The Cu-catalyzed asymmetric conjugate addition with chiral diphosphite ligands derived from D-(-)-tartaric acid

Article abstract of DOI:10.1080/00397911.2016.1278231

A series of diphosphite ligands, which were derived from D-(-)-tartaric acid, have been synthesized and successfully applied in the Cu-catalyzed asymmetric conjugate addition of organozincs to enones. There was a synergic effect between the stereogenic ce

Full text of DOI:10.1080/00397911.2016.1278231

The Cu-catalyzed asymmetric conjugate addition with chiral diphosphite ligands
derived from D-(-)-tartaric acid
1
,2
1,2
1
1
Zeng-Bo Pang , Mi Tian , Hai-Feng Li ,Lai-Lai Wang
1
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of
2
Chemical Physics, Chinese Academy of Sciences, Lanzhou , P.R. China, University of
Chinese Academy of Sciences, Beijing, P.R. China
Address correspondence to Lai-Lai Wang, State Key Laboratory for Oxo Synthesis and
Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou 730000, P.R. China. E-mail:wll@licp.cas.cn
Abstract
A series of diphosphite ligands, which were derived from D-(-)-tartaric acid, have been
synthesized and successfully applied in the Cu-catalyzed asymmetric conjugate addition
of organozincs to enones. There was a synergic effect between the stereogenic centers of
the D-(-)-tartaric acid skeleton and the axially H -binaphthyl moieties of ligand 2c. And
8
ligand
2c
show
comparative
catalytic
performance
to
ligand
1
-N-benzylpyrrolidine-3,4-bis[(S)-1,1'-H - -binaphthyl-2,2'-diyl]phosphite-L-tartaric acid
8
1
d derived from L-(+)-tartaric acid. Therefore, for cyclic enones, both enantiomers of the
addition products can be obtained in high enantioselectivity (ees up to 96%) by simply
selecting ligands 1d or 2c derived from D-(-)-tartaric acid or L-(+)-tartaric acid.
Moreover, the sense of the enantiodiscrimination of the products was mainly determined
by the configuration of the binaphthyl phosphite moieties.
1

GRAPHICALABSTRACT
KEYWORDS: D-(-)-tartaric acid; Phosphite ligand; 1,4-Conjugate addition; Copper salt;
Enone
1
INTRODUCTION
The synthesis of optically active products is an important aspect of synthetic organic
[
1]
chemistry due to the ever-increasing demands for chiral chemicals . Asymmetric
conjugate addition (ACA) with transition-metal / chiral ligand is a highly attractive
[
2]
method for the synthesis of optically active organic molecules . To achieve maximum
chiral multiplication, many research groups have focused on designing simple and highly
efficient ligands. Up to now, many efficient trivalent phosphorus ligands (i.e.
[
3]
[4]
[5]
phosphines , phosphites , phosphoromidites ) have been synthesized. And among the
above ligands, phosphite ligands have been extremely attractive for ACA because they
can be simply prepared from readily accessible precursors, are highly effective and less
[
4a]
sensitive to air . As is well known, the structure of phosphite ligands has an important
influence on the activity and enantioselectivity of the reactions, thus the search for
efficient chiral ligands in terms of high activity and enantioselectivity remains one of the
2

most important goals in asymmetric catalysis.
The careful selection of a suitable backbone has become vital in the design of any chiral
ligands. Tartaric acid is a white crystalline organic acid that occurs in many plants, most
notably in grapes. As an α-hydroxy-carboxylic acid, tartaric acid is widely used to
[
6]
synthesize chiral ligands . In our previous work, we reported on the synthesis of
bidentatephosphite ligands 1a-d using (3R,4R)-N-benzyltartarimide 3 as the diol skeleton
(Figure 1). These ligands were successfully used in the Cu-catalyzed ACA of organozincs
to cyclic enones. The stereochemically matched combination of L-(+)-tartaric acid
backbone and (R)-binaphthyl in ligand 1a was essential to afford 95% ee for
3
3
-ethylcyclopentanone, 95% ee for 3-ethyl-cyclohexanone, and 63% ee for
-ethylcycloheptanone in ether as solvent, using (CuOTf) ·C H as a catalytic precursor .
[
7]
2
6
6
The above-mentioned results clearly indicated that axially chiral binaphthyl, and
L-(+)-tartaric acid backbone in ligand 1a had a synergic effect on the enantioselectivity.
Based on this discovery, we wondered whether there would be a synergic effect between
D-(-)-tartaric acid backbone and axially chiral binaphthyl phosphite moieties or not.
Herein, we report the synthesis and application of a set of
(3S,4S)-N-benzyltartarimide-derived diphosphite ligands 2a-d. The results indicated that
these ligands gave high activity and enantioselectivity (up to 96% ee) in the Cu-catalyzed
ACA of organozincs to cyclic enones.
3

