Facile one-pot synthesis of cinchona alkaloid-based P,N ligands and their application to Pd-catalyzed asymmetric allylic alkylation

Article abstract of DOI:10.1016/j.tetasy.2008.10.030

A novel class of bidentate chiral P,N donor ligands based on cinchona alkaloids is described. These ligands are easily synthesized in one-pot from commercially available enantiopure 1,2-diphenyl-1,2-ethanediol and cinchona alkaloids in two steps. Their ap

Full text of DOI:10.1016/j.tetasy.2008.10.030

Tetrahedron: Asymmetry 19 (2008) 2447–2450
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Facile one-pot synthesis of cinchona alkaloid-based P,N ligands
and their application to Pd-catalyzed asymmetric allylic alkylation
*
Qiao-Feng Wang, Wei He, Xue-Ying Liu, Hui Chen, Xiang-Yang Qin, Sheng-Yong Zhang
Department of Chemistry, Fourth Military Medical University, Xi’an, Shaanxi 710032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 September 2008
Accepted 22 October 2008
A novel class of bidentate chiral P,N donor ligands based on cinchona alkaloids is described. These ligands
are easily synthesized in one-pot from commercially available enantiopure 1,2-diphenyl-1,2-ethanediol
and cinchona alkaloids in two steps. Their application to the palladium(II)-catalyzed asymmetric allylic
alkylation of 1,3-diphenyl-2-propenyl acetate gave the corresponding products in excellent yields and
up to 94% ee. The effect of ligands, substrates, nucleophiles, and temperature on the reaction was also
investigated.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
pure 1,2-diol was coupled with cinchona alkaloids by substituting
the hydroxyl group at C9, a family of phosphites with a retentive
Readily accessible cinchona alkaloids play a significant role in or-
ganic chemistry as chiral base catalysts, ligands, and chromato-
graphic selectors in asymmetric synthesis.1,2 There are already a
number of papers on them. However, compared with their broad
applications as organocatalysts, cinchona alkaloids, and their deriv-
atives as ligands attached to transition metals have developed
more slowly despite the fact that the osmium-complexed cinchona
alkaloid derivatives designed by Sharpless et al. achieved great suc-
cess in asymmetric catalysis.3 To date, with the exception of one
type of N,N-bidentate cinchona alkaloid ligand as reported by our
group,3 there have been no published reports on P,N-bidentate li-
gands derived from cinchona alkaloids. Moreover, palladium-cata-
lyzed asymmetric allylic substitution is versatile, and widely
used in organic synthesis for the enantioselective formation of C–
C and C-heteroatom bonds.4 Over the past decade, we have seen
a huge advance in enantiocontrol in Pd-catalyzed allylic substitu-
tion reactions.5 However, there still remains some drawbacks
about the catalytic systems which have been reported to date.4
Herein, we report the synthesis of a new family of P,N-bidentate
ligands which was derived from cinchona alkaloids and their cata-
lytic action in asymmetric palladium-catalyzed asymmetric allylic
alkylation (AAA).
configuration at C9 was achieved. Characterized by seven stereo-
genic centers and two donor sites (quinuclidine N atom and P
atom), these cinchona alkaloid derivatives can provide a chelate
ring when coordinated to transition metal.
The chiral ligands 2a–d were easily prepared from (S,S)-1,2-di-
phenyl-1,2-ethane diol and cinchona alkaloids in ‘one-pot’ via two
steps (Scheme 1). Initially, (S,S)-1,2-diphenyl-1,2-ethanediol was
added into phosphorus trichloride in dry THF to give a phosphoro-
chloridite intermediate. The phosphorochloridite intermediate was
not isolated in its pure form but used directly in solution to react
with cinchona alkaloids 1a–d in the presence of triethylamine as
an acid-binding agent. After stirring overnight at 60 °C, the hetero-
geneous system produced ligands 2a–d. The total yields ranged
from 63% to 75%.
With target ligands 2 in hand, we turned our attention to inves-
tigating their potential utilities in asymmetric catalysis. The palla-
dium-catalyzed AAA reaction was chosen as a model reaction to
test them.
The steric properties of ligands 2a–d were identified to affect
the activity and enantioselectivity of the AAA reaction of 1,3-di-
phenyl-3-acetoxyprop-1-ene. The results are shown in Table 1.
Cinchonine and quindine-derived ligands 2a and 2d exhibited bet-
ter catalytic activity and enantioselectivity than their pseudo-
enantiomers 2b and 2c (Table 1, entries 1–4).
