Co(II)-salen catalyzed stereoselective cyclopropanation of fluorinated styrenes

Article abstract of DOI:10.1002/chir.23144

Three cis-selective Co(II)-salen complexes have been developed for the asymmetric cyclopropanation of para-fluorinated styrenes with ethyl diazoacetate. Increasing the steric reach of the C₂-symmetric ligand side chains improved the enantiomeric ratio of the reaction from 28:1 to 66:1. The methodology was exemplified by the gram-scale synthesis of a lead compound for the treatment of castration-resistant prostate cancer (CRPC), as well as a structurally related analog.

Full text of DOI:10.1002/chir.23144

Received: 20 July 2019
DOI: 10.1002/chir.23144
Revised: 10 October 2019
Accepted: 13 October 2019
S P E C I A L I S S U E A R T I C L E
Co(II)‐salen catalyzed stereoselective cyclopropanation of
fluorinated styrenes
Serene Tai | Taber S. Maskrey | Prasanth R. Nyalapatla | Peter Wipf
Department of Chemistry, University of
Abstract
Pittsburgh, Pittsburgh, Pennsylvania
Three cis‐selective Co(II)‐salen complexes have been developed for the asym-
Correspondence
Peter Wipf, Department of Chemistry,
metric cyclopropanation of para‐fluorinated styrenes with ethyl diazoacetate.
Increasing the steric reach of the C ‐symmetric ligand side chains improved
2
University of Pittsburgh, Pittsburgh, PA
1
5260.
the enantiomeric ratio of the reaction from 28:1 to 66:1. The methodology
was exemplified by the gram‐scale synthesis of a lead compound for the treat-
ment of castration‐resistant prostate cancer (CRPC), as well as a structurally
related analog.
Email: pwipf@pitt.edu
Funding information
U.S. Department of Defense, Grant/Award
Number: W81XWH‐15‐PCRP‐IA; UPMC
Enterprises
KEYWORDS
asymmetric synthesis, Co(II)‐salen complex, fluorinated styrenes, JJ‐450, stereoselective
cyclopropanation
1
| INTRODUCTION
Metal‐catalyzed cyclopropanation reactions have his-
torically been well investigated, and several catalysts are
1
0-12
Due to their strain and rigidity, as well as their unique
electronic properties, cyclopropanes cover a privileged
space in natural products and pharmaceuticals. Com-
pounds possessing cyclopropane rings have been clini-
cally investigated for CNS, antibacterial, and anticancer
activity, among other therapeutic roles. Cyclopropanes
are also successfully used as bioisosteres for alkenes in
pharmaceuticals, polyene natural products, and in pep-
available for both trans‐ and cis‐selective variants.
The most common cyclopropanation method involves the
reaction of a monosubstituted or disubstituted terminal
olefin with a diazocarbonyl compound. In these catalytic
cyclopropanations, a carbene is transferred to the alkene,
resulting in the generation of two new stereogenic carbons.
Diazo compounds substituted with electron‐withdrawing
groups are stable and frequently available from commer-
cial sources. Trans‐selective catalysts were introduced by
1-3
4
,5
6
7
tide mimetics. In 2016, we disclosed the structure of a
1
3
14
15
cis‐cyclopropyl carboxamide, JJ‐450, developed through
an extensive structure‐activity relationship (SAR) study,
with single digit micromolar activity in a castration‐
Nishiyama (Ru), Zhang (Ru), Sunjic (Cu), Furuta
16
17
18
19
(Rh), Woo (Fe), , Zhang (Co) , and Gallo (Co). Opti-
mizing both the ligand and metal catalyst has enabled
nearly quantitative trans‐selective transformations.
In comparison, fewer catalysts have been able to
impart synthetically useful stereoselectivities and high
8
,9
resistant prostate cancer (CRPC) model. Significantly,
the two enantiomers of the cis‐cyclopropane lead struc-
ture showed a 10‐fold difference in activity, and the8
trans‐cyclopropane was much less active (Figure 1).
Based on our goal to investigate the active enantiomer
of JJ‐450 in further SAR and preclinical studies, we
aspired to develop a convergent enantioselective synthe-
sis of the core cyclopropyl carboxamide.
20-
yields for cis‐cyclopropanations. Katsuki (Ru, Ir, Co),
23
24
25
26
Mezzetti (Ru), Kim (Ru), and Tilset (Rh) have
developed cis‐selective metal/ligand systems, but there is
still considerable room for improvement in terms of
27
overall yields and enantiomeric ratios. Furthermore, to
the best of our knowledge, a general method for the cis‐
cyclopropanation of electron‐deficient, fluorinated sty-
renes has not yet been reported.
This work is dedicated to the memory of Prof Koji Nakanishi, a true pioneer
and outstanding leader in natural products chemistry and chemical biology.
Chirality. 2019;1–14.
wileyonlinelibrary.com/journal/chir
© 2019 Wiley Periodicals, Inc.
1

2
TAI ET AL.
MHz instrument. Chemical shifts were reported in parts
per million (ppm) with the residual solvent peak used
1
13
as an internal standard, δ H/ C (Solvent): 7.26/77.16
1
(
CDCl ); 2.50/39.52 (DMSO‐d6); H NMR spectra are tab-
3
ulated as follows: chemical shift, multiplicity (br = broad,
s = singlet, d = doublet, t = triplet, q = quartet, m = mul-
tiplet, brs = broad singlet, dd = doublet of doublets, app t
FIGURE 1 Cis‐cyclopropanes (−)‐JJ‐450 and (+)‐JJ‐450 showed
IC50 = 1.7μM and 15.2μM, respectively, in a luciferase reporter
assay for the translocation of androgen receptor
=
apparent triplet), coupling constant(s), number of pro-
13
8
tons. C NMR spectra were obtained at 75, 100, or 125
MHz using a proton‐decoupled pulse sequence and are
tabulated by observed peak. HRMS (ESI+) data were
obtained on a Thermo Scientific Exactive Orbitrap LC‐
MS coupled to a Thermo Scientific Accela HPLC system
using a 2.5μM Waters XBridge C18 column (2.1 × 50
For the preparation of cis‐cyclopropanes (−)‐JJ‐450
and (+)‐JJ‐450, we considered the work of Katsuki et al
with Co(II)‐salen complexes as most relevant. The cata-
lyst shown in Figure 2 delivered excellent yields and up
to a 99:1 cis:trans ratio in the cyclopropanation of styrene
with ethyl diazoacetate on a 0.5‐mmol scale. Most impor-
tantly, the reaction afforded an enantiomeric ratio (e.r.) of
mm; 10‐min gradient elution with MeCN/H O/MeOH
2
containing 0.1% formic acid at a flow rate of 500
μL/min from 3:92:5 at 0‐0.5 minutes to 93:2:5 at 4.0
minutes, back to 3:92:5 from 6.0 to 7.5 min). Chromatog-
raphy on SiO2 (Silicycle, Silia‐P Flash Silica Gel or
SiliaFlash P60, 40‐63 μm) was used to purify crude reac-
tion mixtures. High performance liquid chromatography
22
9
6:4 to 98:2. Therefore, we selected this catalytic system
to explore an enantioselective synthesis of our lead com-
pound, (−)‐JJ‐450, and selected fluorinated analogs.
(
HPLC) analysis was performed on a Rainin instrument
2
2
| MATERIALS AND METHODS
.1 | General
with a Chiralpak AD‐H column (4.6 × 250 mm, 5 μm).
Supercritical fluid chromatography (SFC) analysis was
performed on a Mettler Toledo instrument with a
Chiralpak IC column (10 × 250 mm, 5 μm). Calculations
used Spartan 18 v.1.4.1 (Wavefunction, Inc) at the UHF 3‐
All reagents and solvents were used as received unless
otherwise specified. THF and Et O were distilled from
1
13
19
21G(*) level. For copies of H NMR, C NMR, and
F
2
sodium/benzophenone ketyl. Toluene and CH Cl were
NMR spectra of new compounds, HPLC and SFC analy-
ses with chiral stationary phases, and circular dichroism
(CD) spectra, please see the Supporting Information.
2
2
distilled over CaH . Reactions were monitored by TLC
2
analysis (precoated silica gel 60 F254 plates, 250‐μm layer
thickness) and visualization was accomplished with a
2
54/280‐nm UV light and/or by staining with KMnO4
solution (1.5‐g KMnO and 1.5‐g K CO in 100 mL of a
4
2
3
2.2 | Synthesis of Co(II)‐salen complexes
0
.1% NaOH solution), or a PMA solution (5 g
phosphomolybdic acid in 100‐mL EtOH). Melting points
were determined on a Mel‐Temp II capillary melting
point apparatus fitted with a Fluke 51 II digital
thermometer. Infrared spectra were recorded on an ATR
spectrometer. Specific rotations were determined using a
Perkin‐Elmer 241 polarimeter. Circular dichroism (CD)
spectra were recorded on a JASCO J‐815 instrument.
NMR spectra were recorded on a 300, 400, 500, or 600
2
2
.2.1 | (S)‐2′‐Hydroxy‐[1,1′‐binaphthalen]‐
‐yl trifluoromethanesulfonate (2)
General procedure A
To a mixture of (S)‐(−)‐1,1′‐binaphthalene‐2,2′‐diol (1,
5.00 g, 17.3 mmol), 4‐dimethylaminopyridine (0.254 g,
2.07 mmol) and N‐phenyl‐bis (trifluoromethanesul‐
fonimide) (6.24 g, 17.3 mmol) was added 2,4,6‐collidine
(
2.35 mL, 17.3 mmol) and anhydrous CH Cl (70 mL).
2 2
The reaction mixture was heated at reflux for 19 hours
and then cooled to room temperature. The solution was
concentrated in vacuo and purified by chromatography
on SiO (toluene) to afford 2 (4.78 g, 11.4 mmol, 66%) as
2
18
a light orange viscous oil: [α]
+ 63.5 (c 2.05, MeOH);
D
IR (CH Cl ) 3538, 3061, 1417, 1206, 1136, 931, 728, 676
2
2
−
1 1
cm ; H NMR (500 MHz, CDCl ) δ 8.13 (d, J = 9.1 Hz,
3
FIGURE
enantioselective cyclopropanation
2
Katsuki's Co‐salen catalyst for cis‐selective
1H), 8.03 (d, J = 8.2 Hz, 1H), 7.99 (d, J = 8.9 Hz, 1H),
7.90 (d, J = 8.1 Hz, 1H), 7.63‐7.60 (m, 2H), 7.46‐7.45 (m,
2
2

