Synthesis of novel cyclohexanediol-derived chiral phosphite ligands and their application in the Cu-catalyzed conjugate addition of organozinc to cyclic enones

Article abstract of DOI:10.1016/j.cclet.2015.10.009

A series of novel chiral diphosphite ligands have been synthesized from (1R,2R)-trans-1,2-cyclohexanediol, (1S,2S)-trans-1,2-cyclohexanediol, racemic trans-1,2-cyclohexanediol and chlorophosphoric acid diary ester, and were successfully employed in the Cu

Full text of DOI:10.1016/j.cclet.2015.10.009

G Model
CCLET-3456; No. of Pages 6
Chinese Chemical Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Synthesis of novel cyclohexanediol-derived chiral phosphite
ligands and their application in the Cu-catalyzed conjugate
addition of organozinc to cyclic enones
a,b
a
a,
Zeng-Bo Pang , Hai-Feng Li , Lai-Lai Wang *
a
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China
b
University of Chinese Academy of Sciences, Beijing 100039, China
A R T I C L E I N F O
A B S T R A C T
A series of novel chiral diphosphite ligands have been synthesized from (1R,2R)-trans-1,2-
Article history:
Received 25 August 2015
Received in revised form 1 October 2015
Accepted 13 October 2015
Available online xxx
cyclohexanediol, (1S,2S)-trans-1,2-cyclohexanediol, racemic trans-1,2-cyclohexanediol and chloropho-
sphoric acid diary ester, and were successfully employed in the Cu-catalyzed asymmetric 1,4-conjugate
0
addition of diethylzinc to cyclohexenone with up to 99% ee. It was found that ligand 1,2-bis[(R)-1,1 -
0
binaphthyl-2,2 -diyl]phosphitecyclohexanediol 6a derived from racemic diol skeleton can show similar
0
0
catalytic performance compared with ligand (1R,2R)-bis[(R)-1,1 -binaphthyl-2,2 -diyl]phosphitecyclo-
Keywords:
0
hexanediol 6a derived from enantiopure starting material. A significant dependence of stereoselectivity
Racemic and chiral cyclohexanediol
Phosphite ligands
on the type of enone and the ring size of the cyclic enone was observed. Moreover, the configuration of
the products was mainly determined by the configuration of the binaphthyl moieties of diphosphite
ligands in the 1,4-addition of cyclic enones.
Organozinc
Cyclic enones
Cu-catalyzed conjugate addition
ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
1
. Introduction
The development of efficient methodologies to provide
understand how to obtain an efficient enantiocontrol [36,37]. In
this context, the design of new ligands is still an important area of
research, thus the careful selection of a suitable alcohol backbone
has become a meaningful procedure for us.
1,2-Cyclohexanediol (CHD) is widely used in preparing
polyester, epoxy resin thinner, o-dihydroxybenzene and so on.
As an important organic intermediate, CHD has enjoyed great
success over the years in the fields of medicine, pesticides, spices
and organic synthesis [38–41]. For example, Spilling et al. [42]
optically active products has aroused great interest between
academia and industry due to the ever increasing demands for
chiral chemicals. Among the various approaches employed for this
purpose, asymmetric catalysis represents one of the most general
and attractive strategies in terms of chirality economy and
environment considerations [1,2]. The asymmetric conjugate
addition (ACA) of carbon nucleophiles to
a
,
b
-unsaturated com-
found that catalysts formed by mixing (1S,2S)-trans-1,2-cyclohex-
i
pounds is an important method for carbon–carbon bond formation
in asymmetric catalysis [3–6]. To achieve maximum chiral
multiplication, an impressive array of chiral ligands, such as
phosphoramidite [7–14], phosphite ligands [15–21], P,N-ligands
anediol 1 and Ti(O Pr)
4
at a 1.1:1 ratio proved to be effective for the
phosphonylation of cinnamaldehyde providing hydroxyphospho-
nate with good enantiomeric excesses (up to 70% ee) (Fig. 1.).
Subsequently, RajanBabu et al. [43] undertook a study of the
hydrocyanation of 1,3-dienes using bis-1,2-diphenylphosphinite 2
derived from racemic trans-1,2-cyclohexanediol, and over 95%
yield was gained. Recently, the Merc e` Rocamora group [44] used
N,N’-dibenzylcyclohexane-1,2-diamine and CHD as starting mate-
rials, and prepared enantiopure bidentate bis(diamidophosphite)
ligand 3, which is employed in Rh-catalyzed asymmetric
[
22–26] and others [27–35], have been developed to control the
stereochemistry of ACA. Among these ligands, phosphite ligands
have shown significant promise because of their facile synthetic
method, and efficiency for 1,4-addition. In spite of huge achieve-
ments in this area, however, further research is needed to
hydrogenation of methyl (Z)-
6% ee. Previous results found the CHD skeleton was successfully
applied in asymmetric catalytic reactions, and extremely useful for
a-acetamidocinnamate with up to
7
*
Corresponding author.
