Stereoselective synthesis of cis -2-fluorocyclopropanecarboxylic acid

Article abstract of DOI:10.1021/jo501219n

A rhodium-catalyzed cyclopropanation of 1-fluoro-1-(phenylsulfonyl)ethylene and diazo esters is described as an effective method for the stereoselective synthesis of cis-2-fluorocyclopropanecarboxylic acid. This process provides an example of the cyclopro

Full text of DOI:10.1021/jo501219n

Note
pubs.acs.org/joc
Stereoselective Synthesis of cis-2-Fluorocyclopropanecarboxylic Acid
Taku Shibue and Yasumichi Fukuda*
Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., 2399-1, Nogi, Nogi-Machi, Shimotsuga-Gun, Tochigi, 329-0114,
Japan
*
S Supporting Information
ABSTRACT: A rhodium-catalyzed cyclopropanation of 1-fluoro-1-(phenylsulfonyl)-
ethylene and diazo esters is described as an effective method for the stereoselective
synthesis of cis-2-fluorocyclopropanecarboxylic acid. This process provides an
example of the cyclopropanation of electron-deficient olefin and diazoacetates.
6,7
he N-1 cyclopropyl group of quinolone antibiotics plays
cyclopropanations of bromofluoroethene with diazoacetates.
T
an important role in their potent antibacterial activities.
Structure−activity relationship (SAR) studies of a substituent
on the cyclopropyl group revealed that a fluoro group at the C-
The second approach (ii) involves the synthesis of precursors
of 1 by way of cyclopropanation of butadiene with
8
,9
fluorocarbenoid species, and the last approach (iii) includes
10,11
2
position with cis configuration plays a role in the good
a fluorination step of suitable intermediates using an F gas.
2
1
−5
antibacterial activity.
cis-2-Fluorocyclopropanecarboxylic acid (S,S)-1 is one of the
useful precursors of cis-2-fluorocyclopropylamine (R,S)-2,
which is a key component of the antibacterial agent sitafloxacin
The synthesis of optically active (S,S)-1 was achieved via
enantioselective hydrolysis of the racemic esters of 1 by
microorganisms or diastereomeric separation of the racemate 1
1
2,13
by recrystallization with chiral amine.
On the other site,
3
3
(Figure 1). The fluorine atom in both (S,S)-1 and (R,S)-2 is
asymmetric synthesis of N-protected 2 (iv) was accomplished
with cyclopropanation of optically active N-vinyl oxazolidinone
1
4−17
or N-vinyl lactam with fluorocarbenoid species.
Though
many of the efforts have focused on the stereoselective
synthesis of racemic or optically active 1 and 2, there is room
to improve the stereoselectivity. We herein report an efficient
synthesis of dl- and (S,S)-1 via the stereoselective cyclo-
propanation of sulfonylalkene and diazoacetates. Though a
large number of researches on the cyclopropanation of olefins
with diazoacetates have been reported and their methods
widely applied, due to the electrophilic nature of metal−
carbene species, the cyclopropanation with electron-deficient
Figure 1. cis-Fluorocyclopropanecarboxylic Acid 1, cis-2-Fluorocyclo-
propylamine 2 and Sitafloxacin 3
23−34
arranged in a cis configuration next to the carboxyl and amine
groups, and complicates their stereoselective synthesis.
Accordingly, numerous synthetic approaches to control the
stereochemistry of the two adjacent stereogenic centers of these
olefins and diazoacetates remains a challenge.
Indeed, to
our knowledge there have been only a few reports of
35
cyclopropanation between sulfonylalkenes and diazoacetates.
The synthesis of 1 is outlined in Scheme 1. Our plan was to
install the cis configuration of 1 through metal-catalyzed
6
−22
fluorine-containing cyclopropanes have been investigated.
Representative approaches toward 1 can be categorized into
three types (Figure 2). The first type (i) consists of
Scheme 1. Plan for Synthesis of Cyclopropanecarboxylic
Acid 1
36−39
cyclopropanation of 1-fluoro-1-(phenylsulfonyl)ethylene 4
and diazoacetates 5. One of the products of this cyclo-
t
propanation, the tert-butyl ester trans-6b (R = Bu), was
11
reported as a useful precursor of dl-1.
Received: May 31, 2014
Published: July 10, 2014
Figure 2. Representative Approaches to 1 and 2.
©
2014 American Chemical Society
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The Journal of Organic Chemistry
Note
Our initial study of the synthesis of 6a consisted of a
screening of the metal catalysts of cyclopropanation between 4
and ethyl diazoacetate 5a (runs 1−5, Table 1). Among the
Table 2. Cyclopropanation of 4 and 5a Using
[Rh(O CCPh ) ]
2
3 2 2
Table 1. Cyclopropanation of 4 with 5a
a
b
c
run
solvent
temp (°C)
yield (%)
trans/cis
1
DCM
DCM
DCM
DCM
DCM
heptanes
toluene
THF
25
25
78
84/16
82/18
82/18
79/21
80/20
85/15
d
2
3
4
5
6
7
8
9
73
a
b
c
run
catalyst
Rh(OAc)2
yield (%)
trans/cis
4
67
1
2
3
4
5
6
7
8
9
18
86/14
−78
40
15
AgSbF6
N.D.
