Structural Features and Asymmetric Environment of i-Pr-SPRIX Ligand

Article abstract of DOI:10.1002/chir.22467

Novel chiral diisopropyl spiro bis(isoxazoline) ligands, anti-i-Pr-SPRIX and syn-i-Pr-SPRIX, were designed and synthesized. Their catalytic utility, X-ray crystallographic analyses, and complexation studies demonstrated the structural features of tetraisopropyl spiro bis(isoxazoline) ligand, i-Pr-SPRIX, which is a prominent ligand in various enantioselective Pd catalytic processes: All i-Pr groups work in collaboration to create an effective asymmetric environment. Chirality 27:532-537, 2015.

Full text of DOI:10.1002/chir.22467

CHIRALITY 27:532–537 (2015)
Special Issue Article
Structural Features and Asymmetric Environment
of i-Pr-SPRIX Ligand
KAZUHIRO TAKENAKA, XIANJIN LIN, SHINOBU TAKIZAWA, AND HIROAKI SASAI
*
The Institute of Scientific and Industrial Research (ISIR), Osaka University, Mihogaoka, Ibaraki-shi, Osaka, Japan
ABSTRACT
Novel chiral diisopropyl spiro bis(isoxazoline) ligands, anti-i-Pr-SPRIX and syn-i-
Pr-SPRIX, were designed and synthesized. Their catalytic utility, X-ray crystallographic analyses,
and complexation studies demonstrated the structural features of tetraisopropyl spiro bis
(isoxazoline) ligand, i-Pr-SPRIX, which is a prominent ligand in various enantioselective Pd cat-
alytic processes: All i-Pr groups work in collaboration to create an effective asymmetric environ-
ment. Chirality 27:532–537, 2015. © 2015 Wiley Periodicals, Inc.
KEY WORDS: chiral ligand; spiro framework; isoxazoline; asymmetric environment; palladium;
enantioselective catalysis; oxidative cyclization
expressed as chemical shift (δ) in ppm downfield from Me4Si used as
The development of novel chiral ligands is one of the most
imperative tasks in asymmetric catalysis. Notably, chiral spiro
ligands have been attracting broad interest, as they exhibit
excellent enantioselectivity based on their entirely rigid back-
bone.1–7 We have successfully developed unique chiral spiro
ligands and have been investigating their utility. A series of
spiro bis(isoxazoline) 1, abbreviated SPRIX, are the first ex-
amples of chiral ligands possessing an isoxazoline coordina-
tion unit (Fig. 1).8 Asymmetric synthesis of SPRIX 2 has
been achieved by using an optically pure starting material.9,10
Spiro bis(isoxazole) ligands (3)11 and spiro (isoxazole-
isoxazoline) hybrid ligands (4)12,13 have also been prepared.
These chiral ligands exert a peculiar accelerative effect on
various Pd-catalyzed oxidative cyclizations stemming from the
low σ-donor ability of the isoxazoline and/or isoxazole coordina-
tion sites. For example, catalytic reactions through a Pd(II)/Pd
(IV) redox couple, which are able to realize unprecedented
transformations complementary to the conventional Pd(0)/Pd
(II) catalysis, proceed with high enantioselectivity.14–16 Re-
cently, we succeeded in the development of the cyclative
diacetoxylation of alkynyl cyclohexadienones involving an un-
usual Pd enolate umpolung.17 In addition, 5-endo-trig-type cycli-
zation of 3-alkenoic acids,18,19 oxidative allylic C À H
esterification of 4-alkenoic acids,20 and other asymmetric Pd-
catalyzed reactions21–24 are also feasible. In these processes,
i-Pr-SPRIX 1d displayed the best performance. For a
better understanding of the notable features of 1d, we de-
signed anti-i-Pr-SPRIX 1e and syn-i-Pr-SPRIX 1 f whose
stereoconfiguration at the C5 center of the isoxazoline rings
was regulated (Fig. 2). Herein, we report the preparation,
properties, and structures of these new SPRIX ligands, which
contribute to the development of more valuable SPRIX-type
chiral ligands.
