Novel MOP-type H8-binaphthyl monodentate phosphite ligands and their applications in transition metal-catalyzed asymmetric 1,4-conjugate additions and hydroformylations

Article abstract of DOI:10.1016/j.tetasy.2017.01.011

A new series of monodentate phosphites based on the rigid, axially chiral monoesterified H₈-BINOL, which are easy to prepare from the readily accessible phosphorylating reagents (S_a)- or (R_a)-1,1′-binaphthyl-2,2′-diylchlorophosphite and (S_a)- or (R_a)-1,1′-H₈-binaphthyl-2,2′-diylchlorophosphite, have been synthesized. All ligands were purified on a silica gel column under a nitrogen atmosphere with moderate yields, and were white solids and air-stable at room temperature. These ligands afforded good to excellent enantioselectivities in the Cu-catalyzed 1,4-conjugate addition of 2-cyclohexenone with nucleophiles Et₂Zn (96% ee) and with Ph₂Zn (65% ee), 2-cyclopentenone with Et₂Zn (95% ee), 2-cycloheptenone with Et₂Zn (76% ee), and 5,6-dihydro-2H-pyran-2-one with Et₂Zn (90% ee). In the Rh-catalyzed asymmetric hydroformylation of styrene, these ligands showed a chemoselectivity of >99% in aldehydes, and a satisfactory branched over linear ratio (96/4). Moreover, the sense of the enantiodiscrimination of the products was mainly determined by the configuration of the BINOL-based or H₈-BINOL-based phosphocycle.

Full text of DOI:10.1016/j.tetasy.2017.01.011

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Novel MOP-type H8-binaphthyl monodentate phosphite ligands
and their applications in transition metal-catalyzed asymmetric
1,4-conjugate additions and hydroformylations
Mi Tian a,b, Zeng-bo Pang a,b, Hai-feng Li a, Lai-lai Wang a,
⇑
a State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, PR China
b University of Chinese Academy of Sciences, Beijing 100039, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of monodentate phosphites based on the rigid, axially chiral monoesterified H8-BINOL,
which are easy to prepare from the readily accessible phosphorylating reagents (Sa)- or (Ra)-1,10-binaph-
thyl-2,20-diylchlorophosphite and (Sa)- or (Ra)-1,10-H8-binaphthyl-2,20-diylchlorophosphite, have been
synthesized. All ligands were purified on a silica gel column under a nitrogen atmosphere with moderate
yields, and were white solids and air-stable at room temperature. These ligands afforded good to excel-
lent enantioselectivities in the Cu-catalyzed 1,4-conjugate addition of 2-cyclohexenone with nucle-
ophiles Et2Zn (96% ee) and with Ph2Zn (65% ee), 2-cyclopentenone with Et2Zn (95% ee), 2-
cycloheptenone with Et2Zn (76% ee), and 5,6-dihydro-2H-pyran-2-one with Et2Zn (90% ee). In the Rh-cat-
alyzed asymmetric hydroformylation of styrene, these ligands showed a chemoselectivity of >99% in
aldehydes, and a satisfactory branched over linear ratio (96/4). Moreover, the sense of the enantiodis-
crimination of the products was mainly determined by the configuration of the BINOL-based or H8-
BINOL-based phosphocycle.
Received 17 November 2016
Revised 30 December 2016
Accepted 8 January 2017
Available online xxxx
Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction
destruction, and are inexpensive.4 Five types of monodentate phos-
phite ligands La–Le (Fig. 1) have been applied in the Cu-catalyzed
The synthesis of chiral compounds plays a vital role in impor-
tant areas such as pharmaceuticals, fine chemicals, agrochemicals,
and natural product chemistry.1 Asymmetric catalysis using transi-
tion-metal/ligand complexes has emerged as the basis for a vast
array of stereoselective reactions and has become a powerful tool
for producing enantiopure compounds in modern synthetic chem-
istry.2 In this respect, the Cu-catalyzed asymmetric 1,4-conjugate
addition and the Rh-catalyzed asymmetric hydroformylation are
two types of powerful reactions for the construction of enan-
tioriched synthons for both biologically active and natural
compounds.3
Key to these reactions has been the design of simple and highly
efficient chiral ligands to achieve maximum chiral multiplication.
To date, many chiral trivalent phosphorus compounds, such as
phosphines, phosphites and phosphoromidites, have been synthe-
sized. Among the above mentioned ligands, phosphites are extre-
mely attractive because they can be simply synthesized from
readily accessible precursors, exhibit high resistance to oxidative
asymmetric 1,4-conjugate addition of 2-cyclohexenone with Et2Zn,
and afforded 30% ee,5 96% ee,6 19% ee,6,7 83% ee,8 57% ee,9 respec-
tively. However, the enantioselectivities in analogous Cu-catalyzed
asymmetric 1,4-conjugate additions of organozinc to 2-cyclopen-
tenone and 2-cycloheptenone were disappointingly low. Thus, it
is desirable to search for simple and efficient phosphite ligands,
which overcome the limitations of substrate specificity. In the
Rh-catalyzed asymmetric hydroformylation, there are only a few
reports concerning monodentate phosphite so far, because the
use of monodentate phosphorus donor usually provides only poor
to moderate enantioselectivities.7 For instance, ligand Lf (Fig. 1)
gave 38% ee, 43% ee and 8% ee in the Rh-catalyzed asymmetric
hydroformylation of styrene, allyl cyanide and vinyl acetate
respectively.10 The search for efficient chiral monodentate phos-
phite ligands in terms of high enantioselectivity remains one of
the most important goals in the Rh-catalyzed asymmetric
hydroformylation.
In 2007, Lyubimov et al. used readily accessible O-methyl-
BINOL as starting materials, and synthesized MOP-type binaphthyl
monodentate phosphite Lg (Fig. 2). This ligand was employed in the
Pd-catalyzed allylic substitution of (E)-1,3-diphenylallyl acetate
⇑
Corresponding author. Tel.: +86 931 4968161; fax: +86 931 4968129.