E-mail address: wll@licp.cas.cn (L.-L. Wang).
http://dx.doi.org/10.1016/j.cclet.2015.10.009
1
001-8417/ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Z.-B. Pang, et al., Synthesis of novel cyclohexanediol-derived chiral phosphite ligands and their
application in the Cu-catalyzed conjugate addition of organozinc to cyclic enones, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/
j.cclet.2015.10.009

G Model
CCLET-3456; No. of Pages 6
2
Z.-B. Pang et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
HO
OH
O
O
R
R
1
N
P
P
N
N
N
R
R
Ph PO
OPPh2
2
3
: R= CH2C6H5
2
Fig. 1. The representative examples of the application of trans-1,2-cyclohexanediol
in organic synthesis.
the synthesis of chiral ligands. Based on these findings and
considering the importance of the electron density at the
phosphorus atom and the configuration of the biaryl moieties in
inducing high enantioselectivity, a series of new chiral aryl
diphosphite ligands 6a through 6d using racemic trans-1,2-
cyclohexanediol as the diol skeleton were designed and synthe-
0
00
00
sized. At the same time, ligands 6a , 6a and 6b derived from
enantiopure trans-1,2-cyclohexanediol were also prepared to
compare to the asymmetric inducing ability of ligands 6a through
6
d. The results indicated that ligand 6a gave high activity (97%
yield) and enantioselectivity (97% ee) in the Cu-catalyzed ACA of
ZnEt
2
to 2-cyclohexenone. To our delight, similar results were
0
obtained (98% yield, 99% ee) when ligand 6a was used.
Scheme 1. The synthesis of diphosphite ligands derived from racemic trans-1,2-
cyclohexanediol,
cyclohexanediol.
(1R,2R)-trans-1,2-cyclohexanediol,
and
(1S,2S)-trans-1,2-
2
. Experimental
The NMR spectra were recorded on a Bruker 300 MHz, or Bruker
1
13
31
4
00 MHz spectrometer. The H and C NMR spectra were reported
= 0.00 ppm) as an internal
standard. The P NMR spectra were reported in ppm with 85%
PO as an external reference. Proton chemical shifts ( ) and
the integrated area of two singlets in the P NMR of ligands were
1.18, 1.00, 1.43 and 1.12, respectively. It is worth mentioning that
the ratio was changed slightly each time when the same ligand was
synthesized.
in parts per million (ppm) with TMS (
d
31
H
3
4
d
coupling constants (J) were reported in ppm and Hz, respectively.
Spin multiplicities were given as s (singlet), d (doublet), t (triplet)
and m (multiplet). High resolution mass spectra (HRMS) were
recorded on a Bruker microTOF-QII mass spectrometer. All the
melting points were determined on an X-4 melting point apparatus
and are uncorrected. Optical rotations were measured on a Perkin–
Elmer 241 MC polarimeter at 20 8C.
0
0
2.1.1. 1,2-bis[(R)-1,1 -binaphthyl-2,2 -diyl]phosphitecyclohexanediol
6a
To a 100 mL Schlenk flask equipped with a condenser were
added 2.0 g of (R)-binaphthol, 20 mL of toluene, and 12 mL of
PCl
3
. Under a nitrogen atmosphere the mixture was refluxed for
and toluene, the residue
20 h. After removal of the excessive PCl
3
All non-aqueous reactions and manipulations were performed
was dissolved in 20 mL of toluene, and then was transferred to
another Schlenk flask, and toluene was removed in vacuo to obtain
2
under an N atmosphere with standard Schlenk techniques.
0
0
Reactions were monitored by thin layer chromatography (TLC,
silica gel GF254 plates). Column chromatography separations were
compound (R)-1,1 -binaphthyl-2,2 -diyl-chlorophosphite (5a) as a
white powder, which was used directly in the following step
without further purification. To a stirred solution of compound 4
(87.5 mg, 0.75 mmol), compound 5a (529.3 mg, 1.51 mmol), and 4-
dimethylaminopyridine (DMAP) (18.4 mg, 0.15 mmol) in THF
conducted on silica gel (200–300 mesh). Reagents Et
and toluene were distilled with Na and benzophenone as an
indicator, and CH Cl was dried over CaH before use. The H
binaphthol was prepared according to a literature procedure
45]. All the other chemicals were obtained commercially and used
without further purification.
3 2
N, THF, Et O
2
2
2
8
-
(10 mL) at ꢀ15 8C, Et
3
N (0.32 mL) was slowly added using a
[
syringe over 1 min, and the solution was stirred at ꢀ15 8C for 0.5 h.
The mixture was then stirred at r.t. for 1 h. THF was distilled off in
vacuo, and then toluene (20 mL) was added. The solid was removed
by filtration through a pad of silica gel, and the solvent was
removed under reduced pressure. The residue was purified by flash
0
00
00
2
.1. Synthesis of diphosphites 6a–6d, 6a , 6a and 6b
As shown in Scheme 1, diphosphite ligands 6a through 6d, 6a,
chromatography (R
f
= 0.53, n-hexane:THF = 3:1, v:v), and furn-
0
0
00
6
a
and 6b were easily synthesized in one step from racemic
ished ligand 6a as a white foamy solid (169.3 mg, 30.34% yield).
