Chiral phosphite ligands derived from l-(+)-tartaric acid: Synthesis and application in the Cu-catalyzed 1,4-conjugate addition of organozincs to cyclic enones

Article abstract of DOI:10.1016/j.tet.2012.11.038

A new series of chiral phosphite ligands derived from readily available l-(+)-tartaric acid and binaphthol derivatives were designed and prepared in convenient synthetic routes. These ligands were successfully employed in the Cu-catalyzed asymmetric conju

Full text of DOI:10.1016/j.tet.2012.11.038

Tetrahedron 69 (2013) 455e459
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chiral phosphite ligands derived from
L
and application in the Cu-catalyzed 1,4-conjugate addition
of organozincs to cyclic enones
-(þ)-tartaric acid: synthesis
Ai-ping Xing , Cui-bing Bai , Lai-lai Wang a
a
,
b
c
,
*
a
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China
Graduate University of Chinese Academy of Sciences, Beijing 100039, China
Key Laboratory of Polymer Materials of Gansu Province, College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, China
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 July 2012
Received in revised form 7 November 2012
Accepted 9 November 2012
Available online 15 November 2012
A new series of chiral phosphite ligands derived from readily available
L
-(þ)-tartaric acid and binaphthol
derivatives were designed and prepared in convenient synthetic routes. These ligands were successfully
employed in the Cu-catalyzed asymmetric conjugate addition of organozincs to cyclic enones. The li-
0
0
0
gands bearing (R)- and (S)-binaphthol and/or 3,3 -bis(trimethylsilyl)-2,2 -dihydroxy-1,1 -binaphthol af-
forded both enantiomers of the product in high yields and good enantioselectivities (up to 95% ee). The
chiral organocopper reagent did exhibit high enantioselectivities for cyclic enones bearing different ring
Keywords:
sizes. The stereochemically matched combination of
ligand 1-N-benzylpyrrolidine-3,4-bis[(R)-1,1 -binaphthyl-2,2 -diyl]phosphite-
L
-(þ)-tartaric acid backbone and (R)-binaphthyl in
Phosphite ligands
Copper precursor
Organozincs
0
0
L
-tartaric acid was essential
to afford 95% (R) ee for 3-ethylcyclopentanone, 95% ee (S) for 3-ethyl-cyclohexanone, and 63% ee (R) for
3-ethylcycloheptanone in ether as solvent, using (CuOTf) $C as a catalytic precursor. Moreover, the
Cyclic enones
2
6 6
H
Conjugate addition
sense of the enantio discrimination of the products was mainly determined by the configuration of the
binaphthyl phosphite moieties.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
catalytic reactions.11e15 Ligand 1, in which the phosphorus atom
was incorporated into a five-membered ring with 1-(R)-endo-
The asymmetric 1,4-conjugate addition (ACA) of organometallic
reagents to -unsaturated carbonyl compounds is one of the most
useful methods for carbonecarbon bond formation in the synthesis
(þ)-fenchol as the chiral exocyclic component, gave 65% ee in the
12
a,
b
2
ACA of Et Zn to benzalacetone.
1
2
of biologically active compounds, such as erogorgiaene,
3
4
(
ꢀ)-pumiliotoxin C, clavularin B. Ever since the discovery of the
Cu-catalyzed ACA of dialkylzinc reagents to -unsaturated car-
a,b
bonyl compounds in the early 1990s by Alexakis and co-workers,
considerable efforts have been put into this area during the past
1
,4e6
decades by many research groups.
To date, several chiral
7
8
phosphorus ligands, such as phosphoramidite, phosphite ligands,
P, N-ligands and others, have been successfully employed in the
reaction.
9
10
L
-(þ)-Tartaric acid is one of the most naturally occurring hy-
Fig. 1. Selected phosphorus ligands based on naturally occurring chiral compounds.
droxyl acids and is extremely useful for the synthesis of chiral li-
gands, since they are of high enantiomeric purity and are readily
available. Versatile chiral ligands (Fig. 1, ligands 1e3) derived from
-(þ)-tartaric acid were synthesized and applied in asymmetric
Despite the variety of structures similar to ligand 1 tested, only
low-to-moderate ee values were attained in the Cu-catalyzed ACA.
L
13
Alexakis and co-workers synthesized a large variety of TADDOL-
based phosphite ligands, and screened these ligands in ACA.
When ligand 2 was used, 96% ee was obtained in ACA of Et
2
Zn to 2-
cyclohexenone, however, the enantioselectivities in analogous ACA
of organozinc to 2-cyclopentenone were disappointingly low.
*
Corresponding author. E-mail addresses: hn_xap@163.com (A.-P. Xing), wll@
14
licp.cas.cn (L.-I. Wang).