2. Results and discussion
Moreover, the effect of nucleophiles on the reaction was also
investigated. The reaction with acetylacetone in place of dimethyl
malonate gave the corresponding product with an (S)-configura-
tion in higher yields and moderate to excellent ees (Table 2). A
similar improvement was also found in the same reaction with
3-methyl-2,4-pentanedione 4 as a nucleophile (Table 2) and (S)-
3-acetyl-3-methyl-4,6-diphenylhex-5-en-2-one was obtained.
Cinchona alkaloids contain five stereogenic centers: N1, C3, C4, C8,
and C9.6 When chiral phosphorochloridite derived from an enantio-
* Corresponding author. Tel./fax: +86 029 84776945.
E-mail address: syzhang@fmmu.edu.cn (S.-Y. Zhang).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.10.030

2448
Q.-F. Wang et al. / Tetrahedron: Asymmetry 19 (2008) 2447–2450
(R)
(S)
R
N
OH
OH
O
1,
PCl3 ,THF
100%
Et3N,THF
63-75%
PCl
O
O
O
O
P
N
2a-d
(R)
1a
1b
1c
1d
cinchonine (8R,9S)
cinchonidine (8S,9R)
R = H
( S)
R
N
R = H
N
quinine (8S,9R)
R = OMe
R = OMe
8
quinidine (8R,9S)
9
OH
Scheme 1. The synthesis of ligands 2a–d.
Table 1
Table 2
AAA reaction with dimethyl malonate as a nucleophile catalyzed by Pd–ligand 2
AAA reaction catalyzed by Pd–ligand 2 complex with 3 or 4 as nucleophilea
complexa
OAc
Ph
Nu
CO2Me
Ph
MeO2C
[Pd(C3H5)Cl]2
OAc
Ph
NuH
O
CO2Me
CO2Me
+
[Pd(C3H5)Cl]2
(S)
Ligand 2a-d
Ph
Ph
Ph
+
(R)
Ligand 2a-d
Ph
Ph
Entry
Ligand
Temp (°C)
Time (h)
Yieldb (%)
eec (%) (config.d)
O
O
O
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2a
2a
2d
2d
28
28
28
28
0
15
32
32
24
24
24
48
48
100
65
75
93
100
72
70 (R)
55 (R)
45 (R)
62 (R)
83 (R)
94 (R)
75 (R)
88 (R)
NuH
=
3
4
Entry
Ligand
NuH
Temp (°C)
Time (h)
Yieldb (%)
eec (%) (config.d)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2c
2d
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
28
28
28
28
0
0
0
0
28
28
28
28
0
0
0
0
9
24
18
18
24
24
24
24
12
24
12
15
24
24
24
24
100
85
82
95
80
65
60
75
100
85
73
100
75
65
Scarce
70
80 (S)
66 (S)
66 (S)
73 (S)
92 (S)
75 (S)
77 (S)
85 (S)
75 (S)
65 (S)
59 (S)
66 (S)
90 (S)
78 (S)
N.D
ꢀ30
0
74
45
ꢀ30
a
All reactions were performed using 2 mol % [Pd(
g
3-C3H5)Cl]2, 6 mol % ligand,
3 mol % KOAc, 300 mol % BSA, 300 mol % dimethyl malonate, and 1 equiv substrate
in 5 mL dry CH2Cl2 under N2.
b
Isolated yield.
c
The ee values were determined by chiral HPLC (Chiral OD-H column, n-hexane/
i-propanol = 90:10, 0.5 mL/min).
d
The absolute configuration was assigned by comparison of the sign of specific
rotation with reported data.7
The experiment suggested that the activity and stability of the
nucleophile’s carbanion had a great influence on the reaction effi-
ciency, as ‘soft nucleophiles’ 3 and 4 were generally more active
than dimethyl malonate under basic conditions.
Furthermore, the AAA reaction was also temperature depen-
dent. Similar to most asymmetric catalytic reactions, the substrate
conversion decreased but the enantioselectivity was improved
when the temperature was lowered (Tables 1 and 2).
It is known that cinchona alkaloids 1a and 1b behave as pseudo-
enantiomers, as do 1c and 1d.2,6 When they are used to catalyze
asymmetric reactions, such as asymmetric dihydroxylation and
enantioselective decarboxylation, enantiomers with similar enan-
tiomeric excesses but opposite absolute configuration are often
obtained.6,9 However, in our experiments, ligands 2a–d always
gave the same configuration of product in the AAA reaction under
the same conditions. Obviously, it is not the backbone structure of
cinchona alkaloid in ligands 2a–d but that of (S,S)-1,2-diphenyl-
1,2-ethanediol, which is responsible for the configuration of the
85 (S)
All reactions were performed using 2 mol % [Pd(g
3-C3H5)Cl]2, 6 mol % ligand,
3 mol % KOAc, 300 mol % BSA, 300 mol % 3 or 4, and 1 equiv substrate in 5 mL dry
CH2Cl2 under N2.
