Practical, general, and systematic method for optical resolution of gem-dihalo- and monohalocyclopropanecarboxylic acids utilizing chiral 1,1′-binaphtholmonomethyl ethers: Application to the synthesis of three chiral pesticides

Article abstract of DOI:10.1039/b714614k

We performed an efficient practical and systematic optical resolution method for gem-dihalo- and monohalocyclopropanecarboxylic acids 1 and 5 utilizing chiral 1,1′-binaphthol monomethyl ether (R)-2 as the key auxiliary. Direct esterification of 1 with (R)-2 gave two 1R- and 1S-diastereomeric esters 3 with marked different R_f values, both of which were easily separated using simple column chromatography. Monodehalogenation of separated chiral esters 3 using t-BuMgCl and cat. Co(dppe)₂Cl₂ gave two 1,2-trans- and 1,2-cis-diastereomers 4 with markedly different R_f values, both of which were similarly separated using simple column chromatography. The obtained diastereomers 3 and 4 were easily hydrolyzed to the desired enantiopure acids 1 (>99%) and 5 (>99%), respectively, with recovery of (R)-2, both in good to excellent yields. Utilizing the present method, important chiral agrochemicals, carpropamid 6 and fencyclate 7, were readily synthesized. Pyrethroid 9 with three asymmetric centers was efficiently synthesized in a much better yield compared with the reported method. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b714614k

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Practical, general, and systematic method for optical resolution of
gem-dihalo- and monohalocyclopropanecarboxylic acids utilizing chiral
1,1ꢀ-binaphtholmonomethyl ethers: Application to the synthesis of
three chiral pesticides†‡
Hiroaki Yasukochi,a Takayuki Atago,a Akihiro Tanaka,a Hidefumi Nakatsuji,a Eri Yoshida,b Akikazu Kakehi,b
Yoshinori Nishiib and Yoo Tanabe*a
Received 24th September 2007, Accepted 15th November 2007
First published as an Advance Article on the web 18th December 2007
DOI: 10.1039/b714614k
We performed an efficient practical and systematic optical resolution method for gem-dihalo- and
monohalocyclopropanecarboxylic acids 1 and 5 utilizing chiral 1,1ꢀ-binaphthol monomethyl ether (R)-2
as the key auxiliary. Direct esterification of 1 with (R)-2 gave two 1R- and 1S-diastereomeric esters 3
with marked different Rf values, both of which were easily separated using simple column chromato-
graphy. Monodehalogenation of separated chiral esters 3 using t-BuMgCl and cat. Co(dppe)2Cl2 gave
two 1,2-trans- and 1,2-cis-diastereomers 4 with markedly different Rf values, both of which were
similarly separated using simple column chromatography. The obtained diastereomers 3 and 4 were
easily hydrolyzed to the desired enantiopure acids 1 (>99%) and 5 (>99%), respectively, with recovery
of (R)-2, both in good to excellent yields. Utilizing the present method, important chiral agrochemicals,
carpropamid 6 and fencyclate 7, were readily synthesized. Pyrethroid 9 with three asymmetric centers
was efficiently synthesized in a much better yield compared with the reported method.
a highly general and efficient method for the optical resolution of
Introduction
various, not only gem-dihaloyclopropanecarboxylic acids 1, but
gem-Dihalocyclopropanecarboxylic acids 1, representative cy-
also related monohalocyclopropanecarboxylic acids 5, utilizing
clopropane derivatives, comprise a number of useful synthetic
easily accessible column chromatographic separation.
intermediates in many fields of organic chemistry.1 There are,
however, only two methods for the preparation of optically active
gem-dihalocyclopropanecarboxylic acids. One is optical resolution
using chiral amines: dehydroabiethylamine,2 cinchonidine,3 and
(S)-1-(1-naphthyl)ethylamine,3 but the resolution efficiency is
not high. The other is a biotransformation method utilizing
Rhodococcus sp. AJ270,4 which is efficient in yield with high
enantiomeric excess, but is limited to the use of 3-phenyl-2,2-
dihalo(or dimethyl)cyclopropanes.
The crucial problem of these methods lies in the lack of
substrate generality. As a part of our ongoing program of synthetic
studies on the transformation of gem-dihalocyclopropanes,3,5 we
previously disclosed a chirality exchange benzannulation from sp3
chirality to axial chirality3 and a synthesis of unique pyrethroids
bearing three asymmetric centers (Scheme 1).6 The investigation
into this asymmetric version required a more practical protocol for
obtaining enantiopure gem-dihalocyclopropanes. We present here
Scheme 1 Examples of the utility of chiral gem-dihalo- and monohalo-
cyclopropanecarboxylic acids.
aDepartment of Chemistry, School of Science and Technology, Kwansei
Gakuin University, 2-1 Gakuen, Sanda, Hyogo 669-1337, Japan. E-mail:
tanabe@kwansei.ac.jp; Fax: +81-795-65-9077; Tel: +81-795-65-8394
Results and discussion
bDepartment of Chemistry, Faculty of Textile Science and Technology,
Shinshu University, Ueda, Nagano 386-8567, Japan. E-mail: nishii@
giptc.shinshu-u.ac.jp; Fax: +81-268-21-5391; Tel: +81-268-51-5403
Chiral 1,1ꢀ-binaphthol derivatives are well-recognized chiral cata-
lysts and auxiliaries for the production of various useful optically
active compounds. Yamamoto and Ishihara’s group developed
a monomethyl ether of chiral 1,1ꢀ-binaphthol (R)-2 that was
utilized for the SnCl4-mediated enantioselective protonation of
† Electronic supplementary information (ESI) available: Experimental
data of known and new compounds. See DOI: 10.1039/b714614k
‡ CCDC reference number 646350. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b714614k
540 | Org. Biomol. Chem., 2008, 6, 540–547
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
enol silyl ethers.7 A convenient preparation of (R)-2 from (R)-
1,1ꢀ-binaphthol and MeOH was reported utilizing the Mitsunobu
reaction.8
(A) Optical resolution of gem-dihaloyclopropanecarboxylic acids 1
We utilized (R)-2 as the auxiliary for the present column chromato-
graphic optical resolution of gem-dihaloyclopropanecarboxylic
acids 1 as outlined in Scheme 2.