0
040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.038

456
A.-P. Xing et al. / Tetrahedron 69 (2013) 455e459
Although many existing phosphite ligands, which derived from
entry 2). These results suggested that ligands 6a or 6b with (R)- or
(S)-H -binaphthyl moieties and
strong mismatched character. Interestingly, 95% ee (S) was ach-
ieved using ligand 6c (Table 1, entry 3), and ligand 6d, bearing with
opposite axially chirality of the binaphthyl moiety to 6c and the
L
-(þ)-tartaric acid, had induced good-to-excellent enantioselectiv-
8
L-(þ)-tartaric acid skeleton showed
ities, it is desirable to search for an alternative approach in the
synthesis of efficient phosphite ligands with a novel attempt of
L
-(þ)-tartaric acid as the starting material and new ligands over-
coming the limitation of substrate specificity. Bisdiamidophosphite
ligand 3, which was accessible from (3R,4R)-N-benzyl-tartarimide 4
same
L
-(þ)-tartaric acid skeleton as ligand 6c, gave 91% ee (R) and
18
high yield (80%) (Table 1, entry 4). Di eꢀ guez had reported that the
presence of bulky substituents trimethylsilyl in the 3,3 -position of
0
(
Scheme 1), gave 96% ee, 83% ee, and 65% ee in the Pd-catalyzed
allylic alkylation of (E)-1,3-diphenylallyl acetate, the Rh-catalyzed
hydrogenation of -dehydrocarboxylic acid esters, and the
Rh-catalyzed addition of phenylboronic acid to 2-methoxybenz-
aldehyde, respectively.15 Based on previous results that
the binaphthyl backbone had a positive effect on the catalytic ac-
tivity of the asymmetric reactions. Surprisingly, ligand 6e, con-
a
taining the same
L
-(þ)-tartaric acid skeleton as ligand 6a and bulky
0
L-(þ)-tar-
trimethylsilyl groups in the 3,3 -position of the (R)-binaphthyl
moieties, afforded 90% yield and 82% ee (S) (Table 1, entry 5). Ligand
taric acid skeletons were successfully applied in asymmetric cata-
lytic reactions, we report the synthesis and application of the new
chiral aryl diphosphite ligands 6aef (Scheme 1). The results in-
dicated that these ligands gave high activity and enantioselectivity
3
6f, in which the binaphthyl moiety was replaced by (S)-SiMe -
binaphthyl, produced higher yield (95%) than ligand 6e, and 79% ee
(R) (Table 1, entries 5 vs 6). The above-mentioned results clearly
(
2
up to 95% ee) in the Cu-catalyzed ACA of organozincs to
-cyclopentenone and 2-cyclohexenone.
indicated that axially chiral binaphthyl, and/or SiMe
moieties and
-(þ)-tartaric acid backbone in ligands 6c, 6d, 6e, and
f had a synergic effect on the enantioselectivity. In addition, no
matter axially chiral binaphthyl and/or SiMe -binaphthyl moieties
3
-binaphthyl
L
6
3
was (R)- or (S)-configuration, high enantioselectivity of both en-
antiomers of the product had been achieved.
Table 1
The Cu-catalyzed enantioselective 1,4-addition of Et
2
Zn to 2-cyclohexenonea
Entry
Cu salts
L.
L/Cu
Con.b (%)
Y.b (%)
% ee (Conf.)c
Scheme 1. The synthesis of diphosphite ligands derived from (3R,4R)-N-
benzyltartarimide.
1
2
3
4
5
6
7
8
9
(CuOTf) $C H
6a
6b
6c
6d
6e
6f
6c
6c
6c
6c
1
1
1
1
1
1
1
0.5
1.1
2
87
40
58
23
92
80
90
95
91
89
84
47
25 (S)
36 (R)
95 (S)
91 (R)
82 (S)
79 (R)
90 (S)
94 (S)
92 (S)
93 (S)
2
6
6
6
6
6
6
6
(CuOTf) $C H
2
2
2
2
2
2
2
2
2
6
6
6
6
6
(CuOTf)
(CuOTf)
(CuOTf)
(CuOTf)
Cu(OTf)
(CuOTf)
(CuOTf)
(CuOTf)
$C
$C
$C
$C
H
H
H
H
>99
>99
>99
>99
>99
>99
89
2
2
. Results and discussion
.1. Synthesis of phosphite ligands 6aef
6
$C H
6
$C H
6
$C H
6
6
6
AsshowninScheme 1, diphosphite ligands6aef were synthesized
10
54
stereospecificallyinone stepfrom compound4andchlorophosphoric
a
Reaction conditions: Cu(OTf)
2
(0.005 mmol) or (CuOTf)
2
$C
6
H
6
(0.0025 mmol),
0
acid diary ester 6, which derived from 2,2 -dihydroxy-
ligand (0.005e0.01 mmol), Et
2
Zn (1.0 M in hexane, 0.6 mmol), 7a (0.25 mmol), ether
0
0
0
0
0
0
5
,5 ,6,6 ,7,7 ,8,8 -octahydro-1,1 -binaphthol (H
8
-binaphthol), 2,2 -
ꢁ
(
4 mL), 0 C, 4 h.
0
0
b
dihydroxy-1,1 -binaphthol(binaphthol), and3,3 -bis-(trimethylsilyl)-
The data on conversion and yield were determined by GC using dodecane as an
0
0
16
internal standard with a SE-30 column (30 mꢂ0.32 mm I.D.).
2
,2 -dihydroxy-1,1 -binaphthol (SiMe -binaphthol). Though com-
3
c
The enantiomeric excess of 8a was determined by GC equipped with a Chiral-
pound 4 is a known compound, its single crystal is first reported.
Mixing with THF induced crystallization and after recrystallization
from THF, the colorless crystals were obtained. All ligands were pu-
rified on a silica gel column under the nitrogen atmosphere with
moderate to good yields.
dex A-TA column (50 mꢂ0.25 mm I.D.). The absolute configuration of 8a was de-
termined by comparison with an authentic sample.