a
b
Isolated yield.
c
The ee values were determined by chiral HPLC (entries 1–8: chiral AD column,
n-hexane/2-propanol = 99:1, 1.0 mL/min; entries 9–16: chiral OJ-H column: n-
hexane/i-propanol = 90:10, 0.8 mL/min).
d
The absolute configuration was assigned by comparison of the sign of specific
rotation with reported data.7,8
products. The oppositely configured (S)-product was prepared
when ligands derived from the (R,R)-1,2-diphenyl-1,2-ethanediol
were used to catalyze the AAA reaction under the reaction
conditions.
Instead of 1,3-diphenyl-3-acetoxyprop-1-ene, the asymmetric
allylic alkylation of 3-acetoxy-cyclohexene was also examined

Q.-F. Wang et al. / Tetrahedron: Asymmetry 19 (2008) 2447–2450
2449
under the same conditions as shown in Table 1. However, it re-
sulted in a low enantiomeric excess (<29% ee) and chemical yield
(<45%), which were unsatisfactory.
(2H), 5.13 (1H), 5.08 (1H), 4.87 (2H), 3.32 (1H), 2.66– 3.08 (6H),
1.09–2.03 (4H); 13C NMR (75 MHz, CDCl3): d 149.5, 148.1, 146.3,
139.8, 136.1, 134.3, 130.1, 128.8, 128.5, 128.3, 128.2, 128.0,
127.9, 127.5, 127.2, 127.0, 126.5, 126.4, 126.1, 125.0, 123.0,
118.8, 114.3, 86.1, 86.0, 82.9, 60.4, 49.5, 48.7, 39.5, 27.6, 25.9,
23.3; 31P NMR (202 MHz, CDCl3): d 143.5; HRMS (ESI): calcd for
C33H33N2O3P+H: 537.2, found: 537.0.
3. Conclusion
In conclusion, we have described the first case of cinchona
alkaloid-based P,N ligands. They were easily synthesized from
cinchona alkaloids and optically active C2-symmetric 1,2-diols.
The application for palladium-catalyzed enantioselective allylic
alkylation gave high yields and moderate to excellent ees. The
effects of steric changes in the ligands, substrates, nucleophiles,
and reaction temperature were investigated. Further evaluation
on the applications of this novel class of P,N ligands in asymmetric
catalysis is currently in progress.
4.2.3. Quinine-9-yl phosphite (ligand 2c)
Using quinine, ligand 2c was obtained as a white foam solid
(70%). Mp = 62–64 °C.
½
a 2D5
ꢁ
¼ ꢀ29:5 (c 1, CHCl3), 1H NMR
(300 MHz, CDCl3): d 8.77 (1H, d), 8.05 (1H, d), 7.13–7.51 (13H),
5.78–5.85 (2H, m), 4.85–5.09 (4H, m), 3.88 (3H, s), 1.25–3.3
(11H); 13C NMR (75 MHz, CDCl3): d 157.3, 147.1, 144.8, 144.3,
141.4, 136.1, 135.6, 135.5, 131.5, 128.3, 128.2, 128.1, 128.0,
127.9, 127.8 126.5, 126.4, 126.3, 126.1, 121.2, 119.2, 113.9, 101.2,
86.1, 86.0, 83.3, 59.9, 56.4, 55.1, 46.1, 42.1, 39.4, 29.2, 27.5; 31P
4. Experimental
NMR (202 MHz, CDCl3):
d 142.8; HRMS (ESI): calcd for
C34H35N2O4P+H: 567.2, found: 567.1.
4.1. General remarks
4.2.4. Quindine-9-yl phosphite (ligand 2d)
All reactions were performed under a nitrogen atmosphere in
freshly dried and distilled solvents. Solvents were treated prior to
use according to the standard method. 1H NMR, 13C NMR, and
31P NMR were recorded on a Bruker AMX-300 spectrometer in
CDCl3 at room temperature. Optical rotations were measured using
a Perkin–Elmer 343 polarimeter at 25 °C. Mass spectra were per-
formed on Waters Quattro-Premier instrument. Ee values were
determined by HPLC on a chiracel OJ-H, AD, and OD-H columns.
(S,S)-1,2-diphenyl-1,2-ethanediol was prepared as described.10
The commercially available reagents were used without further
purification.
Using quindine, ligand 2d was prepared as a white foam solid
(63%). Mp = 64–65 °C.
