Pd-catalyzed asymmetric allylation with a novel C2-symmetric bisphosphinite ligand: 3R,3′R-bis(diphenylphosphinoxy)-6,6,6′,6′-tetramethyl-2S, 2′S-di-4H-pyran

Article abstract of DOI:10.1016/S0040-4039(01)01624-0

A novel C₂-symmetric chiral bisphosphinite ligand, 3R,3′R-bis(diphenylphosphinoxy)-6,6,6′,6′-tetramethyl-2S, 2′S-di-4H-pyran, was synthesized from D-mannitol and examined for palladium-catalyzed asymmetric allylic substitution. Under the optimized conditions, the allylation product can be obtained in up to 91.2% ee.

Full text of DOI:10.1016/S0040-4039(01)01624-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7659–7662
Pd-catalyzed asymmetric allylation with a novel C2-symmetric
bisphosphinite ligand: 3R,3%R-bis(diphenylphosphinoxy)-
6,6,6%,6%-tetramethyl-2S,2%S-di-4H-pyran
Ruzhou Zhang, Libing Yu, Li Xu, Zhiqin Wang and Kuiling Ding*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
The Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, P.R. China
Received 17 July 2001; accepted 30 August 2001
Abstract—A novel C2-symmetric chiral bisphosphinite ligand, 3R,3%R-bis(diphenylphosphinoxy)-6,6,6%,6%-tetramethyl-2S,2%S-di-
4H-pyran, was synthesized from
D-mannitol and examined for palladium-catalyzed asymmetric allylic substitution. Under the
optimized conditions, the allylation product can be obtained in up to 91.2% ee. © 2001 Elsevier Science Ltd. All rights reserved.
Asymmetric synthesis based on transition metal-cata-
lyzed processes has attracted a great deal of interest
because of its high efficiency for construction of enan-
tiomerically enriched molecules.1 How to design and
develop efficient chiral ligands for transition metal-cata-
lyzed reactions has become one of the most intense
areas of investigation. Chiral phosphines represent one
type of the most useful and versatile ligands for metal-
catalyzed asymmetric reactions. In contrast to chiral
phosphine ligands, phosphinites have not been well
developed due to their lower stability in protic solvents
and air. However, some, such as TADDOP, BINAPO
and others, have demonstrated sufficient stability, par-
ticularly in the pure form.2 The advantages of such
kinds of ligands are their convenient preparation and
high availability. Recently, several types of superior
C2-symmetric bisphosphinite ligands with various scaf-
folds such as BDPAB, SpiroP and BICPO, have been
prepared and successfully utilized in asymmetric cataly-
sis.3 In the present work, we report preliminary results
on the synthesis of a novel C2-symmetric bisphosphinite
ligand, 3R,3%R-bis-(diphenylphosphinoxy)-6,6,6%,6%-tet-
ramethyl-2S,2%S-di-4H-pyran 1, and its application in
asymmetric allylic substitution.
A synthesis of the precursor of 1, the C2-symmetrical
scaffolded diol 6, was first reported by Wang in 1997.4
Starting from
D
-mannitol, 2,2-dimethyl-4,5-bis-oxi-
Ph
Ph
NHPPh2
NHPPh2
OPPh2
OPPh2
O
O PPh2
O PPh2
Ph
O
Ph
TADDOP
BINAPO
BDPAB
H
O
O
H
Ph2PO
OPPh2
OPPh2
Ph2PO
SpiroP
OPPh2
Ph2PO
BICPO
1
* Corresponding author. Tel.: 86-21-64163300; fax: 86-21-6416-6128; e-mail: kding@pub.sioc.ac.cn
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01624-0