N.D
6
61
Cu(acac)2
25
70
Ru(TPP)(CO)
Co(TPP)
>99/1
25
N.D.
N.D
N.D.
N.D.
trace
trace
13
25
[Rh[O CC(Me) ] ]
DME
25
2
3
2
2
[Rh(O CCF ) ]
a
2
3
2
2
Reactions were carried out for 1.5 h under Ar with 4 (1.0 equiv), 5a
b c
1
[Rh(O CC H ) ]
79/21
83/17
84/16
84/16
2
5
11
2
2
(2.0 equiv), and catalyst (10 mol%). Total yields. Determined by H
NMR analysis (400 MHz). Reaction time was 6 h.
d
[Rh(O CC H ) ]
32
2
7
15 2
2
1
1
0
Rh (esp)
2
19
2
1
[Rh(O CCPh ) ]
3 2 2
78
Table 3. Stereoselectivity of Cyclopropanation with Bulky
Esters 5b and 5c
2
a
Reactions were carried out for 1.5 h under Ar with 4 (1.0 equiv), 5a
b
c
1
(
2.0 equiv), and catalyst (10 mol %). Total yields. Determined by H
NMR analysis (400 MHz).
catalysts tested, Rh (OAc) gave the desired ethyl 2-fluoro-2-
2
4
yield
phenylsulfonylcyclopropanecarboxylate 6a in the best yield
18%) with good stereoselectivity (trans/cis = 86/14, run 1).
a
b
c
run
R
solvent
DCM
product
(%)
trans/cis (dr)
(
d
tBu 5b
tBu 5b
tBu 5b
tBu 5b
1
2
3
4
6b
6b
6b
6b
30
32
80
51
94/6
95/5
93/7
95/5
The relative stereochemistry of 6a was unambiguously
confirmed by NOE experiments (see the Supporting
Information [SI]). The ruthenium catalyst Ru(TPP)(CO)
also worked to obtain 6a with good stereoselectivity, albeit in a
DCM
1
9
heptane
DCM−
40−42
heptane
lower yield (run 4). The other catalysts tested,
AgSbF6,
d
5
6
7
8
l-menthyl
DCM
6c
6c
6c
6c
76
85
65
49
>99/1 (53/47)
>99/1 (51/49)
>99/1 (50/50)
>99/1 (51/49)
Cu(acac) and Co(TPP) failed to give 6a. We therefore set out
2
5c
to identify other rhodium catalysts for our purposes (runs 6−
l-menthyl
DCM
1
1). The use of [Rh(O CCPh ) ] afforded an improved yield
5c
2
3 2 2
of 6a in dichloromethane at room temperature (78%, trans/cis
l-menthyl
heptane
4
3,44
5c
=
84/16, run 11).
The difference in the ligands of the
l-menthyl
DCM−
rhodium catalysts would have influence on the stability or
reactivity of the carbene species, rather than the stereo-
selectivity of cyclopropanation.
Both the stereoselectivity and yield of 6a were little affected
by the prolonged reaction time (run 2, Table 2). Either a lower
or a higher reaction temperature resulted in decreased yields of
5
c
heptane
a
Reactions were carried out for 6 h under Ar with 4 (1.0 equiv), 5 (2.0
b
equiv), and [Rh(O CCPh ) ] (10 mol %). Total yields.
2
3 2 2
c
1
d
Determined by H NMR analysis (400 MHz). Reaction time was
1
.5 h.
6
a (runs 3−5). Among the solvents tested (runs 6−9), in
Table 4. Impact on Stereoselectivity of Phenylsulfonyl
Group
addition to dichloromethane, heptane was also a suitable
solvent for the cyclopropanation to give 6a in a good yield with
similar stereoselectivity (70%, trans/cis = 85/15, run 6).
In our next experiments, we expected that the larger steric
repulsion between the bulky ester and phenylsulfonyl groups
would favor trans-stereoselectivity in the cyclopropanation
a
b
c
run
R
solvent
yield (%)
80
trans/cis
(Table 3). Our results showed that, compared with ethyl ester
1
2
3
SO Ph
2
heptane
heptane
heptane
DCM
93/7
d
5
a (trans/cis = 85/15, run 6 in Table 3), both tert-butyl ester 5b
S(O)Ph
SPh
38
78/22
76/24
1/3.4
and l-menthyl ester 5c greatly improved the stereoselectivity
and afforded 6b and 6c in good yields (trans/cis = 93/7 and
86
e
4
H
−
>
5
99/1, runs 3 and 6 in Table 3). The l-menthyl ester group of
c did not affect the diastereoselectivity of 6c.
We further confirmed that the steric repulsion between the
a
Reactions were carried out for 6 h under Ar with olefin (1.0 equiv),
b
5
b (2.0 equiv), and [Rh(O CCPh ) ] (10 mol %). Total yields.