E-mail address: wll@licp.cas.cn (L.-l. Wang).
http://dx.doi.org/10.1016/j.tetasy.2017.01.011
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Tian, M.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.01.011

2
M. Tian et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Ph
Ph
O
Ph
EtOOC
EtOOC
O
O
O
O
O
P
O
P
O
La
Ph
Ph
Lb
O
O
O
P
N
O
P
O
O
O
Ts
O
N
Ts
tBu
Lc
tBu
Ld
O
O
R2
O
R3
R1
R1 = tBu
2 = H
O
O
R
O
O
R4
R4
O
O
P
OR
P
O
R1 = R4 = Me
R = Ph
R3
R1
R2
Lf
Le
Figure 1. Monodentate phosphite ligands for the Cu-catalyzed asymmetric 1,4-conjugate addition and the Rh-catalyzed asymmetric hydroformylation.
2. Results and discussion
X = OMe
X
2.1. Synthesis of monodentate phosphate ligands
O
P
O
The novel MOP-type monodentate phosphites were easily
O
obtained by direct phosphorylation of (Ra)- or (Sa)-20-hydroxy-
5,50,6,60,7,70,8,80-octahydro-[1,10-binaphthalen]-2-yl 4-chloroben-
zoate 2 in the presence of NEt3 in THF (Scheme 1). All of the ligands
were purified on a silica gel column under a nitrogen atmosphere
with moderate yields, and were white solids and air-stable at room
(
,
)-, ( )-Lg
Sa Sa Ra Sa
,
temperature. The 31P, 1H and 13C NMR spectra were consistent
with the expectation for these ligands.
Figure 2. Structure of MOP-type binaphthyl monodentate phosphite.
2.2. Cu-catalyzed asymmetric 1,4-conjugate addition
with sodium p-toluenesulfinate (99% ee), pyrrolidine (97% ee),
dipropylamine (95% ee), dimethyl malonate (99% ee), in the Pd-cat-
alyzed deracemization of ethyl (E)-1,3-diphenylallyl carbonate
with 96% ee, and in the Rh-catalyzed hydrogenation of dimethyl
itaconate with 90% ee.11 Inspired by this excellent work, we under-
took phosphite ligand development and focused on MOP-type
binaphthyl monodentate phosphite. The partially hydrogenated
H8-binaphthyl scaffold is also of interest in addition to the chiral
element from the binaphthyl skeleton. Chiral phosphorus donors
based on the H8-binaphthyl moiety have recently received
considerable attention.12 The improved stereo-communication in
H8-BINOL compared to BINOL in enantioselective transformations
has been explicitly highlighted.13 Herein, we describe that the
synthesis of novel monodentate phosphites (Scheme 1)
using monoesterified H8-BINOL as well as their catalytic perfor-
mance in the Cu-catalyzed asymmetric 1,4-conjugate addition
and the Rh-catalyzed asymmetric hydroformylation. The results
indicated that these ligands gave 95% ee and 96% ee in the
Cu-catalyzed asymmetric 1,4-conjugate addition of organozincs
to 2-cyclopentenone and 2-cyclohexenone respectively, and
provided high chemoselectivity (>99%) and regioselectivity
(96/4, b/n) in the Rh-catalyzed asymmetric hydroformylation of
styrene.
For the Cu-catalyzed asymmetric 1,4-conjugate addition
(Scheme 2), we choose 2-cyclohexenone 5 as the substrate, which
has been performed with ligands La–Le. In the Cu-catalyzed asym-
metric 1,4-conjugate addition of 2-cyclohexenone with Ph2Zn,
ligand (Sa,Ra)-L2 shown good activity and enantioselectivity (68%
yield, 65% ee, Table 1, entries 3 and 4). Its diastereoisomer (Ra,
Ra)-L1 afforded product 6 with low enantioselectivity (43% ee,
Table 1, entries 1–2). Compounds(Ra,Ra)-L3 and (Ra,Sa)-L4 gave
30% and 35% ee, respectively, and afforded product 6 with the
opposite absolute configuration (Table 1, entries 5–8). The ligands
with O-methyl-BINOL (Sa,Sa)-Lg and (Ra,Sa)-Lg demonstrated mod-
erate enantioselectivity up to 45% ee and 55% ee, respectively
(Table 1, entries 9–12). Moreover, it was found that the absolute
configuration of product 6 depended on the configuration of the
BINOL-based and H8-BINOL-based phosphocycle (Table 1, entries
1–12). Rather unexpectedly, these ligands gave no conversion in
the Cu-catalyzed asymmetric 1,4-conjugate addition of 2-
cyclopentenone 8 and 2-cycloheptenone 10 with Ph2Zn as nucle-
ophiles. When Me2Zn was used in the reaction instead of Ph2Zn,
these ligands showed very low activity under the same conditions.
As is well known, compared with Ph2Zn and Me2Zn, Et2Zn is a
more effective organozinc reagent in the Cu-catalyzed asymmetric
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M. Tian et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
O
P
Cl
O
O
O
Cl
X=
X
(Ra)- or (Sa)-3
O
O
P
O
NEt3, THF
OH
OH
X
(Ra,Ra)-L1
(Sa,Ra)-L2
4-chlorobenzoyl
chloride
THF, NEt3
DMAP
OH
(Ra)- or (Sa)-1
(Ra)- or (Sa)-2
X
O
O
P
O
O
O
P
Cl
(Ra,Ra)-L3
(Ra,Sa)-L4
(Ra)- or (Sa)-4
Scheme 1. The synthesis of the novel MOP-type monodentate phosphites.
O
O
O
O
*
n=1
Ph2Zn, cat
+
5
Et2Zn, cat
8
n=0
+
*
6
9
O
O
O
n
O
O
5
+ Et2Zn, cat
n=1
Et2Zn, cat
n=2
10
+
*
*
7
11
Scheme 2. The Cu-catalyzed asymmetric conjugate addition.