We next examined the influence of the copper precursor as well
as ligand 6c/copper ratio on the catalytic activity and enantiose-
lectivity (Table 1, entries 7e10). In comparison to (CuOTf)
Cu(OTf) as a catalytic precursor gave 90% ee (S) (Table 1, entry 7).
No significant changes in catalytic performance were observed by
changing a ratio of ligand 6c/Cu(OTf) $C (mol/mol) from 0.5/1 to
1/1 (Table 1, entries 3 and 8). Further increase of the ratio of ligand
6c/Cu(OTf) $C (mol/mol) brought no obvious change of the
enantioselectivity, but the yield of the reactions significantly de-
creased (Table 1, entries 3, 8e10).
With ligand 6c being identified as the most effective ligand,
using (CuOTf) $C H as a catalyst precursor, ACA of Et Zn to 7a in
2 6 6 2
2 6 6
$C H ,
2
.2. Enantioselective 1,4-conjugate addition of R
2
Zn to cyclic
2
enones
2
6 6
H
With ligands 6aef in hand, we evaluated their asymmetric
induction ability in the Cu-catalyzed ACA of Et Zn to
-cyclohexenone 7a, and the results were summarized in Table 1.
2
2
6 6
H
2
7a
17
Alexakis and Feringa proposed that the catalytically active
species was a Cu(I) complex. Therefore, in the first set of experi-
ments, we tested, separately, ligands 6aef by using ether as solvent
and (CuOTf)
2
$C
6
H
6
as a catalytic precursor separately (Table 1, en-
different solvents and at various temperatures were carried out
separately. A profound solvent effect on the reactions was observed
(Table 2, entries 1e3). When the reaction was carried out in tolu-
ene, low yield and good enantioselectivity of the reaction were
obtained (80% ee) (Table 2, entry 1). Low enantioselectivities were
tries 1e6). Ligand 6a afforded the desired addition product in
moderate yield with poor enantiomeric excess (Table 1, entry 1).
And ligand 6b, bearing with the same diol skeleton as ligand 6a and
8
(S)-H -binaphthyl moieties, gave 23% yield and 36% ee (R) (Table 1,

A.-P. Xing et al. / Tetrahedron 69 (2013) 455e459
457
Table 2
ethylcyclohexanone (Table 1, entry 3), and 63% ee (R) for 3-
ethylcycloheptanone (Table 3, entry 2). Under the optimal re-
action conditions, a survey of the reaction scope was undertaken.
The Cu-catalyzed enantioselective 1,4-addition of R
2
Zn to cyclic enonesa
2 2
When Me Zn or Ph Zn was utilized in the reaction, the enantio-
selectivity decreased to 67% (S) and 22% (R), respectively (Table 3,
entries 3 and 4).
3. Conclusion
ꢁ
Con.b (%)
Y.b (%)
% ee (Conf.)b
Entry
Sol
T ( C)
t (h)
In conclusion, we disclosed a new series of diphosphite ligands
aef, which were derived from (3R,4R)-N-benzyltartarimide. The
1
2
3
4
5
6
7
8
Toluene
0
0
0
20
4
4
4
19
16
15
50
80
>99
90
13
10
10
3
26
70
65
63
11
80 (S)
30 (S)
39 (S)
75 (S)
92 (S)
85 (S)
69 (S)
55 (S)
6
CH
2
Cl
2
ligands were successfully applied in the Cu-catalyzed ACA of
organozincs to cyclic enones. A synergic effect of
-(þ)-tartaric acid
THF
Ether
Ether
Ether
Ether
Ether
4
L
ꢀ10
ꢀ20
ꢀ30
ꢀ40
12
12
12
12
skeleton and the axially chiral diaryl moieties of the ligands 6cef on
the catalytic activity and enantioselectivity of the reaction was
observed. The sense of the enantio discrimination was pre-
dominantly controlled by the configuration of the biaryl moieties of
ligands 6aef. The work presented here paves the way for the de-
velopment of new diphosphite ligands for the asymmetric re-
actions. The application of these ligands to other transition metal-
catalyzed asymmetric reactions is ongoing in our laboratory.
a
2 6 6
Reaction conditions: (CuOTf) $C H (0.0025 mmol), ligand 6c (0.005 mmol),
Zn (1.0 M in hexane, 0.6 mmol), cyclic enone (0.25 mmol), solvent (4 mL).
The data on conversion, yield, enantiomeric excess, and the absolute configura-
tion of the products were determined using the same conditions as noted in Table 1.
Et
2
b
received in solvents CH
and 3). Ether was proven to be an appropriate solvent in our cases
2 2
Cl and THF, respectively (Table 2, entries 2
4
4
. Experimental
(Table 1, entry 3 vs Table 2, entries 1e3). By lowering the reaction
.1. General
ꢁ
temperature from 0 to ꢀ40 C, the ee values of the product 8a
decreased from 95% (S) to 55% (S), and the yield of the reaction
significantly decreased accordingly. The best enantioselectivity was
Melting points were determined using an X-4 melting point
apparatus and were uncorrected. Optical rotations were measured
on a PerkineElmer 241 MC polarimeter at 20 C. NMR spectra were
recorded on Bulker 400 MHz spectrometers. H NMR and C NMR
ꢁ
achieved at 0 C in our cases (Table 1, entry 3 vs Table 2, entries
e8).