2 3 2 2
d
c
1
Determined by H NMR analysis (400 MHz). The product was
e
ester and phenylsulfonyl groups plays an important role in the
high stereoselectivity of this cyclopropanation (Table 4). In the
case of cyclopropanation of sulfoxide and 5b, the product was a
sulfide rather than the expected sulfoxide. Deoxygenation of the
isolated as a sulfide; 59% of SM recovered. Data from ref 44.
sulfoxide group by carbene species generated from diazoacetate
45
5b was assumed to have occurred. In addition, a previously
7
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The Journal of Organic Chemistry
Note
reported study revealed that cyclopropanation of vinylfluoride
and 5b using [Rh(O CCPh ) ] directly afforded tert-butyl
nation of 4 and 5 using a rhodium catalyst to give 6 in good
yields with high stereoselectivity. Our results have also provided
an example of a metal-catalyzed cyclopropanation employing
electron-deficient olefin and diazoacetates.
2
3 2 2
ester of 1 with lower stereoselectivity (trans/cis = 1:3.4, run
3
9
4
). From the present results shown in Tables 2−4, the
stereoselectivity of this cyclopropanation of sulfonylalkene and
diazo esters showed a tendency similar to other cyclo-
propanations such as the cyclopropanation of styrene with
diazo esters, in that it could be improved by increasing the bulk
of the ester functionality.
As shown in Scheme 2, the relative stereochemistry of trans-
EXPERIMENTAL SECTION
■
General Considerations. All reagents were purchased from
chemical suppliers and used without additional purification unless
noted. Unless otherwise noted, all the experiments were carried out
using anhydrous solvents under an atmosphere of argon.
46−48
The chemical shifts are expressed in parts per million (δ value)
downfield from tetramethylsilane, using tetramethylsilane (δ = 0) and/
or residual solvents such as chloroform (δ = 7.26) as an internal
standard. Splitting patterns are indicated as s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet; br, broad peak. Unless otherwise
noted, all the experiments were carried out using anhydrous solvents
under an atmosphere of argon. All melting points were uncorrected.
Measurements of optical rotations were carried out by automatic
digital polarimeter. High resolution mass spectroscopy (HRMS) was
performed on chemical ionization (CI) and TOF instrument with ESI
in positive ionization mode. Data for elemental analyses are within
±0.3% of the theoretical values. Analytical and preparative HPLC was
carried out using an apparatus equipped with a HPLC pump and oven.
6
b was elucidated by conversion to dl-1 according to the
11
reported procedure.
Scheme 2. Relative Stereochemistry Elucidation of trans-6b
Similarly, the l-menthyl ester 6c was converted to the
enantiomeric pair of 1 after diastereomeric HPLC separation
3
6
Preparation of 1-Fluoro-1-(phenylsulfonyl)ethylene 4. Accord-
ing to the procedure reported by McCarthy et.al, 4 was prepared from
β-chloroethyl phenyl sulfoxide as shown below.
(
Scheme 3). The dephenylsulfonylation of (S,R)-6c was carried
Scheme 3. Conversion of 6c to Tosylates of Optically Active
via Enantiomeric Pair of 1
2
General Procedure for Cyclopropanation Reaction. A
solution of diazo esters (4.0 mmol) in solvents (5 mL) was added
dropwise to a stirred solution of 4 (2.0 mmol) and Rh-catalyst (10 mol
%
of 4) in solvents (2 mL) at 25 °C over 1.5 or 6 h. After addition of
diazo esters, the solution was concentrated in vacuo. Flash
chromatography of the residue gave the desired cyclopropanes. The
structure and diastereomer ratio of the products were determined by
1
H NMR.
Ethyl trans-2-Fluoro-2-(phenylsulfonyl)cyclopropane-1-carboxy-
late (trans-6a) and Ethyl cis-2-Fluoro-2-(phenylsulfonyl)cyclo-
propane-1-carboxylate (cis-6a) (Table 1 run 11). A solution of
ethyl diazoacetate (85% CH Cl solution, 537.0 mg 4.0 mmol) in
2
2
CH Cl (5 mL) was added dropwise to a stirred solution of 4 (372.4
2
2
mg, 2.0 mmol) and [Rh(O CCPh ) ] (28.9 mg, 0.02 mmol) in
2
3 2 2
CH Cl2 (2 mL) at 25 °C over 1.5 h. After addition of ethyl
2
diazoacetate, the mixture was stirred at room temperature for 1 h and
concentrated in vacuo. Flash chromatography (silica, hexane/ethyl
acetate = 4:1) of the residue gave a mixture of trans- and cis-6a (423.5
mg, 78%). The mixture of trans- and cis-6a was separated by HPLC
[
=
Kanto Mightysil, si 60 (5 μ), ϕ 2.0 cm × 25 cm: hexane/ethyl acetate
85:15, flow rate 20 mL/min, HPLC analysis; Kanto Mightysil, si 60
(
5 μ), ϕ 0.46 cm × 25 cm, hexane/ethyl acetate = 85:15, flow rate 1.0
mL/min; t = 16.2 min (trans-6a) and 19.7 min (cis-6a)] to give the
R
pure samples of trans- and cis-6a. The relative stereochemistry of 6a
4
9
out successfully using magnesium powder in methanol, and
removal of the l-menthyl group with aqueous lithium hydroxide
solution in tetrahydrofuran and methanol gave (S,S)-1 as a
colorless solid. The enantiomeric excess (% ee) of (S,S)-1 was
determined to be >99% ee by chiral HPLC analysis (Chiralpak
AD-H). Finally, by employing the previously reported
was unambiguously confirmed by NOE experiments as shown below.