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R. Zhang et al. / Tetrahedron Letters 42 (2001) 7659–7662
ranyl-[1,3]dioxolane 2 can be easily prepared according
to the literature procedure.5 Grignard addition of 2-
methyl propenyl mangnesium chloride to 2 afforded 3
in 83% yield. Treatment of 3 with benzoyl chloride in
the presence Et3N gave the corresponding benzoate
ester 4 in 97% yield. Quantitative HClO4-catalyzed
cyclization of 4 yielded 5, which can be transformed to
6 upon alkaline hydrolysis in 89% yield (Scheme 1).
Compound 6 has four stereogenic centers with a C2-
symmetric backbone containing two tetrahydropyran
rings and should be an interesting chiral ligand scaffold
for asymmetric catalysis. With this interesting precursor
in hand, we tried to transform 6 into its phosphinite by
reacting with Ph2PCl. The reaction of 6 with Ph2PCl in
the presence of Et3N at room temperature was found to
be highly efficient and gave the bisphosphinite 1 in 99%
yield.
In order to evaluate the asymmetric induction efficiency
of 1, palladium-catalyzed allylic substitution of 1,3-
diphenyl-2-propen-1-yl acetate 7 with dimethyl mal-
onate was taken as the model reaction. Reactions of
racemic 7 with dimethyl malonate were carried out in
the presence of [Pd(h3-C3H5)Cl]2 (2.5 mol%), ligand 1
(5 mol%) and base (2.0 equiv.). Table 1 shows the
details of our results. It was found that the choice of
O
O
OR
O
C4H7MgCl
83%
Ref. 5
D-Mannitol
O
O
O
OR
2
3 R=H
BzCl
97%
HClO4(aq.)
quant.
4 R=Bz
Ph2PCl/Et3N
CH2Cl2
O
O
OPPh2
OPPh2
OR
OR
99%
O
O
5 R=Bz
6 R=H
1
KOH
89%
Scheme 1. Preparation of C2-symmetric bisphosphinite ligand 1.
Table 1. Asymmetric allylation of 7 with dimethyl malonate promoted by Pd-1 complexa
[Pd(η3−C3Η5)Cl]2(2.5mol%)
MeO2C
CO2Me
Ph
OAc
Ph
Ligand 1(5mol%),
Ph
Ph
CH2(COOMe)2 (2.0eq.)
CH2Cl2
7
(S)-8
Entry
Base
Additive
Solvent
THF
Temp. (°C)
Time (h)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
BSA
BSA
BSA
BSA
BSA
BSA
CsCO3
NaH
Et2Zn
Et2Zn
Et2Zn
Et2Zn
Et2Zn
KOAc
KOAc
KOAc
KOAc
KOAc
LiOAc
KOAc
KOAc
KOAc
LiOAc
KOAc
LiOAc
KOAc
0
0
0
0
0
0
0
0
0
1
1.5
0.5
2
0.5
3
92
97
97
98
91
76
77
95
95
96
95
97
49
69.7
69.5
68.7
65.9
77.4
64.2
78.7
73.2
81.0
81.9
88.1
88.3
91.2
Toluene
CH3CN
ClCH2CH2Cl
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
3
0.7
0.3
1.5
10
15
24
9
10
11
12
13
0
−20
−20
−40
a Reactions were carried out using standard Schlenk techniques; the catalysts were generated in situ from the Pd precursor and bisphosphinite
ligand: [Pd(C3H7)Cl]2/1/base/malonate/7=0.025:0.05:2:2:1.
b Isolated yield based on 1,3-diphenyl-2-propenyl acetate.
c Determined by HPLC on Chiralpak AD column (hexane:ipropanol=90:10; 1.0 mL/min; tS=9.5 min, tR=13.0 min); the absolute configuration
of the product was assigned to be S by comparison of chiroptical values with those of the literature.8