Under the aforementioned reaction conditions, we next studied
the ACA of Et Zn to 2-cyclopentenone 7b and 2-cycloheptenone 7c
as substrates respectively. Encouragingly, ligand 6c afforded 95% ee
R) in the ACA of Et Zn to 7b (Table 3, entry 1). However, the yield of
ꢁ
4
1
13
spectra were reported in parts per million with TMS (d¼0.00 ppm)
31
2
as an internal standard. P NMR spectra was reported in parts per
3 4
million with 85% H PO as an external reference. Proton chemical
(
2
shifts (d) and coupling constants (J) were reported in ppm and in
Hertz, respectively. Spin multiplicities were given as s (singlet),
d (doublet), t (triplet), and m (multiplet). HRMS were recorded on
a Bulker micrOTOF-QII mass instrument. X-ray crystallographic
data were collected on a Bruker SMART CCD1000 diffractometer
the reaction was lower (21%) (Table 3, entry 1). It was due to the
difficult separation from side products and the high volatility of the
product.14 A significant dependence of enantioselectivity on the
ring size of the substrates was observed: 95% ee (R) for 3-
ethylcyclopentanone (Table 3, entry 1), 95% ee (S) for 3-
ꢁ
with graphite monochromated Mo K
2) K. All reactions and manipulations under rigorous water and
oxygen free conditions were performed under an N atmosphere
a radiation (0.71073 A) at 293
(
2
Table 3
with standard Schlenk techniques. The reactions were monitored
by thin layer chromatography (TLC, silica gel GF254 plates). Column
chromatography separations were conducted on silica gel
The Cu-catalyzed enantioselective 1,4-addition of R
2
Zn to cyclic enonesa
(
200e300 mesh). NEt
3
, THF, Et
2
O, and toluene were distilled with
Cl was dried over
-binaphthol was
Na and benzophenone as an indicator, and CH
CaH
2
2
16a
19
2
before use. H
8
-Binaphthol
and SiMe
3
prepared according to a literature procedure. All the other chem-
icals were obtained commercially.
4.2. Synthesis of ligands 6aef
0
0
8
-binaphthyl-2,2 -diyl]
4
.2.1. 1-N-Benzylpyrrolidine-3,4-bis[(R)-1,1 -H
-tartaric acid (6a). To a 100 mL Schlenk flask equipped
with a condenser were added 2.0 g of (R)-H -binaphthol, 20 mL of
toluene, and 12 mL of PCl . Then the mixture was refluxed for 20 h
under a nitrogen atmosphere. After removal of the excessive PCl
Entry
1
Sub.
Prod.
t (h)
Con.b (%)
Y.b (%)
% ee (Conf.)b
phosphite-
L
7b
7c
7a
7a
8b
8c
8d
8e
4
4
24
24
>99
39
30
21
25
21
34
95 (R)
63 (R)
67 (S)
22 (R)
8
c
2
3
4
3
c,d
e
3
99
and toluene, the residue was dissolved in 20 mL of toluene, and
then was transferred to another Schlenk flask, and toluene was
removed in vacuo to obtain compound (R)-1,1 -H -binaphthyl-2,2 -
a
2 6 6
Reaction conditions: (CuOTf) $C H (0.0025 mmol), ligand 6c (0.005 mmol),
2
R Zn (1.0 M in hexane, 0.6 mmol), cyclic enone (0.25 mmol), ether (4 mL).
0
0
b
8
The data on conversion, yield, enantiomeric excess, and the absolute configura-
tion of the products were determined using the same conditions as noted in Table 1.
diyl-chlorophosphite (5a) as a white powder, which was used di-
rectly in the following step without further purification. To a stirred
solution of compound 4 (132.7 mg, 0.6 mmol), compound 5a
c
The enantiomeric excess was determined by GC equipped with a CP-Chirasil-
Dex CB (25 mꢂ0.25 mm I.D.).
d
2
Me Zn (1.2 M in toluene, 1.2 mmol), 24 h.
e
(463 mg, 1.32 mmol), and DMAP (14.6 mg, 0.12 mmol) in THF
(
2 6 6 2
CuOTf) $C H (0.0025 mmol), 6c (0.0015 mmol), Ph Zn (1.2 M in toluene,
ꢁ
(
10 mL) at ꢀ15 C, NEt
3
(0.34 mL) was slowly added using a syringe
0
.6 mmol), 24 h, isolated yield, the ee of 8e was determined by HPLC (Daicel Chir-
ꢁ
ꢁ
alcel AD-H, hexane/i-PrOH¼99/1, 0.5 mL/min at 20 C, detected at 209 nm).
over 2 min, and the solution was stirred for 0.5 h at ꢀ15 C. The

458
A.-P. Xing et al. / Tetrahedron 69 (2013) 455e459
mixture was then stirred at rt 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 chro-
d 42.07, 74.46, 120.67, 121.43, 123.91, 124.26, 125.14, 125.86, 127.19,
128.00, 129.01, 129.52, 130.19, 130.66, 133.53, 145.85, 168.45; HRMS
þ
(ESI) calcd for C51
H34NO
8
P
2
[MþH] : 850.1760, found: 850.1754.