0
20
1
trans-1,2-cyclohexanediol 4, (1R,2R)-trans-1,2-cyclohexanediol 4 ,
[a
]
D
ꢀ253(c 0.19, CH
2 2
Cl ); Mp 153–154 8C; H NMR (400 MHz,
(
1S,2S)-trans-1,2-cyclohexanediol 1, and chlorophosphoric acid
DMSO-d ): 8.16 (dd, 2H, J = 8.8, 6.4 Hz, Ar), 8.10–7.98 (m, 6H, Ar),
6
d
diary ester 5, which derived from 2,2’-dihydroxy-1,1’-binaphthol(-
binaphthol), and 2,2’-dihydroxy-5,5’,6,6’,7,7’,8,8’-octahydro-1,1’-
7.58 (d, 1H, J = 8.8 Hz, Ar), 7.56–7.45 (m, 7H, Ar), 7.34 (dd, 4H,
J = 12.4, 7.4 Hz, Ar), 7.27 (d, 1H, J = 8.8 Hz, Ar), 7.21 (dd, 3H, J = 8.4,
0
00
00
binaphthol (H
8
-binaphthol). Ligand 6a through 6d, 6a , 6a and 6b
2.8 Hz, Ar), 4.35–4.13 (m, 2H, CH), 2.24–2.09 (m, 1H, CH
1H, J = 12.8 Hz, CH ), 1.63 (s, 1H, CH ), 1.57–1.41 (m, 3H, CH
). C NMR (101 MHz, DMSO-d ): 148.10, 148.06,
2
), 1.91 (d,
were purified on a silica gel column under a nitrogen atmosphere
2
2
2
), 1.27
31
1
13
13
with low to general yields. The P NMR, H NMR and C NMR
were consistent with the expectation for these ligands. The ratios
of the two diastereoisomers for ligands 6a through 6d obtained by
(m, 2H, CH
2
6
d
147.94, 147.91, 147.34, 147.31, 132.45, 132.16, 131.57, 131.28,
131.22, 131.08, 130.46, 130.36, 129.06, 128.93, 127.12, 127.11,
Please cite this article in press as: Z.-B. Pang, et al., Synthesis of novel cyclohexanediol-derived chiral phosphite ligands and their
application in the Cu-catalyzed conjugate addition of organozinc to cyclic enones, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/
j.cclet.2015.10.009

G Model
CCLET-3456; No. of Pages 6
Z.-B. Pang et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
3
+
+
1
1
7
26.98, 126.39, 126.34, 125.71, 125.51, 124.07, 123.96, 123.86,
149.32. HRMS (ESI ): calcd. for C46
found: 767.1732.
H
6 2
34NaO P [M + Na] 767.1723;
23.81, 122.45, 122.35, 122.32, 122.11, 122.02, 121.95, 77.59,
31
7.38, 77.12, 76.95, 32.76, 31.96, 23.30, 22.62. P NMR (162 MHz,
+
0
0
DMSO-d
6
+
):
d
150.75, 149.31. HRMS (ESI ): calcd. for C46
H
34NaO
6
P
2
2.1.5. (1S,2S)-Bis[(S)-1,1 -binaphthyl-2,2 -diyl]phosphitecyclohexanediol
00
[
M + Na] 767.1723; found: 767.1738.
6b
Treatment of compound 1 (62.3 mg, 0.54 mmol), 5b (412.7 mg,
0
0
2
.1.2. (1R,2R)-Bis[(R)-1,1 -binaphthyl-2,2 -diyl]phosphitecyclohexanediol
1.18 mmol), and DMAP (14.4 mg, 0.12 mmol) as described for the
0
00
6
a
synthesis of ligand 6a afforded ligand 6b , which was purified by
0
Treatment of compound
507.5 mg, 1.45 mmol), and DMAP (17.7 mg, 0.15 mmol) as
described for the synthesis of ligand 6a afforded ligand 6a ,
4
(77.6 mg, 0.67 mmol), 5a
flash chromatography (R
f
= 0.50, n-hexane:THF = 3:1) to produce a
2
0
(
white solid (175.1 mg, 39.13% yield). [
a
]
D
98 (c 0.14, CH
2 2
Cl ); Mp
0
1
135–136 8C; H NMR (400 MHz, DMSO-d ): d 8.14 (d, 2H, J = 8.8 Hz,
6
which was purified by flash chromatography (R
hexane:THF = 3:1) to produce a white solid (223.2 mg, 44.77%
f
= 0.48, n-
Ar), 8.10–8.03 (m, 4H, Ar), 8.00 (d, 2H, J = 8.8 Hz, Ar), 7.57–7.47 (m,