Table 1
The Cu-catalyzed enantioselective conjugate addition of diphenylzinc to 2-cyclohexenonea
Entry
Catalyst
L/Cu
Conversion (%)b
Yield.b
ee (%)b
1
2
3
4
5
6
7
8
(CuOTf)2ꢀC6H6/(Ra,Ra)-L1
(CuOTf)2ꢀC6H6/(Ra,Ra)-L1
(CuOTf)2ꢀC6H6/(Sa,Ra)-L2
(CuOTf)2ꢀC6H6/(Sa,Ra)-L2
(CuOTf)2ꢀC6H6/(Ra,Ra)-L3
(CuOTf)2ꢀC6H6/(Ra,Ra)-L3
(CuOTf)2ꢀC6H6/(Ra,Sa)-L4
(CuOTf)2ꢀC6H6/(Ra,Sa)-L4
(CuOTf)2ꢀC6H6/(Sa,Sa)-Lg
(CuOTf)2ꢀC6H6/(Sa,Sa)-Lg
(CuOTf)2ꢀC6H6/(Ra,Sa)-Lg
(CuOTf)2ꢀC6H6/(Ra,Sa)-Lg
1
2
1
2
1
2
1
2
1
2
1
2
55
60
87
89
44
48
50
56
46
58
54
62
30
41
60
68
33
38
40
45
35
50
38
49
33 (R)
43 (R)
46 (R)
65 (R)
26 (R)
30 (R)
18 (S)
35 (S)
38 (S)
45 (S)
40 (S)
55 (S)
9
10
11
12
a
Reaction conditions: (CuOTf)2ꢀC6H6 (0.005 mmol), ligand (0.005–0.010 mmol), Ph2Zn (1.2 mol/L in toluene, 0.6 mmol), solvent: THF (2.5 mL), temperature: 0 °C, 24 h.
Isolated yield, conversion, the ee of 6 was determined by HPLC (Daicel Chiralcel AD-H, hexane/i-PrOH = 99/1, 0.5, mL/min at 20 °C, detected at 209 nm.
b
1,4-conjugate addition. We turned our attention to the applica-
tions of these ligands in the Cu-catalyzed asymmetric 1,4-conju-
gate addition with Et2Zn as nucleophiles. In the Cu-catalyzed
asymmetric 1,4-conjugate addition of 2-cyclohexenone with Et2Zn,
(Ra,Ra)-L1 gave 3-ethylcyclohexanone 7 in 30% yield and with 73%
ee (Table 2, entry 1). (Ra,Ra)-L3 gave 38% yield and with 60% ee
(Table 2, entry 3). 48% yield and 69% ee were gained when using
(Ra,Sa)-L4 as the ligand (Table 2, entry 4). The use of (Sa,Ra)-L2
showed 88% yield and with 83% ee (Table 2, entry 2). (Sa,Sa)-Lg
and (Ra,Sa)-Lg showed moderate yield and enantioselectivity (46%
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4
M. Tian et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Table 2
The Cu-catalyzed enantioselective conjugate addition of diethylzinc to cyclic enonesa
Entry
Catalyst
L/Cu
T (°C)
Solvent
Conversion (%)b
Yieldb
ee (%)c
2-Cyclohexenone
1
2
3
4
5
6
7
8
(CuOTf)2ꢀC6H6/(Ra,Ra)-L1
(CuOTf)2ꢀC6H6/(Sa,Ra)-L2
(CuOTf)2ꢀC6H6/(Ra,Ra)-L3
(CuOTf)2ꢀC6H6/(Ra,Sa)-L4
(CuOTf)2ꢀC6H6/(Sa,Sa)-Lg
(CuOTf)2ꢀC6H6/(Ra,Sa)-Lg
CuTc/(Sa,Ra)-L2
Cu(acac)2/(Sa,Ra)-L2
Cu(OTf)2/(Sa,Ra)-L2
CuCl/(Sa,Ra)-L2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
0.5
2
2
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Toluene
CH2Cl2
Et2O
Et2O
Et2O
Et2O
42
94
49
57
52
61
42
70
71
16.
21
18
56
22
98
92
>99
>99
30
88
38
48
46
58
25
56
63
9
73 (R)
83 (R)
60 (R)
69 (S)
59 (S)
66 (S)
37 (R)
50 (R)
54 (R)
35 (R)
29 (R)
28 (R)
55 (R)
15 (R)
78 (R)
75 (R)
96 (R)
90 (R)
9
10
11
12
13
14
15
16
17d
18
CuBr/(Sa,Ra)-L2
CuF2/(Sa,Ra)-L2
4
5
(CuOTf)2ꢀC6H6/(Sa,Ra)-L2
(CuOTf)2ꢀC6H6/(Sa,Ra)-L2
(CuOTf)2ꢀC6H6/(Sa,Ra)-L2
(CuOTf)2ꢀC6H6/(Sa,Ra)-L2
(CuOTf)2ꢀC6H6/(Sa,Ra)-L2
(CuOTf)2ꢀC6H6/(Sa,Ra)-L2
47
17
93
84
95
92
ꢁ20
20
2-Cyclopentenone
19d
20d
21d
22d
23d
24d
(CuOTf)2ꢀC6H6/(Ra,Ra)-L1
(CuOTf)2ꢀC6H6/(Sa,Ra)-L2
(CuOTf)2ꢀC6H6/(Ra,Ra)-L3
(CuOTf)2ꢀC6H6/(Ra,Sa)-L4
(CuOTf)2ꢀC6H6/(Sa,Sa)-Lg
(CuOTf)2ꢀC6H6/(Ra,Sa)-Lg
2
2
2
2
2
2
ꢁ20
ꢁ20
ꢁ20
ꢁ20
ꢁ20
ꢁ20
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
48
30
46
58
51
56
37
27
36
49
40
47
73 (R)
95 (R)
57 (R)
64 (S)
58 (S)
62 (S)
2-Cycloheptenone
25d
26d
27d
28d
29d
30d
(CuOTf)2ꢀC6H6/(Ra,Ra)-L1
(CuOTf)2ꢀC6H6/(Sa,Ra)-L2
(CuOTf)2ꢀC6H6/(Ra,Ra)-L3
(CuOTf)2ꢀC6H6/(Ra,Sa)-L4
(CuOTf)2ꢀC6H6/(Sa,Sa)-Lg
(CuOTf)2ꢀC6H6/(Ra,Sa)-Lg
2
2
2
2
2
2
ꢁ20
ꢁ20
ꢁ20
ꢁ20
ꢁ20
ꢁ20
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
35
50
40
47
51
58
26
45
31
38
42
56
57 (R)
76 (R)
40 (R)
44 (S)
54 (S)
68 (S)
a
b
c
Reaction conditions: Cu precursor (0.005 mmol), ligand (0.0025–0.01 mmol), Et2Zn (1.0 mol/L in hexane, 0.6 mmol), substrate (0.25 mmol), solvent (4 mL), 0 °C, 4 h.