TAI ET AL.
3
2
H), 7.39‐7.33 (m, 2H), 7.30 (app t, J = 7.7 Hz, 1H), 7.04
2.2.4 | (R)‐2′‐(4‐(Naphthalen‐2‐yl)phenyl)‐
[1,1′‐binaphthalen]‐2‐ol (28)
13
(d, J = 8.4 Hz, 1H), 4.94 (br s, 1H); C NMR (125 MHz,
CDCl ) δ 151.8, 146.1, 133.2 (2C), 132.9, 131.6, 131.4,
3
1
1
1
29.1, 128.5, 128.3, 128.2, 127.6, 127.0, 126.4, 125.2,
According to general procedure B, (R)‐2′‐hydroxy‐[1,1′‐
binaphthalen]‐2‐yl trifluoromethanesulfonate (25, 1.05 g,
24.2, 123.8, 119.8, 118.4 (q, J C‐F = 320 Hz), 117.9,
19
22
12.1; F NMR (470 MHz, CDCl ) δ −74.3 (s, 3F).
2.51 mmol), NiCl (dppe) (26.8 mg, 0.0502 mmol), and a
3
2
THF solution of (4‐(2‐naphthyl)phenyl)magnesium bro-
mide (26, 0.34M, 14.8 mL, 5.02 mmol, 2 equiv.) afforded 28
2
0
(
0.797 g, 1.69 mmol, 67%) as a pale yellow solid: [α]
+
D
2
2
.2.2 | (R)‐2′‐Hydroxy‐[1,1′‐binaphthalen]‐
‐yl trifluoromethanesulfonate (25)
1
1
8
1
27.5 (c 0.38, CHCl ); IR (CH Cl ) 3506, 3055, 2917, 2849,
3 2 2
−1 1
620, 1597, 813, 748 cm ; H NMR (500 MHz, CDCl ) δ
3
.13 (d, J = 8.5 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.92 (s,
H), 7.84‐7.78 (m, 6H), 7.62 (dd, J = 8.6, 1.8 Hz, 1H), 7.53
According to general procedure A, (R)‐(−)‐1,1′‐
binaphthalene‐2,2′‐diol (24, 3.00 g, 17.3 mmol), 4‐
dimethylaminopyridine (0.153 g, 1.26 mmol) and N‐phe-
nyl‐bis (trifluoromethanesulfonimide) (3.78 g, 10.5 mmol)
were combined with 2,4,6‐collidine (1.42 mL, 10.5 mmol)
and anhydrous CH Cl (40 mL) to afford 25 (2.81 g, 6.72
mmol, 64%) as a yellow viscous foam: H NMR (500
MHz, CDCl ) δ 8.14 (d, J = 9.1 Hz, 1H), 8.03 (d, J = 8.3
Hz, 1H), 7.98 (d, J = 8.9 Hz, 1H), 7.88 (d, J = 8.1 Hz,
(
ddd, J = 8.1, 6.4, 1.7 Hz, 1H), 7.48‐7.43 (m, 4H), 7.36‐7.24
(
m, 6H), 7.17 (d, J = 9.0 Hz, 1H), 7.15 (d, J = 8.3 Hz, 1H),
13
4
1
1
1
1
.89 (br s, 1H); C NMR (125 MHz, CDCl ) δ 151.0, 141.1,
3
39.9, 139.4, 137.8, 134.3, 133.6, 133.3, 133.2, 132.6, 129.9,
29.5 (2C), 129.2, 128.8, 128.6, 128.3, 128.2, 128.1, 127.6,
27.2, 126.7, 126.6 (2C), 126.5, 126.4, 126.2, 125.9, 125.6,
25.3, 125.0, 123.3, 117.7, 117.3.
2
2
1
3
1
2
H), 7.63‐7.59 (m, 2H), 7.47‐7.43 (m, 2H), 7.38‐7.33 (m,
H), 7.28 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H), 7.00 (d, J = 8.3
19
2.2.5 | (R)‐2′‐(3‐(Naphthalen‐2‐yl)phenyl)‐
1,1′‐binaphthalen]‐2‐ol (29)
Hz, 1H), 4.82 (s, 1H); F NMR (470 MHz, CDCl ) δ
3
[
−
74.4 (s, 3F); HRMS (ESI) m/z calcd for C H F O S
21 14 3 4
+
28
[
M + H] 419.0559, found 419.0558.
According to general procedure B, (R)‐2′‐hydroxy‐[1,1′‐
binaphthalen]‐2‐yl trifluoromethanesulfonate (25, 1.40 g,
3
.35 mmol), NiCl (dppe) (35.7 mg, 0.0669 mmol), and a
2
2
.2.3 | (S)‐2′‐Phenyl‐[1,1′‐binaphthalen]‐2‐
THF solution of (3‐(2‐naphthyl)phenyl)magnesium bro-
mide (27, 0.45M, 14.8 mL, 6.62 mmol, 2 equiv.) in THF
ol (4)
(
5 mL) afforded 29 (1.16 g, 2.44 mmol, 73%) as a colorless
General procedure B
To a mixture of (S)‐2′‐hydroxy‐[1,1′‐binaphthalen]‐2‐yl
trifluoromethanesulfonate (2, 4.76 g, 11.4 mmol) and
20
solid: [α]
3
−6.9 (c 0.79, CHCl ); IR (CH Cl ) 3497, 3427,
3 2 2
055, 1619, 1596, 1380, 1205, 1146, 907, 731 cm ; H
D
−
1 1
NMR (500 MHz, CDCl ) δ 8.13 (d, J = 8.5 Hz, 1H), 8.03
(
=
1
3
NiCl (dppe) (0.126 g, 0.228 mmol) in anhydrous diethyl
2
d, J = 8.5 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.86 (d, J
9.0 Hz, 1H), 7.82‐7.80 (m, 2H), 7.77 (d, J = 7.5 Hz,
H), 7.73 (d, J = 8.5 Hz, 1H), 7.55 (t, J = 8.5 Hz, 1H),
ether (95 mL) under nitrogen was slowly added a solution
of phenylmagnesium bromide in Et O (3, 3.0M, 19.0 mL,
2
5
6.9 mmol, 5 equiv.). The reaction mixture was heated at
7
.49‐7.32 (m, 11H), 7.27‐7.22 (m, 1H), 7.21 (d, J = 9.0
reflux for 3 hours, cooled to room temperature, quenched
with aqueous NH Cl (60 mL) and extracted with Et O (2
1
3
Hz, 1H), 7.15 (d, J = 8.5 Hz, 1H), 4.89 (br s, 1H);
NMR (125 MHz, CDCl ) δ 151.1, 141.5, 141.3, 140.2,
1
1
1
C
4
2
3
×
60 mL). The combined organic extracts were washed
38.1, 134.8, 133.7, 133.5, 133.4, 132.6, 130.1, 129.7,
29.0, 128.9, 128.6, 128.5, 128.4 (2C), 128.3, 128.2, 128.1,
27.7, 127.6, 127.4, 127.1, 126.7, 126.6, 126.2, 126.1,
with saturated NaHCO (60 mL), brine (2 × 60 mL), dried
3
(
MgSO ), and concentrated in vacuo. Purification by
4
chromatography on SiO (1:3, hexanes:toluene) afforded
2
20
125.9, 125.6, 125.5, 125.4, 123.6, 118.1, 117.6.
4
(3.15 g, 9.09 mmol, 80%) as a pale yellow foam: [α]
D
−
10.7 (c 2.15, CHCl ); IR (CH Cl ) 3503, 3056, 1619,
3 2 2
−
1 1
1
8
596, 905, 726, 699 cm ; H NMR (500 MHz, CDCl ) δ
.08 (d, J = 8.5 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.80
3
2
1
.2.6 | (S)‐2‐(Methoxymethoxy)‐2′‐phenyl‐
,1′‐binaphthalene (5)
(d, J = 8.7 Hz, 2H), 7.71 (d, J = 8.5 Hz, 1H), 7.56‐7.53
(
m, 1H), 7.40‐7.23 (m, 5H), 7.19‐7.08 (m, 7H), 4.92 (br s,
General procedure C
To a solution of (S)‐2′‐phenyl‐[1,1′‐binaphthalen]‐2‐ol (4,
3.10 g, 8.95 mmol) in distilled CH Cl (35 mL) under
nitrogen was added N,N‐diisopropylethylamine (4.40
mL, 26.8 mmol) and chloromethyl methyl ether (2.00
13
1
1
1
1
H); C NMR (125 MHz, CDCl ) δ 151.1, 141.7, 140.9,
3
34.3, 133.3 (2C), 130.0, 129.5, 128.9, 128.8, 128.7 (3C),
28.3, 128.2, 127.8 (2C), 127.3, 127.1, 126.7, 126.5, 126.5,
25.1, 123.3, 117.8, 117.3.
2
2