2
RESULTS AND DISCUSSION
.1 Synthesis of Phosphite Ligands 2a-2d
As shown in Scheme 1, ligands 2a-d were synthesized in one step from
3S,4S)-N-benzyltartarimide 4 and the corresponding diarylchlorophosphines 5, which
were derived from 2,2'-dihydroxy-1,1'-binaphthol (binaphthol), and 2,2'-dihydroxy-
,5',6,6',7,7',8,8'- octahydro-1,1'-binaphthol (H -binaphthol) by the procedures reported
2
(
5
8
[
7-8]
previously . All the ligands were purified on a silica gel column under nitrogen
3
1
1
13
atmosphere with moderate to good yields. The P, H and C NMR spectra were
3
1
consistent with the expectation for these ligands. In the P NMR spectrum of 2a, a
singlet at 146.71 ppm was observed for the two equivalent phosphorus atoms. However,
the chemical shift of 2c moved to high field (142.73 ppm) when the biaryl moieties
3
1
changed to H -binaphthol. Similarly, in the P NMR spectrum of 2b, the two phosphorus
8
3
1
atoms appeared as a sharp singlet at 142.90 ppm. As expected, the P NMR spectrum of
2
d contained a singlet for the two equivalent phosphorus atoms and moved to a high field
[
8a]
(140.02 ppm). This rule also applies to our previous literature data.
2
.2 Asymmetric Conjugate Addition of Organozincs to Enones and α, β-Unsaturated
Lactone
In the first set of experiments, the catalytic ability of ligands 2a-d was examined in the
Cu-catalyzed conjugate addition of diethylzinc to 2-cyclohexenone 6a, which was used as
a model substrate. The catalysts were prepared in situ by adding the corresponding
4

o
ligands to the catalyst precursor Cu(OTf) . The reaction proceeded smoothly at 0 C
2
using toluene as the solvent and the results were summarized in Table 1. In all cases, no
1
,2-addition products were detected by the analysis of GC-MS. 53% yield and 14% ee (R)
were obtained when using 2a/Cu(OTf) as the catalyst (Table 1, entry 1). Ligand 2b,
2
which bore (S)-binaphthyl moieties in comparison with ligand 2a, gave 32% yield and
2
0% ee (S) (Table 1, entry 2). Ligand 2c gave 64% yield and 22% ee (R) for the product
7
a (Table 1, entry 3), in contrast, the configuration of the H -binaphthyl moiety was
8
opposite to that of 2c and also gave 22% ee (S) (Table 1, entry 4) when 2d was used as
the ligand.
The results clearly indicated that the matched combination of
(
3S,4S)-N-benzyltartarimide and (R)-H -binaphthyl moieties of ligand 2c was essential
8
for inducing higher enantioselectivity and activity. It was proved that the stereogenic
centers of the D-(-)-tartaric acid backbone and the axially chiral H -binaphthyl moieties
8
had a synergic effect on the reactive activity and enantioselectivity of the reaction.
Moreover, the sense of enantioselectivity was mainly determined by the configuration of
the binaphthyl or H -binaphthyl moiety of ligands 2a-d, and an (S)-binaphthyl fragment
8
gives an (S)-product, and conversely an (R)-product for an (R)-binaphthyl.
Using the catalyst prepared in situ from Cu(OTf) and ligand 2c, the ACA of ZnEt to
2
2
substrate 6a with a variety of solvents was investigated, and a profound solvent effect on
5

the reaction was observed (Table 1, entries 5-7). Low enantioselectivities were received
in solvents Et O and CH Cl , respectively (Table 1, entries 5 and 6). When the reaction
2
2
2
was carried out in THF, low catalytic activity but good enantioselectivity were obtained
Table 1, entry 7). In order to further improve the yield, we attempted to use mixed
(
solvents in this reaction. To our delight, the yield increased from 20% to 48% when 2 mL
of Toluene was added into 2 mL of THF (Table 1, entry 8). Obviously, Toluene and THF
as mixed solvents were beneficial for obtaining higher yield and ee values.
It is well known that the copper precursor has an important impact on the catalytic
activity and enantioselectivity of this reaction. So the influence of the copper precursor as
well as the copper/ligand ratio on the catalytic performance was also examined. High ee
value but poor yield were achieved when (CuOTf) ·C H was used (Table 2, entry 1). In
2
6
6
comparison with Cu(OTf) , Cu(acac) and CuTc were proven to be detrimental to this
2
2
reaction (Table 2, entries 2 and 3). Thus, Cu(OTf) was chosen as the catalytic precursor
2
for the next experiments to examine the influence of ligand 2c/Cu(OTf) molar ratio on
2
reactive activity and enantioselectivity. No obvious enhancement in yield and
enantioselectivity was observed when the molar ratio of ligand 2c to Cu(OTf) ranged
2
from 1/2 to 1/1 (Table 2, entry 4 vs Table 1, entry 8). However, further increase of the
ratio of ligand 2c/Cu(OTf) brought no effective change of the enantioselectivity, but the
2
yield of the reactions significantly decreased (Table 1, entry 8 vs Table 2, entry 5).
6