an internal standard (δ = 0.00 ppm). Chemical shifts of the 13C NMR sig-
nals are reported as δ referenced to CDCl3 (δ = 77.0 ppm). Electrospray
ionization (ESI) mass spectra (MS) were recorded on a Thermo Fisher
LTQ ORBITRAP XL spectrometer. Optical rotations were measured with
a JASCO P-1030 polarimeter. High-performance liquid chromatography
(HPLC) analyses were performed on a JASCO HPLC system (JASCO
PU 2080 pump and MD-2010 UV/Vis detector). Melting points were mea-
sured with a Yanaco micro melting point apparatus model MP-S9 and
were uncorrected. Anhydrous diethyl ether, tetrahydrofuran (THF), and
toluene were purchased from Kanto Chemicals and further purified by
passage through activated alumina using a GlassContour solvent purifica-
tion system.25 Other solvents were purified prior to use by standard tech-
niques.26 p-Benzoquinone was purified by sublimation under vacuum.
Compounds 5a (CAS registry number [134287-57-3])27 and 5b (CAS reg-
istry number [101971-37-3])28 were prepared according to previously re-
ported methods. All other chemicals were purchased from commercial
suppliers and used as received. Column chromatography was performed
using Kishida Silica Gel 60 (63–200 μm). Merck silica gel 60 F254 plates
were used for TLC.
Synthetic Procedures
Diethyl 2,2-bis((E)-5-methylhex-3-enyl)malonate (7a). To a sus-
pension of NaH (60% in oil, 0.32 g, 7.9 mmol) in dimethyl sulfoxide
(DMSO) (7 mL) was added diethyl malonate (6a) (0.48 g, 3.0 mmol) at
0 °C, which was then stirred for 1 h at room temperature (rt). To this mix-
ture was added (E)-1-bromo-5-methylhex-3-ene (5a)27 solution (1.4 g,
7.9 mmol) in DMSO (3 mL). After being stirred for 24 h at 50 °C, the reac-
tion mixture was quenched with saturated aq. NH4Cl and extracted with
EtOAc. The organic layer was washed with 1 M aq. HCl and brine succes-
sively and dried over Na2SO4. The volatiles were removed by evaporation
under reduced pressure, and the residue was purified by column chroma-
tography using silica gel (hexane/EtOAc = 5/1) to give desired com-
1
pound 7a (0.73 g, 69%) as a pale yellow oil. H NMR (400 MHz, CDCl3):
δ 5.40 (dd, J = 15.6 Hz, J = 6.4 Hz, 2H), 5.31 (dt, J = 15.6 Hz, J = 6.4 Hz,
MATERIALS AND METHODS
*Correspondence to: H. Sasai, The Institute of Scientific and Industrial
Research (ISIR), Osaka University, Mihogaoka, Ibaraki-shi, Osaka 567-0047,
Japan. E-mail: sasai@sanken.osaka-u.ac.jp
Received for publication 7 March 2015; Accepted 15 April 2015
DOI: 10.1002/chir.22467
Published online 12 June 2015 in Wiley Online Library
(wileyonlinelibrary.com).
General Information
All reactions were performed with standard Schlenk techniques under
nitrogen atmosphere. 1H and 13C nuclear magnetic resonance (NMR)
spectra were recorded on a JEOL JNM-ECS400 spectrometer (400 MHz
for 1H and 100 MHz for 13C). All signals in the 1H NMR spectra were
© 2015 Wiley Periodicals, Inc.

SPIRO BIS(ISOXAZOLINE) LIGANDS
533
31.1, 26.6, 23.2, 21.0. HRMS (ESI): calcd. for C17H32NaO2: m/z 291.2300
([M + Na]+), found: m/z 291.2296.
2,2-Bis((E)-5-methylhex-3-enyl)malonaldehyde dioxime (9a). To
a solution of oxalyl chloride (1.28 g, 9.9 mmol) in CH2Cl2 (6 mL) was
slowly added DMSO (1.05 g, 13.5 mmol) at –78 °C, which was then
stirred for 30 min. While maintaining the temperature, a solution of 8a
(0.74 g, 2.6 mmol) in CH2Cl2 (7 mL) was added and stirred for additional
30 min. To this mixture was added triethylamine (2.39 g, 23.4 mmol) at
–78 °C. After being stirring for 1.5 h at rt, the reacion mixture was
quenched with saturated aq. NH4Cl and was extracted with CH2Cl2.