4
TAI ET AL.
2
0
mL, 26.8 mmol) at room temperature. The mixture was
stirred for 24 hours, quenched with water (50 mL), and
vacuum: [α]
67.8 (c 0.58, CHCl ); IR (CH Cl ) 3054,
D
3
2
1 1
2
−
2924, 1593, 1507, 1264, 1148, 1013, 733 cm ; H NMR
extracted with CH Cl2 (2 × 50 mL). The combined
(500 MHz, CDCl ) δ 8.07 (d, J = 8.4 Hz, 1H), 7.98 (d, J =
2
3
organic extracts were washed with water (2 × 30 mL),
dried (Na SO ), and concentrated in vacuo. The crude
8.1 Hz, 1H), 7.91 (t, J = 7.4 Hz, 2H), 7.80‐7.77 (m, 3H),
7.72 (d, J = 8.4 Hz, 1H), 7.53 (d, J = 9.1 Hz, 1H), 7.48‐7.24
(m, 13H), 7.18 (d, J = 8.4 Hz, 1H), 4.96 (d, J = 7.0 Hz, 1H),
2
4
residue was purified by chromatography on SiO (19:1,
2
13
hexanes: Et O) to afford 5 (2.22 g, 5.69 g, 64%) as a white
4.80 (d, J = 7.0 Hz, 1H), 3.08 (s, 3H); C NMR (125 MHz,
2
20
solid: [α]
–60.4 (c 0.79, CHCl ); IR (CH Cl ) 3056,
CDCl ) δ 153.1, 142.6, 140.0, 139.9, 138.4, 134.9, 133.7,
D
3
2
2
3
−
1
2
954,2847, 1592, 1506, 1241, 1147, 1012, 906, 731 cm ;
133.4, 133.1, 132.6, 132.1, 129.8, 129.6, 128.3, 128.24 (3C),
128.22, 128.17, 128.1 (2C), 128.0, 127.6, 127.0, 126.9, 126.4,
126.2, 126.1, 125.9, 125.8, 125.5 (3C), 124.1, 123.3, 116.7,
95.2, 55.9; HRMS (ESI) m/z calcd for C H O Na [M +
1
H NMR (500 MHz, CDCl ) δ 8.03 (d, J = 8.5 Hz, 1H),
3
7
(
(
(
.96 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 9.1 Hz, 1H), 7.80
d, J = 8.2 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.48‐7.44
m, 2H), 7.32‐7.20 (m, 4H), 7.17‐7.14 (m, 3H), 7.05‐7.02
m, 3H), 4.92 (d, J = 7.0 Hz, 1H), 4.79 (d, J = 7.0 Hz,
38 28 2
+
Na] 539.1982, found 539.1980.
13
1
1
1
1
1
H), 3.12 (s, 3H); C NMR (125 MHz, CDCl ) δ 153.0,
3
2
.2.9 | (S)‐2‐(Methoxymethoxy)‐2′‐phenyl‐
42.2, 140.1, 134.6, 133.3, 132.9, 131.9, 129.61, 129.47,
29.0 (2C), 128.4, 128.1, 128.1, 128.0, 127.4 (2C),
26.9, 126.6, 126.5, 126.3, 125.9, 125.8, 123.9, 123.1,
16.4, 95.2, 55.8.
[
1,1′‐binaphthalene]‐3‐carbaldehyde (6)
General procedure D
To a solution of (S)‐2‐(methoxymethoxy)‐2′‐phenyl‐1,1′‐
binaphthalene (5, 2.20 g, 5.63 mmol) in THF (31 mL) at
−
78°C under nitrogen was added a solution of t‐BuLi
2
.2.7 | (R)‐2‐(Methoxymethoxy)‐2′‐(4‐
(
1.65M in pentane, 7.50 mL, 12.4 mmol) by syringe
(
naphthalen‐2‐yl)phenyl)‐1,1′‐
dropwise. The mixture was stirred for 3 hours at −78°C.
DMF (2.20 mL, 28.2 mmol) was added and the mixture
was allowed to warm to room temperature and was
stirred for an additional 1 hour. The reaction mixture
was quenched with aqueous NH Cl (50 mL) and
extracted with EtOAc (2 × 30 mL). The combined organic
layers were washed with saturated NaHCO (50 mL),
brine (50 mL), dried (Na SO ), filtered, and concentrated
in vacuo. Purification by chromatography on SiO (6:1,
hexanes: Et O) afforded 6 (2.24 g, 5.35 mmol, 95%) as
binaphthalene (30)
According to general procedure C, (R)‐2′‐(4‐(naphthalen‐2‐
yl)phenyl)‐[1,1′‐binaphthalen]‐2‐ol (28, 0.920 g, 1.95
mmol), N,N‐diisopropylethylamine (1.00 mL, 5.86 mmol)
and chloromethyl methyl ether (0.450 mL, 5.86 mmol) in
CH Cl (10 mL) provided 30 (0.700 g, 1.35 mmol, 69%) as a
4
3
2
2
20
white solid: [α]
168.5 (c 0.31, CHCl ); IR (CH Cl ) 3056,
2
4
D
3
2
2
−
1 1
2
954,2847, 1592, 1506, 1241, 1147, 1012, 906, 731 cm ; H
2
NMR (500 MHz, CDCl ) δ 8.06 (d, J = 8.5 Hz, 1H), 7.97 (d,
J = 8.2 Hz, 1H), 7.92 (s, 1H), 7.87‐7.81 (m, 5H), 7.75 (d, J =
2
3
20
an off‐white solid: [α]
23.3 (c 0.68, CHCl ); IR
3
D
(
CH Cl ) 3055, 2951, 2888, 1687, 1618, 1586, 1156, 960,
8
6
7
.5 Hz, 1H), 7.62 (dd, J = 8.6, 1.6 Hz, 1H), 7.49‐7.42 (m,
H), 7.32 (t, J = 7.0 Hz, 1H), 7.29‐7.19 (m, 6H), 4.96 (d, J =
.0 Hz, 1H), 4.84 (d, J = 7.0 Hz, 1H), 3.12 (s, 3H);
2 2
−
1 1
7
8
00 cm ; H NMR (500 MHz, CDCl ) δ 10.34 (s, 1H),
.43 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.9
3
13
C
Hz, 2H), 7.69 (d, J = 8.5 Hz, 1H), 7.50 (t, J = 7.5 Hz,
NMR (125 MHz, CDCl ) δ 152.9, 141.2, 139.5, 138.8, 138.0,
3
1
7
1
H), 7.46 (t, J = 7.4 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H),
.35‐7.24 (m, 4H), 7.10‐7.02 (m, 5H), 4.60 (d, J = 6.0 Hz,
H), 4.43 (d, J = 6.0 Hz, 1H), 2.88 (s, 3H); C NMR
1
1
34.5, 133.6, 133.2, 132.9, 132.5, 131.8, 129.6, 129.4, 129.3,
28.2 (2C), 128.1, 128.0, 127.9, 127.6, 126.8, 126.5, 126.2
1
3
(3C), 125.8, 125.7 (2C), 125.4, 125.3, 123.8, 123.0, 116.4,
(
125 MHz, CDCl ) δ 190.9, 153.2, 141.5, 140.8, 137.6,
3
9
5.0, 55.7; HRMS (ESI) m/z calcd for C H O Na [M +
38 28 2
+
1
1
1
33.2, 132.7, 131.3, 130.2, 129.3 (2C), 128.7 (4C), 128.4,
28.1, 127.5, 126.72 (2C), 126.69 (2C), 126.5, 125.9,
25.8, 99.6, 56.8.
Na] 539.1982, found 539.1981.
2
.2.8 | (R)‐2‐(Methoxymethoxy)‐2′‐(3‐
(naphthalen‐2‐yl)phenyl)‐1,1′‐
binaphthalene (31)
2.2.10 | (R)‐2‐(Methoxymethoxy)‐2′‐(4‐
(
naphthalen‐2‐yl)phenyl)‐[1,1′‐
According to general procedure C, (R)‐2′‐(3‐(naphthalen‐2‐
yl)phenyl)‐[1,1′‐binaphthalen]‐2‐ol (29, 1.13 g, 2.39 mL), N,
N‐diisopropylethylamine (1.20 mL, 7.17 mmol) and
chloromethyl methyl ether (0.540 mL, 7.17 mmol) in
CH Cl (12 mL) afforded 31 (0.856 g, 1.66 mmol, 69%) as a
binaphthalene]‐3‐carbaldehyde (32)
According to general procedure D, (R)‐2‐(methoxymethoxy)‐
2′‐(4‐(naphthalen‐2‐yl)phenyl)‐1,1′‐binaphthalene
0.650 g, 1.26 mmol), t‐BuLi (1.65M in pentane, 1.50 mL,
(30,
2
2
colorless oil that generated a foam upon drying under
2.52 mmol), DMF (0.50 mL, 6.30 mmol) and THF (7 mL)