1
trans-6a: Colorless oil. H NMR (400 MHz, CDCl ): δ 1.23 (t, J =
3
7.3 Hz, 3H), 2.02 (dt, J = 7.9, 9.8 Hz, 1H), 2.15 (dt, J = 7.9, 18.4 Hz,
1H), 2.84 (ddd, J = 3.1, 7.9, 10.4 Hz, 1H), 4.11−4.21 (m, 2H), 7.60−
1
3
7.66 (m, 2H), 7.72−7.77 (m, 1H), 7.94−8.01 (m, 2H). C NMR
(
100 MHz, CDCl ): δ 14.0, 15.7, 15.8, 24.8, 24.9, 61.9, 89.1, 91.9,
3
−1
1
4
129.2, 129.5, 134.8, 135.9, 165.4, 165.5. IR (ATR): 1735, 1145 cm .
MS (CI ) m/z: 273 (MH ). HRMS (CI ) for C H FO S (MH ):
procedure, we demonstrated the synthesis of tosylate of
R,S)-2 from (S,S)-1. The antipode (S,R)-2 as the tosylate was
also prepared from (R,S)-6c in the same manner as described
for (R,S)-2.
In conclusion, we have accomplished the stereoselective
synthesis of dl-1, (S,S)-1, and (R,S)-2, which are intermediates
of quinolone antibiotics. This synthesis involved cyclopropa-
+
+
+
+
12
14
4
(
calcd, 273.0597; found, 273.0606.
1
cis-6a: Colorless oil. H NMR (400 MHz, CDCl ): δ 1.32 (t, J = 7.3
3
Hz, 3H), 1.77 (ddd, J = 8.6, 11.0, 18.3 Hz, 1H), 2.34 (ddd, J = 7.9, 9.8,
1
1.0 Hz, 1H), 2.61 (ddd, J = 9.8, 11.0, 19.0 Hz, 1H), 4.22−4.30 (m,
2H), 7.58−7.64 (m, 2H), 7.70−7.76 (m, 1H), 7.98 (d, J = 7.9 Hz,
2H). 13C NMR (100 MHz, CDCl ): δ 14.0, 15.2, 15.3, 28.8, 28.9, 62.2,
3
7
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The Journal of Organic Chemistry
Note
8
9.0, 91.7, 129.2, 134.7, 136.4, 164.85, 164.87. IR (ATR): 1736, 1150
11.0 Hz, 1H), 7.62 (d, J = 7.9 Hz, 2H), 7.75 (d, J = 7.9 Hz, 2H), 7.97
−1
+
+
+
13
cm . MS (CI ) m/z: 273 (MH ). HRMS (CI ) for C H FO S
(d, J = 7.9 Hz, 1H). C NMR (100 MHz, CDCl
3
): δ 15.6, 15.7, 16.2,
12
14
4
+
(
MH ): calcd, 273.0597; found, 273.0638.
20.7, 21.9, 23.2, 25.2, 25.3, 26.1, 31.3, 34.1, 40.6, 46.8, 76.3, 89.0, 91.8,
1
1
29.1, 129.4, 134.7, 136.0, 164.93, 164.95. IR (ATR): 1733, 1208,
−1
+
+
+
147 cm . MS (CI ) m/z: 383 (MH ). HRMS (CI ) for C H FO S
2
0
28
4
+
(MH ): calcd, 383.1692; found, 383.1651.
Synthesis of dl- cis-2-Fluorocyclopropanecarboxylic Acid (dl-
8,11
1
).
To a solution of trans-6b (660 mg, 2.20 mmol) in ethanol (11
mL) were added magnesium powder (160 mg, 6.59 mmol) and HgCl2
25.8 mg, 9.50 μmol); the mixture was stirred at room temperature for
6 h. The mixture was poured into a mixture of water (10 mL) and 0.5
(
1
mol/L aqueous HCl solution (1 mL), the resulting mixture was
extracted with pentane. The organic extracts were dried over
anhydrous sodium sulfate, filtered, and then concentrated in vacuo
(45 °C, 756 mmHg) to give crude tert-butyl cis-2-fluorocyclopropa-
necarboxylate (418 mg). To a solution of the crude ester (418 mg) in
tetrahydrofuran (6 mL) was added a 10% aqueous HCl solution (1.5
mL), the mixture was heated under reflux for 6 h. After dilution of the
mixture with ethyl acetate (10 mL) and water (10 mL), the mixture
was extracted with ethyl acetate. The organic layer was extracted with
saturated sodium hydrogen carbonate solution, and the aqueous layer
was washed with ethyl acetate. The aqueous layer was adjusted to pH 5
by a 10% aqueous HCl solution, and the resulting mixture was
extracted with ethyl acetate. The organic extracts were dried over
anhydrous sodium sulfate, filtered, and then concentrated in vacuo.