Scheme 3 Optical resolution procedure of monohalocyclopropanecar-
boxylic acids 5.
procedure in good to excellent yields. The obtained aqueous
reaction phase was washed with ether, and then acidified with
HCl aq., followed by re-extraction with AcOEt. The organic phase
contained sufficiently pure products 1a–g and 1aꢀ–gꢀ. Note that
chiral auxiliary (R)-2 was recovered in ca. 95% yield by the initial
ether extraction. Table 2 lists these results.
The absolute configurations of 1 were unambiguously deduced
by comparing with the corresponding known compounds for
1a, d–g. That of new compound (1S,3S)-1b was determined by
X-ray crystallographic analysis of the corresponding amide de-
rived from (S)-1-phenylethylamine. (Fig. 1). The absolute con-
figuration of diastereomeric acids (1R,3S)- and (1S,3R)-1c was
deduced by analogy with the result of (1S,3S)-1b.
Scheme 2 Optical resolution procedure of gem-dihalocyclopropane-
carboxylic acids 1.
An initial examination of TsCl–N-methylimidazole-mediated
direct esterification9 between ( )-2,2-dichloro-1-methylcyclo-
propanecarboxylic acid [( )-1a] and (R)-2 resulted in the forma-
tion of diastereomeric mixtures of (1R)-3a and (1S)-3a, which
displayed significantly different Rf values, 0.37 and 0.46, respec-
tively, on a SiO2-thin-layer chromatography (hexane–AcOEt =
5 : 1). Thus, esters (1R)-3a and (1S)-3a were easily separated by
SiO2-column chromatography in 39% and 41% yield, respectively.
This protocol showed high generality for various acids 1a–
g in good yield (Table 1). The salient features are as follows.
(i) All 7 examples examined had distinctively different Rf values
between (1R)-3 and (1S)-3 diastereomers. (ii) Diastereomers (1S)-
3a–g showed consistently higher Rf values compared with those
of the corresponding diastereomers (1R)-3a–g. (iii) Important
chiral acid precursors for the fungicide carpropamid10 (1S,3R)-1e
(entry 5) and the synthetic pyrethroid fencyclate11 (1S)-1f (entry 6),
were readily prepared (vide infra, Schemes 4 and 5). (iv) A gem-
dibrominated analog 1g also produced good results (entry 7).
Separated diastereomers 3a–g and 3aꢀ–gꢀwere readily hydrolyzed
under conventional conditions (KOH/THF–H2O, 60–65 ◦C) to
give the desired chiral gem-dihaloyclopropanecarboxylic acids 1a–
g and 1aꢀ–gꢀ, respectively, which were isolated by a facile extraction
Fig. 1 X-ray structure of (S)-1-phenylethylamide of (1S,3S)-1b (50%
probability thermal ellipsoids).
(B) Optical resolution of monohalocyclopropanecarboxylic acids 5
Next, we focused our attention on the optical resolution of three
sets of analogous monohalocyclopropanecarboxylic acids 5 using
a similar simple column chromatographic separation (Scheme 3).
The ester precursors 4a–c were prepared by reductive monodechlo-
rination utilizing t-BuMgCl–cat. Co(dppe)2Cl2 reduction12 of the
corresponding chiral 1,1ꢀ-binaphthol esters 3. Table 3 lists these
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 540–547 | 541
©

View Article Online
Table 1 Optical resolution of gem-dihalocyclopropanecarboxylic acids ( )-1 utilizing chiral auxiliary (R)-2
Entry
1
RCO2H ( )-1
Product 3
Rfa
Yield (%)b
Entry
5
RCO2H ( )-1
Product 3
Rf
Yield (%)b
(1R)-3a
(1S)-3a
0.37
0.46
39
41
(1R,3S)-3e
(1S,3R)-3e
0.54
0.59
37
38
2
(1R,3R)-3b
(1S,3S)-3b
0.33
0.40
39
38
6
7
(1R)-3f
(1S)-3f
0.27
0.33
39
40
3
4
(1R,3S)-3c
(1S,3R)-3c
0.40
0.49
39
39
(1R)-3g
(1S)-3g
0.18c
0.27c
38
39
(1R,3S)-3d
(1S,3R)-3d
0.40
0.49
37
36
a Hexane–AcOEt = 5 : 1. b Isolated. c Hexane–AcOEt = 10 : 1
Table 2 Hydrolysis of chiral gem-dihalocyclopropanecarboxylic esters 3
Entry
RCO2R* 3
Product 1
Time/h
Yield (%)a
Entry
RCO2R* 3
Product 1
Time/h
Yield (%)a
1
2
3
4
5
6
7
(1R)-3a
(1R)-1a
4.5
4.5
15.0
15.0
5.0
5.0
4.5
93
96
92
92
89
88
87
8
9
10
11
12
13
14
(1S,3R)-3d
(1R,3S)-3e
(1S,3R)-3e
(1R)-3f
(1S,3R)-1d
(1R,3S)-1e
(1S,3R)-1e
(1R)-1f
3.0
2.5
2.5
7.0
7.0
6.5
7.0
82
94
95
98
94
89
93
(1S)-3a
(1S)-1a
(1R,3R)-3b
(1S,3S)-3b
(1R,3S)-3c
(1S,3R)-3c
(1R,3S)-3d
(1R,3R)-1b
(1S,3S)-1b
(1R,3S)-1c
(1S,3R)-1c
(1R,3S)-1d
(1S)-3f
(1S)-1f
(1R)-3g
(1S)-3g
(1R)-1g
(1S)-1g
a Isolated.
successful results. Notice that all six diastereomer pairs had
distinctively different Rf values. 1,2-trans Diastereomers showed
consistently higher Rf values, which was quite different from the
result of the separation of esters 3. Eventually, all 12 diastereomers
were produced in pure form (>99% de). KOH hydrolysis of 4a–
c gave three sets of each of the four chiral acids 5a–c in good
yield (Table 4). The purification procedure of all 4a–c (×4) was as
convenient as the aforementioned case of acids 1.