The organic layer was dried over Na2SO4 and concentrated. To the
crude aldehyde product were added NH2OH · HCl (0.90 g, 13 mmol)
and pyridine (5.2 mL) at 0 °C, which was then stirred for 12 d at rt (fur-
ther NH2OH · HCl (0.90 g, 13 mmol) was added after 3 d and 6 d for a
total of 2.70 g (39 mmol)). The reaction mixture was diluted with EtOAc,
and the organic layer was washed with water and brine, and dried over
Na2SO4. After evaporation of the volatiles, the residue was purified by col-
umn chromatography using silica gel (hexane/EtOAc = 5/1) to give de-
sired compound 9a (0.74 g, 88%) as a colorless oil. 1H NMR (400 MHz,
CDCl3): δ 8.59 (s, 2H), 7.40 (s, 2H), 5.39 (dd, J = 15.1 Hz, J = 6.4 Hz, 2H),
5.27 (dt, J = 15.1 Hz, J = 6.4 Hz, 2H), 2.26–2.15 (m, 2H), 2.00–1.95 (m,
4H), 1.73–1.69 (m, 4H), 0.94 (d, J = 6.4 Hz, 12H). 13C NMR (100 MHz,
CDCl3): δ 154.0, 138.3, 126.0, 45.7, 36.0, 31.0, 27.0, 22.5. HRMS (ESI):
calcd. for C17H30N2NaO2: m/z 317.2205 ([M + Na]+), found: m/z 317.2195.
Fig. 1. Structures of spiro bis(isoxazoline) ligand 1 and its derivatives.
Fig. 2. Structures of anti-i-Pr-SPRIX 1e and syn-i-Pr-SPRIX 1 f.
2H), 4.17 (q, J = 6.9 Hz, 4H), 2.25–2.17 (m, 2H), 1.96–1.92 (m, 4H),
1.89–1.84 (m, 4H), 1.24 (t, J = 6.9 Hz, 6H), 0.95 (d, J = 6.9 Hz, 12H). 13C
NMR (100 MHz, CDCl3): δ 171.7, 138.2, 125.8, 61.0, 57.2, 32.3, 31.0,
27.2, 22.5, 14.1. HRMS (ESI): calcd. for C21H36NaO4: m/z 375.2511
([M + Na]+), found: m/z 375.2502.
2,2-Bis((Z)-5-methylhex-3-enyl)malonaldehyde dioxime (9b). Ac-
cording to the procedure for the preparation of 9a, the desired compound
9b was obtained (0.63 g, 75%) as a colorless oil using oxalyl chloride
(1.37 g, 10.6 mmol), DMSO (1.13 g, 14.5 mmol), 8b (0.76 g, 2.85 mmol),
triethylamine (2.58 g, 25.2 mmol) CH2Cl2 (7 + 7 mL), NH2OH · HCl (total:
1
2.99 g, 2.97 mmol), and pyridine (5.2 mL). H NMR (400 MHz, CDCl3): δ
Bis(2,2,2-trifluoroethyl) 2,2-bis((Z)-5-methylhex-3-enyl)malonate
(7b). To a solution of bis(2,2,2-trifluoroethyl) malonate (6b) (1.4 g,
5.2 mmol), (Z)-5-methylhex-3-en-1-ol (5b)28 (1.4 g, 12.0 mmol), and Ph3P
7.44 (s, 2H), 7.28 (s, 2H), 5.23–5.14 (m, 4H), 2.59–2.50 (m, 2H), 2.07–2.01
(m, 4H), 1.73–1.69 (m, 4H), 0.93 (d, J = 6.9 Hz, 12H). 13C NMR (100 MHz,
CDCl3): δ 154.0, 138.3, 126.0, 45.7, 36.0, 30.9, 27.0, 22.5. HRMS (ESI):
calcd. for C17H30N2NaO2: m/z 317.2205 ([M + Na]+), found: m/z 317.2197.
(5.7 g, 21.8 mmol) in toluene (45 mL) was added
a solution of
1,1′-(azodicarbonyl)dipiperidine (6.0 g, 23.9 mmol) in toluene (75 mL),
which was then stirred for 13 h at 50 °C. The resulting mixture was con-
centrated, and passed through a pad of silica gel and rinsed with CH2Cl2.