0 0
4.2.5. 1-N-Benzylpyrrolidine-3,4-bis[(R)-1,1 -binaphthyl-2,2 -diyl-
matography (toluene, R
f
¼0.36) and furnished ligand 6a as a white
ꢁ
20
D
0 0
3,3 -di(trimethylsilyl)]phosphite-L-tartaric acid (6e). (R)-3,3 -Trime-
foamy solid (457 mg, 66% yield), mp 173e174 C; ½
a
ꢃ
ꢀ96.4 (c 0.11,
31
1
0
0
CH
2
Cl
2
); P NMR (161 MHz, CDCl
3
)
d
140.17; H NMR (400 MHz,
thylsilyl-1,1 -binaphtyl-2,2 -diol (1.00 g, 2.31 mmol) was azeo-
tropically dried by dissolving it in anhydrous toluene (10 mL)
followed by the evaporation of the solvent (two times) in vacuo.
The dry starting material was then dissolved in toluene (25 mL).
CDCl
3
)
d
1.45 (d, J¼8.0 Hz, 4H), 1.66 (d, J¼16.0 Hz, 12H), 2.13e2.20
(
(
(
m, 4H), 2.55e2.75 (m,12H), 4.53 (s, 2H), 4.85 (d, J¼4.0 Hz, 2H), 6.83
d, J¼8.0 Hz,1H), 6.97e7.01 (m, 5H), 7.08 (d, J¼4.0 Hz, 2H), 7.15e7.18
m, 4H), 7.25 (s,1H); 13C NMR (100 MHz, CDCl
)
d
21.38, 21.57, 26.72,
PCl
(242 mL, 381 mg, 2.77 mmol) and triethylamine (1.3 mL, 0.93 g,
3
3
ꢁ
2
8.09, 41.93, 74.52, 117.78, 124.27, 127.19, 128.06, 128.33, 133.26,
9.2 mmol) were dissolved in toluene (50 mL) at ꢀ5 C and were
ꢁ
1
C
34.13, 136.62, 137.45, 144.77, 169.01; HRMS (ESI) calcd for
added dropwise to the SiMe
3
-binaphthol solution at 0 C. After
þ
ꢁ
51
H
49NNaO
8
P
2
[MþNa] : 888.2831, found: 888.2826.
stirring overnight, the resulting suspension was stirred at 50 C for
1
3
h. After removal of the excessive PCl and toluene, the residue was
0
0
0
4
.2.2. 1-N-Benzylpyrrolidine-3,4-bis[(S)-1,1 -H
8
-binaphthyl-2,2 -diyl]
dissolved in 20 mL of toluene, and then was transferred to another
0
phosphite-
L
-tartaric acid (6b). (S)-1,1 -H
8
-Binaphthyl-2,2 -diyl-
Schlenk flask, and toluene was removed in vacuo to obtain a yellow,
31
chlorophosphite 5b was synthesized by the same procedure as that
of 5a, and was used directly without further purification. Treatment
of compound 4 (132.7 mg, 0.6 mmol), 5b (632 mg, 1.76 mmol), and
DMAP (14.6 mg, 0.12 mmol) as described for the synthesis of ligand
air-sensitive powder 5e ( P NMR d 175.48 ppm). This compound
was not characterized further, but used immediately in next re-
actions. Treatment of compound 4 (177 mg, 0.8 mmol), 5e (832 mg,
1.68 mmol), and DMAP (19.5 mg, 0.16 mmol) as described for the
synthesis of ligand 6a afforded ligand 6e, which was purified by
6
a afforded ligand 6b, which was purified by flash chromatography
(
toluene, R
f
¼0.40) to produce a white solid (301 mg, 58% yield), mp
flash chromatography (toluene, R
f
¼0.24) to produce a white solid
ꢁ
20
D
31
ꢁ
20
D
31
1
50e151 C; ½
a
ꢃ
þ270.1 (c 0.11, CH
2
Cl
1.18 (s, 3H),1.45e1.48 (m, 3H),
.67e1.71 (m, 9H), 2.16e2.21 (m, 4H), 2.27 (s, 2H), 2.54e2.61 (m,
H), 2.66e2.74 (m, 7H), 4.63 (s, 2H), 4.86 (d, J¼4.0 Hz, 2H), 6.80 (d,
J¼8.0 Hz, 2H), 6.89e6.94 (m, 4H), 6.99 (d, J¼8.0 Hz, 2H), 7.05e7.10
m, 1H), 7.15e7.19 (m, 2H), 7.26e7.29 (m, 2H), 7.34e7.36 (m, 2H);
2
); P NMR (161 MHz, CDCl
3
)
(383 mg, 42% yield), mp 79e80 C; ½
a
ꢃ
ꢀ259.3 (c 0.68, CH
2
Cl
2
);
P
1
1
d
142.69; H NMR (400 MHz, CDCl
3
)
d
NMR (161 MHz, CDCl
3
)
d
137.31; H NMR (400 MHz, CDCl
3
)
d
0.33 (s,
1
3
18H), 0.41 (s, 18H), 4.18 (d, J¼4.0 Hz, 1H), 4.50 (s, 2H), 4.87e4.91 (m,
1H), 6.96 (d, J¼8.0 Hz, 1H), 7.10e7.11 (m, 4H), 7.17e7.18 (m, 4H),
7.22e7.23 (m, 4H), 7.31e7.34 (m, 4H), 7.80e7.85 (m, 4H), 7.99e8.02
13
(
(m, 4H); C NMR (100 MHz, CDCl
3
) d 0, 42.67, 73.37, 122.62, 125.25,
1
3
3
C NMR (100 MHz, CDCl ) d 21.44, 21.61, 26.74, 28.13, 41.93, 74.64,
126.59, 128.17, 128.66, 128.93, 130.59, 131.11, 134.62, 136.72, 137.30,
1
18.30, 124.27, 127.38, 128.01, 128.23, 133.12, 134.08, 136.41, 137.56,
151.19, 169.91, 172.14; HRMS (ESI) calcd for C63
H
65NO
8
P
2
Si
4
[M-
þ
þ
144.77, 168.87; HRMS (ESI) calcd for C51
H
49NNaO
8
P
2
[MþNa] :
CH
5
Si] : 1092.3101, found: 1092.4630.