542 | Org. Biomol. Chem., 2008, 6, 540–547
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
Table 3 Optical resolution of monohalocyclopropanecarboxylic esters 4a–c utilizing chiral auxiliary 2
Entry
1
Substrate
t-BuMgCl/eq.
Product
1,2-Configuration
Rfa
Yield (%)b
3.3
(1R,2R)-4a
(1R,2S)-4a
1,2-cis
1,2-trans
0.52
0.65
19
51
2
3
4
3.3
4.0
4.0
(1S,2R)-4a
(1S,2S)-4a
1,2-trans
1,2-cis
0.60
0.46
46
24
(1R,2R,3S)-4b
(1R,2S,3S)-4b
1,2-cis
1,2-trans
0.62
0.66
40
38
(1S,2R,3R)-4b
(1S,2S,3R)-4b
1,2-trans
1,2-cis
0.62
0.56
40
37
5
6
1.9
1.9
(1R,2R)-4c
(1R,2S)-4c
1,2-cis
0.56
0.69
35
42
1,2-trans
(1S,2R)-4c
(1S,2S)-4c
1,2-trans
1,2-cis
0.45
0.33
40
33
a Hexane–AcOEt = 5 : 1. b Isolated.
Table 4 Hydrolysis of chiral monohalocyclopropanecarboxylic esters 5
Entry
RCO2R* 4
Product 5
Yield (%)a
Entry
RCO2R* 4
Product 5
Yield (%)a
1
2
3
4
5
6
(1R,2R)-4a
(1R,2S)-4a
(1R,2R)-5a
(1R,2S)-5a
92
95
92
92
93
92
7
8
9
10
11
12
(1S,2R,3R)-4b
(1S,2S,3R)-4b
(1R,2R)-4c
(1R,2S)-4c
(1S,2R,3R)-5b
(1S,2S,3R)-5b
(1R,2R)-5c
(1R,2S)-5c
93
92
97
94
92
96
(1S,2R)-4a
(1S,2R)-5a
(1S,2S)-4a
(1R,2R,3S)-4b
(1R,2S,3S)-4b
(1S,2S)-5a
(1R,2R,3S)-5b
(1R,2S,3R)-5b
(1S,2R)-4c
(1S,2R)-5c
(1S,2S)-4c
(1S,2S)-5c
a Isolated.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 540–547 | 543
©

View Article Online
(C) Application to the synthesis of three pesticides
dihalocyclopropanecarboxylic acids. Because of its high efficiency
and generality, the present method provides a new avenue for the
practical preparation of various cyclopropane derivatives. Further
investigation, especially ofnew chirality exchange benzannulations
utilizing the present method, is in progress.
With these results in hand, we applied the present protocol to
the synthesis of three chiral pesticides (Schemes 4 and 5). First,
amide formation of acid (1S,3R)-1e with (S)-1-(4-chlorophenyl)-
ethylamine gave (1S,3R,1ꢀS)-carpropamid 6, the most active ingre-
dient among the stereoisomers, in good yield. The present method
was more convenient, compared to the reported method6b using
thin layer column chromatographic separation of diastereomers
derived from ( )-4a and (S)-1-(4-chlorophenyl)ethylamine. Sec-
ond, (1S)-fencyclate 7, a synthetic pyrethroid with a unique gem-
dichlorocyclopropane structure, was readily synthesized by the
condensing acid (1S)-1f with 3-phenoxybenzyl(bromo)acetonitrile
in good yield.
Experimental
Melting points were determined on a hot stage microscope
apparatus (Yanagimoto) and are uncorrected. NMR spectra
were recorded on a JEOL DELTA300 spectrometer, operating at
300 MHz for 1H NMR and 75 MHz for 13C NMR. Chemical shifts
(d ppm) in CDCl3 were reported downfield from TMS (= 0 ppm)
for 1H NMR. For 13C NMR, chemical shifts on a scale relative to
(77.00 ppm) as an internal reference. IR spectra were recorded on
JASCO FT/IR-5300 spectrophotometer. Optical rotations were
measured on a JASCO DIP-370 (k 589 nm). Mass spectra were
measured on a JEOL JMS-T100LC spectrometer.
Data of known and new compounds: (1R,3R)-3b, (1S,3S)-
3b, (1R,3S)-3c, (1S,3R)-3c, (1R,3S)-3d, (1S,3R)-3d, (1R,3S)-3e,
(1S,3R)-3e, (1R)-3f, (1S)-3f, (1R)-3g, (1S)-3g, (1S)-1a,3 (1R,3R)-
1b,5b,c (1S,3S)-1b,5b,c (1R,3S)-1c,5b,c (1S,3R)-1c,5b,c (1R,3S)-1d,6b
(1S,3R)-1d,6b (1R,3S)-1e, (1S,3R)-1e, (1R)-1f,11 (1S)-1f,11 (1R)-
1g,2 (1S)-1g,2 (1S,2R)-4a, (1S,2S)-4a, (1R,2R,3S)-4b, (1R,2S,3S)-
4b, (1S,2R,3R)-4b, (1S,2S,3R)-4b, (1R,2R)-4c, (1R,2S)-4c,
(1S,2R)-4c, (1S,2S)-4c, (1R,2S)-5a (1S,2R)-5a, (1S,2S)-5a,
(1R,2R,3S)-5b, (1R,2S,3S)-5b,6b (1S,2R,3R)-5b,6b (1S,2S,3R)-5b,
(1R,2R)-5c, (1R,2S)-5c, (1S,2R)-5c, and (1S,2S)-5c, are described
in the electronic supporting information.†
Scheme 4 Synthesis of chiral carpropamid 6 and fencyclate 7.