Furthermore, the effect of reaction temperature on the enantioselectivity was investigated.
o
By lowering the temperature from 20 to -30 C, the yield of the product 7a increased from
o
3
6% to 88% (Table 2, entries 6-9). However, when the temperature decreased to -78 C,
the reaction became sluggish and only 27% yield was obtained (Table 2, entry 12). The
o
best result was achieved at -30 C in our cases (Table 2, entry 9).
To evaluate the effectiveness of this catalytic system, the 1,4-conjugate addition of Et Zn
2
to other cyclic enones was carried out. To our delight, ligand 2c afford 96% ee (R) in the
ACA of Et Zn to 2-cyclopentenone 6b although the yield was only 18% (Table 3, entry 3).
2
Moderate ee but poor yield were obtained when 2-cycloheptenone 6c was used as the
substrate (Table 3, entry 5). The yield and enantioselectivity showed a significant
dependence on the ring size of the substrates.
As discussed in Table 1, (3S,4S)-N-benzyltartarimide backbone and (R)-H -binaphthyl in
8
the ligand 2c was proven to be an matched combination. So we assumed that
(
3R,4R)-N-benzyltartarimide backbone and (S)-H -binaphthyl would also be an matched
8
combination under the same reaction conditions. This hypothesis was confirmed
subsequently when ligand 1d was applied in this reaction. By comparing entries 1-6 of
Table 3, it can be seen that these results obtained for ligand 1d were comparable to the
results obtained for ligand 2c which derived from D-(-)-tartaric acid (Table 3, entries
1
,3,5 vs entries 2,4,6). Therefore, both enantiomers of addition products can be afforded
7

by simply changing the configuration of chiral diol backbone of diphosphite ligands 1d
and 2c. Moreover, the Cu-catalyzed asymmetric 1,4-conjugate additions of other
organozinc reagents, such as Me Zn and Ph Zn were also assessed. However, the catalyst
2
2
in situ prepared from Cu(OTf) and ligand 2c gave much lower catalytic activity and
2
enantioselectivity (Table 3, entry 7). No product was determined when Ph Zn was used as
2
the organozinc reagent (Table 3, entry 8).
In addition, the 1,4-additions of ZnEt to aryl acyclic enones were examined (Scheme 2).
2
Unfortunately, low enantioselectivities were observed: 11% ee (S) for
1
,3-diphenyl-2-propenone 6d, 6% ee (S) for 3-(4-chlorophenyl)-1-phenyl-2-propenone 6e,
and 14% ee (S) for 3-(4-methylphenyl)-1-phenyl-2-propenone 6f (Scheme 2). The results
indicated that ligand 2c was inferior to these acyclic enones. It is interesting to note that
the products of opposite configuration were gained for these substrates when using
2
c/Cu(OTf) as the catalyst.
2
The enantioselective 1,4-conjugate addition to α,β-unsaturated lactones is a reaction of
high interest because the chiral lactone products constitute important subunits in many
[
9]
natural products such as sesquiterpenes, α-methylene lactones and macrolides.
Therefore, ligands 2a-d were applied in the Cu-catalyzed conjugate addition of ZnEt to
2
5
,6-dihydro-2H-pyran-2-one, and the results were summarized in Table 4. Ligand 2a was
proven to be the best ligand in this reaction, however, moderate enantioselectivity (52%
8

ee) but poor catalytic activity (12% yield) were received when (CuOTf) ·C H /2a was
2
6
6
used as the catalyst under the optimized conditions. It was also found that the sense of the
enantiodiscrimination of the products was mainly determined by the configuration of the
binaphthyl phosphite moieties.
3
CONCLUSION
In conclusion, we prepared a class of chiral diphosphite ligands from
3S,4S)-N-benzyltartarimide. These ligands were successfully utilized in the Cu-catalyzed
ACA of diethylzinc to cyclic enones. The stereochemically matched combination of
3S,4S)-N- -benzyltartarimide backbone and (R)-H -binaphthyl in ligand
(
(
8
1
-N-Benzylpyrrolidine-3,4-bis[(R)- -1,1'-H -binaphthyl-2,2'-diyl]phosphite-D-tartaric
8
acid 2c was essential to afford 96% ee for 3-ethylcyclohexanone, 96% ee for
-ethylcyclopentanone, and 77% ee for 3-ethylcycloheptanone. It was proven that both of
3
ligands 2c and 1d derived from D-(-)-tartaric acid and L-(+)-tartaric acid show excellent
catalytic performance for cyclic enones in this reaction. The sense of the
enantiodiscrimination of the products was mainly controlled by the configuration of the
binaphthyl phosphite moieties. Research concerning the use of these ligands in other
transition metal-catalyzed asymmetric reactions is currently underway.
4
EXPERIMENTAL
4
.1 General
9