6H, Ar), 7.44 (d, 2H, J = 8.8 Hz, Ar), 7.36 (dd, 4H, J = 15.6, 7.6 Hz, Ar),
7.26 (d, 2H, J = 8.4 Hz, Ar), 7.23–7.17 (m, 2H, Ar), 4.18 (m, 2H, CH),
2
0
1
yield). [
400 MHz, DMSO-d
J = 8.2 Hz, Ar), 7.99 (d, 2H, J = 8.8 Hz, Ar), 7.47–7.57 (m, 6H, Ar),
a
]
D
-449 (c 0.15, CH
2 2
Cl ); Mp 132–133 8C; H NMR
(
6
): d 8.14 (d, 2H, J = 8.8 Hz, Ar), 8.06 (d, 4H,
2.23–2.11 (m, 2H, CH
2
), 1.63 (s, 2H, CH
2
), 1.48 (d, 2H, J = 10.0 Hz,
1
3
CH ), 1.23 (d, 2H, J = 7.2 Hz, CH
2
2
). C NMR (101 MHz, DMSO-d ):
6
d
7
7
.44 (d, 2H, J = 8.8 Hz, Ar), 7.35 (dd, 4H, J = 15.6, 8.0 Hz, Ar), 7.25–
.29 (m, 2H, Ar), 7.22 (s, 2H, Ar), 4.17 (m, 2H, CH), 2.14 (t, 2H,
147.94, 147.33, 132.45, 132.17, 131.57, 131.29, 131.09, 130.37,
129.08, 128.93, 127.14, 127.00, 126.38, 126.34, 125.73, 125.52,
31
J = 12.0 Hz, CH
2
), 1.62 (s, 2H, CH
2
), 1.47 (d, 2H, J = 10.0 Hz, CH
2
),
124.00, 123.96, 122.45, 122.34, 77.57, 77.39, 32.76, 23.30. P NMR
1
3
+
1
1
1
1
.17–1.27 (m, 2H, CH
2
). C NMR (101 MHz, DMSO-d ): 147.94,
6
d
(162 MHz, DMSO-d
6
): d 150.72. HRMS (ESI ): calcd. for
+
47.34, 132.46, 132.17, 131.58, 131.28, 131.09, 130.36, 129.08,
28.93, 127.13, 126.98, 126.39, 126.34, 125.72, 125.68, 124.02,
C
46
H
34NaO [M + Na] 767.1723; found: 767.1733.
6 2
P
3
1
0
0
23.97, 122.45, 121.95, 77.56, 77.39, 32.75, 23.30. P NMR
2.1.6. 1,2-Bis[(R)-1,1 -H
8
-binaphthyl-2,2 -diyl]phosphitecyclohexanediol
+
(
162 MHz, DMSO-d
6
):
d
150.74. HRMS (ESI ): calcd. for
6c
+
0
0
C
46
H
34NaO
6
P
2
[M + Na] 767.1723; found: 767.1725.
(R)-1,1 -H
8
-Binaphthyl-2,2 -diyl-chlorophosphite 5c was syn-
thesized by the same procedure as 5a, and was used directly
without further purification. Treatment of compound 4 (77.9 mg,
0.67 mmol), 5c (530.0 mg, 1.48 mmol), and DMAP (18.0 mg,
0.15 mmol) as described for the synthesis of ligand 6a afforded
0 0
.1.3. (1S,2S)-Bis[(R)-1,1 -binaphthyl-2,2 -diyl]phosphitecyclohexanediol
2
00
6
a
0
Treatment of compound 4 (77.6 mg, 0.67 mmol), 5a (507.5 mg,
.45 mmol), and DMAP (17.7 mg, 0.15 mmol) as described for the
1
ligand 6c, which was purified by flash chromatography (R
f
= 0.54,
0
0
synthesis of ligand 6a afforded ligand 6a , which was purified by
flash chromatography (R = 0.48, n-hexane:THF = 3:1) to produce a
white solid (184.0 mg, 36.90% yield). [
n-hexane:toluene = 2:1) to produce a white solid (124.0 mg,
2
0
1
f
24.34% yield). [
NMR (400 MHz, DMSO-d
3H, J = 15.2, 8.0 Hz, Ar), 6.98 (d, 1H, J = 8.0 Hz, Ar), 6.86 (dd, 2H,
J = 16.0, 8.2 Hz, Ar), 4.09 (m, 2H, CH), 2.90–2.54 (m, 12H, CH ),
2.23–2.02 (m, 6H, CH ), 1.86–1.59 (m, 14H, CH ), 1.58–1.32 (m, 8H,
). C NMR (101 MHz, DMSO-d ): 146.32, 146.17, 145.83,
a
]
D
ꢀ153 (c 0.11, CH
2 2
Cl ); Mp 91–92 8C; H
2
0
a
]
D
ꢀ246 (c 0.11, CH
Mp 112–113 8C; H NMR (400 MHz, DMSO-d ): 8.17 (d, 2H,
J = 8.8 Hz, Ar), 8.09 (t, 2H, J = 6.8 Hz, Ar), 8.03 (t, 4H, J = 8.2 Hz, Ar),
.61 (d, 2H, J = 8.8 Hz, Ar), 7.51 (q, 6H, J = 6.2 Hz, Ar), 7.35 (t, 4H,
J = 8.0 Hz, Ar), 7.30–7.23 (m, 4H, Ar), 4.31 (m, 2H, CH), 1.92 (d, 2H,
J = 11.8 Hz, CH ), 1.79–1.74 (m, 1H, CH ), 1.60–1.39 (m, 5H, CH ).