½
a 2D5
ꢁ
¼ ꢀ69:6 (c 1, CHCl3). 1H NMR
(300 MHz, CDCl3): d 8.77 (1H, d), 8.05 (1H, d), 7.13–7.51 (13H),
5.78–5.85 (2H, m), 4.85–5.09 (4H, m), 3.88 (3H, s), 1.25–3.3
(11H); 13C NMR (75 MHz, CDCl3): d 157.3, 147.1, 144.8, 144.3,
141.4, 136.1, 135.6, 135.5, 131.5, 128.3, 128.2, 128.1, 128.0,
127.9, 127.8 126.5, 126.4, 126.3, 126.1, 121.2, 119.2, 113.9, 101.2,
86.1, 86.0, 83.3, 59.9, 56.4, 55.1, 46.1, 42.1, 39.4, 29.2, 27.5; 31P
NMR (202 MHz, CDCl3):
d 142.8; HRMS (ESI): calcd for
C34H35N2O4P+H: 567.2, found: 567.1.
4.3. General procedure for the palladium-catalyzed AAA
reaction of rac-1,3-diphenyl-2-propenyl acetate
4.2. General procedure for the preparation of ligands 2a–d
[Pd(g
3-C3H5)Cl]2 (3.7 mg, 0.01 mmol) and the appropriate
A solution of (S,S)-1,2-diphenyl-1,2-ethanediol (1.07 g, 5 mmol)
in absolute THF was added dropwise to phosphorus trichloride
(0.69 g, 5 mmol) under nitrogen. The mixture was stirred at room
temperature until no starting material was detected by TLC. Sub-
sequently, selected cinchona alkaloids (5 mmol) and triethylamine
(3 mL) were added to the clear system, then the system was heated
to 60 °C. After being stirred for 17 h, the suspension was filtered
and the mother liquor was concentrated to give a light yellow
solid. This solid was dissolved in water and extracted with
degassed CH2Cl2. The combined organic layers were dried over
anhydrous Na2SO4. After being concentrated, light yellow crude
product was obtained and purified by flash column chromatogra-
phy on silica gel using n-hexane/acetone/triethylamine (3:3:1) as
the eluent.
ligand (0.03 mmol) were dissolved in dry CH2Cl2 (5 mL) and then
stirred for 0.5 h at room temperature under nitrogen. rac-1,3-Di-
phenyl-2-propenyl acetate (126 mg, 0.5 mmol) was added to this
solution and continuously stirred for 10 min. To the resulting solu-
tion were successively added dimethyl malonate (0.17 mL,
1.5 mmol), N,O-bis(trimethylsilyl) acetamide (0.37 mL, 1.5 mmol),
and potassium acetate (0.015 mmol). The reaction mixture was
stirred at a suitable temperature and monitored by TLC. After that,
the reaction solution was diluted with CH2Cl2 (15 mL) and washed
with saturated aqueous ammonium chloride. The organic phase
was dried over anhydrous Na2SO4 and then concentrated under
reduced pressure. The residue was purified by column chromato-
graphy (ethyl acetate/n-hexane = 1:10) to give the pure product.
The enantiomeric excess was determined by HPLC.
4.2.1. Cinchonine-9-yl phosphite (ligand 2a)
Using cinchonine, ligand 2a was obtained as a white foam solid
Acknowledgments
(75%). Mp = 37–38 °C. ½a D25
ꢁ
¼ ꢀ108 (c 1, CHCl3). 1H NMR (300 MHz,
CDCl3): d 8.85 (1H), 8.19 (2H), 7.05–7.69 (13H), 6.02 (2H), 5.13
(1H), 5.08 (1H), 4.87 (2H), 3.32 (1H), 2.66–3.08 (6H), 1.09–2.03
(4H); 13C NMR (75 MHz, CDCl3): d 149.5, 148.1, 146.3, 139.8,
136.1, 134.3, 130.1, 128.8, 128.5, 128.3, 128.2, 128.0, 127.9,
127.5, 127.2, 127.0, 126.5, 126.4, 126.1, 125.0, 123.0, 118.8,
114.3, 86.1, 86.0, 82.9, 60.4, 49.5, 48.7, 39.5, 27.6, 25.9, 23.3; 31P
Financial support from the National Natural Science Foundation
of China (NSFC, Nos. 20572131, 20702063, 30600163) and the
Fourth Military Medical University, No. 2007D18, is gratefully
acknowledged. In addition, special thanks are due to Professor H.
Kagan for helpful suggestions.
NMR (202 MHz, CDCl3):
C33H33N2O3P+H: 537.2, found: 537.0.
d 143.5; HRMS (ESI): calcd for
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ꢁ
¼ ꢀ35 (c 1, CHCl3). 1H NMR
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