1
NMR spectra were recorded on Bruker 300 MHz or Bruker 400 MHz spectrometers. H
1
3
and C NMR spectra were reported in parts per million (ppm) with TMS (δ = 0.00 ppm)
3
1
as an internal standard. P NMR spectra were reported in ppm with 85% H PO as an
3
4
external reference. Proton chemical shifts (δ) and coupling constants (J) were reported in
ppm and Hz, respectively. Spin multiplicities were given as s (singlet), d (doublet), t
(triplet) and m (multiplet). HRMS were recorded on a Bruker microTOF-QII mass
instrument. All the melting points were determined on an X-4 melting point apparatus
and were uncorrected. Optical rotations were measured on a Perkin–Elmer 241 MC
o
polarimeter at 20 C. All non-aqueous reactions and manipulations were performed under
an N atmosphere with standard Schlenk techniques. Reactions were monitored by thin
2
layer chromatography (TLC, silica gel GF254 plates). Column chromatography
separations were conducted on silica gel (200-300 mesh). Reagents NEt , THF, Et O,
3
2
hexane and toluene were distilled with Na and benzophenone as an indicator, and CH Cl
2
2
was dried over CaH before use. H -Binaphthol was prepared according to a literature
2
8
[
10]
procedure . All the other chemicals were obtained commercially and used without
further purification.
4
4
1
.2 Synthesis of Ligands 2a-d
.2.1
-N-Benzylpyrrolidine-3,4-Bis[(R)-1,1'-Binaphthyl-2,2'-Diyl]Phosphite-D-Tartaric
Acid (2a)
1
0

To a 100 mL Schlenk flask equipped with a condenser were added 2.0 g of (R)-binaphthol,
0 mL of toluene, and 12 mL of PCl . Under a nitrogen atmosphere, the mixture was
2
3
refluxed for 20 h. After removal of the excess PCl and toluene, the residue was dissolved
3
in 20 mL of toluene, and then was transferred to another Schlenk flask, and toluene was
removed in vacuo to obtain (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 (132.7 mg, 0.60 mmol), compound 5a (463.0 mg, 1.32
mmol), and 4-dimethylaminopyridine (DMAP) (14.6 mg, 0.12 mmol) in THF (10 mL) at
o
-
15 C, NEt (0.51 mL, 3.66 mmol) was slowly added using a syringe over 2 min., after
3
o
which the solution was stirred for 0.5 h at -15 C. The mixture was then stirred at room
temperature for 1 h. Next, THF was distilled off in vacuo, and 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 chromatography (R =
f
0
.47, toluene), and furnished ligand 2a as a white foamy solid (306.0 mg, 60.0% yield).
2
0
o
1
[
α]D = -426 (c 0.15, CH Cl ); Mp 157-158 C; H NMR (400 MHz, CDCl ) δ 7.99 (d, J
2 2 3
=
8.8 Hz, 2H, Ar), 7.94 (d, J = 8.2 Hz, 2H, Ar), 7.63 (d, J = 8.0 Hz, 2H, Ar), 7.57 (d, J =
8
7
4
1
1
.8 Hz, 2H, Ar), 7.48 (d, J = 7.2 Hz, 4H, Ar), 7.46-7.40 (m, 5H, Ar), 7.40 (s, 1H, Ar),
.36 (dd, J = 8.4, 4.4 Hz, 7H, Ar), 7.30-7.26 (m, 4H, Ar), 5.05 (d, J = 6.4 Hz, 2H, CH2),
13
.75-4.63 (m, 2H, CH) ppm. C NMR (101 MHz, CDCl ) δ 169.48, 147.59, 146.87,
3
34.57, 132.78, 132.31, 131.71, 131.24, 130.53, 130.04, 129.16, 128.89, 128.46, 128.39,
27.08, 126.91, 126.40, 126.16, 124.94, 124.26, 124.21, 122.45, 122.40, 122.38, 121.70,
11