A typical esterification procedure to give (1R)- and (1S)-[(R)-2ꢀ-
methoxy-1,1ꢀ-binaphth-2-yl] 2,2-dichloro-1-methylcyclo-
propanecarboxylate [(1R)-3a and (1S)-3a] (Table 1, entry 1)
TsCl (127 mg, 0.66 mmol) in CH3CN (0.60 ml) was added
to a stirred solution of ( )-2,2-dichloro-1-methylcyclopropane-
carboxylic acid [( )-1a; 112 mg, 0.66 mmol] and N-methyl-
imidazole (136 mg, 1.66 mmol) in CH3CN (0.60 ml) at 0–5 ◦C
under an Ar atmosphere, followed by being stirred at the same
temp. for 0.5 h. (R)-Monomethyl ether of 1,1ꢀ-binaphthol (2;
166 mg, 0.55 mmol) in CH3CN (0.60 ml) was added to the reaction
mixture at 0–5 ◦C, followed by being stirred at 20–25 ◦C for
2 h. Water was added to the mixture, which was extracted with
AcOEt (5 ml × 3). The combined organic phase was washed
with water, brine, dried (Na2SO4), and concentrated. The obtained
crude product was purified by silica gel column chromatography
(hexane–AcOEt = 15 : 1) to give the desired products (1R)-3a
[99 mg, 39%; Rf = 0.37 (hexane–AcOEt = 5 : 1)] and (1S)-3a
[105 mg, 41%; Rf = 0.46 (hexane–AcOEt = 5 : 1)].
(1R)-3a. Colorless crystals; Rf = 0.37 (hexane–AcOEt = 5 : 1);
mp 141–143 ◦C; [a]D24 +99.0 (c 0.59, CHCl3). 1H NMR (300 MHz,
CDCl3): d 0.84 (3H, s), 1.17 (1H, d, Jgem = 7.6 Hz), 1.98 (1H, d,
Jgem = 7.6 Hz), 3.73 (3H, s), 7.16 (1H, d, J = 8.3 Hz), 7.20–7.49
(7H, m), 7.83 (1H, d, J = 7.9 Hz), 7.88–8.02 (3H, m). 13C NMR
(75 MHz, CDCl3): d 17.3, 30.5, 35.3, 56.7, 62.1, 113.6, 117.4, 121.4,
123.7, 125.2, 125.6, 126.2, 126.5, 126.7, 127.8, 128.1, 128.9, 129.2,
130.1, 131.9, 133.6, 133.8, 146.5, 155.0, 167.2. IR (KBr) 1752,
1507, 1275, 1250, 1215, 1140, 1090, 818, 754 cm−1. HRMS (ESI)
calcd for C26H20Cl2O3 (M + Na+) 473.0687, found 473.0692.
Scheme
(1R,2S,3S)-9.
5
Synthesis of pyrethroid with three asymmetric centers
A monochlorocyclopropane pyrethroid with three asymmetric
centers, (1R,2S,3S)-9, was efficiently synthesized (Scheme 5).
LAH reduction of (1R,2S,3S)-5b gave alcohol (1R,2S,3S)-8
(95%), which was coupled with 3-phenoxybenzyl bromide to give
the desired product (1R,2S,3S)-9 (84%). Our first synthesis of
(1R,2S,3S)-9 required a tedious optical resolution step for the
corresponding racemic acid (1R*,2S*,3S*)-5b; four recrystalliza-
tions using (S)-naphthylethylamine resulted in a poor yield (3.5%)
of 5b.6b Thus, total yield and efficiency were greatly increased up
to ca. 40 times by the present method.
In conclusion, we developed an efficient general practical
optical resolution method for gem-dihalo and monohalocyclo-
propanecarboxylic acids using simple column chromatographic
separation. The present systematic protocol was successfully
applied to the short synthesis of three pesticides The use of equally
available (S)-2 will also provide complementary antipodal gem-
544 | Org. Biomol. Chem., 2008, 6, 540–547
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
(1S)-3a. Colorless crystals; Rf = 0.46 (hexane–AcOEt = 5 : 1);
data was collected by a Rigaku AFC5S four-circle diffractometer
mp 74–76 ◦C; [a]D −53.1 (c 0.66, CHCl3). 1H NMR (300 MHz,
with graphite-monochromated MoKa radiation (k = 0.71069 A).
24
˚
CDCl3): d 0.82 (3H, s), 1.11 (1H, d, Jgem = 7.6 Hz), 1.93 (1H, d,
Jgem = 7.6 Hz), 3.77 (3H, s), 7.12 (1H, d, J = 8.3 Hz), 7.17–7.34
(4H, m), 7.39–7.49 (3H, m), 7.83 (1H, d, J = 7.9 Hz), 7.93 (1H,
d, J = 8.3 Hz), 7.96 (2H, d, J = 8.9 Hz). 13C NMR (75 MHz,
CDCl3): d 17.2, 30.5, 35.3, 56.6, 62.2, 113.4, 121.6, 123.7, 125.0,
125.2, 125.6, 126.1, 126.5, 126.7, 127.7, 128.2, 128.9, 129.1, 130.0,
131.9, 133.6, 133.7, 146.5, 154.9, 167.3. IR (KBr) 1755, 1508,
1273, 1252, 1215, 1146, 1084, 806 cm−1. HRMS (ESI) calcd for
C26H20Cl2O3 (M + Na+) 473.0687, found 473.0681.