8
88.2831, found: 888.2826.
0
0
4
.2.6. 1-N-Benzylpyrrolidine-3,4-bis[(S)-1,1 -binaphthyl-2,2 -diyl-
0
0
0
0
4
.2.3. 1-N-Benzylpyrrolidine-3,4-bis[(R)-1,1 -binaphthyl-2,2 -diyl]
3,3 -di(trimethylsilyl)]phosphite-
L
-tartaric
acid
(6f). (S)-1,1 -
0
0
0
0
phosphite-
L
-tartaric acid (6c). (R)-1,1 -Binaphthyl-2,2 -diyl-chlor-
Binaphthyl-2,2 -diyl-3,3 -di(trimethylsilyl)chlorophosphite 5f was
synthesized by the same procedure as that of 5e, and was used
directly without further purification. Treatment of compound 4
(177 mg, 0.8 mmol), 5f (832 mg, 1.68 mmol), and DMAP (19.5 mg,
0.16 mmol) as described for the synthesis of ligand 6a afforded li-
gand 6f, which was purified by flash chromatography (toluene,
ophosphite 5c was synthesized by the same procedure as that of 5a,
and was used directly without further purification. Treatment of
compound 4 (132.7 mg, 0.6 mmol), 5c (632 mg, 1.76 mmol), and
DMAP (14.6 mg, 0.12 mmol) as described for the synthesis of ligand
6
a afforded ligand 6c, which was purified by flash chromatography
(
1
CDCl
4
4
(
(
toluene, R
f
¼0.63) to produce a white solid (204 mg, 40% yield), mp
R
f
¼0.21) to produce a white solid (301 mg, 58% yield), mp
ꢁ
20
D
31
ꢁ
20
D
31
57e158 C; ½
a
ꢃ
ꢀ297.2 (c 0.11, CH
2
Cl
2
); P NMR (161 MHz,
90e91 C; ½
a
ꢃ
þ320.3 (c 0.39, CH
2
Cl
2
); P NMR (161 MHz, CDCl
3
)
1
1
3
)
d
142.80; H NMR (400 MHz, CDCl
3
)
d
4.50 (dd, J¼20.0,
d
136.39; H NMR (400 MHz, CDCl
3
)
d
0.34 (s, 18H), 0.41 (s, 18H),
.0 Hz, 2H), 4.93 (d, J¼16.0 Hz, 2H), 7.09e7.11 (m, 2H), 7.17e7.18 (m,
4.18 (d, J¼4.0 Hz, 1H), 4.51 (s, 2H), 4.87e4.91 (m, 1H), 6.96 (d,
H), 7.21e7.24 (m, 4H), 7.27e7.31 (m, 4H), 7.33e7.41 (m, 5H), 7.49
J¼8.4 Hz, 1H), 7.10e7.12 (m, 4H), 7.17e7.18 (m, 4H), 7.22e7.24 (m,
13
d, J¼12.4 Hz, 2H), 7.56 (d, J¼8.0 Hz, 2H), 7.72 (d, J¼8.0 Hz, 2H), 7.86
4H), 7.37e7.41 (m, 4H), 7.80e7.91 (m, 4H), 7.99e8.06 (m, 4H);
C
13
d, J¼8.0 Hz, 2H), 7.92 (d, J¼8.0 Hz, 2H); C NMR (100 MHz, CDCl
3
)
3
NMR (100 MHz, CDCl ) d 0, 42.66, 73.35, 122.61, 125.25, 126.59,
128.18, 128.66, 128.94, 130.58, 131.09, 134.61, 136.72, 137.30, 151.19,
169.92, 172.15; HRMS (ESI) calcd for C63
1087.3340, found: 1087.0484.
d
43.04, 75.65, 121.60, 122.43, 124.18, 125.08, 126.43, 126.94, 128.33,
þ
1
(
28.78, 130.10, 130.64, 131.18, 132.72, 134.34, 146.79, 169.53; HRMS
ESI) calcd for C51
H65NO P
8 2
Si
4
[MꢀH
3
PO] :
þ
H
33NNaO
8
P
2
[MþNa] : 872.1579, found: 872.1574.