3
1
+
7
5.66, 75.52, 43.13 ppm. P NMR (162 MHz, CDCl ) δ 146.71 ppm. HRMS (ESI ):
3
+
calcd for C H NNaO P [M+Na] 872.1574; found: 872.1553.
5
1
33
8 2
4
1
.2.2
-N-Benzylpyrrolidine-3,4-Bis[(S)-1,1'-Binaphthyl-2,2'-Diyl]Phosphite-D-Tartaric
Acid (2b)
S)-1,1'-Binaphthyl-2,2'-diyl-chlorophosphite 5b was synthesized by the same procedure
as 5a, and was used directly without further purification. Treatment of compound 4
132.7 mg, 0.60 mmol), 5b (463.0 mg, 1.32 mmol), DMAP (14.6 mg, 0.12 mmol), and
(
(
NEt (0.51 mL, 3.66 mmol) as described for the synthesis of ligand 2a afforded ligand 2b,
3
which was purified by flash chromatography (R = 0.44, toluene) to produce a white solid
f
2
0
o
1
(
264.4 mg, 51.9% yield). [α]D = +361 (c 0.13, CH Cl ); Mp 142-143 C; H NMR (400
2 2
MHz, CDCl ) δ 7.99 (d, J = 8.8 Hz, 2H, Ar), 7.94 (d, J = 8.2 Hz, 2H, Ar), 7.80 (d, J = 8.2
3
Hz, 2H, Ar), 7.64 (d, J = 8.8 Hz, 2H, Ar), 7.57 (d, J = 8.8 Hz, 2H, Ar), 7.48-7.42 (m, 4H,
Ar), 7.40 (d, J = 9.2 Hz, 3H, Ar), 7.38-7.35 (m, 2H, Ar), 7.34 (d, J = 3.2 Hz, 3H, Ar),
7
4
1
1
7
.31 (d, J = 6.4 Hz, 2H, Ar), 7.28 (d, J = 6.6 Hz, 5H, Ar), 5.02 (q, J = 7.2 Hz, 2H, CH2),
13
.67-4.55 (m, 2H, CH) ppm. C NMR (100 MHz, CDCl ) δ 169.59, 147.48, 146.85,
3
34.40, 132.78, 132.41, 131.76, 131.23, 130.68, 130.14, 129.06, 128.83, 128.45, 128.37,
27.08, 126.99, 126.47, 126.33, 125.38, 125.12, 124.24, 124.18, 122.49, 121.79, 121.65,
3
1
+
5.69, 75.58, 43.08 ppm. P NMR (162 MHz, CDCl ) δ 142.90 ppm. HRMS (ESI ):
3
+
calcd for C H NNaO P [M+Na] 872.1574; found: 872.1569.
5
1
33
8 2
1
2

4
1
.2.3
-N-Benzylpyrrolidine-3,4-Bis[(R)-1,1'-H -Binaphthyl-2,2'-Diyl]Phosphite-D-Tartari
8
c Acid (2c)
R)-1,1'-H -Binaphthyl-2,2'-diyl-chlorophosphite 5c was synthesized by the same
(
8
procedure as 5a, and was used directly without further purification. Treatment of
compound 4 (151.6 mg, 0.69 mmol), 5c (540.0 mg, 1.51 mmol), DMAP (16.7 mg, 0.14
mmol), and NEt (0.58 mL, 4.16 mmol) as described for the synthesis of ligand 2a
3
afforded ligand 2c, which was purified by flash chromatography (R = 0.43, toluene) to
f
2
0
produce a white solid (283.3 mg, 47.8% yield). [α]D = -158 (c 0.15, CH Cl ); Mp
2
2
o
1
1
33-134 C; H NMR (400 MHz, CDCl ) δ 7.11-7.03 (m, 5H, Ar), 6.99 (d, J = 8.2 Hz, 2H,
3
Ar), 6.96-6.87 (m, 4H, Ar), 6.81 (d, J = 8.2 Hz, 2H, Ar), 4.85 (d, J = 6.4 Hz, 2H, CH2),
.60 (d, J = 17.4 Hz, 2H, CH), 2.86-2.44 (m, 12H, CH ), 2.24-2.12 (m, 4H, CH ), 1.68
4
2
2
1
3
(
m, 12H, CH ), 1.52-1.39 (m, 4H, CH ) ppm. C NMR (100 MHz, CDCl ) δ 169.86,
2 2 3
1
1
2
45.80, 145.47, 138.56, 137.41, 135.08, 134.60, 134.11, 129.34, 129.22, 129.00, 128.81,
28.19, 127.59, 119.31, 118.94, 75.64, 75.45, 42.93, 29.13, 27.74, 22.60, 22.56, 22.44,
31
+
2.37 ppm. P NMR (161 MHz, CDCl ) δ 142.73 ppm. HRMS (ESI ): calcd for
3
+
C H NNaO P [M+Na] 888.2826; found: 888.2806.
51
49
8 2
4
1
.2.4
-N-Benzylpyrrolidine-3,4-Bis[(S)-1,1'-H -Binaphthyl-2,2'-Diyl]Phosphite-D-Tartari
8
c Acid (2d)
1
3