The data on conversion and yield were determined by GC using dodecane as internal standard with a SE-30 column (30 m ꢂ 0.32 mm I.D.).
The enantiomeric excess of 7 and 9 was determined by GC equipped with a Chiraldex A-TA column (50 m ꢂ 0.25 mm I.D.). The ee of 11 was determined by GC equipped
with a CP-ChirasilDex CB (25 m ꢂ 0.25 mm I.D.). The absolute configuration of yjr product was determined by comparison with yjr authentic sample.
d
Reaction time: 12 h.
yield and 59% ee, 58% yield and 66% ee, respectively, Table 2,
entries 5 and 6). It is interesting to note that the sense of enantios-
electivity was also determined by the configuration of the BINOL-
based and H8-BINOL-based phosphocycle .
In order to examine the substrate scope and limitations of the
reaction, other cyclic enones were investigated regarding the effect
of the structural differences of the substrates on the yield and
enantioselectivity (Table 2, entries 19–30). The reactions were car-
ried out under the optimized reaction conditions: Et2O as the sol-
vent, 4 mol % of the ligand, 2 mol % of (CuOTf)2ꢀC6H6 at ꢁ20 °C for
12 h. In the Cu-catalyzed asymmetric 1,4-conjugate addition of
The enantiomeric excess depends significantly on the copper
salt and solvent. In all cases, (CuOTf)2ꢀC6H6 was the optimal copper
salt. In comparison to (CuOTf)2ꢀC6H6, the reaction using CuTc as a
catalytic precursor significantly decreased the enantioselectivity
with 37% ee (Table 2, entry 7). The use of a Cu(II) salt, such as Cu
(acac)2 or Cu(OTf)2 resulted in almost the same enantioselectivity
with a slightly lower yield (Table 2, entry 8–9). The Cu precatalysts
such as CuCl, CuBr and CuF2 did not work efficiently (only 9%, 4%
and 5% yield respectively, Table 2, entries 10–12). The reaction pro-
ceeded with significantly higher enantioselectivity in the coordi-
nating solvent Et2O (Table 2, entry 2) compared with non-
coordinating solvents toluene and CH2Cl2 (Table 2, entries 13 and
14). On the contrary, the L/Cu molar ratio has basically no effect
on enantioselectivity. The reaction with a L/Cu ratio of 0.5:1, 1:1,
and 2:1 occurred in a similar manner to afford the corresponding
adduct in 75% ee, 78% ee, and 83% ee, respectively (Table 2, entries
2, 15, and 16). One can conclude that the same catalytic active spe-
cies were probably formed under these reaction conditions. In the
Cu-catalyzed asymmetric 1,4-conjugate addition, it is known that
the reaction temperature has an important impact on the enantios-
electivity. Therefore, by employing (Sa,Ra)-L2, this parameter was
investigated. We observed that ꢁ20 °C was the optimal tempera-
ture for the enantioselectivity; (Sa,Ra)-L2 showed up to 99% conver-
sion and 96% ee (Table 2, entry 17).
2-cyclopentenone
8 and 2-cycloheptenone 10 with Et2Zn;
(Sa,Ra)-L2 was more effective than that from either ligand (up to
95% and 76% ee respectively) (Table 2, entries 19–30). The
excellent enantioselectivity (95%) achieved in this reaction of
2-cyclopentenone 8 is the best result for all known chiral mon-
odentate phosphite ligands, since it exceeds the previously
reported enantiomeric excess shown by the monodentate
phosphites La–Le.
These ligands were also screened in the Cu-catalyzed asymmet-
ric 1,4-conjugate addition of Et2Zn to 5,6-dihydro-2H-pyran-2-one
12 (Scheme 3). The results are summarized in Table 3. It should be
noted that the Cu-catalyzed asymmetric 1,4-conjugate addition to
O
O
O
O
+ Et2Zn
*
Cu precursor/2L
12
13
Scheme 3. The Cu-catalyzed asymmetric conjugate addition of 5,6-dihydro-2H-
pyran-2-one.