0
0
4
.2.4. 1-N-Benzylpyrrolidine-3,4-bis[(S)-1,1 -binaphthyl-2,2 -diyl]
4.3. Representative procedure for the 1,4-addition of Et
2-cyclohexenone 7a
2
Zn to
0
0
phosphite-
L
-tartaric acid (6d). (S)-1,1 -Binaphthyl-2,2 -diyl-chlor-
ophosphite 5d was synthesized by the same procedure as that of
a, and was used directly without further purification. Treatment of
5
2 6 6
A solution of (CuOTf) $C H (0.0025 mmol,1.3 mg) and ligand 6c
compound 4 (177 mg, 0.8 mmol), 5d (617 mg, 1.76 mmol), and
DMAP (19.5 mg, 0.16 mmol) as described for the synthesis of ligand
(0.005 mmol, 4.3 mg) in ether (4 mL) was stirred for 1 h at rt under
nitrogen. After the solution was cooled to 0 C, 2-cyclohexenone 7a
ꢁ
6
a afforded ligand 6d, which was purified by flash chromatography
(0.25 mmol, 0.025 mL) was added and the solution was stirred for
ꢁ
(
toluene, R
f
¼0.56) to produce a white solid (326 mg, 48% yield), mp
10 min at 0 C. Then Et
2
Zn (1.2 mmol, 1.2 mL of 1.0 M solution in
ꢁ
20
D
31
1
CDCl
38e139 C; ½
a
ꢃ
þ191.7 (c 0.16, CH
2
Cl
2
); P NMR (161 MHz,
hexane) was added dropwise using a syringe within 2 min. After
4 h, the reaction was quenched by H O (2 mL) and 2 M HCl (2 mL),
and extracted with ethyl acetate (5 mLꢂ3). 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 product. The conversion and the yield were
1
3
)
d
146.65; H NMR (400 MHz, CDCl
3
)
d
4.54 (dd, J¼20.0,
2
4
5
.4 Hz, 2H), 4.94 (d, J¼4.0 Hz, 2H), 7.06e7.09 (m, 3H), 7.14e7.18 (m,
H), 7.24e7.26 (m, 3H), 7.28e7.29 (m, 2H), 7.31e7.35 (m, 5H), 7.39
3
(
(
d, J¼4.0 Hz, 3H), 7.47 (d, J¼8.0 Hz, 2H), 7.52 (d, J¼8.0 Hz, 2H), 7.82
2
4
13
d, J¼8.8 Hz, 2H), 7.88 (d, J¼8.0 Hz, 2H); C NMR (100 MHz, CDCl
3
)

A.-P. Xing et al. / Tetrahedron 69 (2013) 455e459
459
determined by GC equipped with a SE-30 column (30 mꢂ0.32 mm
I.D.) using dodecane as an internal standard. The enantiomeric
excess was determined by GC analysis with a Chiraldex A-TA col-
umn (50 mꢂ0.25 mm I.D.). The absolute configuration was de-
termined by comparison with authentic samples. The analytic
conditions of the 1,4-adducts are as follows.
5. (a) Zhang, H.; Fang, F.; Xie, F.; Yang, G.-Q.; Zhang, W.-B. Tetrahedron Lett. 2010,
1, 3119e3122; (b) Yang, B.; Xie, F.; Yu, H.; Shen, K.-J.; Ma, Z.-N.; Zhang, W.-B.
Tetrahedron 2011, 67, 6197e6201.
5
6
. For selected papers, see: (a) Xie, Y.-J.; Huang, H.-M.; Hu, X.-Q. Tetrahedron:
Asymmetry 2009, 20, 1425e1432; (b) Harutyunyan, S. R.; Hartog, T. D.; Geurts,
K.; Minnaard, A. J.; Feringa, B. L. Chem. Rev. 2008, 108, 2824e2852; (c) Reetz, M.
T.; Gosberg, A.; Moulin, D. Tetrahedron Lett. 2002, 43, 1189e1191; (d) Arnold, L.
A.; Imbos, R.; Mandoli, A.; Naasz, R.; Feringa, B. L. Tetrahedron 2000, 56,
2865e2878.
7
. (a) Alexakis, A.; Benhaim, C.; Rosset, S.; Humam, M. J. Am. Chem. Soc. 2002, 124,
4
(
.3.1. 3-Ethylcyclohexanone
(8a). Chiraldex
50 mꢂ0.25 mm I.D.) at 120 C constant, 15 psi N
enantiomer (R), and t
¼13.55 min for enantiomer (S).
A-TA
column
5262e5263; (b) Alexakis, A.; Rosset, S.; Allamand, J.; March, S.; Guillen, F.;
ꢁ
2
. t
R
¼13.11 min for
Benhaim, C. Synlett 2001, 1375e1378; (c) Zhang, F.-Y.; Chan, A. S. C. Tetrahedron:
Asymmetry 1998, 9, 1179e1182.
. (a) Zhao, Q.-L.; Wang, L.-L. Tetrahedron: Asymmetry 2011, 22, 1885e1890; (b)
Zhao, Q.-L.; Wang, L.-L.; Xing, A.-P. Tetrahedron: Asymmetry 2010, 21,
R
8
4.3.2. 3-Ethylcyclopentanone (8b). Chiraldex A-TA
column
2993e2998; (c) Zhao, Q.-L.; Tse, M. K.; Wang, L.-L.; Xing, A.-P.; Jiang, X.-X.
ꢁ
(
50 mꢂ0.25 mm I.D.) at 120 C constant, 15 psi N
2
R
. t ¼12.43 min for
Tetrahedron: Asymmetry 2010, 21, 2788e2793; (d) Zhao, Q.-L.; Wang, L.-L.;
Kwong, F. Y.; Chan, A. S. C. Tetrahedron: Asymmetry 2007, 18, 1899e1905; (e)
Wang, L.-L.; Li, Y.-M.; Yip, C. W.; Qiu, L.-Q.; Zhou, Z.-Y.; Chan, A. S. C. Adv. Synth.
Catal. 2004, 346, 947e953; (f) Liang, L.; Au-Yeung, T. T. L.; Chan, A. S. C. Org. Lett.
2002, 4, 3799e3801; (g) Yan, M.; Zhou, Z.-Y.; Chan, A. S. C. Chem. Commun.