(
S)-1,1'-H -Binaphthyl-2,2'-diyl-chlorophosphite 5d was synthesized by the same
8
procedure as 5a, and was used directly without further purification. Treatment of
compound 4 (151.6 mg, 0.69 mmol), 5d (540.0 mg, 1.51 mmol), DMAP (16.7 mg, 0.14
mmol), and NEt (0.58 mL, 4.16 mmol) as described` for the synthesis of ligand 2a
3
afforded ligand 2d, which was purified by flash chromatography (R = 0.34, toluene) to
f
2
0
produce a white solid (283.8 mg, 47.9% yield). [α]D = +55 (c 0.13, CH Cl ); Mp
2
2
o
1
1
64-165 C; H NMR (400 MHz, CDCl ) δ 7.32 (s, 2H, Ar), 7.26 (s, 3H, Ar), 7.13-6.98
3
(
m, 6H, Ar), 6.92 (d, J = 8.0 Hz, 2H, Ar), 4.93 (d, J = 6.6 Hz, 2H, CH ), 4.61 (s, 2H, CH),
2
2
1
1
.95-2.54 (m, 12H, CH ), 2.25 (t, J = 13.2 Hz, 4H, CH ), 1.76 (d, J = 17.6 Hz, 12H, CH ),
2 2 2
1
3
.53 (s, 4H, CH ) ppm. C NMR (100 MHz, CDCl ) δ 170.00, 145.78, 145.51, 138.46,
2
3
37.62, 135.13, 134.42, 134.27, 129.48, 129.32, 129.00, 128.72, 128.19, 127.51, 119.02,
3
1
1
18.79, 75.53, 75.37, 42.93, 29.14, 29.09, 27.71, 22.57, 22.54, 22.38 ppm. P NMR (161
+
+
MHz, CDCl ) δ 140.02 ppm. HRMS (ESI ): calcd for C H NNaO P [M+Na]
3
51 49
8 2
8
88.2826; found: 888.2809.
4
.3 Representative Procedure for the 1,4-Conjugate Addition of Et Zn to Enones
2
and α, β-Unsaturated Lactone
A solution of Cu(OTf) (0.005 mmol, 1.8 mg) and ligand 2a (0.005 mmol, 4.2 mg) in
2
Toluene (4 mL) was stirred for 1 h at r.t. under nitrogen. After the solution was cooled to
o
0
C, 2-cyclohexenone 6a (0.25 mmol, 0.025 mL) was added and the solution was stirred
o
for 10 min at 0 C. Then Et Zn (0.6 mmol, 0.6 mL of 1.0 mol/L solution in hexane) was
2
1
4

added dropwise using a syringe within 2 min. After 4 h, the reaction was quenched by
H O (2 mL) and 2 mol/L HCl (2 mL), and extracted with ethyl acetate (5 mL × 3). The
2
combined organic layer was washed with saturated NaHCO solution, brine, and then
3
dried over anhydrous Na SO , filtered, and concentrated in vacuo to obtain the crude
2
4
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.
The 1,4-addition of ZnEt to acyclic enone substrates was the same as for substrate the
2
cyclic enones. However, the 1,4-adducts were separated by column chromatography on
silica gel (200-300 mesh) and eluted with Petroleum ether/EtOAc (40/1-20/1), and the
enantiomeric excess was determined by HPLC (Daicel Chiralcel AD-H 25 cm × 4.6 mm
ID).
REFERENCES
[
1] Scafato, P.; Labano, S.; Cunsolo, G.; Rosini, C. Tetrahedron: Asymmetry 2003, 14,
873-3877.
2] (a) Alexakis, A.; Backvall, J. E.; Krause, N.; Pamies, O.; Dieguez, M. Chem. Rev.
008, 108, 2796-2823; (b) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.; Minnaard, A.
3
[
2
1
5