TAI ET AL.
5
afforded 32 (0.581 g, 1.07 mmol, 85%) as an off‐white solid:
aqueous NaHCO (50 mL), filtered, and extracted with
3
20
[
α]
39.6 (c 0.42, CHCl ); IR (CH Cl ) 3055, 2953, 2887,
CH Cl2 (2 × 30 mL). The combined organic extracts
D
3
2
2
2
−1
1
688, 1618, 1586, 1499, 1156, 1069, 961, 813, 735 cm ;
were washed with water (2 × 30 mL), dried (MgSO4),
filtered, and concentrated in vacuo. Purification by
1
H NMR (500 MHz, CDCl ) δ 10.38 (s, 1H), 8.46 (s, 1H),
3
8.09 (d, J = 8.4 Hz, 1H), 8.00 (t, J = 7.7 Hz, 2H), 7.92 (s,
chromatography on SiO (3:7, hexanes:toluene) and sub-
2
1H), 7.84‐7.80 (m, 3H), 7.75 (d, J = 8.5 Hz, 1H), 7.62 (dd,
sequent recrystallization (CH Cl /hexanes) afforded 7
2
2
J = 8.6, 1.8 Hz, 1H), 7.52 (ddd, J = 8.1, 6.8, 1.2 Hz, 1H),
(1.42 g, 3.79 mmol, 71%) as a yellow crystalline solid:
20
7
4
3
1
1
1
.49‐7.40 (m, 6H), 7.35‐7.32 (m, 2H), 7.27‐7.21 (m, 3H),
[α]
55.3 (c 0.70, CHCl ); IR (CH Cl ) 3196, 3056,
D 3 2 2
−
1 1
.64 (d, J = 6.0 Hz, 1H), 4.47 (d, J = 5.5 Hz, 1H), 2.91 (s,
2848, 1655, 1630, 1340, 1292, 1115, 730 cm ; H NMR
13
H); C NMR (125 MHz, CDCl ) δ 191.1, 153.3, 140.8,
(500 MHz, CDCl ) δ 10.44 (s, 1H), 10.08 (s, 1H), 8.15
3
3
40.5, 139.4, 137.96, 137.85, 133.8, 133.4, 132.9, 132.7,
31.7, 130.5, 130.4, 129.8, 129.6, 129.5, 129.4 (2C), 129.0,
28.9, 128.6, 128.4, 128.3 (2C), 127.7, 126.9, 126.8, 126.7
(s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.2 Hz,
1H), 7.84 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.5 Hz,
1H), 7.49 (t, J = 7.3 Hz, 1H), 7.34‐7.26 (m, 4H), 7.23‐
(
5
2C), 126.6, 126.4, 126.1, 126.0 (2C), 125.7, 125.4, 99.8,
7.21 (m, 2H), 7.14 (d, J = 8.4 Hz, 1H), 7.05‐7.02 (m,
+
13
7.0; HRMS (ESI) m/z calcd for C H O Na [M + Na]
3H); C NMR (125 MHz, CDCl ) δ 196.7, 153.6, 141.8,
39
28
3
3
567.1931, found 567.1931.
140.7, 137.84, 137.78, 133.0, 132.6, 130.3, 129.8, 129.6,
1
1
28.6 (2C), 128.5, 128.3, 128.2, 127.4 (2C), 127.1, 126.6,
26.5, 126.0, 125.8, 125.4, 124.1, 121.5, 121.3; HRMS
2
(
.2.11 | (R)‐2‐(Methoxymethoxy)‐2′‐(3‐
napthalen‐2‐yl)phenyl)‐[1,1′‐
binaphthalene]‐3‐carbaldehyde (33)
‐
(
ESI) m/z calcd for C H O [M‐H] 373.1223, found
27
17 2
3
73.1219.
According
to
general
procedure
D,
(R)‐2‐
2.2.13 | (R)‐2‐Hydroxy‐2′‐(4‐(naphthalen‐
2‐yl)phenyl)‐[1,1′‐binaphthalene]‐3‐
carbaldehyde (34)
(methoxymethoxy)‐2′‐(3‐(naphthalen‐2‐yl)phenyl)‐1,1′‐
binaphthalene (31, 0.845 g, 1.64 mmol), t‐BuLi (1.65M in
pentane, 2.00 mL, 3.27 mmol), DMF (0.640 mL, 8.18
mmol) and THF (9 mL) afforded 33 (0.713 g, 1.31 mmol,
According
to
general
procedure
E,
(R)‐2‐
20
(
methoxymethoxy)‐2′‐(4‐(naphthalen‐2‐yl)phenyl)‐[1,1′‐
8
0%) as an off‐white solid: [α]
−28.5 (c 0.74, CHCl3);
D
binaphthalene]‐3‐carbaldehyde (32, 0.540 g, 0.991 mmol)
and bromotrimethylsilane (0.670 mL, 4.96 mmol) in
IR (CH Cl ) 3055, 2921, 2850, 1689, 1587, 1158, 1072,
2
2
−
1 1
9
1
8
2
7
8
6
1
1
1
1
1
64, 750 cm ; H NMR (500 MHz, CDCl ) δ 10.38 (s,
3
CH Cl (8.5 mL) afforded 34 (0.356 g, 0.711 mmol, 77%)
H), 8.49 (s, 1H), 8.10 (d, J = 8.4 Hz, 2H), 8.01 (d, J =
.2 Hz, 1H), 7.78 (t, J = 6.9 Hz, 2H), 7.71 (t, J = 7.7 Hz,
H), 7.55 (dt, J = 16.7, 8.1 Hz, 2H), 7.49‐7.41 (m, 5H),
.37‐7.32 (m, 4H), 7.28 (d, J = 4.9 Hz, 2H), 7.11 (dd, J =
.5, 1.5 Hz, 1H), 4.65 (d, J = 5.5 Hz, 1H), 4.49 (d, J =
2
2
20
as a yellow crystalline solid: [α]
−71.7 (c 1.00, CHCl3);
D
IR (CH Cl ) 3200, 3055, 2923, 2851, 1656, 1680, 1501,
2
2
−
1 1
1
339, 1291, 814, 750 cm ; H NMR (500 MHz, CDCl )
3
δ 10.47 (s, 1H), 10.10 (s, 1H), 8.19 (s, 1H), 8.08 (d, J =
.5 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.91 (s, 1H), 7.87
d, J = 7.9 Hz, 1H), 7.83‐7.80 (m, 3H), 7.72 (d, J = 8.4
13
8
(
.0 Hz, 1H), 2.91 (s, 3H); C NMR (125 MHz, CDC ) δ
l3
91.0, 153.4, 142.1, 140.9, 140.0, 138.14, 138.01, 133.7,
33.4, 132.9, 132.6, 131.6, 130.7, 130.5, 129.9, 129.71,
29.67, 129.1, 129.0, 128.50, 128.47, 128.4, 128.24,
28.23, 128.1, 127.9, 127.7, 127.0, 126.9, 126.8, 126.3,
Hz, 1H), 7.61 (dd, J = 8.6, 1.7 Hz, 1H), 7.50 (t, J = 8.0
Hz, 1H), 7.47‐7.41 (m, 4H), 7.38‐7.28 (m, 6H), 7.18 (d, J
13
=
8.4 Hz, 1H); C NMR (125 MHz, CDCl ) δ 196.9,
3
1
1
1
1
53.8, 141.2, 140.4, 139.1, 138.1 (3C), 133.8, 133.2, 132.9,
32.7, 130.6, 130.1, 129.9, 129.3 (2C), 128.8, 128.4 (3C),
28.3, 127.7, 127.3, 126.8, 126.5 (2C), 126.4, 126.2, 126.0,
26.2, 126.1, 125.9, 125.8, 125.44, 125.36, 99.9, 57.0;
+
HRMS (ESI) m/z calcd for C H O Na [M + Na]
39
28 3
5
67.1931, found 567.1940.
25.9, 125.6, 125.5, 125.4, 124.4, 121.8, 121.5; HRMS
+
(
ESI) m/z calcd for C H O [M + H] 501.1849, found
37
25 2
2
.2.12 | (S)‐2‐Hydroxy‐2′‐phenyl‐[1,1′‐
501.1849.
binaphthalene]‐3‐carbaldehyde (7)
General procedure E
A solution of (S)‐2‐(methoxymethoxy)‐2′‐phenyl‐[1,1′‐
binaphthalene]‐3‐carbaldehyde (6, 2.22 g, 5.30 mmol)
2.2.14 | (R)‐2‐Hydroxy‐2′‐(3‐(naphthalen‐
2‐yl)phenyl)‐[1,1′‐binaphthalene]‐3‐
carbaldehyde (35)
in anhydrous CH Cl2 (45 mL) under nitrogen was
2
treated with 4 Å molecular sieves (5 g) followed by
bromotrimethylsilane (3.60 mL, 26.5 mmol). The reac-
tion mixture was stirred for 1 hour, quenched with
According to general procedure E, (R)‐2‐(methoxymethoxy)‐
2′‐(3‐(naphthalen‐2‐yl)phenyl)‐[1,1′‐binaphthalene]‐3‐
carbaldehyde (33, 0.689 g, 1.27 mmol) and bromotrimethylsilane