R. Zhang et al. / Tetrahedron Letters 42 (2001) 7659–7662
7661
Table 2. Asymmetric allylic amination of 7 with sodium diformylamide promoted by Pd-1 complexa
Entry
Solvent
SDFA (equiv.)
Et3N (equiv.)
Temp. (°C)
Time (h)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
ClCH2CH2Cl
ClCH2CH2Cl
CH3CN
THF
Toluene
CH2Cl2
DMF
ClCH2CH2Cl
ClCH2CH2Cl
3
3
3
3
3
3
3
3
5
24
24
24
24
24
24
24
0
20
18
5
42
60
75
38
35
60
15
56
80
59.6
69.7
67.0
70.3
68.7
70.5
67.8
74.2
76.7
2
2
2
2
2
2
1
2
5
22
22
22
20
19
0
a Reactions were carried out using standard Schlenk techniques; the catalysts were generated in situ from the Pd precursor and the bisphosphinite
ligand 1: Pd/ligand/7=0.025:0.05:1.
b Isolated yield based on 1,3-diphenyl-2-propenyl acetate.
c Determined by HPLC on Chiralpak AD column (hexane:ipropanol=95:5; 0.8 mL/min; tS=28.7 min, tR=31.8 min). The absolute configuration
of the product was assigned to be S by comparison of chiroptical values with those of the literature.9
the solvent for the reaction is very important both in
terms of yield and enantioselectivity. When N,O-
bis(trimethylsilyl)acetamide (BSA) combined with cata-
lytic amount of KOAc6 was taken as base,
dichloromethane was disclosed to be superior to other
solvents including THF, toluene, acetonitrile and 1,2-
dichloroethane (entry 5 versus entries 1–4). Further
screening of bases included in the reaction (entries
6–10) showed that diethylzinc combined with small
amount of KOAc or LiOAc as the base was better than
BSA, CsCO3 or NaH. This result was consistent with
that reported by Fuji.7 By decreasing the reaction tem-
perature to −20°C (entries 11–12) with Et2Zn as a base
in the presence of KOAc or LiOAc, the enantioselectiv-
ities of the reaction can be further improved to 88.1 and
88.3%, respectively. A remarkable increase in enan-
tiomeric excess (up to 91.2% ee) with moderate yield
was observed at −40°C (entry 13).
synthesis of other C2-symmetric ligands derived from 6
and their applications in asymmetric catalysis are
undergoing in our laboratory.
Acknowledgements
Financial supports from the National Natural Science
Foundation of China, the Chinese Academy of Sci-
ences, the Major Basic Research Development Program
of China (Grant No. G2000077506) and Science and
Technology Commission of Shanghai Municipality are
grateful acknowledged.
References
1. (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994; (b) Catalytic Asymmetric Synthe-
sis; Ojima, I., Ed.; VCH: New York, 1993; (c) Comprehen-
sive Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A;
Yamamoto, H., Eds.; Springer: Berlin, 1999; (d) Lin, G.
Q.; Li, Y. M.; Chan, A. S. C. Principles and Applications of
Asymmetric Synthesis; Wiley: New York, 2001.
2. (a) Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem.,
Int. Ed. 2001, 40, 92–138; (b) Trost, B. M.; Murphy, D. J.
Organometallics 1985, 4, 1143–1145; (c) Clyne, D. S.;
Mermet-Bouvier, Y. C.; Nomura, N.; RajanBabu, T. V. J.
Org. Chem. 1999, 64, 7601–7611.
3. (a) Chan, A. S. C.; Hu, W.; Pai, C.; Lau, C.; Jiang, Y.; Mi,
A.; Yan, M.; Sun, J.; Lou, R.; Deng, J. J. Am. Chem. Soc.
1997, 119, 9570–9571; (b) Zhang, F.; Pai, C.; Chan, A. S.
C. J. Am. Chem. Soc. 1998, 120, 5808–5809; (c) Zhu, G.;
Zhang, X. J. Org. Chem. 1998, 63, 3133–3136.
Sodium diformylamide (SDFA) has been found to be
an advantageous amination reagent for Pd-catalyzed
allylic amination in our laboratory.9 We then examined
the asymmetric induction efficiency of our bisphos-
phinite ligand 1 in the palladium-catalyzed asymmetric
allylic amination of ( )-7 with SDFA. Table 2 summa-
rizes the details of our results. After optimization of the
reaction by altering the reaction solvents, the amount
of additive and reaction temperature, the aminated
product (S)-9 can be obtained in up to 80 yield and
76.4% ee. This is the first example of a bisphosphinite–
Pd-catalyzed asymmetric allylic amination with SDFA
as nucleophile.
In conclusion, a novel bisphosphinite ligand with C2-
symmetry has been prepared from the easily available
natural product
D
-mannitol. Its application in palla-
4. Yu, L.; Xu, L.; Wang, Z. Chin. Chem. Lett. 1997, 8,
653–654.
5. Merrer, Y. L.; Dureault, A.; Gravier, C.; Languin, D.;
Depezay, J. C. Tetrahedron Lett. 1985, 20, 319–322.
dium-catalyzed asymmetric allylation and amination
was examined and products with up to 91.2 and 76.7%
ee were obtained, respectively. Further studies on the

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R. Zhang et al. / Tetrahedron Letters 42 (2001) 7659–7662
6. (a) Fuji, K.; Ohnishi, H.; Moriyama, S.; Tanaka, K.;
Kawabata, T.; Tsubaki, K. Synlett 2000, 253–351; (b)
You, S.; Zhou, Y.; Hou, X.; Dai, L. Chem. Commun. 1998,
2765–2766; (c) You, S.; Hou, X.; Dai, L. Tetrahedron:
Asymmetry 2000, 11, 1495–1500.
1895–1896.
8. The absolute configuration of 8 was deterimined by the
comparison of chiroptical values with those of the litera-
ture: Wang, Y.; Guo, H.; Ding, K. Tetrahedron: Asymme-
try 2000, 11, 4153–4162.
7. Fuji, K.; Kinoshita, N.; Tanaka, K. Chem. Commun. 1999,
9. Wang, Y.; Ding, K. J. Org. Chem. 2001, 66, 3238–3241.