Representative data is as follows: C14H17Cl2NO; M = 286.20;
˚
monoclinic, space group P21 (#4), Z = 4 with a = 9.82 (3) A, b =
◦
3
˚
˚
˚
9.82 (3) A, c = 16.09 (3) A, b = 101.08 (16) , V = 1522.0 (66) A
and Dcalc. = 1.249g cm−3. All calculations were performed using the
teXsan package.14 The structure was solved by a direct method
. The non-hydrogen atoms were refined anisotropically, and the
hydrogen atoms were attached at the idealized position and not
refined. The final R1 (I > 2.00r(I)), R all reflections, and wR2 all
reflections factors after full-matrix least-squares refinements were
0.060, 0.228, and 0.214, respectively, for 3608 observed reflections,
and the Flack parameter was −0.09 (16).
A typical hydrolysis procedure to give (1R)-2,2-dichloro-1-methyl-
cyclopropanecarboxylic acid [(1R)-1a]3 (Table 2, entry 1)
Typical monodehalogenation procedure of gem-dihalocyclo-
propanecarboxylate (1R)-3a to give (1R,2R)- and (1R,2S)-[(R)-2ꢀ-
methoxy-1,1ꢀ-binaphth-2-yl]2-chloro-1-methylcyclopropane-
carboxylate [(1R,2R)-4a and (1R,2S)-4a] (Table 3, entry 1)
(1R)-3a (3.53 g, 7.82 mmol) and KOH (1.32 g, 23.5 mmol) in THF
(36 ml), and H2O (22 ml) were heated with stirring at 60–65 ◦C for
4.5 h. After cooling down, water was added to the mixture, which
was extracted twice with ether. The combined organic phase was
washed with water, brine, dried (Na2SO4) and concentrated to give
(R)-2 (recovery, 2.25 g, 96%). Next, the separated aqueous phase
was adjusted to pH 1 ∼ pH 2 using aqueous 1 M HCl, and then
re-extracted with ether twice. The separated organic phase was
washed with water, brine, and dried (Na2SO4) and concentrated
to give the desired product (1R)-1a (1.33 g, 93%).
t-BuMgCl (1.0 M in THF, 2.94 ml, 2.94 mmol) was added to a
stirred mixture of (1R)-3a (400 mg, 0.89 mmol) and CoCl2(dppe)2
(23 mg, 0.04 mmol) in THF (2.0 ml) at 50–55 ◦C under an Ar
atmosphere, followed by stirring at the same temp. for 0.5 h.
Water was added to the mixture, which was extracted with AcOEt
(5 ml × 3). The combined organic phase was washed with
water, brine, dried (Na2SO4), and concentrated. The obtained
crude product was purified by silica gel column chromatography
(hexane–AcOEt = 15 :1) to give the desired product (1R,2R)-4a
(70 mg, 19%) and (1R,2S)-4a (189 mg, 51%).
Yellow oil : [a]D +51.4 (c 1.77, CHCl3). 1H NMR (400 MHz,
25
CDCl3): d 1.48 (1H, d, Jgem = 7.6 Hz), 1.16 (3H, s), 2.30 (1H,
d, Jgem = 7.6 Hz). 13C NMR (100 MHz, CDCl3): d 18.02, 31.18,
35.12, 62.61, 175.52. IR (neat) 3001, 1709, 1416, 1316, 945 cm−1.
(1R,2R)-4a. Pale yellow crystals; Rf = 0.52 (hexane–AcOEt =
Preparation13 of (1S,3S)-2,2-dichloro-1,3-dimethyl-N-[(S)-1-
phenylethyl]cyclopropancarboxamide for X-ray analysis
5 : 1); mp 58–60 ◦C; [a]D +36.9 (c 0.35, CHCl3). 1H NMR
23
(300 MHz, CDCl3): d 0.70 (3H, s), 0.91 (1H, t, J = 7.2 Hz), 1.47
(1H, dd, J = 5.2, 7.2 Hz), 2.84 (1H, dd, J = 5.2, 7.2 Hz), 3.75 (3H,
s), 7.15 (1H, d, J = 8.3 Hz), 7.20–7.37 (4H, m), 7.39–7.52 (3H, m),
7.84 (1H, d, J = 8.3 Hz), 7.90–8.04 (3H, m). 13C NMR (75 MHz,
CDCl3): d 18.7, 22.0, 27.2, 38.5, 56.7, 113.6, 117.7, 121.9, 123.6,
125.0, 125.4, 125.4, 126.1, 126.4, 126.5, 127.7, 128.1, 129.0, 129.9,
131.7, 133.6, 133.8, 146.8, 155.0, 168.4. IR (KBr) 3484, 3059, 3005,
2965, 2936, 2839, 1752, 1622, 1593, 1508, 1318, 1138, 1084, 808,
747 cm−1. HRMS (ESI) calcd for C26H21ClO3 (M + Na+) 439.1077,
found 439.1073.
(1S,3S)-2,2-Dichloro-1,3-dimethylcyclopropanecarbonyl chlo-
ride (129 mg, 0.64 mmol) prepared from acid (1S,3S)-3b was
added to a stirred suspension of (S)-1-phenylethylamine (78 mg,
0.64 mmol), N-methylimidazole (5 mg, 0.06 mmol), TMEDA
(7 mg, 0.06 mmol), and K2CO3 (134 mg, 0.97 mmol) in CH3CN
(0.5 mL) at 0–5 ◦C under an Ar atmosphere. The mixture was
stirred at the same temperature for 1 h. Water was added to
the mixture, which was extracted with AcOEt. The organic phase
was washed with water, brine, dried (Na2SO4), and concentrated.
