron: Asymmetry 2010, 21, 1.

1084
T. Satoh et al. / Tetrahedron 68 (2012) 1071e1084
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propylidenes, derived from 1,1-dibromocyclopropanes with methyllithium, has
been reported: (a) Baird, M. S. J. Chem. Soc., Chem. Commun. 1971, 1145; (b)
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19. Data Collection: SMART Version 5.631; Bruker AXS: Madison, WI, USA, 2003.
20. Data Reduction: SAINT Version 6.45A; Bruker AXS: Madison, WI, USA, 2003.
21. Sheldrick, G. M. Absorption Correction: SADABS Version 2.10; University of
€
Gottingen: Germany, 2003.
€
22. Sheldrick, G. M. Structure Solution: SHELXS-97; University of Gottingen: Ger-
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Hoffmann, R. W. Chem. Soc. Rev. 2003, 32, 225; (c) Mitsunaga, S.; Ohbayashi, T.; Su-
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many, 1997.
€
23. Sheldrick, G. M. Structure Refinement: SHELXL-97; University of Gottingen:
Germany, 1997.