The solvents were evaporated and the residue was purified by column
chromatography using silica gel (hexane/EtOAc = 10/1) to give desired
compound 7b (1.7 g, 72%) as a colorless liquid. 1H NMR (400 MHz,
CDCl3): δ 5.27–5.16 (m, 4H), 4.52 (q, J = 8.2 Hz, 4H), 2.57–2.45 (m, 2H),
2.04–1.93 (m, 8H), 0.93 (d, J = 6.9 Hz, 12H). 13C NMR (100 MHz, CDCl3):
δ 169.2, 139.0, 124.9, 122.7 (q, J = 276 Hz), 61.0 (q, J = 37.4 Hz), 57.4, 32.6,
26.5, 23.0, 22.0. HRMS (ESI): calcd. for C21H30F6NaO4: m/z 483.1946
([M + Na]+), found: m/z 483.1935.
(M,S,S)- and (P,R,R)-Anti-i-Pr-SPRIX (1e). To a solution of 9a
(0.74 g, 2.3 mmol) in CH2Cl2 (46 mL) was added aq. NaOCl (>5.0%,
7.3 mL) at 0 °C, which was then stirred for 4 d at rt. The reaction mixture
was quenched with H2O and extracted with CH2Cl2. The organic phase
was washed with brine, dried over Na2SO4, and concentrated under re-
duced pressure. The residue was purified by column chromatography
using silica gel (hexane/EtOAc = 5/1) to give the desired compound
rac-(M,S,S)-1e (0.19 g, 28%) as a white solid with a diastereomeric mix-
ture of rac-(M,R,R)-1e and rac-(M,S,R)-1e (0.44 g, 67%). Mp: 122–124 °C.
1H NMR (400 MHz, CDCl3): δ 4.01 (dd, J = 12.4 Hz, J = 7.3 Hz, 2H), 3.40
(dt, J = 12.4 Hz, J = 7.3 Hz, 2H), 2.54 (dd, J = 12.4 Hz, J = 6.9 Hz, 2H), 2.15
(dt, J = 12.4 Hz, J = 6.9 Hz, 2H), 2.05–1.94 (m, 4H), 1.82–1.72 (m, 2H), 1.05
(d, J = 6.9 Hz, 6H), 0.93 (d, J = 6.9 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ
176.3, 94.1, 56.9, 43.7, 41.5, 31.1, 27.5, 19.7, 18.6. HRMS (ESI): calcd. for
2,2-Bis((E)-5-methylhex-3-enyl)propane-1,3-diol (8a). To a solu-
tion of LiAlH4 (0.27 g, 7.0 mmol) in THF (14 mL) was added a solution
of 7a (1.21 g, 3.5 mmol) in THF (6 mL) at 0 °C. After being stirred for
4 h at rt, the reaction mixture was quenched with Na2SO4 · 10H2O and
Et2O. The resulting suspension was filtered, and the preciptate was
washed with Et2O. The combined organic layer was concentrated and
the residue was purified by column chromatography using silica gel (hex-
ane/EtOAc = 3/1) to give desired compound 8a (0.74 g, 80%) as a color-
less oil. 1H NMR (400 MHz, CDCl3): δ 5.38 (dd, J = 15.1 Hz, J = 6.4 Hz,
2H), 5.31 (dt, J = 15.1 Hz, J = 6.0 Hz, 2H), 3.62 (s, 2H), 3.49 (s, 4H),
2.25–2.13 (m, 2H), 1.92–1.86 (m, 4H), 1.30–1.25 (m, 4H), 0.92 (d,
J = 6.4 Hz, 12H). 13C NMR (100 MHz, CDCl3): δ 137.5, 127.0, 68.2, 41.0,
30.9, 30.5, 25.9, 22.5. HRMS (ESI): calcd. for C17H32NaO2: m/z 291.2300
([M + Na]+), found: m/z 291.2291.
C
17H26N2NaO2: m/z 313.1892 ([M + Na]+), found: m/z 313.1883. The enan-
tiomers were separated using a Daicel Chiralpak AD column [2 cm
Φ × 25 cm, EtOH, 8 mL/min, 223 nm]: T1 = 8 min for (P,R,R)-1e and
22
T2 = 24 min for (M,S,S)-1e. (P,R,R)-1e: [α]D
=
À242.9 (c = 0.45,
23
CHCl3). (M,S,S)-1e: [α]D = +248.6 (c = 0.57, CHCl3).