The obtained crude product was purified by silica gel column
chromatography (hexane–AcOEt = 6 : 1) to give the desired
product (122 mg, 80%).
(1R,2S)-4a. Pale yellow crystals; Rf = 0.65 (hexane–AcOEt =
5 : 1); mp 55–56 ◦C; [a]D +46.3 (c 3.15, CHCl3). 1H NMR
23
(300 MHz, CDCl3): d 0.60 (1H, t, J = 5.2 Hz), 1.10 (3H, s), 1.20
(1H, dd, J = 5.2, 7.9 Hz), 2.70 (1H, dd, J = 5.2, 7.9 Hz), 3.76 (3H,
s), 7.05 (1H, d, J = 8.3 Hz), 7.19–7.39 (4H, m), 7.40–7.50 (3H, m),
7.85–8.06 (4H, m). 13C NMR (75 MHz, CDCl3): d 14.3, 24.0, 24.4,
39.4, 56.4, 113.2, 117.1, 121.6, 123.7, 124.9, 125.1, 125.5, 126.1,
126.4, 126.6, 127.9, 128.1, 128.8, 129.0, 130.2, 131.7, 133.4, 133.5,
146.8, 155.0, 168.4. IR (KBr) 3449, 3059, 2938, 2839, 1746, 1622,
1593, 1508, 1319, 1138, 1086, 810, 748 cm−1. HRMS (ESI) calcd
for C26H21ClO3 (M + Na+) 439.1077, found 439.1078.
Colorless crystals; mp 104.0–105.0 ◦C; [a]D −35.4 (c 0.42,
23
CHCl3). 1H NMR (300 MHz, CDCl3): d 1.34 (3H, d, J = 6.5 Hz),
1.49 (1H, t, J = 6.2), 1.51 (3H, d, J = 6.5), 1.58 (3H, s), 5.13 (1H,
quint, J = 7.2), 5.89–5.73 (1H, br), 7.40–7.23 (5H, m). 13C NMR
(75 MHz, CDCl3) d 11.6, 21.5, 22.6, 35.3, 38.2, 49.0, 68.0, 126.1,
127.5, 128.8, 142.7, 166.9, IR (KBr) 3289, 3068, 2975, 2932, 1672,
1642, 1539, 1453 cm−1.
Data from the X-ray crystallographic analysis was deposited
at Cambridge crystallographic data base centre (CCDC).‡ OR-
TEP drawing (50% probability thermal ellipsoids) is of (S)-1-
phenylethylamide of (1S,3S)-1b. There are two unsymmetrical
molecules in this lattice and only of them is shown.
Typical hydrolysis procedure to give (1R,2R)-2-chloro-1-methyl-
cyclopropanecarboxylic acid [(1R,2R)-5a] (Table 4, entry 1)
A colorless prismatic single crystal (0.68 × 0.38 × 0.06 mm)
A mixture of (1R,2R)-4a (60 mg, 0.14 mmol), KOH (24 mg,
0.43 mmol) in water (0.20 ml), THF (1.0 ml), and MeOH (0.10 ml)
grown from solvent was used for the unit-cell determinations and
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 540–547 | 545
©

View Article Online
was heated with stirring at 60–65 ◦C for 2 h. After cooling
down, water was added to the mixture, which was extracted twice
with ether (5 ml × 3). The combined organic phase was washed
with water, brine, dried (Na2SO4) and concentrated to give (R)-2
(recovery, 40 mg, 95%). Next, the separated aqueous layer was
adjusted to pH 1 ∼ 2 using 6 M aqueous HCl solution, and was
re-extracted with AcOEt (5 ml × 3). The combined organic phase
was washed with water, brine, dried (Na2SO4), and concentrated
to give the desired product (1R,2R)-5a (17 mg, 92%).
114.4, 115.1, 115.2, 117.4, 117.5, 119.2, 119.4, 120.30, 120.35,
121.8, 122.3, 124.0, 124.1, 124.5, 124.6, 129.9, 130.0, 130.5, 130.6,
131.9, 132.7, 132.9, 156.2, 156.3, 158.0, 158.2, 159.4, 166.1
(1R,2S,3S)-2-Chloro-1-methyl-3-phenylcyclopropylmethanol
[(1R,2S,3S)-8]6b
Compound (1R,2S,3S)-5 (50 mg, 0.10 mmol) in THF was added to
a stirred suspension of LiAlH4 (2 mg, 0.05 mmol) in THF at 0–5 ◦C
and the mixture was stirred at room temperature for 2 h. Water was
added to the mixture, which was extracted twice with Et2O. The
combined organic phase was washed with water, brine, dried
(Na2SO4), and concentrated. The obtained crude product was
purified by silica gel column chromatography (hexane–AcOEt =
6 :1) to give the desired product (1R,2S,3S)-8 (19 mg, 95%).
Pale yellow oil; [a]D −29.7 (c 0.55, CHCl3). 1H NMR
23
(300 MHz, CDCl3) d 1.24 (1H, t, J = 6.9 Hz), 1.38 (3H, s), 1.81
(1H, dd, J = 5.5, 6.9 Hz), 3.13 (1H, dd, J = 5.5, 6.9 Hz). 13C NMR
(75 MHz, CDCl3) d 19.3, 23.1, 26.9, 39.5, 177.1. IR (KBr) 2928,
2731, 2617, 1699, 1466, 1422, 1329, 1238, 1209, 941, 909 cm−1.
Anal. Calcd for C5H7ClO2; C, 44.63; H, 5.24, found: C, 44.3; H,
4.9%.