Flash chromatography (silica, hexane/ethyl acetate = 1:1) of the
residue gave dl-1 as colorless solid (185 mg, 78%). An analytic sample
tert-Butyl trans-2-Fluoro-2-(phenylsulfonyl)cyclopropane-1-car-
boxylate (trans-6b) and tert-Butyl cis-2-Fluoro-2-(phenylsulfonyl)-
cyclopropane-1-carboxylate (cis-6b). A mixture of trans- and cis-6b
was obtained by flash chromatography (silica, hexane/ethyl acetate =
9
:1) of the residue of the reaction mixture. The mixture of trans- and
cis-6b was further separated by HPLC [Kanto Mightysil, si 60 (5 μ), ϕ
.0 cm × 25 cm: hexane/ethyl acetate = 95:5, flow rate 20 mL/min,
HPLC analysis; Kanto Mightysil, si 60 (5 μ), ϕ 0.46 cm × 25 cm,
hexane/ethyl acetate = 95:5, flow rate 1.0 mL/min; tR = 14.8 min
2
(
6
trans-6b) and 18.5 min (cis-6b)] to give pure samples trans- and cis-
b.
1
trans-6b: Colorless oil. H NMR (400 MHz, CDCl ): δ 1.39 (s,
3
was obtained by trituration of the product with hexane. Mp: 71−72 °C
9
1
7
1
1
(
3
H), 1.96 (ddd, J = 8.0, 9.8, 11.0 Hz, 1H), 2.07 (dt, J = 8.0, 18.3 Hz,
8
1
(
lit. 73−74 °C). H NMR (400 MHz, CDCl ): δ 1.14−1.30 (m, 1H),
3
H), 2.76 (ddd, J = 3.1, 8.6, 11.0 Hz, 1H), 7.60−7.66 (m, 2H), 7.72−
1
3
1
3
1.74−1.91 (m, 2H), 4.80 (ddd, J = 6.1, 10.4, 12.2, 64.2 Hz, 1H). C
NMR (100 MHz, CDCl ): δ 13.1, 13.2, 19.5, 19.6, 70.9, 73.2, 174.6. IR
(ATR): 1686, 1211 cm . MS (ESI ) m/z: 103 (MH ). HRMS
(ESI ) for C
.77 (m, 2H), 7.94−8.00 (m, 1H). C NMR (100 MHz, CDCl ): δ
3
3
5.3, 15.4, 26.0, 26.1, 27.9, 88.9, 91.7, 129.1, 129.4, 134.7, 136.1,
64.18, 164.21. IR (ATR): 1731, 1142 cm . MS (CI ) m/z: 301
−1
−
−
−1
+
−
−
+
+
+
H FO (MH ): calcd, 103.0195; found, 103.0198.
4 4 2
MH ). HRMS (CI ) for C H FO S (MH ): calcd, 301.0910; found,
14 18 4
Anal. (C H FO ) C, H, N. calcd: C, 46.16; H, 4.84. found: C, 46.50;
4
5
2
01.0891.
1
H, 4.83.
cis-6b: Colorless oil. H NMR (400 MHz, CDCl ): δ 1.53 (s, 9H),
3
Synthesis of (S,S)-1. Step 1. (1S,2S)-((1R,2S,5R)-2-Isopropyl-5-
methylcyclohexyl)-2-fluorocyclopropanecarboxylate. To a solution
of (S,R)-6c (1.03 g, 2.69 mmol) in methanol (13.5 mL) was added
magnesium powder (197 mg, 8.08 mmol) at 4 °C, the mixture was
stirred at the same temperature for 1.5 h. The mixture was poured into
1
1
7
1
1
(
3
.69 (ddd, J = 7.9, 11.0, 19.0 Hz, 1H), 2.23 (ddd, J = 8.0, 9.8, 11.0 Hz,
H), 2.57 (ddd, J = 9.8, 11.0, 19.6 Hz, 1H), 7.58−7.64 (m, 2H), 7.69−
1
3
.75 (m, 2H), 7.98−8.03 (m, 1H). C NMR (100 MHz, CDCl ): δ
3
5.3, 15.4, 27.9, 30.0, 30.1, 82.9, 89.1, 91.8, 129.2, 129.3, 134.6, 136.6,
63.70, 163.73. IR (ATR): 1733, 1147 cm . MS (CI ) m/z: 301
−1
+
5
% aqueous HCl solution (20 mL), the mixture was extracted with
+
+
+
MH ). HRMS (CI ) for C H FO S (MH ): calcd, 301.0910; found,
14 18 4
ether. The organic extracts were washed with saturated sodium
hydrogen carbonate solution and brine, dried over anhydrous sodium
sulfate, filtered, and then concentrated in vacuo. Flash chromatography
01.0895.