(M,S,S)- and (P,R,R)-Syn-i-Pr-SPRIX (1 f). According to the proce-
dure for the preparation of 1e, the desired compound rac-(M,S,S)-1 f
was obtained as a white solid (0.31 g, 45%) with a diastereomeric mixture
of rac-(M,R,R)-1 f and rac-(M,S,R)-1 f (0.36 g, 51%) using 9b (0.77 g,
2.4 mmol), CH2Cl2 (48 mL) and aq. NaOCl (>5.0%, 7.7 mL). Mp:
141–143 °C. 1H NMR (400 MHz, CDCl3): δ 4.12 (t, J = 10.1 Hz, 2H), 3.83
(ddd, J = 12.4 Hz, J = 10.1 Hz, J = 7.3 Hz, 2H), 2.52 (ddd, J = 12.4 Hz,
J = 5.5 Hz, J = 1.8 Hz, 2H), 2.15 (ddd, J = 12.4 Hz, J = 11.4 Hz, J = 7.3 Hz,
2H), 2.05–1.94 (m, 6H), 1.01 (d, J = 6.4 Hz, 6H), 0.79 (d, J = 6.4 Hz, 6H).
13C NMR (100 MHz, CDCl3): δ 174.0, 88.5, 57.0, 43.5, 40.3, 27.9, 24.0, 19.2,
18.9; HRMS (ESI): calcd. for C17H26N2NaO2: m/z 313.1892 ([M + Na]+),
found: m/z 313.1886. The enantiomers were separated using a Daicel
Chiralpak AD column [2 cm Φ × 25 cm, EtOH, 4 mL/min, 235 nm]:
2,2-Bis((Z)-5-methylhex-3-enyl)propane-1,3-diol (8b). According
to the procedure for the preparation of 8a, the desired compound 8b
was obtained as a white solid (0.76 g, 77%) using LiAlH4 (0.28 g,
7.4 mmol) and 7b (1.7 g , 3.7 mmol) in THF (18 + 7 mL). Mp: 62–64 °C.
1H NMR (400 MHz, CDCl3): δ 5.26–5.17 (m, 4H), 3.60 (s, 4H), 2.63–2.54
(m, 2H), 2.15 (s, 2H), 2.03–1.97 (m, 4H), 1.37–1.32 (m, 4H), 0.95 (d,
J = 6.9 Hz, 12H). 13C NMR (100 MHz, CDCl3): δ 137.9, 127.1, 69.1, 41.3,
Chirality DOI 10.1002/chir

534
TAKENAKA ET AL.
22
T1 = 16 min for (P,R,R)-1 f and T2 = 24 min for (M,S,S)-1 f. (P,R,R)-1 f: [α]D
= À115.8 (c = 0.82, CHCl3). (M,S,S)-1 f: [α]D23 = +119.4 (c = 0.13, CHCl3).
General Procedure for Enantioselective Pd(II)/Pd(IV)
Cyclization of Enyne 1013
Pd(OCOCF3)2 (2.7 mg, 8.0 μmol, 10 mol %) and SPRIX ligand (12 μmol,
15 mol %) were dissolved in a 9:1 mixture of MeCN and AcOH (0.3 mL),
which was then stirred at 25 °C for 2 h. To this solution was added
2-methylallyl phenylpropiolate (10) (16.0 mg, 0.080 mmol), PhI(OAc)2
(103 mg, 0.32 mmol), and a 9:1 mixture of MeCN and AcOH (0.5 mL).
After being stirred at 50 °C for 30 h, the reaction mixture was filtered
through a short pad of silica gel and rinsed with EtOAc. The filtrate was
concentrated under reduced pressure and the residue was purified by col-
umn chromatography using silica gel (hexane/EtOAc = 4/1) to give
1-benzoyl-5-methyl-3-oxabicyclo[3.1.0]hexan-2-one (11).
General Procedure for Enantioselective Allylic C–H
Esterification of 4-Alkenoic Acid 1214
Pd(OAc)2 (1.1 mg, 5.0 μmol, 10 mol %) and SPRIX ligand (7.5 μmol,
15 mol %) were dissolved in CH2Cl2 (0.25 mL), which was then stirred at
25 °C for 2 h. To this solution was added p-benzoquinone (10.8 mg,
0.10 mmol, 2 equiv) and 5-methyl-2,2-diphenylhex-4-enoic acid (12)
(14.0 mg, 0.050 mmol) in CH2Cl2 (0.25 mL). After being stirred at 25 °C
for 12 h, the reaction mixture was directly filtered through a short pad
of silica gel and rinsed with EtOAc. The filtrate was concentrated under
reduced pressure and the residue was purified by flash column chroma-
tography using silica gel (hexane/EtOAc = 5/1 or CH2Cl2) to give
3,3-diphenyl-5-(prop-1-en-2-yl)dihydrofuran-2(3H)-one (13).