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M. Tian et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
Table 3
The Cu-catalyzed enantioselective conjugate addition of diethylzinc to 5,6-dihydro-2H-pyran-2-onea
Entry
Catalyst
Solvent
Conversion (%)b
Yieldb
ee (%)b
1
2
3
4
5
6
7
8
(CuOTf)2ꢀC6H6/(Ra,Ra)-L1
(CuOTf)2ꢀC6H6/(Ra,Ra)-L1
(CuOTf)2ꢀC6H6/(Sa,Ra)-L2
(CuOTf)2ꢀC6H6/(Sa,Ra)-L2
(CuOTf)2ꢀC6H6/(Ra,Ra)-L3
(CuOTf)2ꢀC6H6/(Ra,Ra)-L3
(CuOTf)2ꢀC6H6/(Ra,Sa)-L4
(CuOTf)2ꢀC6H6/(Ra,Sa)-L4
(CuOTf)2ꢀC6H6/(Sa,Sa)-Lg
(CuOTf)2ꢀC6H6/(Sa,Sa)-Lg
(CuOTf)2ꢀC6H6/(Ra,Sa)-Lg
(CuOTf)2ꢀC6H6/(Ra,Sa)-Lg
CuTc/(Sa,Ra)-L2
THF
Et2O
THF
Et2O
THF
Et2O
THF
Et2O
THF
Et2O
THF
Et2O
Et2O
Et2O
Et2O
10
30
55
60
28
34
36
49
23
38
40
51
48
51
42
5
11
44
46
20
30
28
37
18
25
36
41
40
36
35
—
6 (R)
69 (R)
90 (R)
34 (R)
42 (R)
38 (S)
44 (S)
36 (S)
54 (S)
30 (S)
64 (S)
46 (R)
65 (R)
41 (R)
9
10
11
12
13
14
15
Cu(acac)2/(Sa,Ra)-L2
Cu(OTf)2/(Sa,Ra)-L2
The absolute configuration of 13 was determined by comparison with an authentic sample.
a
Reaction conditions: Cu precursor (0.005 mmol), ligand (0.01 mmol), Et2Zn (1.0 mol/L in hexane, 0.6 mmol), 12 (0.25 mmol), solvent (4 mL), 0 °C, 6 h.
The data on conversion, yield and the enantiomeric excess were determined by GC equipped with a Chiraldex A-TA column (50 m ꢂ 0.25 mm I.D.).
b
a
, b-unsaturated lactones is a transformation of high interest
of the copper precursor on the catalytic performance was also
examined, the yield and enantioselectivity showed (CuOTf)2ꢀC6H6
to be the optimal copper salts (Table 3, entries 13–15).
because the chiral lactone products constitute important subunits
in many natural products such as
macrolides.14
a-methylene lactones and
Ligands (Ra,Ra)-L3 and (Ra,Sa)-L4 afforded products 13 in 30%
yield, 42% ee (R) and 37% yield, 44% ee (S), respectively (Table 3,
entries 5 and 8). Ligand (Sa,Ra)-L2 showed significantly higher yield
and asymmetric induction (44% and 90% ee respectively, Table 3,
entry 4), while the asymmetric induction and the activity of its
diastereoisomer (Ra,Ra)-L1 were rather low (11% yield and 6% ee,
Table 3, entry 2). This is probably due to the mismatched combina-
tion of (Ra)-BINOL with (Ra)-monoesterification H8-BINOL frag-
ment. Ligands (Sa,Sa)-Lg and (Ra,Sa)-Lg in this reaction exhibited
25% yield, 54% ee (S) and 41% yield, 64% ee (S), respectively (Table 3,
entries 9–12). Focusing on ligand (Sa,Ra)-L2, the enantioselectivi-
ties increased when the reactions were carried out in Et2O (90%
ee) instead of THF (69% ee) (Table 3, entries 3 and 4). The influence
2.3. The Rh-catalyzed hydroformylation of styrene
The efficacy of the ligands was evaluated in the Rh-catalyzed
asymmetric hydroformylation of styrene 14 (Scheme 4). The cat-
alytic systems were formed in situ by the addition of 1–3 equiv
of the ligand to a solution of [Rh(acac)(CO)2], followed by addition
of the substrate, and pressurization of the autoclave at 40 bar with
a 1:1 mixture of syngas at the working temperature. The results are
shown in Table 4. All ligands show a chemoselectivity of >99% in
the aldehydes. Other products resulting from the hydrogenation
or polymerization of styrene were not observed. A satisfactory
branched over linear ratio (from 85% to 96%) was achieved.
The use of (Sa,Ra)-L2 was more effective than that from either
ligand in toluene, at room temperature for 20 h (Table 4, entries
1–6), but the enantioselectivities were low. Thus, the effect of
the solvent and L/Rh ratio on the enantioselectivity was investi-
gated using (Sa,Ra)-L2 (Table 4, entries 7–13). The ee did not change
significantly with the change of L/Rh ratio (Table 4, entries 2, 7 and
8). The solvent has a significant influence on the enantioselectivity
of the reaction. The reaction proceeded with significantly higher
enantioselectivity in nonpolar solvents such as hexane (Table 4,
CHO
∗
CHO
Rh(acac)(CO)2/L
CO/H2
+
14
15
16
Scheme 4. The Rh-catalyzed asymmetric hydroformylation of styrene.
Table 4
The Rh-catalyzed asymmetric hydroformylation of styrenea
Entry
Ligand
L/Rh
Solvent
Conversion (%)b
b/nb
ee (%)b
1
2
3
4
5
6
7
8
(Ra,Ra)-L1
(Sa,Ra)-L2
(Ra,Ra)-L3
(Ra,Sa)-L4
(Sa,Sa)-Lg
(Ra,Sa)-Lg
(Sa,Ra)-L2
(Sa,Ra)-L2
(Sa,Ra)-L2
(Sa,Ra)-L2
(Sa,Ra)-L2
(Sa,Ra)-L2
(Sa,Ra)-L2
1
1
1
1
1
1
2
3
1
1
1
1
1
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
tBuOMe
Hexane
Ether
98
80
60
85
67
90
82
81
68
27.5
90
55
36
96/4
92/8
85/15
94/6
95/5
94/6
91/9
91/9
95/5
92/8
95/5
93/7
96/4
5 (R)
28 (R)
10 (R)
8 (S)
10 (S)
18 (S)
29 (R)
31 (R)
17 (R)
10 (R)
34 (R)
19 (R)
9 (R)
9
10
11
12
13
THF
a
Reaction conditions: Rh(acac)(CO)2 (1.9 ꢂ 10ꢁ3 mmol); ligands (1.9 ꢂ 10ꢁ3 –5.7 ꢂ 10ꢁ3 mmol), solvent (0.5 mL); styrene (40
lL); CO, 20 bar; H2, 20 bar; room
temperature.
b
The data on conversion, b/n and the enantiomeric excess were determined by GC equipped with a Beta DEX225 column (30 m ꢂ 0.25 mm I.D.). The absolute configuration
was determined by comparison with authentic sample.