C NMR (101 MHz, DMSO-d ): 148.12, 147.32, 132.46, 132.17,
2
Cl
2
);
6
): 7.13 (d, 2H, J = 8.8 Hz, Ar), 7.04 (dd,
d
1
6
d
2
7
2
2
1
3
CH
2
6
d
2
2
2
145.80, 138.37, 138.26, 137.35, 137.29, 134.99, 134.90, 133.89,
133.81, 129.84, 129.82, 129.40, 129.39, 127.75, 127.61, 127.60,
119.37, 119.23, 119.06, 118.99, 77.18, 77.15, 76.97, 76.95, 32.76,
28.83, 27.70, 27.67, 27.58, 23.39, 22.49, 22.40, 22.38, 22.32, 22.27.
1
3
6
d
1
1
7
1
31.58, 131.24, 131.10, 130.48, 129.08, 128.96, 127.12, 127.00,
26.42, 126.36, 125.54, 123.88, 123.83, 122.33, 122.13, 122.04,
3
1
31
+
7.17, 77.01, 31.99, 22.65.
P NMR (162 MHz, DMSO-d
6
):
d
6
P NMR (162 MHz, DMSO-d ): d 145.11, 142.80. HRMS (ESI ):
+
+
+
49.44. HRMS (ESI ): calcd. for C46
H34NaO
6
P
2
[M + Na] 767.1723;
calcd. for C46
H
50NaO
6
P
2
[M + Na] 783.2975; found: 767.3010.
found: 767.1738.
0
0
2
.1.7. 1,2-Bis[(S)-1,1 -H
8
-binaphthyl-2,2 -diyl]phosphitecyclohexanediol
0
0
2.1.4. 1,2-Bis[(S)-1,1 -binaphthyl-2,2 -diyl]phosphitecyclohexanediol
6d
0
0
8
-Binaphthyl-2,2 -diyl-chlorophosphite 5d was syn-
6
b
(S)-1,1 -H
thesized by the same procedure as 5a, and used directly without
further purification. Treatment of compound (64.9 mg,
0
0
(
S)-1,1 -Binaphthyl-2,2 -diyl-chlorophosphite 5b was synthe-
sized by the same procedure as 5a, and was used directly without
further purification. Treatment of compound (62.3 mg,
.54 mmol), 5b (412.7 mg, 1.18 mmol), and DMAP (14.4 mg,
.12 mmol) as described for the synthesis of ligand 6a afforded
= 0.51,
n-hexane:THF = 3:1) to produce a white solid (160.1 mg, 39.83%
4
4
0.56 mmol), 5d (500.0 mg, 1.40 mmol), and DMAP (17.1 mg,
0.14 mmol) as described for the synthesis of ligand 6a afforded
ligand 6d, which was purified by flash chromatography (R
0
0
f
= 0.45,
ligand 6b, which was purified by flash chromatography (R
f
n-hexane:toluene = 2:1) to produce a white solid (132.7 mg,
2
0
1
31.16% yield). [
NMR (400 MHz, DMSO-d
3H, J = 15.4, 8.2 Hz, Ar), 6.98 (d, 1H, J = 8.4 Hz, Ar), 6.86 (dd, 2H,
J = 16.0, 8.0 Hz, Ar), 4.10 (m, 2H, CH), 2.79 (m, 8H, CH ), 2.68–2.54
(m, 4H, CH ), 2.26–1.97 (m, 6H, CH ), 1.84–1.60 (m, 14H, CH ),
1.58–1.36 (m, 8H, CH ). C NMR (101 MHz, DMSO-d ): 146.32,
a
]
D
170 (c 0.10, CH
2 2
Cl ); Mp 105–106 8C; H
20
D
1
yield). [
a]
180 (c 0.18, CH
): 8.16 (dd, 2H, J = 8.8, 6.4 Hz, Ar), 8.05 (dt,
H, J = 22.0, 7.6 Hz, Ar), 7.59 (d, 1H, J = 8.8 Hz, Ar), 7.57–7.42 (m,
H, Ar), 7.36 (m, 4H, Ar), 7.30–7.21 (m, 4H, Ar), 4.24 (m, 2H, CH),
.15 (t, 1H, J = 12.6 Hz, CH ), 1.91 (d, 1H, J = 11.6 Hz, CH ), 1.63 (s,
H, CH ), 1.49 (d, 3H, J = 21.6 Hz, CH ), 1.25 (d, 2H, J = 12.0 Hz, CH ).