Scheme 1. Synthesis of anti-i-Pr-SPRIX 1e. Reagents and conditions: (a)
5a (2.5 equiv), 6a (1 equiv), NaH (2.5 equiv), DMSO, 50 °C; (b) LiAlH4 (2
equiv), THF, 0 °C to rt; (c) (COCl)2 (3.8 equiv), DMSO (5.2 equiv), Et3N (9
equiv), CH2Cl2, –78 °C to rt; (d) NH2OH · HCl (15 equiv), pyridine, rt; (e)
aq. NaOCl (2.2 equiv), CH2Cl2, rt.
RESULTS AND DISCUSSION
Preparation
A key step in the preparation of SPRIX is an intramolecular
nitrile oxide cycloaddition of dioxime, which is known to be a
stereospecific reaction.29 Target compounds 1e and 1 f were
obtained using the corresponding homoallyl compounds (E)-
1-bromo-5-methylhex-3-ene (5a)27 and (Z)-5-methylhex-3-en-
1-ol (5b),28 respectively. Anti-i-Pr-SPRIX 1e was prepared
from 5a and diethyl malonate (6a) in 46% yield over five
steps: alkylation in the presence of NaH, reduction with
LiAlH4, Swern oxidation, oxime formation by treatment with
NH2OH · HCl, and intramolecular double nitrile oxide cyclo-
addition of dioxime 9a (Scheme 1). Syn-i-Pr-SPRIX 1 f was
prepared from 5b and bis(2,2,2-trifluoroethyl) malonate
(6b) in 40% overall yield, where the Mitsunobu reaction was
employed as the initial alkylation process (Scheme 2).10 In
each case, the desired rac-(M,S,S)-isomer was readily sepa-
rated from other diastereomers by column chromatography
using silica gel. The structures of rac-(M,S,S)-1e and
rac-(M,S,S)-1 f were identified by NMR spectroscopy and
MS. Stereochemistry at C5 of the isoxazoline rings was
determined on the basis of the coupling constant between
the hydrogen on C5 and the bridgehead hydrogen as well
3
as the chemical shift of C5: JHH = 12.4Hz and 94.1 ppm for
3
rac-(M,S,S)-1e, JHH = 10.1Hz and 88.5 ppm for rac-(M,S,S)-
1f.30 As with SPRIX ligands 1a–d, these compounds were sta-
ble towards acid (1 M aq. HCl), base (1 M aq. NaOH), and oxi-
dant (30% H2O2). Enantiopure materials were isolated through
optical resolution using HPLC equipped with a preparative-scale
chiral stationary phase column (Daicel Chiralpak AD).
Scheme 2. Synthesis of syn-i-Pr-SPRIX 1 f. Reagents and conditions: (a) 5b
(2.5 equiv), 6b (1 equiv), PPh3 (4.2 equiv), 1,1′-(azodicarbonyl)dipiperidine (4.6
equiv), toluene, 50 °C; (b) LiAlH4 (2 equiv), THF, 0 °C to rt; (c) (COCl)2 (3.8
equiv), DMSO (5.2 equiv), Et3N (9 equiv), CH2Cl2, –78 °C to rt; (d) NH2OH · HCl
(15 equiv), pyridine, rt; (e) aq. NaOCl (2.2 equiv), CH2Cl2, rt.
Catalytic Utility
With new SPRIX ligands 1e and 1 f in hand, we conducted
Pd-catalyzed reactions using them as well as H-SPRIX 1a and
i-Pr-SPRIX 1d to determine the effect of the i-Pr group on
asymmetric induction. These chiral ligands were first applied
Chirality DOI 10.1002/chir
to enantioselective Pd(II)/Pd(IV) cyclization of 2-methylallyl
phenylpropiolate (10), leading to bicyclic lactone 11.14 These re-
sults are summarized in Table 1. Treatment of 10 with 10 mol %

SPIRO BIS(ISOXAZOLINE) LIGANDS
535
TABLE 1. Enantioselective Pd(II)/Pd(IV) catalysis of 10
rings are vital to create an effective asymmetric environment
for the SPRIX ligand.