J.; Feringa, B. L. Chem. Rev. 2008, 108, 2824-2852; (c) van Leeuwen, P. W.; Kamer, P. C.;
Claver, C.; Pamies, O.; Dieguez, M. Chem. Rev. 2011, 111, 2077-2118.
[
3] (a) Tissot, M.; Muller, D.; Belot, S.; Alexakis, A. Org. Lett. 2010, 12, 2770-2773; (b)
Dogan, Ö.; Bulut, A.; Polat, S.; Ali Tecimer, M. Tetrahedron: Asymmetry 2011, 22,
601-1604; (c) Mauduit, M.; Ratovelomanana-Vidal, V.; Crévisy, C.; Morin, M.; Vives,
T.; Baslé, O. Synthesis 2015, 47, 2570-2577.
4] (a) Gavrilov, K. N.; Shiryaev, A. A.; Zheglov, S. V.; Bochelyuk, M. S.; Chuchelkin, I.
V.; Tafeenko, V. A.; Chernyshev, V. V.; Zamilatskov, I. A.; Mikhel, I. S. Tetrahedron Lett.
015, 56, 4756-4761; (b) Palais, L.; Babel, L.; Quintard, A.; Belot, S.; Alexakis, A. Org.
1
[
2
Lett. 2010, 12, 1988-1991; (c) Ladjel, C.; Fuchs, N.; Zhao, J.; Bernardinelli, G.; Alexakis,
A. Eur. J. Org. Chem. 2009, 2009, 4949-4955; (d) Pang, Z. B.; Xing, A. P.; Wang, L. L.
Chem. Res. Chin. Univ. 2015, 31, 756-760; (e) Pamies, O.; Dieguez, M.; Net, G.; Ruiz, A.;
Claver, C. Tetrahedron: Asymmetry 2000, 11, 4377-4383; (f) Iuliano, A.; Scafato, P.;
Torchia, R. Tetrahedron: Asymmetry 2004, 15, 2533-2538; (g) Liang, L.; Yan, M.; Li, Y.
M.; Chan, A. S. C. Tetrahedron: Asymmetry 2004, 15, 2575-2578.
[
5] (a) Monnier, F.; Taillefer, M. Angew. Chem. Int. Ed. 2009, 48, 6954-6971; (b) Zou, D.
Y.; Duan, Z. C.; Hu, X. P.; Zheng, Z. Tetrahedron: Asymmetry 2009, 20, 235-239; (c)
Westmeier, J.; von Zezschwitz, P. Chem. Commun. 2014, 50, 15897-15900; (d) Lee, A.;
Kim, H. J. Am. Chem. Soc. 2015, 137, 11250-11253; (e) Roth, P. M.; Fletcher, S. P. Org.
Lett. 2015, 17, 912-915.
1
6

[
6] Alexakis, A.; Burton, J.; Vastra, J.; Mangeney, P. Tetrahedron: Asymmetry 1997, 8,
987-3990.
3
[
[
7] Xing, A. P.; Bai, C. B.; Wang, L. L. Tetrahedron 2013, 69, 455-459.
8] (a) Pang, Z. B.; Li, H. F.; Tian, M.; Wang, L. L. Tetrahedron: Asymmetry 2015, 26,
1
1
389-1393; (b) Zhao, Q. L.; Miao, X.; Wang, L. L. Tetrahedron: Asymmetry 2013, 24,
04-107.
[
[
9] Yan, M.; Zhou, Z. Y.; Chan, A. S. C. Chem. Commun. 2000, 115-116.
10]Korostylev, A.; Tararov, V. I.; Fischer, C.; Monsees, A.; Borner, A. J. Org. Chem.
2
004, 69, 3220-3221.
1
7

Table 1 The effect of ligand structures and solvents on the enantioselectivity for the ACA
a
of ZnEt to 2-cyclohexenone
2
b
b
c
Entry Ligand
Solvent
Conv.
%)
Yield (%)
%ee
(
(conf.)
14 (R)
20 (S)
22 (R)
22 (S)
28 (R)
11 (R)
89 (R)
94 (R)
47 (R)
90 (R)
1
2
3
4
5
6
7
2a
2b
2c
2d
2c
2c
2c
2c
2c
2c
Toluene
Toluene
Toluene
Toluene
84
67
86
74
52
87
41
92
22
66
53
32
64
48
25
55
20
48
10
24
Et O
2
CH Cl
2
2
THF
d
8
9
Toluene/THF
CH Cl /THF
d
2
2
d
1
0
Et O/THF
2
a
Reaction conditions: Cu(OTf) (0.005 mmol), ligand (0.005 mmol), ZnEt (1.0 mol/L in
2
2
o
hexane, 0.6 mmol), 6a (0.25 mmol), solvent (4 mL), 0 C, 4 h.
b
The data on conversion and yield were determined by GC using dodecane as internal
standard with a SE-30 column (30 m × 0.32 mm I.D.).
1
8

c
The enantiomeric excess of compound 7a was determined by GC equipped with a
Chiraldex A-TA column (50 m × 0.25 mm I.D.). The absolute configuration of 7a was
determined by comparison with authentic sample.
d
The volume ratio of all mixed solvent was 1:1.
1
9