C NMR (101 MHz, DMSO-d ): 148.11, 148.06, 147.93, 147.92,
2
Cl
2
); Mp 138–139 8C; H NMR
6
): 7.13 (d, 2H, J = 8.2 Hz, Ar), 7.04 (dd,
d
(
400 MHz, DMSO-d
6
d
6
7
2
1
2
2
2
2
1
3
2
2
2
6
d
2
2
2
146.17, 145.82, 145.80, 138.37, 138.26, 137.34, 137.28, 134.99,
134.90, 133.89, 133.81, 129.84, 129.82, 129.40, 129.39, 127.75,
127.60, 119.37, 119.23, 119.05, 118.99, 77.18, 77.13, 76.97, 76.94,
32.77, 30.17, 28.83, 27.70, 27.67, 27.58, 23.39, 22.49, 22.40, 22.38,
1
3
6
d
1
1
1
1
3
47.34, 147.31, 132.45, 132.16, 131.57, 131.27, 131.22, 131.08,
30.46, 130.36, 129.06, 128.93, 127.12, 127.10, 126.97, 126.40,
26.34, 125.68, 124.02, 123.97, 123.87, 123.82, 122.45, 122.34,
22.32, 122.11, 122.02, 121.95, 77.56, 77.39, 77.15, 76.98, 32.77,
3
1
6
22.33, 22.27. P NMR (162 MHz, DMSO-d ): d145.14, 142.85. HRMS
+
+
(ESI ): calcd. for
767.3002.
46 6 2
C H50NaO P [M + Na] 783.2975; found:
3
1
6
1.98, 23.30, 22.63. P NMR (162 MHz, DMSO-d ): d 150.77,
Please cite this article in press as: Z.-B. Pang, et al., Synthesis of novel cyclohexanediol-derived chiral phosphite ligands and their
application in the Cu-catalyzed conjugate addition of organozinc to cyclic enones, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/
j.cclet.2015.10.009

G Model
CCLET-3456; No. of Pages 6
4
Z.-B. Pang et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
2
2
.2. Representative procedure for the 1,4-addition of Et
2
Zn to
2
in situ from Cu(OTf) and ligand 6a was more effective than that
-cyclohexenone 7a
from either ligands 6b, 6c, or 6d (Table 1, entries 2, 3, and 4 vs.
entry 1). It is interesting to note that the sense of enantioselectivity
was mainly determined by the configuration of the binaphthyl or
A solution of CuTc (0.005 mmol, 1.0 mg) and ligand 6a
0.005 mmol, 3.7 mg) in Et O (4 mL) was stirred for 1 h at r.t.
(
2
H
8
-binaphthyl moiety of ligands 6a through 6d from Table 1.
under nitrogen. After the solution was cooled to 0 8C, 2-
cyclohexenone 7a (0.25 mmol, 0.025 mL) was added and the
A screening of the solvents revealed that the reaction proceeded
with significantly higher enantioselectivity in coordinating sol-
vents (Et O and THF, Table 1, entries 5 and 6) than non-
coordinating solvents (toluene and CH Cl , Table 1, entries
solution was stirred for 10 min at 0 8C. Then Et
.2 mL of 1.0 mol/L solution in hexane) was added dropwise using
a syringe within 2 min. After 4 h, the reaction was quenched by
O (2 mL) and 2 mol/L HCl (2 mL), and extracted with ethyl
acetate (5 mL ꢁ 3). The combined organic layer was washed with
saturated NaHCO solution, brine, and then dried over anhydrous
Na SO , filtered, and concentrated in vacuo to obtain the crude
2
Zn (1.2 mmol,
2
1
2
2
1 and 7). This result was consistent with the observations of
Alexakis et al. [46] and Chan et al. [47] that the asymmetric
conjugate addition of diethylzinc to enones gave higher ee values
using coordinating solvents when compared to other reaction
H
2
3
2
4
2
media. Although THF leads to slightly higher ee values, Et O was
product. The conversion and the yield were determined by GC
equipped with a SE-30 column (30 m ꢁ 0.32 mm ID) using
dodecane as an internal standard. The enantiomeric excess was
determined by GC with a Chiraldex A-TA column (50 m ꢁ 0.25 mm
ID), or a CP-Chirasil-Dex CB column (25 m ꢁ 0.25 mm ID). The
absolute configuration was determined by comparison with
authentic samples.
chosen as an appropriate solvent among the solvents examined
because of the higher yield.