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6
M. Tian et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
entry 11) than in polar solvents (tBuOMe, THF, Table 4, entries 10
and 13).
The conversion and the yield were determined by GC equipped
with an SE-30 column (30 m ꢂ 0.32 mm i.d.) using dodecane as
an internal standard. The enantiomeric excess was determined
by GC analysis with a Chiraldex A-TA column (50 m ꢂ 0.25 mm i.
d.). The absolute configuration was determined by comparison
with authentic samples.
3. Conclusion
In conclusion, we have shown that novel MOP-type monoden-
tate phosphite ligands are useful for the Cu-catalyzed asymmetric
1,4-conjugate addition and the Rh-catalyzed asymmetric
hydroformylation. The stereochemically matched combination of
(Sa)-monoesterification H8-BINOL fragment and (Ra)-BINOL in
ligand (Sa)-(2-(4-chlorobenzoic acid)-1,10-H8-binaphthalen-20-yl)-
((Ra)-1,10-binaphthalen-2,20-yl)phosphite (Sa, Ra)-L2 was essential
to afford 96% ee for 2-cyclohexenone with Et2Zn and 65% ee with
Ph2Zn, 95% ee for cyclopentenone with Et2Zn, 76% ee for 2-cyclo-
heptenone with Et2Zn, and 90% ee for 5,6-dihydro-2H-pyran-2-
one with Et2Zn. The sense of enantioselectivity was mainly deter-
mined by the configuration of the BINOL-based and H8-BINOL-
based phosphocycle. In the Rh-catalyzed asymmetric hydroformy-
lation of styrene, this MOP-type phosphite ligands show chemose-
lectivity of >99% in aldehydes, and a satisfactory branched over
linear ratio (96/4) were achieved. We think that these benefits will
stimulate further applications of the organic synthesis especially in
the field of natural product synthesis.
4.1.2. Representative procedure of the Rh-catalyzed asymmetric
hydroformylation of styrene
A 50 mL stainless steel autoclave was charged with styrene
(40
l
L), toluene (0.5 mL), ligand (5.7 ꢂ 10ꢁ3 mmol), and Rh(acac)
(CO)2 (1.9 ꢂ 10ꢁ3 mmol) under a nitrogen atmosphere. The auto-
clave was pressurized with CO and H2. The reaction mixture was
stirred with a magnetic stirrer at room temperature. After a pre-
scribed reaction time, the residue gas was released. The data on
the conversion, b/n ratio and enantiomeric excess was determined
by GC analysis with a Beta-Dex 225 column (30 m ꢂ 0.25 mm i.d.).
The absolute configuration was determined by comparison with
authentic samples.
4.2. Synthesis of monodentate phosphite ligands
4.2.1. General protocol for the preparation of carboxylic acid
esters of H8-BINOL
A flame-dried flask was charged with H8-BINOL (3 mmol),
10 mL of THF, and Et3N (3.78 mmol), and cooled to ꢁ5 °C.
4-Chlorobenzoyl chloride (3 mmol) was added to the above-men-
tioned solution dropwise. Once the addition was complete, the
reaction mixture was left at room temperature until the near com-
plete disappearance of the starting material. After 20 h, the reac-
tion was quenched with distilled water (2.5 mL) and the mixture
was extracted with ethyl acetate (5 mL ꢂ 3). The combined organic
phases were washed successively with a saturated aqueous solu-
tion of NaHCO3, NaCl, and then dried over anhydrous sodium sul-
fate, filtered, and concentrated in vacuo. The crude product was
purified by flash chromatography (EtOAc/Petroleum ether) to pro-
vide the title compound (Ra)-2, (Sa)-2 as a solid with >85% yield.
(Ra)-2 1H NMR (400 MHz, CDCl3) d 7.76 (d, J = 1.6 Hz, 1H, Ar),
7.75–7.73 (m, 1H, Ar), 7.33 (d, J = 1.8 Hz, 1H, Ar), 7.31 (d,
J = 1.8 Hz, 1H, Ar), 7.22 (d, J = 8.4 Hz, 1H, Ar), 7.05 (d, J = 8.0 Hz,
1H, Ar), 6.86 (d, J = 8.4 Hz, 1H, Ar), 6.68 (d, J = 8.4 Hz, 1H, Ar),
4.78 (s, 1H, OH), 2.94–2.37 (m, 8H, CH2), 1.75–1.61 (m, 8H, CH2)
4. Experimental section
4.1. General
All experiments were carried out under nitrogen using standard
Schlenk techniques. NMR spectra were recorded on Bruker
300 MHz or 400 MHz spectrometers. 1H and 13C NMR spectra were
reported with tetramethylsilane (TMS) as an internal standard. 31
P
NMR spectra were reported with 85% (volume fraction) H3PO4 as
an external reference. Coupling constants (J) were reported in
Hertz (Hz). 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 instrument. Melting
points were determined with an X-4 melting point apparatus
uncorrected. Optical rotations were measured on a Perkin-Elmer
241 MC polarimeter at 20 °C. Enantiomeric excess determination
was carried out using gel chromatography(GC) with a Chiraldex
A-TA, Beta-Dex 225 and a Chiralsil-DEX-CB capillary column on
an ACME-6100 GC instrument with FID as detector. GC-MS was
performed on an Agilent 5975C with Triple-Axis detector. Reaction
were monitored by thin layer chromatography (TLC, silica gel
GF254 plates). Column chromatography separations were con-
ducted on silica gel (200–300 mesh). NEt3, tetrahydrofuran (THF),
Et2O and toluene were distilled with Na and benzophenone as an
indicator, and CH2Cl2 was dried over CaH2 before use. All the other
chemicals were obtained commercially and used without further
purification.
ppm. 13C NMR (101 MHz, CDCl3)
d 165.16, 150.47, 147.11,
139.90, 138.57, 136.39, 135.65, 131.22, 130.48, 129.96, 129.42,
128.68, 127.90, 127.62, 121.98, 119.52, 113.68, 29.70, 29.23,
27.39, 26.96, 23.25, 23.17, 22.84, 22.69 ppm. HRMS (ESI+): calcd
for C27H25NaClO3 [M+Na]+ 455.1371; found: 455.1385.