Structure
To gain further insight into the role of the i-Pr group, we
performed X-ray crystallographic analyses of rac-(M,S,S)-1e
and rac-(M,S,S)-1 f and compared the structures with those
of rac-(M,S,S)-1d (Figs. 3 and 4).31 Conformational differ-
ences of the i-Pr groups found in the X-ray structures are visu-
alized as a schematic in Figure 5. The i-Pr methine protons of
1e and 1 f were oriented in an antiperiplanar fashion with re-
spect to the C5–H bonds and were considered to be the most
stable conformers. Conversely, the i-Pr groups in the solid
state of 1d were located at the position rotated by ca. 120°
compared to those of 1e and 1 f. This difference can be attrib-
uted mainly to the steric repulsion between the geminal i-Pr
groups and the 3a,4,5,6-tetrahydro-3H-cyclopenta[c]isoxazole
backbone.
Entry
SPRIX Ligand
Yield (%)a
Ee (%)b
1
2
3
4
(M,S,S)-anti-i-Pr-SPRIX 1e
(M,S,S)-syn-i-Pr-SPRIX 1f
(M,S,S)-H-SPRIX 1a
63
62
72
94
32
3
4
(M,S,S)-i-Pr-SPRIX 1d
82
aDetermined by 1H NMR analysis using 1,4-dimethoxybenzene as an internal
standard.
bDetermined by HPLC analysis using a Daicel Chiralpak AS-H column.
of Pd(OCOCF3)2 and 15 mol % of (M,S,S)-anti-i-Pr-SPRIX 1e in
the presence of 4 equiv of PhI(OAc)2 in a 9:1 mixture of
AcOH and MeCN at 50 °C for 30 h gave product 11 in 63%
yield with 32% enantiomeric excess (ee) (entry 1). When
(M,S,S)-syn-i-Pr-SPRIX 1 f was used as the chiral ligand,
the selectivity was as low as 3% ee (entry 2). Similar to 1 f,
(M,S,S)-1a scarcely rendered enantioinduction under other-
wise identical conditions, most likely due to a nonselective
background reaction (entry 3). In the reaction with (M,S,
S)-1d, with four i-Pr groups, the enantiopurity of 11 was
drastically improved to 82% ee (entry 4).
H4
H1
H6
H3
H2
O1
H5
N2
O2
N1
Fig. 3. ORTEP drawing of rac-(M,S,S)-1e. Hydrogen atoms are omitted for
clarity, with the exception of methine hydrogens.
The same trend was observed for the asymmetric oxidative
allylic C À H esterification of 5-methyl-2,2-diphenylhex-4-enoic
acid (12) (Table 2).20 Thus, the reaction of 12 with a Pd
(OAc)2/(M,S,S)-1e catalyst system led to the quantitative for-
mation of γ-lactone product 13 with 34% ee, whereas an inferior
result was obtained in the presence of (M,S,S)-1f or (M,S,S)-1a
(entries 1–3). Not surprisingly, (M,S,S)-1d promoted the reac-
tion in a highly selective manner to give 13 in quantitative yield
with 76% ee (entry 4).
H1*
H1
H2*
H2
N1*
H3
O1*
N1
O1
From the above observations, i-Pr-SPRIX 1d proved to still
be the most effective ligand for Pd-catalyzed asymmetric oxi-
dative cyclizations. Hence, four i-Pr groups on the isoxazoline
H3*
Fig. 4. ORTEP drawing of rac-(M,S,S)-1 f. Hydrogen atoms are omitted for
clarity, with the exception of methine hydrogens.
TABLE 2. Enantioselective allylic C–H esterification of 12
Entry
SPRIX Ligand
Yield (%)a
Ee (%)b
1
2
3
4
(M,S,S)-anti-i-Pr-SPRIX 1e
(M,S,S)-syn-i-Pr-SPRIX 1f
(M,S,S)-H-SPRIX 1a
>98
75
37
34
27
38
76
(M,S,S)-i-Pr-SPRIX 1d
>98
aDetermined by 1H NMR analysis using acetophenone as an internal standard.
bDetermined by HPLC analysis using a Daicel Chiralpak AD-H column.