2000, 2, 115e116.
enantiomer (R), and t
R
¼11.97 min for enantiomer (S).
4
0
.3.3. 3-Ethylcycloheptanone (8c). CP-Chirasil-Dex CB (25 mꢂ
ꢁ
.25mmI.D.) at 120 C constant, 15 psi N
2 R
. t ¼10.85 min for enan-
9
. (a) Mata, Y.; Di eꢀ guez, M.; P aꢂ mies, O.; Biswas, K.; Woodward, S. Tetrahedron:
tiomer (R), and t
R
¼10.61 min for enantiomer (S).
Asymmetry 2007, 18, 1613e1617; (b) Liu, L.-T.; Wang, M.-C.; Zhao, W.-X.; Zhou,
Y.-L.; Wang, X.-D. Tetrahedron: Asymmetry 2006, 17, 136e141; (c) Morimoto, T.;
Mochizuki, N.; Suzuki, M. Tetrahedron Lett. 2004, 45, 5717e5722.
4
.3.4. 3-Methylcyclohexanone (8d). CP-Chirasil-Dex CB (25 mꢂ0.25
ꢁ
ꢁ
ꢁ
10. (a) Kawamura, K.; Fukuzawa, H.; Hayashi, M. Org. Lett. 2008, 10, 3509e3512; (b)
Biradar, D. B.; Gau, H. M. Tetrahedron: Asymmetry 2008, 19, 733e738; (c)
Duncan, A. P.; Leighton, J. L. Org. Lett. 2004, 6, 4117e4119; (d) Shi, M.; Wang, C.;
Zhang, W. Chem.dEur. J. 2004, 10, 5507e5516; (e) Hird, A. W.; Hoveyda, A. H.
Angew. Chem., Int. Ed. 2003, 42, 1276e1279; (f) Degrado, S. J.; Mizutani, H.;
Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 13362e13363; (g) Mizutani, H.;
Degrado, S. J.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 779e781; (h) Yamanoi,
Y.; Imamoto, T. J. Org. Chem. 1999, 64, 2988e2989; (i) Fuchs, N.; Augustin, M. D.;
Humam, M.; Alexakis, A.; Taras, R.; Gladiali, S. Tetrahedron: Asymmetry 2005, 16,
mm I.D.) at 70 C, 2 min, 10 C/min, 120 C, 2 min, 15 psi N
2
.
t
R
¼7.67 min for enantiomer (R), and t ¼7.81 min for enantiomer (S).
R
4
2
.3.5. 3-Phenylcyclohexanone (8e). Daicel Chiralcel AD-H
5 cmꢂ4.6 mm I.D., hexane/i-PrOH¼99/1, flow rate¼0.5 mL/min
ꢁ
at 25 C, detected at 209 nm. t
R
¼15.62 min for enantiomer (R), and
t
R
¼13.09 min for enantiomer (S).
3143e3146.
1
1. (a) Kano, T.; Hato, Y.; Maruoka, K. Tetrahedron Lett. 2006, 47, 8467e8469; (b)
Acknowledgements
Shirakura, M.; Suginome, M. Angew. Chem., Int. Ed. 2010, 49, 3827e3829; (c)
Belokon, Y. N.; Gugakeva, Z. T.; Maleev, V. I.; Moskalenko, M. A.; North, M.;
Tsaloev, A. T. Tetrahedron: Asymmetry 2010, 21, 1793e1796; (d) Hui, A.-L.; Zhang,
J.-T.; Wang, Z.-Y. Synth. Commun. 2008, 38, 2374e2384.
We are grateful for the financial support of this work by the
National Natural Science Foundation of China (Nos. 20343005,
1
2. (a) Alexakis, A.; Frutos, J. C.; Mangeney, P. Tetrahedron: Asymmetry 1993, 4,
2427e2430; (b) Alexakis, A.; Vastra, J.; Burton, J.; Mangeney, P. Tetrahedron:
Asymmetry 1997, 8, 3193e3196; (c) Alexakis, A.; Burton, J.; Vastra, J.; Mangeney,
P. Tetrahedron: Asymmetry 1997, 8, 3987e3990.
2
0473107, 20673130, 20773147, 21073211, and 21174155).
Supplementary data
13. (a) Alexakis, A.; Vastra, J.; Burton, J.; Benhaim, C.; Mangeney, P. Tetrahedron Lett.
1998, 39, 7869e7872; (b) Alexakis, A.; Benhaim, C. Tetrahedron: Asymmetry 2001,
1
2, 1151e1157; (c) Alexakis, A.; Burton, J.; Vastra, J.; Benhaim, C.; Fournioux, X.;
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2012.11.038.
Leveque, J. M.; Maze, F.; Rosset, S. Eur. J. Org. Chem. 2000, 24, 4011e4027; (d)
Alexakis, A.; Benhaim, C. Org. Lett. 2000, 2, 2579e2581.
1
1
4. Escher, I. H.; Pfaltz, A. Tetrahedron 2000, 56, 2879e2888.
5. (a) Gavrilov, K. N.; Zheglov, S. V.; Benetsky, E. B. Tetrahedron: Asymmetry 2009,
0, 2490e2496; (b) Buisman, G. J. H.; Vos, E. J.; Kamer, P. C. J.; van Leeuwen, P.
References and notes
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1. For selected reviews, see: (a) Kamer, P. C. J.; Claver, C.; Pamies, O.; Dieguez, M.
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2
3
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