Table 2 The effect of other factors on the enantioselectivity for the ACA of ZnEt to
2
a
2
-cyclohexenone
o
b
b
b
Entry Cu precursor T ( C)
Conv.
%)
Yield (%)
%ee (conf.)
(
1
(CuOTf) ·C H
0
54
11
87 (R)
2
6
6
2
3
Cu(acac)2
CuTc
0
22
38
74
41
97
91
92
91
94
85
50
3
28 (R)
46 (R)
94 (R)
71 (R)
88 (R)
94 (R)
97 (R)
96 (R)
98 (R)
98 (R)
97 (R)
0
4
c
4
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
0
50
20
36
45
52
88
79
73
27
d
5
0
6
20
-10
-20
-30
-40
-50
-78
e
e
e
7
8
9
e
1
0
e
11
e
1
2
a
Reaction conditions: Cu precursor (0.005 mmol), ligand 2c (0.0025-0.01 mmol), Et Zn
2
2
0

(1.0 mol/L in hexane, 0.6 mmol), 6a (0.25 mmol), mixed solvents (4 mL), -40-20 °C, 4 h.
b
The data on conversion, yield, the enantiomeric excess, and the absolute configuration of
the product were determined by the same condition as noted in Table 1.
c
d
e
L/Cu = 0.5. L/Cu =2. Reaction time : 12 h.
2
1

a
Table 3 The Cu-catalyzed ACA of dialkylzinc to cyclic enones
b
b
b
Entry Ligand Sub./Pro Conv. (%) Yield (%) %ee (conf.)
.
1
2
3
4
2c
1d
2c
1d
2c
1d
2c
2c
6a/7a
6a/7a
6b/7b
6b/7b
6c/7c
6c/7c
6a/7d
6a/7e
91
99
26
99
34
39
20
n.d.
88
92
18
21
27
25
12
n.d.
96 (R)
95 (S)
96 (R)
95 (S)
77 (R)
63 (S)
42 (R)
n.d.
c
5
6
c
c,d
7
e
8
a
Reaction conditions: Cu(OTf) (0.005 mmol), ligand 2c (0.005 mmol), Et Zn (1.0 mol/L
2
2
in hexane, 0.6 mmol), enone (0.25 mmol), mixed solvents (4 mL), 0 °C, 4-24 h.
b
The data on conversion, yield, the enantiomeric excess, and the absolute configuration
of the product were determined by the same condition as noted in Table 1.
c
The enantiomeric excess was determined by GC equipped with a CP-ChirasilDex CB
(25 m × 0.25 mm I.D.).
d
Me Zn (1.2 M in toluene, 1.2 mmol), 24 h.
2
2
2

e
Cu(OTf) (0.005 mmol), 2c (0.010 mmol), Ph Zn (1.2 mol/L in toluene, 0.6 mmol), 24 h,
2
2
isolated yield, the ee of 7e was determined by HPLC (Daicel Chiralcel AD-H,
o
hexane/i-PrOH=99/1, 0.5 mL/min at 20 C, detected at 209 nm.
2
3

a
Table 4 The Cu-catalyzed ACA of ZnEt to 5,6-dihydro-2H-pyran-2-one
2
b
b
b
Entry Ligand Solvent Cu precursor
T
Conv.
(%)
31
Yield(%)
% ee
o
(
C)
0
(Conf.)
31(R)
3(S)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2a
2a
2a
2a
2a
2a
2a
2a
Et O
(CuOTf) ·C H
22
16
7
2
2
6
6
6
6
6
6
6
6
Et O
(CuOTf) ·C H
0
24
2
2
6
Et O
(CuOTf) ·C H
0
15
29(R)
17(S)
17(R)
11(R)
22(R)
44(R)
35(R)
52(R)
35(R)
37(R)
2
2
6
Et O
(CuOTf) ·C H
0
19
10
29
10
3
2
2
6
Toluene (CuOTf) ·C H
0
40
2
6
CH Cl (CuOTf) ·C H
0
21
2
2
2
6
THF
(CuOTf) ·C H
0
12
2
6
Et O
CuOTf2
0
17
7
2
Et O
Cu(acac)2
CuTc
0
16
9
2
1
0
Et O
0
23
12
24
19
2
11
Et O
(CuOTf) ·C H
25
42
2
2
6
6
c
1
2
Et O
(CuOTf) ·C H
0
36
2
2
6
6
a
Reaction conditions: Cu(OTf) (0.005 mmol), ligand (0.005mmol), ZnEt (1.0 mol/L in
2
2
o
hexane, 0.6 mmol), 8 (0.25 mmol), solvent (4 mL), 0 C, 6h.
b
The data on conversion, yield and the enantiomeric excess were determined by GC
2
4

equipped with a Chiraldex A-TA column (50 m × 0.25 mm I.D.). The absolute
configuration of 9 was determined by comparison with authentic sample.
c
Substrate 0.125mmol.
2
5

Scheme 1. The synthesis of diphosphite ligands derived from D-(-)-tartaric acid.
2
6

Scheme 2. The Cu-catalyzed ACA of ZnEt to acyclic enones.
2
2
7

Figure 1. The diphosphite ligands derived from L-(+) and D-(-)-tartaric acid.
2
8