Fig. 5. Schematic for the X-ray structures of (a) rac-(M,S,S)-1e, (b) rac-(M,
S,S)-1f and, (c) rac-(M,S,S)-1d.
Chirality DOI 10.1002/chir

536
TAKENAKA ET AL.
In addition to the orientation of the i-Pr group, there was an-
other structural variation between these SPRIX ligands. Al-
though the N…N distance was nearly identical (3.131 Å for
1d, 3.213 Å for 1e and 3.124 Å for 1 f), the dihedral angle
consisting of the two C–N double bonds was found to vary
significantly depending on the substitution pattern of the i-
Pr groups. The angle for 1d was 21.1°, which was narrower
than that of 1e (32.5°) and roughly half that of 1 f (39.4°).
This angular difference was seemingly reflected in their com-
plexation behavior. On stirring 1d with Pd(OCOCF3)2 in
CH2Cl2, selective formation of the corresponding chelated
1
complex was confirmed in the H NMR spectrum (Fig. 6). A
similar tendency was observed for 1e (Fig. 7). However, for
1 f and 1a, unidentified signals also appeared along with
peaks assignable to the chelated complex, indicating their
ill-defined coordination (Figs. 8 and 9).
Based on these results, functions of the i-Pr groups in
SPRIX ligands were determined. The two i-Pr groups on the
Fig. 8. 1H NMR spectra of (a) rac-(M,S,S)-1f and (b) rac-(M,S,S)-1f + Pd
(OCOCF3)2.
Fig. 6. 1H NMR spectra of (a) rac-(M,S,S)-1d and (b) rac-(M,S,S)-1d + Pd
(OCOCF3)2.
Fig. 9. 1H NMR spectra of (a) rac-(M,S,S)-1a and (b) rac-(M,S,S)-1a + Pd
(OCOCF3)2.
same carbon atom most likely interact with each other in an
interlocking manner to construct an effective chiral pocket.
Moreover, the i-Pr group cis to the bridgehead hydrogen,
which is located at the equatorial position of the isoxazoline
ring, is believed to be necessary for chelation to a metal
through the adjustment of the C–N dihedral angle. Conse-
quently, i-Pr-SPRIX 1d, bearing four i-Pr groups, shows high
enantioselectivity in various asymmetric Pd-catalyzed
reactions.
CONCLUSION
We designed and synthesized novel SPRIX ligands, anti-
i-Pr-SPRIX 1e and syn-i-Pr-SPRIX 1 f, which possess an i-Pr
group on each of the isoxazoline donor moieties. Their cata-
lytic application, X-ray structure, and complexation behavior
analyses revealed the function of the i-Pr substituents on
the isoxazoline rings. The four i-Pr groups of 1d work cooper-
atively to create an effective asymmetric environment,
resulting in high enantioselectivity. Based on the present
Fig. 7. 1H NMR spectra of (a) rac-(M,S,S)-1e and (b) rac-(M,S,S)-1e + Pd
(OCOCF3)2.
Chirality DOI 10.1002/chir

SPIRO BIS(ISOXAZOLINE) LIGANDS
537
15. Takenaka K, Hashimoto S, Takizawa S, Sasai H. Chlorinative cyclization of
1,6-enynes by enantioselective palladium(II)/palladium(IV) catalysis. Adv
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study, development of a new chiral ligand superior to
i-Pr-SPRIX 1d is now in progress.
16. Takenaka K, Dhage YD, Sasai H. Enantioselective Pd(II)–Pd(IV) catalysis
ACKNOWLEDGMENTS
utilizing
a SPRIX ligand: efficient construction of chiral 3-oxy-
This study was supported by Advanced Catalytic Transforma-
tion program for Carbon utilization (ACT-C), Core Research
for Evolutionary Science and Technology (CREST), a Grant-
in-Aid for Scientific Research from MEXT, and the JSPS
Japanese-German Graduate Externship. We thank the techni-
cal staff of the ISIR Comprehensive Analysis Center at Osaka
University for assistance.
tetrahydrofurans. Chem Commun 2013;49:11224–11226.
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diacetoxylation of alkynyl cyclohexadienones promoted by a Pd/SPRIX
catalyst. Angew Chem Int Ed 2014;53:4675–4679.
18. Bajracharya GB, Koranne PS, Nadaf RN, Gabr RKM, Takenaka K,
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