(
1S,2R)-((1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl)-2-fluoro-2-
(
(
(
phenylsulfonyl)cyclopropane-1-carboxylate [(S,R)-6c] and (1R,2S)-
(1R, 2S,5R)-2-Isopropyl-5-methylcyclohexyl)-2-fluoro-2-
phenylsulfonyl)cyclopropane-1-carboxylate [(R,S)-6c]. A mixture
(silica, hexane/ethyl acetate = 20:1) of the residue gave the product as
colorless solid (571 mg, 87%). An analytic sample was obtained by
2
5
trituration of the product with pentane. Mp: 44−46 °C. [α] = −42.6
of the diastereomers of trans-6c was obtained by flash chromatography
silica, hexane/ethyl acetate = 15:1) of the residue of the reaction
mixture. The diastereomers of 6c were separated by HPLC [Daicel
D
1
(
c = 0.5, CHCl ). H NMR (400 MHz, CDCl ): δ 0.77 (d, J = 7.3 Hz,
(
3
3
3
H), 0.80−1.16 (m, 10H), 1.34−1.54 (m, 2H), 1.62−1.72 (m, 2H),
13
Chiralpak AD-H, ϕ 2.0 cm × 25 cm: hexane/ethanol = 80:20, flow rate
1.74−1.94 (m, 3H), 1.96−2.06 (m, 1H), 4.60−4.84 (m, 2H).
NMR (100 MHz, CDCl ): δ 11.87, 11.97, 20.2, 20.3, 20.7, 22.0, 23.5,
C
1
2
[
5.0 mL/min, HPLC analysis; Daicel Chiralpak AD-H, ϕ 0.46 cm ×
3
5 cm, hexane/ethanol = 80:20, flow rate 1.0 mL/min; t = 5.8 min
26.3, 31.4, 34.2, 40.9, 47.1, 70.4, 72.7, 74.9, 167.94, 167.97. IR (ATR):
R
−
1
+
+
+
(R,S)-6c] and 13.6 min [(S,R)-6c]] to give (S,R)-6c and (R,S)-6c,
respectively.
S,R)-6c: Colorless oil. [α]23 = −90.3 (c = 0.5, CHCl ). H NMR
1724, 1179 cm . MS (CI ) m/z: 243 (MH ). HRMS (CI ) for
+
C
H
H
24FO (MH ): calcd, 243.1760; found, 243.1749. Anal.
23FO ) C, H, N. calcd: C, 69.39; H, 9.57. found: C, 69.19; H,
2
14
2
1
(
(C14
D
3
(
3
1
(
7
(
2
1
400 MHz, CDCl ): δ 0.51 (d, J = 6.7 Hz, 3H), 0.73 (d, J = 6.7 Hz,
9.73.
3
3
H), 0.78−1.04 (m, 6H), 1.20−1.30 (m, 1H), 1.30−1.52 (m, 2H),
.58−1.70 (m, 2H), 1.90−2.00 (m, 1H), 2.04−2.24 (m, 2H), 2.74
Step 2. (1S,2S)-2-Fluorocyclopropanecarbocxylic Acid (S,S)-1. To
a solution of (1S,2S)-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)-2-
fluorocyclopropanecarboxylate (558 mg, 2.30mmol) in tetrahydrofur-
an and methanol (18 mL, 2:1) was added a solution of lithium
hydroxide (1.10 g, 46.1 mmol) in water (6 mL) at 4 °C, the mixture
was stirred at room temperature for 72 h. The mixture was
concentrated in vacuo. After dilution of the residue with water (10
mL) and ether (10 mL), the mixture was extracted with ether. The
aqueous layer was adjusted to pH 3 by 2 mol/L aqueous HCl solution
and the resulting mixture was extracted with ethyl acetate. The organic
extracts were dried over anhydrous sodium sulfate, filtered, and then
concentrated in vacuo. Flash chromatography (silica, hexane:ethyl
acetate = 1:1) of the residue gave (S,S)-1 as colorless solid (217 mg,
90%). An analytic sample was obtained by trituration of the product
ddd, J = 3.0, 7.9, 10.3 Hz, 1H), 4.62 (dt, J = 4.2, 10.9 Hz, 1H), 7.58−
13
.65 (m, 2H), 7.71−7.77 (m, 2H), 7.98 (d, J = 7.9 Hz, 1H). C NMR
100 MHz, CDCl ): δ 15.1, 15.2, 15.8, 20.7, 21.9, 23.2, 25.6, 25.7,
3
5.9, 31.3, 34.1, 40.6, 46.8, 76.2, 88.9, 91.7, 129.2, 129.4, 134.7, 135.9,
−
1
+
64.71, 164.74. IR (ATR): 1733, 1208, 1146 cm . MS (CI ) m/z:
+
+
+
3
83 (MH ). HRMS (CI ) for C H FO S (MH ): calcd, 383.1692;
20 28 4
found, 383.1651.