(Sa)-2 1H NMR (400 MHz, CDCl3) d 7.80–7.68 (m, 2H, Ar), 7.35–
7.29 (m, 2H, Ar), 7.22 (d, J = 8.4 Hz, 1H, Ar), 7.05 (d, J = 8.0 Hz, 1H,
Ar), 6.86 (d, J = 8.4 Hz, 1H, Ar), 6.68 (d, J = 8.4 Hz, 1H, Ar), 4.57 (s,
1H, OH), 2.92–2.16 (m, 8H, CH2), 1.81–1.64 (m, 8H, CH2) ppm.
13C NMR (101 MHz, CDCl3) d 165.16, 150.46, 147.11, 139.90,
138.57, 136.39, 135.65, 131.22, 130.49, 129.96, 129.42, 128.68,
127.89, 127.62, 121.99, 119.52, 113.68, 29.70, 29.23, 27.39, 26.96,
23.25, 23.17, 22.84, 22.69 ppm. HRMS (ESI+): calcd for
4.1.1. Representative procedure of Cu-catalyzed 1,4-conjugate
addition of diethylzinc to 2-cyclohexenone
27H25NaClO3 [M+Na]+ 455.1371; found: 455.1392.
A
solution of Cu(OTf)2 (0.005 mmol) and (Ra,Ra)-L1
C
(0.005 mmol) in toluene (4 mL) was stirred for 1 h at room temper-
ature under nitrogen. After the solution was cooled to 0 °C, com-
pound 5 (0.25 mmol) was added to it, and the solution was
stirred for 10 min at 0 °C, then Et2Zn (0.6 mmol, 0.6 mL of
1.0 mol/L solution in hexane) was added dropwise using a syringe
over 2 min. After 4 h, the reaction was quenched by H2O (2 mL) and
2 mol/L HCl (2 mL), and the mixture was extracted with ethyl acet-
ate (5 mL ꢂ 3). The combined extracts were washed using satu-
rated NaHCO3 solution, brine, and then dried over anhydrous
Na2SO4, filtered, and concentrated to afford the crude product.
4.2.2. Synthesis of monodentate phosphite ligands L1–L4
4.2.2.1. (Ra)-(2-(4-Chlorobenzoic acid)-1,10-H8-binaphthalen-
20-yl)-((Ra)-1,10-binaphthalen-2,20-yl)phosphite [(Ra,Ra)-L1]. To
a 100 mL Schlenk flask equipped with a condenser were added
2.0 g of (Ra)-binaphthol, 20 mL of toluene, and 10 mL of PCl3. The
mixture was refluxed under nitrogen atmosphere for 20 h. After
the removal of excess PCl3 and toluene, the residue was dissolved
in 20 mL of toluene, then transferred to another Schlenk flask,
and toluene was removed in vacuo to obtain compound
Please cite this article in press as: Tian, M.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.01.011

M. Tian et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
7
(Ra)-1,10-binaphthyl-2,20-diylchlorophosphite (Ra)-3 as a white pow-
der, which was used directly in the following step without further
purification. To a stirred solution of compound (Ra)-2 (345.7 mg,
0.8 mmol), compound (Ra)-3 (308 mg, 0.88 mmol), and 4-dimethy-
laminopyridine (DMAP) (12.2 mg, 0.1 mmol) in THF (10 mL) at
0 °C, NEt3 (0.28 mL, 2.02 mmol) were slowly added using a syringe
over 2 min. The mixture was then stirred at room temperature 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 resi-
due was purified by flash chromatography (toluene) to furnish
ligand (Ra,Ra)-L1 as a white foamy solid (286.4 mg, yield 48%).
Ar), 6.85 (d, J = 8.2 Hz, 1H, Ar), 3.01–2.53 (m, 8H, CH2), 2.50–1.92
(m, 8H, CH2), 1.88–1.47 (m, 16H, CH2) ppm. 13C NMR (101 MHz,
CDCl3) d 163.92, 151.45, 147.12, 146.33, 145.60, 139.50, 138.51,
137.38, 137.14, 136.96, 135.13, 134.72, 133.68, 131.32, 131.24,
131.02, 129.41, 129.35, 129.25, 129.18, 128.79, 128.58, 128.09,
29.88, 29.40, 29.28, 29.15, 27.83, 27.70, 27.30, 27.14, 22.99, 22.93,
22.64, 22.44 ppm. 31P NMR (162 MHz, CDCl3) d 137.95 ppm. HRMS
(ESI+): calcd for C47H44NaClO5P [M+Na]+ 777.1871; found: 777.1898.
4.2.2.4. (Ra)-(2-(4-Chlorobenzoic acid)-1,10-H8-binaphthalen-
20-yl)-((Sa)-1,10-H8-binaphthalen-2,20-yl)phosphite
[(Ra,Sa)-L4].
Treatment of (Ra)-2 (259.2 mg, 0.6 mmol), compound (Sa)-4
(231 mg, 0.66 mmol), DMAP (9.15 mg, 0.075 mmol) and NEt3
(0.21 mL, 1.51 mmol) as described for the synthesis of (Ra,Ra)-L3
afforded (Ra,Sa)-L4, which was purified by flash chromatography
(toluene) to produce a white foamy solid (196.9 mg, yield 44%).