It is well known that the copper precursor plays a crucial role in
the high catalytic activity and enantioselectivity of these reactions
[48,49]. So the influence of the copper precursor as well as the
copper/ligand ratio on the catalytic performance was examined
(Table 2, entries 1–6). In comparison to Cu(OTf)
2
, (CuOTf)
2
ꢂC
6 6
H as
a catalytic precursor could dramatically enhance the enantios-
electivity in the presence of ligand 6a, but much lower yield was
realized (Table 2, entry 1). Interestingly, a better yield (97%) and
3
. Results and discussion
The asymmetric induction ability of the chiral phosphite
ligands was thoroughly explored in the Cu-catalyzed ACA of
diethylzinc to cyclic enones. Owing to lower sensitivity to air and
enantioselectivity (97% ee) were obtained when (CuOTf)
2
ꢂC
6 6
H was
replaced by CuTc in the presence of ligand 6a (Table 2, entry 4),
which suggested that the matched combination of CuTc and ligand
6a under the reaction conditions gave an excellent enantioselec-
tivity and chemical yield of the product 8a. An enhancement in
2
moisture, Cu(OTf) was chosen as the Cu source for the preparation
of the optically active catalysts. And 2-cyclohexenone was used as
a substrate because this reaction has been performed with a wide
range of ligands with several donor groups enabling the direct
comparison of the efficiency of various ligand systems. The
catalytic system was generated in situ by adding the corresponding
ligand to a suspension of catalyst precursor. Results for the
application of ligands 6a through 6d are shown in Table 1 (entries
Table 2
The Cu-catalyzed enantioselective conjugate addition of diethylzinc to 2-
a
cyclohexenone.
1
–4). The use of ligand 6a gave 3-ethylcyclohexanone (8a) in 29%
yield and 42% ee (R) (Table 1, entry 1). And ligand 6b, which bears
S)-binaphthyl moieties in comparison with ligand 6a, gave 12%
(
yield and 17% ee (S) (Table 1, entry 2). A 35% yield and 20% ee (R)
was gained when using 6c as the ligand (Table 1, entry 3). In
Entry
Cu precursor
L/Cu
Temp
8C)
Time
(h)
Con.
Yield
% ee
contrast, the use of ligand 6d, in which the configuration of the H
binaphthyl moiety was opposite to that of 6c, gave 17% yield and
5% ee (S) (Table 1, entry 4). It was found that the catalyst prepared
8
-
b
b
b
(
(%)
(%)
(Conf.)
1
2
3
4
5
6
7
8
9
(CuOTf)
Cu(OAc)
2
ꢂC
6
H
6
1
1
1
1
0.5
2
1
1
1
1
1
1
1
1
1
1
1
0
4
4
50
80
99
99
99
71
99
99
99
99
99
72
94
99
99
82
99
19
53
98
97
97
43
99
94
91
90
98
18
83
94
91
69
94
98 (R)
12 (R)
70 (R)
97 (R)
94 (R)
97 (R)
91 (R)
92 (R)
90 (R)
62 (R)
99 (R)
30 (R)
95 (R)
98 (R)
94 (R)
51 (S)
99 (R)
1
2
ꢂH
2
O
0
0
Cu(acac)
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
2
4
Table 1
0
4
The Cu-catalyzed enantioselective conjugate addition of diethylzinc to 2-
0
4
a
cyclohexenone.
0
4
20
4
ꢀ10
ꢀ20
ꢀ40
0
12
12
12
4
1
1
1
1
0
1
2
3
c
d
e
f
0
4
0
4
b
b
c
14
0
4
Entry
L.
Solvent
Con. (%)
Yield (%)
% ee (Conf.)
g
h
c
1
5
0
4
1
2
3
4
5
6
7
6a
6b
6c
6d
6a
6a
6a
Toluene
Toluene
Toluene
Toluene
THF
66
45
69
60
59
99
91
29
12
35
17
19
69
61
42 (R)
17 (S)
20 (R)
15 (S)
54 (R)
52 (R)
37 (R)
16
17
0
4
0
2
a
Reaction conditions: Cu precursor (0.005 mmol), ligand 6a (0.0025–
Zn (1.0 mol/L in hexane, 0.6 mmol), 7a (0.25 mmol), Et O (4 mL),
40–20 8C, 4–12 h.
0
.01 mmol), Et
2
2
ꢀ
Et
CH
2
O
b
The data on conversion, yield, the enantiomeric excess, and the absolute
2 2
Cl
configuration of the product were determined by the same condition as noted in
Table 1.
a
Reaction conditions: Cu(OTf)
2
(0.005 mmol), ligand (0.005 mmol), Et
2
Zn
c
d
e
f
0
00
(
1.0 mol/L in hexane, 0.6 mmol), 7a (0.25 mmol), solvent (4 mL), 0 8C, 4 h.
Using ligand 6a .
b
The data on conversion and yield were determined by GC using dodecane as
Using ligand 6a .
0 00
internal standard with a SE-30 column (30 m ꢁ 0.32 mm I.D.).
Ligands 6a /6a = 1:2.
0 00
Ligands 6a /6a = 1:1.
c
The enantiomeric excess of compound 8a was determined by GC equipped with
g
h
0
00
a Chiraldex A-TA column (50 m ꢁ 0.25 mm I.D.). The absolute configuration of 8a
Ligands 6a /6a =2:1.
00
was determined by comparison with authentic sample.
Using ligand 6b .