(
R,S)-6c: Colorless oil. [α]2 = −19.8 (c = 0.5, CHCl ). H NMR
3
1
D
3
(
400 MHz, CDCl ): δ 0.72 (d, J = 6.7 Hz, 3H), 0.80−0.92 (m, 8H),
3
0
1
1
.93−1.09 (m, 1H), 1.25−1.49 (m, 2H), 1.59−1.72 (m, 2H), 1.75−
.92 (m, 2H), 2.00 (ddd, J = 7.9, 10.4, 17.7 Hz, 1H), 2.15 (dt, J = 7.9,
8.3 Hz, 1H), 2.84 (ddd, J = 3.1, 8.6, 11.0 Hz, 1H), 4.62 (dt, J = 4.9,
7
229
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The Journal of Organic Chemistry
Note
with pentane. Mp: 55−56 °C. [α] = +15.4 (c = 1.0, CHCl ) [lit.3
2
5
NMR (400 MHz, CD OD): δ 1.16−1.28 (m, 2H), 2.62−2.70 (m,
D
3
3
1
[
α] = +21.6 (c = 1.1, CHCl )]. H NMR (400 MHz, CDCl ): δ
1H), 2.36, (s, 3H), 2.62−2.70 (m, 1H), 4.84 (dtd, J = 3.7, 5.5, 63.6 Hz,
D
3
3
1
3
1
1
1
.18−1.30 (m, 1H), 1.74−1.90 (m, 2H), 4.80 (dddd, J = 5.5, 10.4,
1H), 7.22 (d, J = 7.9 Hz, 2H), 7.69 (d, J = 7.9 Hz, 2H). C NMR (100
2.8, 68.5 Hz, 1H). 13C NMR (100 MHz, CDCl ): δ 13.1, 13.2, 19.5,
MHz, CDCl ): δ 10.8, 10.9, 21.3, 25.35, 25.44, 68.2, 70.4, 126.9, 129.8,
3
3
−1
+
−1
+
9.6, 70.9, 73.2, 174.9. IR (ATR): 1723, 1425, 1185 cm . MS (EI )
m/z: 104 (M ). HRMS (EI ) for C H FO (M ): calcd, 104.0274;
found, 104.0290. Anal. (C H FO ) C, H, N. calcd: C, 46.16; H, 4.84.
found: C, 46.25; H, 4.97. The optical purity of (S,S)-1 prepared here
141.7, 143.5. IR (ATR): 1616, 1545, 1124 cm . MS (CI ) m/z: 76
+
+
+
+
+
+
(M−O
SC
H
). HRMS (CI ) for C
FN·C H O
7 8 3
H
FN (M−O
SC H ): calcd,
2 7 7
4
5
2
2
7
7
3
7
76.0563, found, 76.0563. Anal. (C
48.57; H, 5.71; N, 5.66. found: C, 48.58; H, 5.52; N, 5.60. According
to the reported procedure, the optical purity of (R,S)-2·TsOH
H
S) C, H, N. calcd: C,
4
5
2
3
6
4
was determined to be >99% ee by HPLC analysis with a chiral column
[
=
(
Daicel Chiralpak AD-H ϕ 0.46 cm × 25 cm, hexane/2-propanol/TFA
prepared here was determined to be >99% ee by HPLC analysis of its
3,5-dinitrobenzamide. The analysis conditions for HPLC: chiral
column [Daicel Chiralpak IA ϕ 0.46 cm × 25 cm, hexane/ethanol =
95:5:0.1, flow rate 1.0 mL/min, t = 9.1 min (S,S)-1 and 10.4 min
R
R,R)-1, detection at 230 nm].
Synthesis of (R,R)-1. Step 1. (1R,2R)-((1R,2S,5R)-2-Isopropyl-5-
60:40, flow rate 1.0 mL/min, t = 10.4 min (R,S)-2·TsOH and 21.0
R
methylcyclohexyl)-2-fluorocyclopropanecarboxylate. (1R,2R)-
(
carboxylate (576 mg, 94%) was prepared from (R,S)-6c (972 mg, 2.54
mmol) in the same manner as described for step 1 of the synthesis of
min (S,R)-2·TsOH. detection at 254 nm].
(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl)-2-fluorocyclopropane-
Synthesis of (S,R)-2·TsOH. Step 1. tert-Butyl N-[(1S,2R)-2-Fluoro-
3
cyclopropyl]carbamate. tert-Butyl N-[(1S,2R)-2-fluorocyclopropyl]-
carbamate (72 mg, 53%) was prepared from (R,R)-1 (80 mg, 0.77
2
4
(
S,S)-1. Colorless solid. Mp: 45−46 °C. [α] = −99.9 (c = 0.5,
mmol) in the same manner as that described for step 1 of the synthesis
D
3
1
of (S,R)-2·TsOH. Colorless solid. Mp: 73−75 °C (lit. Mp: 73 °C).
CHCl ). H NMR (400 MHz, CDCl ): δ 0.76 (d, J = 7.3 Hz, 3H),
3
3
2
5
3
[
α] = +69.2 (c = 0.84, CHCl ), [lit. [α] = +65.57 (c = 0.610,
0
1
2
2
.82−1.18 (m, 10H), 1.34−1.54 (m, 2H), 1.64−1.72 (m, 2H), 1.74−
D 3 D
1
CHCl )]. H NMR, IR, and MS spectra of this sample were identical
.84 (m, 2H), 1.86−2.06 (m, 1H), 1.98−2.06, (m, 1H), 4.60−4.84 (m,
3
H). 13C NMR (100 MHz, CDCl ): δ 11.9, 12.1, 16.2, 20.2, 20.3, 20.8,
to those of tert-butyl N-[(1R,2S)-2-fluorocyclopropyl]carbamate.