6
TAI ET AL.
(
0.850 mL, 6.33 mmol) in CH Cl afforded 35 (0.535 g, 1.07
2.2.17 | Co(II)‐salen complex 37
2
2
20
mmol, 85%) as a yellow crystalline solid: [α] −84.7 (c 0.75,
D
CHCl ); IR (CH Cl ) 3187, 3054, 2851, 1655, 1630, 1505, 1340,
According to general procedure F, (1R,2R)‐(+)‐l,2‐
cyclohexanediamine (0.030 g, 0.26 mmol), (R)‐2‐
hydroxy‐2′‐(3‐(naphthalen‐2‐yl)phenyl)‐[1,1′‐binaphtha‐
lene]‐3‐carbaldehyde (35, 0.260 g, 0.520 mmol), and Co
3
2
1 1
2
−
1
290, 749 cm ; H NMR (500 MHz, CDCl ) δ 10.51 (s, 1H),
3
10.07 (s, 1H), 8.16 (s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 8.00 (d, J
=
8.0 Hz, 1H), 7.91 (d, J = 7.5 Hz, 1H), 7.80 (d, J = 8.0 Hz,
13
1H), 7.77‐7.74 (m, 3H), 7.56 (s, 1H), 7.53‐7.21 (m, 13H);
C
(OAc) (0.046 g, 0.26 mmol) in EtOH (16 mL) afforded
2
NMR (125 MHz, CDCl ) δ 196.9, 153.7, 142.5, 140.8, 139.7,
37 (0.254 g, 0.223 mmol, 86%) as a reddish‐brown solid:
3
20
1
1
1
1
38.3, 138.2, 138.1, 133.7, 133.2, 132.9, 132.6, 130.7, 130.2,
29.9, 128.8, 128.5, 128.3 (2C), 128.28, 128.26, 127.9, 127.8,
27.7, 127.4, 126.8, 126.3, 126.2, 126.1, 125.9, 125.7, 125.6,
25.4, 125.3, 124.4, 121.8, 121.7; HRMS (ESI) m/z calcd for
[α]
−45.7 (c 0.70, CHCl ); IR (CH Cl ) 3051, 2933,
D 3 2 2
2859, 1628, 1595, 1332, 1319, 1263, 1145, 947, 819, 795,
−
1
736 cm ; HRMS (ESI+) m/z calcd for C H CoN O
80 56 2 2
[M + H] 1135.3668, found 1135.3667.
+
C H O Na [M + Na] 523.1669, found 523.1667.
37 24 2
2
.3 | Synthesis of cis‐cyclopropanes
.3.1 | Ethyl (1S,2R)‐2‐(4‐fluorophenyl)
2.2.15 | Co(II)‐salen complex 8
2
cyclopropane‐1‐carboxylate (10)
General procedure F
To a solution of (1S,2S)‐(+)‐l,2‐cyclohexanediamine
General procedure G
(
0.180 g, 1.56 mmol) in EtOH (48 mL) was added (S)‐2‐
hydroxy‐2′‐phenyl‐[1,1′‐binaphthalene]‐3‐carbaldehyde
7, 1.17 g, 3.12 mmol), and the reaction mixture was
To a stirred solution of Co(II)‐salen complex 8 (27 mg,
.027 mmol) in THF (1 mL) was added N‐
0
(
methylimidazole (0.97M in THF, 0.050 mL, 0.053
mmol). The reaction mixture was stirred for 2 minutes,
treated with 1‐fluoro‐4‐vinylbenzene (9, 0.095 mL, 0.80
mmol) and stirred for another 3 minutes before ethyl
diazoacetate (0.064 mL, 0.53 mmol) was added. The
solution was stirred for 25 hours at 23°C and the sol-
vent was removed under reduced pressure. The crude
heated at reflux for 12 hours. The resulting light‐yellow
precipitate was filtered and dried under vacuum. This
precipitate was added to a solution of Co(OAc) (0.276
g, 1.56 mmol) in degassed EtOH (48 mL) under nitrogen.
The mixture was heated at reflux for 18 hours and then
cooled to room temperature. The resulting brown precip-
itate was filtered, washed with degassed EtOH under a
nitrogen atmosphere, and dried under vacuum to give
the corresponding Co(II)‐salen complex 8 (1.07 g, 1.21
mmol, 78%) as a dark‐brown solid: [α]
CHCl ); IR (CH Cl ) 3051, 2935, 2860, 1590, 1546, 1425,
1
calcd for C H CoN O [M + H] 883.2729, found
8
2
product was purified by chromatography on SiO (98:2,
2
hexanes: EtOAc) to afford 10 (0.0830 g, 0.399 mmol,
20
75%) as a colorless oily liquid: [α]
+ 11.4 (c 1.42,
D
20
95.7 (c 0.70,
D
CHCl ); IR (CH Cl ) 3279, 2983, 1725, 1513, 1383,
3 2 2
−
1 1
3
2
2
1228, 1182, 1154, 1096, 838 cm ; H NMR (400 MHz,
−
1
330, 1297, 1146, 952, 818, 743 cm ; HRMS (ESI+) m/z
CDCl ) δ 7.24‐7.20 (m, 2H), 6.97‐6.92 (m, 2H), 3.89 (q,
3
60
44
2
2
J = 7.1 Hz, 2H), 2.52 (q, J = 8.5 Hz, 1H), 2.06 (ddd, J
= 9.1, 7.9, 5.6 Hz, 1H), 1.66 (dt, J = 7.4, 5.4 Hz, 1H),
1.32 (td, J = 8.2, 5.1 Hz, 1H), 1.00 (t, J = 7.1 Hz, 3H);
83.2733. Note: Co (OAc) was prepared by heating Co
2
(OAc) •4H O at 80°C under vacuum for 3 hours. The
2
2
13
color of the solid turned from pink to purple.
C NMR (100 MHz, CDCl ) δ 171.0, 161.8 (d, J =
3
2
1
44.7 Hz), 132.4 (d, J = 3.1 Hz), 130.9 (d, J = 8.0 Hz),
1
9
14.8 (d, J = 21.4 Hz), 60.3, 24.8, 21.8, 14.2, 11.5;
F
NMR (376 MHz, CDCl ) δ −116.2; HRMS (ESI+) m/z
3
2.2.16 | Co(II)‐salen complex 36
calcd for C H O F [M
+
H] 209.0972, found
12
14 2
2
09.0969. The cis:trans diastereomeric ratio was deter-
According to general procedure F, (1R,2R)‐(+)‐l,2‐
cyclohexanediamine (0.030 g, 0.26 mmol), (R)‐2‐
hydroxy‐2′‐(4‐(naphthalen‐2‐yl)phenyl)‐[1,1′‐binaphtha‐
lene]‐3‐carbaldehyde (34, 0.260 g, 0.520 mmol), and
Co(OAc)2 (0.046 g, 0.26 mmol) in EtOH (16 mL)
afforded 36 (0.222 g, 0.195 mmol, 75%) as a brown solid:
1
mined to be >97:3 based on H NMR.
2.3.2 | Ethyl (1S,2R)‐2‐(4‐(trifluoromethyl)
phenyl)cyclopropane‐1‐carboxylate (15)
2
0
[
α]
−382.9 (c 0.70, CHCl ); IR (CH Cl ) 3052, 2933,
According to general procedure G, Co(II)‐salen complex
8 (0.037 g, 0.042 mmol), N‐methylimidazole (0.50M in
THF, 0.17 mL, 0.084 mmol), 1‐(trifluoromethyl)‐4‐
vinylbenzene (0.722 g, 4.19 mmol), and ethyl
D
3
2
2
2
7
859, 1630, 1563, 1535, 1442, 1384, 1337, 1263, 942, 811,
−
1
34 cm ; HRMS (ESI+) m/z calcd for C H CoN O
2
8
0
56
2
[
M + H] 1135.3668, found 1135.3676.