Please cite this article in press as: Z.-B. Pang, et al., Synthesis of novel cyclohexanediol-derived chiral phosphite ligands and their
application in the Cu-catalyzed conjugate addition of organozinc to cyclic enones, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/
j.cclet.2015.10.009

G Model
CCLET-3456; No. of Pages 6
Z.-B. Pang et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
5
0
0
enantioselectivity was obtained when the molar ratio of ligand to
CuTc ranged from 0.5/1 to 1/1 (Table 2, entries 4 and 5). Further
increase of the ratio of ligand 6a/CuTc resulted in no obvious
change of the enantioselectivity, but the yield of the reactions
significantly decreased (Table 2, entries 4 and 6) in agreement with
our previous discovery [15]. Furthermore, the effect of reaction
temperature on the enantioselectivity was investigated and when
the temperature was decreased from 20 to 0 8C, the ee of (R)-
enantiomers improved from 91% to 97% (Table 2, entries 4 and 7).
With a further decrease of the temperature from 0 to ꢀ20 8C, a
lower yield and enantioselectivity were gained (Table 2, entries 7–
ligand 6b , unfortunately, only 51% ee (S) was received (Table 2,
entry 16). Although a standard reaction time of 4 h was chosen,
the addition reaction was nearly complete within 2 h (Table 2,
entry 17).
With the optimal reaction conditions in hand, the 1,4-addition
2
of ZnEt to 2-cyclopentenone 7b and 2-cycloheptenone 7c in the
presence of ligand 6a/CuTc was examined. It can be found that
(S)-3-ethylcyclopentanone 8b was obtained in 62% ee, while (R)-3-
ethylcycloheptanone 8c was obtained in 51% ee (Table 3, entries
1 and 2). It is interesting to note that the opposite configuration of
the product was found when using 2-cyclopentenone instead of
2-cyclohexenone as the substrate. These results indicated a
significant dependence of the enantioselectivity on the ring size
of the cyclic enones. The Cu-catalyzed asymmetric 1,4-additions of
other organozinc reagents, such as ZnMe
cyclohexenone were also assessed. Unfortunately, when Me
Ph Zn was utilized in the reaction, the enantioselectivity decreased
to 25% (R) and 64% (R), respectively (Table 3, entries 3 and 4).
Similarly, we obtained moderate enantioselectivity for 8e using
9
). When the temperature was decreased to ꢀ40 8C, the enantios-
electivity was significantly lowered to 62% (Table 2, entry 10).
From these results, we can conclude that this novel catalytic
system have shown excellent catalytic activity over a wide
temperature range (Table 2, entries 7–9).
The P spectrum of the ligand 6a in DMSO-d
singlets with parameters 150.75 and 149.31 at a 1.18:1 ratio. In
order to verify the authentic catalytic species as racemic diols in
2
and ZnPh
2
, to 2-
2
Zn or
31
6
exhibits two
2
d
p
0
00
0
0
the ligands, ligands 6a and 6a derived from enantiopure diols 4
and 1 were prepared and applied in the same reaction, up to 99% ee
R) and 30% ee (R), respectively, were obtained. No significant
changes in catalytic performance were observed by changing the
6a /CuTc as the catalyst (Table 3, entry 5).
(
4
. Conclusion
0
00
ratio of ligands 6a /6a (mol/mol) from 1/2 to 2/1 (Table 2, entries
We have developed a new class of chiral diphosphite ligands
0
1
3–15). From this we can conclude that 6a /CuTc is the actual
derived from racemic and enantiopure diol materials. These
ligands were successfully utilized in the copper-catalyzed asym-
metric conjugate addition of dialkylzincs to cyclic enones with up
to 99% ee. For substrate 2-cyclohexenone, similar catalytic
0
0
catalytic species, however, noting the effect of ligand 6a was
restrained when mixed ligands were used in the reaction. For
0
ligand 6a , the result was similar to that of catalyst 6a/CuTc. In
other words, this reaction should proceed effectively by using 6a,
performance was obtained when using ligand 6a instead of ligand
which is derived from cheaper racemic starting materials, instead
0
6a . It was proven that the configuration of products was
0
of 6a as the ligand (Table 2, entries 11 and 12 vs. entry 4).
predominately determined by the configuration of the biaryl
moieties of diphosphite ligands. Research concerning the use of
these ligands in other transition metal-catalyzed asymmetric
reactions is currently underway.
Moreover, we can also conclude that the matching combination of
(
1R,2R)-trans-1,2-cyclohexanediol and (R)-binaphthyl moieties of
0
ligand 6a was fundamental to obtaining higher enantioselectivity.
Encouraged by this conclusion, we synthesized ligand 6b to verify
0
0
the hypothesis whether there is a matching combination between
Acknowledgments
(1S,2S)-trans-1,2-cyclohexanediol and (S)-binaphthyl moieties of
We are grateful for the financial support of this work by the
National Natural Science Foundation of China (Nos. 20773147,
21073211, and 21174155).
Table 3
The Cu-catalyzed enantioselective conjugate addition of dialkylzinc to cyclic
a
enones.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2015.10.
009.
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Please cite this article in press as: Z.-B. Pang, et al., Synthesis of novel cyclohexanediol-derived chiral phosphite ligands and their
application in the Cu-catalyzed conjugate addition of organozinc to cyclic enones, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/
j.cclet.2015.10.009