3
+
+
HRMS (CI ) for C H FNO (MH ): calcd, 176.1087; found,
2.0, 23.3, 26.0, 31.4, 34.2, 41.0, 47.0, 70.5, 72.8, 75.0, 168.02, 168.05.
8
15
2
−1
+
+
1
76.1116. Anal. (C H FNO·0.25H O) C, H, N. calcd: C, 53.47; H,
IR (ATR): 1727, 1169 cm . MS (CI ) m/z: 243 (MH ). HRMS
8 14 2
+
+
8.13; N, 7.79. found: C, 53.59; H, 8.03; N, 7.73.
(
(
6
CI ) for C H FO (MH ): calcd, 243.1760; found, 243.1771. Anal.
14
24
2
Step 2. (1S,2R)-2-Fluorocyclopropylammonium p-Toluene-
sulfonate (S,R)-2·TsOH. (1S,2R)-2-Fluorocyclopropylammonium p-
toluenesulfonate (S,R)-2·TsOH (50 mg, 89%) was prepared from tert-
butyl N-[(1S,2R)-2-fluorocyclopropyl]carbamate (40 mg, 0.23 mmol)
in the same manner as described for step 2 of the synthesis of (R,S)-2·
C H FO ·0.1 H O) C, H, N. calcd: C, 68.88; H, 9.58. found: C,
14
23
2
2
8.78; H, 9.43.
Step 2. (1R,2R)-2-Fluorocyclopropanecarbocxylic Acid (R,R)-1.
1R,2R)-2-Fluorocyclopropanecarbocxylic acid (R,R)-1 (224 mg, 92%)
3
(
was prepared from (1R,2R)-((1R,2S,5R)-2-isopropyl-5-methylcyclo-
hexyl)-2-fluorocyclopropanecarboxylate (570 mg, 2.35 mmol) in the
same manner as described for step 2 of the synthesis of (S,S)-1.
2
6
TsOH. Colorless solid. Mp: 168−169 °C. [α] = +8.9 (c = 1.1,
D
1
MeOH). H NMR, IR, and MS spectra of this sample were identical to
+
+
2
5
3
those of (R,S)-2·TsOH. HRMS (CI ) for C H FN (M−O SC H ):
3
7
2
7
7
Colorless solid. Mp: 55−56 °C. [α] = −14.3 ° (c = 1.0, CHCl ) [lit.
D
3
1
calcd, 76.0563; found, 76.0514. Anal. (C H FN·C H O S) C, H, N.
3 6 7 8 3
[
α] = −23.1 (c = 1.0, CHCl )]. H NMR and IR spectra of this
D
3
+ +
calcd: C, 48.57; H, 5.71; N, 5.66. found: C, 48.48; H, 5.54; N, 5.53.
The optical purity of (S,R)-2·TsOH prepared here was determined to
be >99% ee in the same manner as that described for (R,S)-2·TsOH.
sample were identical to those of (S,S)-1. MS (CI ) m/z: 104 (MH ).
+
+
HRMS (CI ) for C H FO (MH ): calcd, 105.0352; found, 105.0365.
Anal. (C H FO ) C, H, N. calcd: C, 46.16; H, 4.84. found: C46.55; H,
4
6
2
4
5
2
4
.80. The optical purity of (R,R)-1 prepared here was determined to
ASSOCIATED CONTENT
be >99% ee in the same manner as that described for (1S,2S)-1.
Synthesis of (R,S)-2. Step 1. tert-Butyl N-[(1R,2S)-2-fluoro-
cyclopropyl]carbamate.
■
*
S
Supporting Information
3,14,15
1
13
To a solution of (S,S)-1 (104 mg,
Copies of H and C NMR spectra for all new compounds and
NOE experiments of trans-6a and cis-6a. This material is
available free of charge via the Internet at http://pubs.acs.org.
1.00 mmol) in tert-butanol (2.6 mL) were added diphenyl phosphoryl
azide (0.28 mL, 1.30 mmol) and triethylamine (0.17 mL, 1.20 mmol);
the mixture was heated under reflux for 4 h. The mixture was
concentrated in vacuo. After dilution of the residue with ethyl acetate,
the mixture was washed with saturated ammonium chloride solution,
saturated sodium hydrogen carbonate solution and brine, dried over
anhydrous sodium sulfate, filtered, and then concentrated in vacuo.
Flash chromatography (silica, hexane/ethyl acetate = 5:1) of the
residue gave the product as colorless solid (114 mg, 65%). Mp: 74−75
AUTHOR INFORMATION
Corresponding Author
*Telephone: 81 (0)280 56 2201. Fax: 81 (0)280 57 1293. E-
mail: yasumichi.fukuda@mb.kyorin-pharm.co.jp
■
Notes
3
14
24
°
C (hexane). (lit. Mp: 63 °C, lit. : 77.5−78.5 °C). [α] = −69.4 (c =
D
3
14
25
D
The authors declare no competing financial interest.
0
.84, CHCl ) [lit. [α] = −60.27 (c = 0.740, CHCl ), lit. [α] =
3
D
3
1
−
66.5 (c = 0.84, CHCl )]. H NMR (400 MHz, CDCl ): δ 0.82−0.98
3
3
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The Journal of Organic Chemistry
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