Colorless oil; [a]D −74.6 (c 0.70, CHCl3). [lit.6b [a]D −82.3 (c
23
23
1
1.31, CHCl3)]. H NMR (300 MHz, CDCl3) d 1.13 (3H, s), 1.53
(1H, s), 2.28 (1H, d, J = 7.9 Hz), 3.45 (1H, d, J = 7.9 Hz), 3.57–
3.71 (2H, m), 7.20–7.37 (5H, m). 13C NMR (75 MHz, CDCl3) d
13.2, 27.8, 27.9, 41.0, 69.7, 126.6, 128.1, 131.0, 134.2. IR (neat)
3432, 3399, 3318, 3272, 2926, 2872, 1447, 1032, 725, 700 cm−1.
Synthesis of (1S,3R,1ꢀS)-carpropamid 6, the most fungicidally
active stereoisomer
TsCl (243 mg, 1.27 mmol) in CH3CN (1.0 mL) was added to
a stirred solution of (1S,3R)-1e (209 mg, 1.06 mmol) and N-
methylimidazole (241 mg, 3.18 mmol) in CH3CN (1.0 mL) at
0–5 ◦C under an Ar atmosphere, and the mixture was stirred for
30 min. (S)-1-(4-Chlorophenyl)ethylamine (165 mg, 1.06 mmol)
(1R,2S,3S)-2-Chloro-1-methyl-3-phenylcyclopropylmethyl
3-phenoxybenzyl ether [(1R,2S,3S)-9],6b a pyrethroid with three
asymmetric centers
◦
in CH3CN (1.0 mL) was added to the stirred mixture at 0–5 C,
A
mixture of (1R,2S,3S)-8 (15 mg, 0.08 mmol) and 3-
followed by being stirred at the same temp. for 2 h. Water was
added to the stirred mixture, which was extracted with ether. The
organic phase was washed with water, brine, dried (Na2SO4), and
concentrated. The obtained crude product was purified by silica
gel column chromatography (hexane–AcOEt = 10 : 1) to give the
desired product (1S,3R,1ꢀS)-6 (205 mg, 57%).
phenoxybenzyl bromide (20 mg, 0.08 mmol) in DMF was added to
a stirred suspension of NaH (2 mg, 0.08 mmol) in DMF at 0–5 ◦C,
followed by stirring at room temperature for 4 h. Water was added
to the mixture, which was extracted twice with Et2O. The combined
organic phase was washed with water, brine, dried (Na2SO4), and
concentrated. The obtained crude product was purified by silica
gel column chromatography (hexane–AcOEt = 50 :1) to give the
desired product (1R,2S,3S)-9 (24 mg, 84%).
Colorless crystals; mp 169.0–169.5 ◦C; [a]D +90.7 (c 1.00,
23
MeOH). [lit.10c [a]D +87.9 (MeOH)] 1H NMR (300 MHz, CDCl3):
d 0.99 (3H, t, J = 7.2 Hz), 1.20 (3H, d, J = 6.5 Hz), 1.53 (3H,
d, J = 6.9 Hz), 1.48–1.61 (1H, m), 1.95 (1H, dt, J = 7.2 Hz),
2.21 (1H, q, J = 6.5 Hz), 5.17 (1H, quint, J = 7.2 Hz), 5.87–
5.93 (1H, br), 7.30 (4H, m). 13C NMR (75 MHz, CDCl3) d 8.6,
10.9, 21.2, 22.1, 29.7,43.2, 48.8, 66.6, 127.9, 128.7, 141.0, 167.2, IR
(KBr) 3270, 3057, 2878, 1644, 1530, 1493, 1456, 1414 cm−1 These
spectroscopic data completely matched with the reported data.10c
Colorless oil; [a]D −47.2 (c 0.50, CHCl3). [lit.6b [a]D −48.3 (c
23
23
1
1.55, CHCl3)]. H NMR (300 MHz, CDCl3) d 1.10 (3H, s), 2.27
(1H, d, J = 7.9 Hz), 3.43 (1H, d, J = 7.9 Hz), 3.48 (2H, s), 4.47–
4.59 (2H, m), 6.90–7.17 (6H, m), 7.20–7.40 (8H, m). 13C NMR
(75 MHz, CDCl3) d 13.6, 25.9, 27.8, 29.7, 41.3, 72.3, 76.3, 117.5,
117.8, 119.1, 122.0, 123.4, 126.5, 128.0, 129.7, 131.0, 134.4, 140.3,
156.9, 157.6.
Synthesis of (1S)-fencyclate 7
Acknowledgements
Et3N (41 mg, 0.406 mmol) was added to a stirred mixture of (1S)-
1f (88 mg, 0.340 mmol) and bromo(3-phenoxyphenyl)acetonitrile
(117 mg, 0.406 mmol) in acetone (0.7 mL) at 0–5 ◦C, and the
mixture was stirred at room temperature for 2 h. Aqueous 1 M HCl
solution was added to the mixture, which was extracted with ether.
The organic phase was washed with water, brine, dried (Na2SO4),
and concentrated. The crude oil was subjected to silica gel column
chromatography (hexane–AcOEt = 10 : 1) to give the desired
product (134 mg, 82%).
This research was partially supported by Grant-in-Aids for
Scientific Research on Basic Areas (B) “18350056”, Priority
Areas (A) “17035087” and “18037068”, and Exploratory Research
“17655045” from the Ministry of Education, Culture, Sports,
Science and Technology (MEXT). We thank Professor Shinzo
Kagabu (Gifu University) for helpful discussions on carpropamid.
We also thank Dr Motoo Shiro (RIGAKU) for his support of the
X-ray crystallographic analysis.