TAI ET AL.
7
diazoacetate (0.100 mL, 0.839 mmol) in THF (4.2 mL)
2.3.5 | (1S,2R)‐2‐(4‐(Trifluoromethyl)phe-
nyl)cyclopropane‐1‐carboxylic acid (16)
afforded 15 (0.181 g, 0.701 mmol, 84%) as a colorless
20
D
1
oil: [α]
+17.0 (c 0.36, CHCl ); H NMR (CDCl , 500
3 3
MHz) δ 7.52 (d, J = 7.6 Hz, 2H), 7.38 (d, J = 7.8 Hz,
H), 3.93‐3.84 (m, 2H), 2.59 (q, J = 8.5 Hz, 1H), 2.14
q, J = 7.6 Hz, 1H), 1.74 (q, J = 5.9 Hz, 1H), 1.40 (q,
According to general procedure H, ethyl (1S,2R)‐2‐(4‐
(trifluoromethyl)phenyl)cyclopropane‐1‐carboxylate (15,
0.180 g, 0.697 mmol) and NaOH (0.139 g, 3.49 mmol) in
MeOH (1.7 mL) afforded 16 which was carried forward
without further purification.
2
(
19
J = 7.1 Hz, 1H), 0.99 (t, J = 6.9 Hz, 3H); F NMR
CDCl , 470 MHz) δ −62.4 (s, 3F). The cis:trans diaste-
(
3
reomeric ratio was determined to be >95:5 based on
1
H NMR.
2
.3.6 | (1R,2S)‐2‐(4‐(Trifluoromethyl)phe-
nyl)cyclopropane‐1‐carboxylic acid (39)
According to general procedure H, ethyl (1R,2S)‐2‐(4‐
2
.3.3 | Ethyl (1R,2S)‐2‐(4‐(trifluoromethyl)
(
trifluoromethyl)phenyl)cyclopropane‐1‐carboxylate (38,
.095 g, 0.37 mmol) and NaOH (0.074 g, 1.8 mmol) in
phenyl)cyclopropane‐1‐carboxylate (38)
0
MeOH (1.5 mL) afforded 39 which was carried forward
without further purification.
According to general procedure G, Co(II)‐salen complex
3
6 or 37 (0.024 g, 0.021 mmol), N‐methylimidazole
(0.50M in THF, 0.085 mL, 0.042 mmol), 1‐(trifluo‐
romethyl)‐4‐vinylbenzene (0.361 g, 2.10 mmol), and ethyl
diazoacetate (0.050 mL, 0.42 mmol) in THF (2.1 mL)
afforded 38 (0.107 g, 0.416 mmol, 99%; Table 1, Entry 2)
or 38 (0.0970 g, 0.376 mmol, 90%; Table 1, Entry 3) as a
2
.3.7 | (4‐(5‐Chloro‐2‐methylphenyl)
piperazin‐1‐yl)((1S,2R)‐2‐(4‐fluorophenyl)
cyclopropyl)methanone (13, (−)‐JJ‐450)
20
1
colorless oil: [α]
−21.5 (c 0.73, CHCl3); H NMR
General procedure I
D
(
=
1
7
0
CDCl , 500 MHz) δ 7.52 (d, J = 8.1 Hz, 2H), 7.38 (d, J
8.6 Hz, 2H), 3.94‐3.85 (m, 2H), 2.59 (q, J = 8.4 Hz,
H), 2.14 (ddd, J = 9.3, 7.9, 5.7 Hz, 1H), 1.74 (dt, J =
To a stirred solution of (1S,2R)‐2‐(4‐fluorophenyl)cyclo-
propane‐1‐carboxylic acid (11, 0.069 g, 0.38 mmol) and
1‐(5‐chloro‐2‐methylphenyl)piperazine monohydrochlo‐
3
.5, 5.4 Hz, 1H), 1.39 (ddd, J = 8.6, 7.9, 5.2 Hz, 1H),
ride (12, 0.142 g, 0.570 mmol) in CH
2
Cl (3 mL) was
2
19
.99 (t, J = 7.1 Hz, 3H); F NMR (CDCl , 470 MHz) δ
added Et N (0.16 mL, 1.2 mmol) at 0°C under a nitrogen
3
3
−
62.4 (s, 3F). The cis:trans diastereomeric ratio was
atmosphere. Tripropylphosphonic anhydride (50 wt%
solution in EtOAc, 0.34 mL, 0.57 mmol) was added
dropwise. The reaction mixture was stirred at 0°C for 30
minutes, allowed to warm to 23°C and stirred for 20
hours. The solution was diluted with CH Cl (10 mL)
1
determined to be >97:3 based on H NMR for each Co
II)‐salen complex.
(
2
2
and washed with 1M HCl (10 mL). The aqueous layer
was extracted with CH Cl (2 × 10 mL), and the com-
2
2
2
.3.4 | (1S,2R)‐2‐(4‐Fluorophenyl)cyclopro-
bined organic layers were dried (Na SO ), filtered, and
2
4
pane‐1‐carboxylic acid (11)
concentrated under reduced pressure. The crude residue
General procedure H
was purified by chromatography on SiO (1:1, hexanes:
2
To a stirred solution of ethyl (1S,2R)‐2‐(4‐fluorophenyl)
cyclopropane‐1‐carboxylate (10, 0.080 g, 0.38 mmol) in
MeOH (2 mL) was added NaOH (0.077 g, 1.9 mmol) at
EtOAc) to afford (−)‐JJ‐450 (13, 0.130 g, 0.349 mmol,
20
91%) as a viscous oil: [α]
−159.4 (c 1.67, CHCl ); IR
D
3
(CH C ) 2916, 2819, 1638, 1593, 1512, 1489, 1465, 1436,
2
l2
−
1 1
2
3°C under a nitrogen atmosphere. The reaction mixture
1224, 1098, 1034, 941, 838, 815, 732 cm ; H NMR (400
was heated at 55°C for 5 hours and then cooled to 23°C.
The methanol was removed under reduced pressure,
and the residue was poured into water (5 mL) and
extracted with CH Cl (3 × 5 mL). The combined organic
MHz, CDCl ) δ 7.16‐7.10 (m, 2H), 7.06 (d, J = 8.1 Hz,
3
1H), 7.01‐6.92 (m, 3H), 6.72 (d, J = 2.0 Hz, 1H), 3.86‐
3.74 (m, 1H), 3.74‐3.57 (m, 2H), 3.40‐3.28 (m, 1H), 2.82‐
2.66 (m, 2H), 2.44 (q, J = 8.9 Hz, 1H), 2.35‐2.26 (m,
1H), 2.26‐2.14 (m, 5H), 1.82 (q, J = 5.8 Hz, 1H), 1.34
2
2
layers were discarded, and the aqueous layer was acidi-
13
fied with 4M HCl to pH > 2 and extracted with CH Cl2
(td, J = 8.4, 5.5 Hz, 1H); C NMR (100 MHz, CDCl ) δ
2
3
(
(
3 × 5 mL). The combined organic layers were dried
Na SO ) and concentrated under reduced pressure to
167.3, 161.7 (d, J = 244.9 Hz), 151.9, 133.2 (d, J = 3.1
Hz), 132.0 (d, J = 19.9 Hz), 131.0, 129.2 (d, J = 7.9 Hz),
123.7, 119.8, 115.1 (d, J = 21.3 Hz), 51.9, 51.7, 45.6, 42.3,
2
4
afford 11, which was carried forward without further
purification.
19
23.9, 23.6, 17.4, 10.8; F NMR (376 MHz, CDCl ) δ
3