[a]D
20 = +45 (c 0.1 CH2Cl2); Mp 112–114 °C; 1H NMR (400 MHz,
CDCl3) d 7.38–8.32 (m, 6H, Ar), 7.16–7.34 (m, 8H, Ar), 6.62–7.09
(m, 6H, Ar), 2.27–2.79 (m, 8H, CH2), 1.45–1.76 (m, 8H, CH2) ppm.
13C NMR (101 MHz, CDCl3) d 163.91, 153.13, 152.10, 146.34,
139.53, 137.89, 135.20, 133.74, 131.27, 130.19, 129.44, 129.05,
128.60, 128.29, 128.24, 128.16, 127.07, 126.93, 126.23, 125.31,
124.83, 119.61, 117.40, 117.29, 29.85, 29.71, 29.40, 27.31, 27.25,
22.93, 22.88, 22.81, 22.79, 22.70, 21.47 ppm. 31P NMR (162 MHz,
CDCl3) d 146.03 ppm. HRMS (ESI+): calcd for C47H36NaClO5P [M
+Na]+ 769.1871; found: 769.1895.
[
a D
]
20 = ꢁ395 (c 0.1 CH2Cl2); Mp 121–124 °C; 1H NMR (400 MHz,
CDCl3) d 7.81–7.58 (m, 2H, Ar), 7.32 (dd, J = 24.4, 15.8 Hz, 2H, Ar),
7.21–7.10 (m, 3H, Ar), 7.09–6.77 (m, 5H, Ar), 3.08–2.51 (m, 10H,
CH2), 2.41 (m, 1H, CH2), 2.32–1.98 (m, 5H, CH2), 1.88–1.40 (m,
16H, CH2) ppm. 13C NMR (101 MHz, CDCl3) d 163.84, 151.37,
147.04, 146.25, 145.52, 139.42, 138.43, 137.30, 137.06, 136.88,
135.05, 134.64, 133.60, 131.24, 131.16, 130.94, 129.33, 129.27,
129.17, 129.10, 128.71, 128.50, 128.01, 29.80, 29.32, 29.20, 29.07,
27.75, 27.62, 27.22, 27.06, 22.91, 22.85, 22.56, 22.36 ppm. 31P
NMR (162 MHz, CDCl3) d 138.65 ppm. HRMS (ESI+): calcd for
4.2.2.2. (Sa)-(2-(4-Chlorobenzoic acid)-1,10-H8-binaphthalen-
20-yl)-((Ra)-1,10-binaphthalen-2,20-yl)phosphite
[(Sa,Ra)-L2].
Treatment of (Sa)-2 (259.2 mg, 0.6 mmol), compound (Ra)-3
(231 mg, 0.66 mmol), DMAP (9.15 mg, 0.075 mmol) and NEt3
(0.21 mL, 1.51 mmol) as described for the synthesis of ligand
(Ra,Ra)-L1 afforded ligand (Sa,Ra)-L2, which was purified by flash
C
47H44NaClO5P [M+Na]+ 777.1871; found: 777.1887.
Acknowledgments
chromatography (toluene) to produce
a white foamy solid
(228.3 mg, yield 51%). [
a
]
20 = +435 (c 0.1 CH2Cl2); Mp 142–
We are grateful for the financial support of this work by the
National Natural Science Foundation of China (Nos. 20773147,
21073211, 21174155, and 21633013).
D
144 °C; 1H NMR (400 MHz, CDCl3) d 7.46–8.13 (m, 6H, Ar),
7.21–7.57 (m, 8H, Ar), 6.45–7.15 (m, 6H, Ar), 2.01–2.88 (m, 8H,
Ar), 1.30–1.72 (m, 8H, Ar) ppm. 13C NMR (101 MHz, CDCl3) d
163.94, 153.16, 152.13, 146.37, 139.56, 137.92, 135.23, 133.77,
131.30, 130.22, 129.47, 129.08, 128.63, 128.32, 128.27, 128.19,
127.10, 126.96, 126.26, 125.34, 124.86, 119.64, 117.43, 117.32,
29.88, 29.74, 29.43, 27.34, 27.28, 22.96, 22.91, 22.84, 22.82,
22.73, 21.50 ppm. 31P NMR (162 MHz, CDCl3) d 146.92 ppm.
HRMS (ESI+): calcd for C47H36NaClO5P [M+Na]+ 769.1871; found:
769.1891.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2017.01.
011.
References
4.2.2.3. (Ra)-(2-(4-Chlorobenzoic acid)-1,10-H8-binaphthalen-20-
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The mixture was refluxed under nitrogen atmosphere for 20 h. After
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20 mL of toluene, then transferred to another Schlenk flask,
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(Ra)-1,10-H8-binaphthyl-2,20-diylchlorophosphite (Ra)-4 as a white
powder, which was used directly in the following step without fur-
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ther purification. To
a stirred solution of compound (Ra)-2
(259.2 mg, 0.6 mmol), compound (Ra)-4 (231 mg, 0.66 mmol), and
4-dimethylaminopyridine (DMAP) (9.15 mg, 0.075 mmol) in THF
(10 mL) at 0 °C, NEt3 (0.21 mL, 1.51 mmol) were slowly added using
a syringe over 2 min. The mixture was then stirred at room temper-
ature 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 pres-
sure. The residue was purified by flash chromatography (toluene) to
furnish ligand (Ra,Ra)-L3 as a white foamy solid (241.7 mg, yield
54%).
[a]D
20 = +55 (c 0.1 CH2Cl2); Mp 101–104 °C; 1H NMR
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Alexandre Alexakis, C. B. Eur. J. Org. Chem. 2002, 3221–3236.
(400 MHz, CDCl3) d 7.71–7.51 (m, 2H, Ar), 7.26–7.20 (m, 4H, Ar),
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