1
Light yellow oil; H NMR (300 MHz, CDCl3) d 1.40 (3H, q,
J = 6.88), 2.079 (1H × 1/2, d, J = 7.91), 2.084 (1H × 1/2, d J =
7.91), 2.61 (1H × 1/2, d, J = 7.91), 2.62 (1H × 1/2, d J = 7.91),
3.92–4.08 (2H, m), 6.29 (1H × 1/2, s), 6.32 (1H × 1/2, s), 6.78–
6.91 (2H, m), 6.91–7.44 (11H, m). 13C NMR (75 MHz, CDCl3)
d 30.7, 30.8, 43.79, 43.84, 61.5, 61.6, 63.5, 63.78, 63.83, 114.3,
References
1 (a) S. Patai, Z. Rappoport, The Chemistry of the Cyclopropyl Group,
Wiley, London, 1987; (b) H.-U. Reissig, Top. Curr. Chem., 1988, 144,
73; (c) H. N. C. Wong, M.-Y. Hon, C.-Y. Tse, Y.-C. Yip, J. Tanko and
546 | Org. Biomol. Chem., 2008, 6, 540–547
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
T. Hudlicky, Chem. Rev., 1989, 89, 165; (d) M. Fedorynski, Chem. Rev.,
2003, 103, 1099.
2 M. S. Baird, P. Licence, V. V. Tverezovsky, I. G. Bolesov and W.
Clegg, Tetrahedron, 1999, 55, 2773. Enantiopure (1R)-2,2-dibromo-
1-methylcyclopropanecarboxylic acid was obtained in 29% yield with
>99% ee by two recrystallizations.
3 Y. Nishii, K. Wakasugi, K. Koga and Y. Tanabe, J. Am. Chem. Soc.,
2004, 126, 5358. Enantiopure (1R)-1a was obtained by three recrys-
tallizations using cinchonine in 5% yield. Enantiopure (1S)-1a was
obtained by three recrystallizations using (S)-1-(1-naphthyl)ethylamine
in 29% yield.
Perkin Trans. 1, 1996, 1243; (c) Y. Nishii, N. Maruyama, K. Wakasugi
and Y. Tanabe, Bioorg. Med. Chem., 2001, 9, 33.
7 (a) K. Ishihara, M. Kaneeda and H. Yamamoto, J. Am. Chem. Soc.,
1994, 116, 11179; (b) K. Ishihara, S. Nakamura, M. Kaneeda and H.
Yamamoto, J. Am. Chem. Soc., 1996, 118, 12854; (c) A. Yanagisawa,
K. Ishihara and H. Yamamoto, Synlett, 1997, 38, 6429.
8 (a) M. Takahashi and K. Ogasawara, Tetrahedron: Asymmetry, 1997,
8, 3125; (b) T. Taniguchi and K. Ogasawara, Tetrahedron Lett., 1997,
38, 6429.
9 K. Wakasugi, A. Iida, T. Misaki, Y. Nishii and Y. Tanabe, Adv. Synth.
Catal., 2003, 345, 1209.
4 M.-X. Wang, G.-Q. Feng and Q.-Y. Zheng, Adv. Synth. Catal., 2003,
345, 695.
10 (a) Y. Kurahashi, S. Kagabu, S. Sakawa, N. Matsumoto, T. Yamada,
Japan Patent 62, 201,855, 1987 (Chem. Abstr., 1988, 108, p. 167121a);
(b) Y. Kurahashi, S. Kagabu, N. Matsumoto, T. Yamada, K. Wada
and T. Kondo, Japan Patent 54 349, 1998, (Chem. Abstr., 1998,
109, 190038h); (c) M. Koketsu, S. Kagabu and M. Matsuoka, Acta
Crystallogr. C, 1999, 55, 1025.
11 (a) D. P. Cartwrite, R. Langcake, J. Pryce, D. P. Leworthy and J. P. Ride,
Nature, 1997, 267, 511; (b) G. Holan, D. F. O’Keefe, C. Vergona and
R. Walser, Nature, 1978, 272, 734.
12 Y. Nishii, K. Wakasugi and Y. Tanabe, Synlett, 1998, 67.
13 H. Nakatsuji, M. Morimoto, T. Misaki and Y. Tanabe, Tetrahedron,
2007, 50, 12071.
14 teXsan for Windows version 1.06: Crystal Structure Analysis Package,
Molecular Structure Corporation, Texas, (1997–9).
5 (a) Y. Tanabe, S. Seko, Y. Nishii, T. Yoshida, N. Utsumi and G.
Suzukamo, J. Chem. Soc., Perkin Trans. 1, 1996, 2157; (b) Y. Nishii
and Y. Tanabe, J. Chem. Soc., Perkin Trans. 1, 1997, 477; (c) Y. Nishii,
T. Yoshida, H. Asano, K. Wakasugi, J. Morita, Y. Aso, E. Yoshida,
J. Motoyoshiya, H. Aoyama and Y. Tanabe, J. Org. Chem., 2005, 70,
2667; (d) T. Nagano, H. Kimoto, H. Nakatsuji, J. Motoyoshiya, H.
Aoyama, Y. Tanabe and Y. Nishii, Chem. Lett., 2007, 62; (e) Y. Nishii,
T. Nagano, H. Gotoh, R. Nagase, J. Motoyoshiya, H. Aoyama and Y.
Tanabe, Org. Lett., 2007, 9, 563, and references cited therein.
6 (a) Y. Nishii, H. Matsumura, Y. Muroya, T. Tsuchiya and Y. Tanabe,
Biosci., Biotechnol., Biochem., 1995, 59, 1355; (b) Y. Nishii, K.
Wakimura, T. Tsuchiya, S. Nakamura and Y. Tanabe, J. Chem. Soc.,
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 540–547 | 547
©