8
TAI ET AL.
−
116.3; HRMS (ESI+) m/z calcd for C H ON ClF [M +
mL, 0.76 mmol), and tripropylphosphonic anhydride (50
wt% solution in EtOAc, 0.27 mL, 0.38 mmol) in CH Cl
(2.5 mL) afforded 40 (0.112 g, 0.245 mmol, 97%) as a vis-
21
23
2
H] 373.1478, found 373.1488. The enantiomeric ratio was
determined as 97:3 er by HPLC (Chiralpak AD‐H, hex-
ane:isopropanol (9:1), 23°C, 254 nm, flow rate: 1
2
2
cous oil that foamed up upon drying under vacuum:
20
1
mL/min; major isomer Rt 12.6 min; minor isomer Rt
[α]
+ 124.1 (c 0.75, MeOH); H NMR (CDCl , 500
D 3
8
1
5.3 min).
MHz) δ 7.53 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.2 Hz,
2
3
2
1
1
1
1
H), 7.25‐7.21 (m, 2H), 6.93 (s, 1H), 3.85‐3.83 (m, 1H),
.71‐3.60 (m, 2H), 3.36‐3.32 (m, 1H), 2.82‐2.74 (m, 2H),
.52 (q, J = 8.0 Hz, 1H), 2.30‐2.25 (m, 5H), 2.16‐2.12 (m,
2
.3.8 | (4‐(2‐Methyl‐5‐(trifluoromethyl)
phenyl)piperazin‐1‐yl)((1S,2R)‐2‐(4‐
trifluoromethyl)phenyl)cyclopropyl)
H), 1.92 (q, J = 6.2 Hz, 1H), 1.43 (td, J = 8.4, 5.6 Hz,
(
13
H); C NMR (CDCl , 100 MHz) δ 166.7, 151.0, 141.9,
3
methanone (18)
36.8, 131.4, 129.1 (q, J = 32 Hz), 128.8 (q, J = 32 Hz),
27.9, 125.0 (q, J = 4 Hz), 124.2 (q, J = 270 Hz), 124.1
According to general procedure I, (1S,2R)‐2‐(4‐
(
q, J = 27 Hz), 120.4 (q, J = 4 Hz), 115.8 (q, J = 4 Hz),
(
(
trifluoromethyl)phenyl)cyclopropane‐1‐carboxylic acid
16, 0.170 g, 0.738 mmol), 1‐(2‐methyl‐5‐(trifluoro‐
1
9
5
1.8, 51.5, 45.5, 42.2, 24.5, 23.9, 17.8, 11.1; F NMR
(
CDCl , 470 MHz) δ −62.47 (s, 3F), −62.53 (s,
3
methyl)phenyl)piperazine monohydrochloride (17, 0.290
g, 1.03 mmol), triethylamine (0.31 mL, 2.2 mmol), and
tripropylphosphonic anhydride (50 wt% solution in
EtOAc, 0.78 mL, 1.1 mmol) in CH Cl (7.4 mL) afforded
3
4
F); HRMS (ESI+) m/z calcd for C H F N O (M + H)
23 23 6 2
57.1709, found 457.1708. The enantiomeric ratio
was determined as 98.5:1.5 er by SFC (Chiralpak‐IC (250
10 mm); 30% MeOH, 220 nm, 7.0 mL/min, 100 bar;
Rt 3.66 min).
2
2
×
1
8 (0.249 g, 0.545 mmol, 74%) as a pale yellow oil:
20
1
[
a]
−123.5 (c 0.78, MeOH); H NMR (CDCl , 500
D 3
MHz) δ 7.54‐7.52 (m, 2H), 7.28 (t, J = 8.0 Hz, 1H), 7.26‐
.25 (m, 1H), 7.24‐7.21 (m, 2H), 6.93 (s, 1H), 3.85‐3.83
br m, 1H), 3.69‐3.67 (br m, 1H), 3.65‐3.63 (br m, 1H),
7
(
2
.4 | Gram‐scale synthesis of (1S,2R)‐cis‐
3
8
1
.34‐3.33 (br m, 1H), 2.82‐2.74 (br m, 2H), 2.53 (td, J =
.9, 7.0 Hz, 1H), 2.30‐2.26 (m, 5H), 2.16‐2.13 (br m, 1H),
.91 (q, J = 6.2 Hz, 1H), 1.43 (td, J = 8.4, 5.6 Hz, 1H);
cyclopropane
1
9
2.4.1 | Ethyl (1S,2R)‐2‐(4‐
F NMR (CDCl , 470 MHz) δ −62.5 (s, 3F), −62.5 (s,
3
(
1
pentafluorosulfanyl)phenyl)cyclopropane‐
3
4
F); HRMS (ESI+) m/z calcd for C H F N O (M + H)
57.1709, found 457.1711. The enantiomeric ratio was
23
23 6 2
‐carboxylate (20)
determined as 96.5:3.5 er by SFC (Chiralpak‐IC (250 ×
To a THF solution (5.7 mL) of Co(II)‐salen complex 8
0.167 g, 0.189 mmol) was added a THF solution of N‐
1
0 mm); 15% MeOH, 220 nm, 6.5 mL/min, 100 bar; Rt
(
6
.15 min).
methylimidazole (0.5M, 0.750 mL, 0.377 mmol). The
reaction mixture was stirred for 2 minutes, treated with
6
pentafluoro(4‐vinylphenyl)‐λ ‐sulfane (19, 1.30 g, 5.66
2
.3.9 | (4‐(2‐Methyl‐5‐(trifluoromethyl)
phenyl)piperazin‐1‐yl)((1R,2S)‐2‐(4‐
trifluoromethyl)phenyl)cyclopropyl)
mmol), stirred for another 3 minutes, and treated with
ethyl diazoacetate (87 wt% in CH Cl , 0.450 mL, 3.77
(
2
2
mmol). The reaction mixture was stirred for 24 hours
at room temperature and then concentrated in vacuo.
The residue was precipitated with hexanes and
filtered to recover the catalyst. The hexanes filtrate
was concentrated and purified by chromatography on
methanone (40)
According to general procedure I (Table 1, Entry 2),
(1R,2S)‐2‐(4‐(trifluoromethyl)phenyl)cyclopropane‐1‐car-
boxylic acid (39, 0.075 g, 0.32 mmol), 1‐(2‐methyl‐5‐
(
(
trifluoromethyl)phenyl)piperazine monohydrochloride
17, 0.119 g, 0.424 mmol), triethylamine (0.14 mL, 0.98
SiO
mmol, 92%) as a colorless oil: H NMR (CDCl , 500
3
2
(9:1, hexanes: EtOAc) to afford 20 (1.10 g, 3.47
1
mmol), and tripropylphosphonic anhydride (50 wt% solu-
tion in EtOAc, 0.35 mL, 0.49 mmol) in CH Cl (3.3 mL)
afforded 40 (0.131 g, 0.286 mmol, 88%) as a viscous oil
that foamed up upon drying under vacuum. Table 1,
Entry 3: (1R,2S)‐2‐(4‐(Trifluoromethyl)phenyl)cyclopro-
pane‐1‐carboxylic acid (39, 0.058 g, 0.25 mmol), 1‐(2‐
MHz) δ 7.64 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.2 Hz,
2H), 3.96‐3.86 (m, 2H), 2.56 (q, J = 8.4 Hz, 1H), 2.15
(ddd, J = 9.2, 8.0, 5.7 Hz, 1H), 1.73 (dt, J = 7.5, 5.5
Hz, 1H), 1.41 (td, J = 8.3, 5.2 Hz, 1H), 1.00 (t, J = 7.1
Hz, 3H); F NMR (CDCl , 470 MHz) δ 84.9 (quintet,
3
J = 150 Hz, 1F), 63.1 (d, J = 150 Hz, 4F). The cis:trans
2
2
19
methyl‐5‐(trifluoromethyl)phenyl)piperazine
drochloride (17, 0.092 g, 0.33 mmol), triethylamine (0.11
monohy‐
diastereomeric ratio was determined to be >97:3 based
on H NMR.
1

TAI ET AL.
9
2
.4.2 | (1S,2R)‐2‐(4‐(Pentafluorosulfanyl)
purified by chromatography on SiO
2
(1:1, hexanes:
phenyl)cyclopropane‐1‐carboxylic acid (21)
EtOAc) to afford 23 (1.98 g, 3.70 mmol, 87%) as a white
2
0
solid: [α]
−94.6 (c 4.69, MeOH); Mp 125.8‐127.7°C;
D
1
A solution of ethyl (1S,2R)‐2‐(4‐(pentafluorosulfanyl)phe-
nyl)cyclopropane‐1‐carboxylate (20, 1.80 g, 5.69 mmol) in
MeOH (5.5 mL) was added to a solution of NaOH (1.14 g,
H NMR (CDCl , 500 MHz) δ 7.68 (d, J = 8.8 Hz, 2H),
3
7.52 (d, J = 8.5 Hz, 1H), 7.27‐7.25 (m, 2H), 7.20 (d, J =
8.5 Hz, 1H), 6.93 (s, 1H), 3.99‐3.96 (br m, 1H), 3.74‐3.71
(br m, 1H), 3.56‐3.52 (br m, 1H), 3.23‐3.19 (br m, 1H),
2.79‐2.74 (br m, 2H), 2.49 (q, J = 8.0 Hz, 1H), 2.29‐2.22
(m, 2H), 1.98‐1.94 (br m, 1H), 1.91 (q, J = 6.2 Hz, 1H),
2
8.5 mmol) in MeOH (1.0 mL). The reaction mixture was
heated at 55°C for 5 hours, cooled to room temperature
and poured into water and extracted with CH Cl (40
mL). The combined organic layers were discarded and
the aqueous layer was acidified with 6M HCl and
extracted with CH Cl2 (3 × 30 mL). The combined
organic layers were dried (Na SO ) and concentrated
under reduced pressure to afford 21 (1.89 g, 6.10 mmol,
quant) as a pale‐yellow oil which was used in next step
without further purification.
2
2
13
1.45 (td, J = 8.4, 5.7 Hz, 1H); C NMR (CDCl , 125
3
MHz) δ 166.4, 152.6, 152.3 (t, J = 18 Hz), 142.1, 139.0,
128.4 (q, J = 5 Hz), 127.7, 126.0 (q, J = 29 Hz), 125.8 (t,
J = 5 Hz), 125.6, 124.7, 122.5 (q, J = 273 Hz), 53.8, 52.8,
2
2
4
19
45.5, 42.2, 24.8, 23.7, 11.4; F NMR (CDCl , 470 MHz)
3
δ 84.8 (quintet, J = 150 Hz, 1F), 63.3 (d, J = 150 Hz,
4F), −60.4 (s, 3F); HRMS (ESI+) m/z calcd for
C H ClF N OS (M + H) 535.0852, found 535.0852.
21
20
8 2
The enantiomeric ratio was enriched to 99:1 er after
recrystallization from CH Cl :hexanes (HPLC Chiralpak
2
2
2
.4.3 | (4‐(5‐Chloro‐2‐(trifluoromethyl)
phenyl)piperazin‐1‐yl)((1S,2R)‐2‐(4‐
pentafluorosulfanyl)phenyl)cyclopropyl)
AD‐H (4.6 × 250 mm, 5 μm); hexanes:isopropanol (9:1),
54 nm, 1.0 mL/min; Rt 12.07 min).
2
(
methanone (23)
A solution of (1S,2R)‐2‐(4‐(pentafluorosulfanyl)phenyl)
cyclopropane‐1‐carboxylic acid (21, 1.32 g, 4.26 mmol)
3 | RESULTS AND DISCUSSION
and
1‐(5‐chloro‐2‐(trifluoromethyl)phenyl)piperazine
In analogy to a protocol developed by Katsuki et al for the
22,28
monohydrochloride (22, 1.67 g, 5.54 mmol) in distilled
preparation of Co‐ and Mn‐salen complexes,
we syn-
CH Cl (43 mL) was treated with Et N (1.80 mL, 12.8
mmol) at 0°C followed by dropwise addition of
tripropylphosphonic anhydride (50 wt% in ethyl acetate,
thesized Co(II)‐salen complex 8 in seven steps and 18%
overall yield from (S)‐(−)‐1,1′‐binaphthalene‐2,2′‐diol
(Scheme 1). We expected catalyst 8 to be sufficiently reac-
tive to provide the desired product stereoselectivity even
2
2
3
4
.50 mL, 6.39 mmol). The reaction mixture was stirred
22
at 0°C for 30 minutes and allowed to warm to room tem-
perature. After 16 hours, the solution was diluted with
CH Cl (50 mL) and washed with 1M HCl (50 mL). The
with a fluorinated styrene. To test this hypothesis, we
selected the more potent enantiomer of our lead com-
8
pound, (−)‐JJ‐450, as the target compound (Scheme 2).
2
2
aqueous phase was extracted with CH Cl (2 × 50 mL)
Reaction of 1‐fluoro‐4‐vinylbenzene (9) with
commercially readily available ethyl 2‐diazoacetate in
the presence of 5 mol% of Co(II)‐salen complex 8 and
2
2
and the combined organic layers were dried (MgSO ), fil-
4
tered, and concentrated in vacuo. The crude residue was
SCHEME 1 Synthesis of Co (II)‐salen complex 8

10
TAI ET AL.
1
‐methylimidazole (NMI) provided cis‐cyclopropane 10
For further synthetic validation, we expanded
the asymmetric cyclopropanation to the preparation of
highly electron‐deficient trifluoromethylated styrene 14
(Scheme 3), and pentafluorosulfanyl styrene 19 (Scheme 4).
In the presence of salen 8, 1‐(trifluoromethyl)‐4‐
vinylbenzene (14) was converted to cis‐cyclopropane
(1S,2R)‐15 in 84% yield in a cis:trans ratio of >95:5
based on NMR analysis of the crude reaction mixture.
Saponification of 15 with sodium hydroxide provided
carboxylic acid (1S,2R)‐16 in quantitative yield. Subse-
quent coupling with 1‐(2‐methyl‐5‐(trifluoromethyl)
phenyl)piperazine monohydrochloride (17) in the pres-
ence of triethylamine and T3P furnished analog
(1S,2R)‐18 in an enantiomeric ratio of 96.5:3.5 based
on SFC analysis. Analysis was performed using a
Chiralpak‐IC column (250 × 10 mm) with 15% MeOH
modifier at a flow rate of 6.5 mL/min and monitoring
in 75% yield. NMI was added to the reaction mixture
as it was previously shown by Yamada et al. to act as
an axial donor ligand and improve both the chemical
29
and enantiomeric yields in a similar system. Saponifi-
cation of ester 10 with sodium hydroxide to carboxylic
acid 11 and coupling with 1‐(5‐chloro‐2‐methylphenyl)
piperazine monohydrochloride (12) in the presence of
triethylamine and tripropylphosphonic anhydride (T3P)
furnished target molecule 13, (−)‐JJ‐450, in 91% yield
over the two steps. The enantiomeric ratio was deter-
mined to be 97:3 by HPLC analysis and comparison to
a racemic sample on a Chiralpak AD‐H column (4.6 ×
2
50 mm, 5 μm) with the mobile phase hexanes:
isopropanol, 9:1, at a flow rate of 1 mL/min and UV
monitoring at 254 nm.
Previously, we had resolved the enantiomers in a time
consuming and costly process by chiral stationary phase
at 220 nm.
8
6
super‐critical fluid chromatography (SFC). Furthermore,
On
a
gram‐scale, pentafluoro(4‐vinylphenyl)‐λ ‐
we lost >50% of the product in this approach, and there-
fore the enantioselective cis‐cyclopropanation of 9 repre-
sented a significant advancement over the resolution
method.
sulfane (19) was reacted with ethyl 2‐diazoacetate in the
presence of 5 mol% Co(II)‐salen complex 8 and NMI to
provide cis‐cyclopropane 20 in 92% yield (Scheme 4).
Saponification of 20 with sodium hydroxide provided car-
SCHEME 2 Asymmetric synthesis of 13 ((−)‐JJ‐450) with cis‐selective Co(II)‐salen complex 8
SCHEME 3 Asymmetric synthesis of (−)‐JJ‐450 analog 18 with cis‐selective Co(II)‐salen complex 8
SCHEME 4 Asymmetric gram‐scale synthesis of (−)‐JJ‐450 analog 23 with cis‐selective Co(II)‐salen complex 8

TAI ET AL.
11
boxylic acid 21 in quantitative yield, and coupling of this
acid with 1‐(5‐chloro‐2‐(trifluoromethyl)phenyl)pipera-
zine monohydrochloride (22) in the presence of
triethylamine and tripropylphosphonic anhydride led to
desired pentafluorosulfanyl product 23 in 87% yield. The
enantiomeric ratio of this product was determined by
the previously described HPLC method to be 93:7, which
could be further improved to 99:1 by recrystallization of
desirable in order to accomplish the goal of >98%
31
purity. Accordingly, we explored more bulky ligand
designs and synthesized two additional, novel Co (II)‐
salen complexes, 36 and 37 (Scheme 5). By replacing the
phenyl substituent in 8 with the much larger (4‐(2‐
naphthyl)phenyl) and (3‐(2‐naphthyl)phenyl) groups in
36 and 37, we hypothesized that the increased bulk pro-
vided by the naphthyl substituents would further increase
cis‐selectivity and enantiomeric ratios by guiding the ester
alkyl group of the diazoacetate closer to the attacking ole-
2
3 from dichloromethane and hexanes. The absolute con-
figurations of 18 and 23 were assigned based on a com-
parison of the circular dichroism (CD) spectra to those
of 13, (‐)‐JJ‐450, and (+)‐JJ‐450, for which we have also
22
fin. For future structure‐activity relationship purposes
in biological screens, we also switched the preferred chi-
rality in these new ligands. Binaphthol triflate 25 was
obtained from binaphthol 24 and N‐phenyltriflimide in
64% yield. Nickel‐catalyzed coupling with (4‐(2‐
naphthyl)phenyl)magnesium bromide (26) or (3‐(2‐
naphthyl)phenyl)magnesium bromide (27) provided
chain‐extended naphthols 28 and 29, respectively, in
30
obtained an X‐ray crystal structure.
While an enantiomeric ratio of >9:1 is synthetically
attractive, and, as shown for compound 23, can be further
improved by crystallization, impurity profiles in pharma-
ceutical products are subject to stringent guidelines by
regulatory agencies, and >98:2 stereoisomer ratios are
SCHEME 5 Synthesis of Co(II)‐salen complexes 36 and 37 containing ligands with additional naphthyl side chains
SCHEME 6 Asymmetric synthesis of (+)‐JJ‐450 analog 40 with highly cis‐ and enantioselective Co(II)‐salen complexes 36 and 37

12
TAI ET AL.
TABLE 1 Asymmetric cyclopropanations of 14 using Co (II)‐
salen complexes 8, 36, and 37 to give cyclopropanes 15 and 38.
configurations were assigned by comparison of CD spec-
tra to those of 18 and 23. Table 1 summarizes the
results with the three salens for the asymmetric
cyclopropanation of styrene 14. Among the salen com-
plexes tested, the novel, bulky complex 36 provides a
superior yield and cis:trans ratio, as well as an excellent
Cyclopropanation Cis:Trans
a
Entry Catalyst Yield, %
Ratio
e.r.
b
c
c
1
2
3
8
36
37
84
99
90
>95:5
>97:3
>97:3
96.5:3.5
98.5:1.5
98.5:1.5
a
1
Determined by H NMR analysis of 15 and 38.
b
Absolute configuration of analyte 18 is (1S,2R).
c
Absolute configuration of analyte 40 is (1R,2S).
6
7% to 73% yield. Protection with MOM‐Cl facilitated
ortho‐formylation of 30 and 31 with DMF to give alde-
hydes 32 and 33. The MOM group was cleaved, and inter-
mediates 34 and 35 were condensed with (1R,2R)‐
cyclohexane‐1,2‐diamine, followed by treatment with Co
(
OAc) to give complexes 36 and 37.
2
In the presence of salens 36 and 37, cis‐cyclopropane
1R,2S)‐38 was obtained in 99% and 90% yield, respec-
(
tively, with a cis:trans ratio of >97:3 based on NMR
analysis (Scheme 6). Further conversion of this ester to
acid 39 and amide 40 was straightforward by routine
transformations, and delivered a product enantiomeric
ratio of 98.5:1.5 for both catalysts based on an analysis
by the previously described SFC method. Absolute
FIGURE 3 Perspective view of transition state 45
SCHEME 7 Proposed catalytic cycle
and computational ground state (42) and
transition state (45) models (UHF 3‐21G
(
*)) for the asymmetric cyclopropanation
of styrene. NMI = N‐methylimidazole

TAI ET AL.
13
enantiomeric ratio as determined by the analysis of
product amide 40. These results are also particularly
noteworthy in the context of the use of fluorinated sty-
renes, which have previously only rarely been studied
in the asymmetric cyclopropanation reaction.
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| CONCLUSION
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enantioselective cis‐cyclopropanation reaction of styrenes
with ethyl diazoacetate, utilizing Co(II)‐salen complexes
for the synthesis of the lead compound (−)‐JJ‐450 and
two highly fluorinated analogs. By switching from a phe-
nyl to a naphthyl substituent in the cobalt salen ligands
2
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6 and 37, we were able to leverage the steric bulk of
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ACKNOWLEDGMENTS
1
5. Portada T, Roje M, Raza Z, Čaplar V, Žinić M, Šunjić V. Chiral
The authors thank UPMC Enterprises and the DOD
I
macrocyclic bis (oxazoline) Cu complexes
– structure/
(W81XWH‐15‐PCRP‐IA) for partial support of this work,
stereoselectivity relationships in catalytic cyclopropanations.
and J. K. Johnson (University of Pittsburgh) for estab-
lishing the resolution route to JJ‐450 and first‐
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of Pittsburgh) for solving the X‐ray structure of (+)‐JJ‐
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14
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