Synthesis of novel carbohydrate-based iminophosphinite ligands in Pd-catalyzed asymmetric allylic alkylations

Article abstract of DOI:10.1016/j.tetasy.2010.06.037

A series of novel carbohydrate-based iminophosphinite ligands have been synthesized for the first time and successfully applied in Pd-catalyzed asymmetric allylic alkylation. The substituent effects on the catalytic reaction were also investigated, and 92% ee was achieved when the p-nitro-substituted ligand 10d was used.

Full text of DOI:10.1016/j.tetasy.2010.06.037

Tetrahedron: Asymmetry 21 (2010) 1936–1941
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of novel carbohydrate-based iminophosphinite ligands
in Pd-catalyzed asymmetric allylic alkylations
a,
Chao Shen a,b, Haijun Xia b, Hui Zheng b, Pengfei Zhang b, , Xinzhi Chen
*
*
a Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China
b College of Material Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel carbohydrate-based iminophosphinite ligands have been synthesized for the first time
and successfully applied in Pd-catalyzed asymmetric allylic alkylation. The substituent effects on the cat-
alytic reaction were also investigated, and 92% ee was achieved when the p-nitro-substituted ligand 10d
was used.
Received 25 May 2010
Accepted 2 June 2010
Available online 24 July 2010
Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
1. Introduction
phite-oxazoline ligands by Dieguez et al. and their ligands were
found to be effective for achieving high enantioselectivities in
Palladium-catalyzed allylic alkylation is known as a very useful
synthetic method for the formation of carbon–carbon bonds.1
asymmetric reactions.12 Recently, Ruffo et al. found some glucosa-
mine-based phosphate–phosphoroamidite ligands, which were
tested in asymmetric allylic substitutions successfully13 (Fig. 1).
However, there are few examples on the study of chiral carbohy-
drate-based phosphinite–imine ligands for asymmetric catalysis.
Inspired by these successful ligand designs, we envisioned that
novel carbohydrate-based iminophosphinite ligands with carbohy-
drate chirality should provide a more effective asymmetric environ-
A
large number of chiral heterobidentate ligands which when
equipped with a strong and a weak heteroatom pair such as P/N,
P/S, or P/O have been successfully prepared and applied in this
reacton.2 Such coordinations have been proven to be effective for
achieving high enantioselectivities through steric and electronic
differentiations. Among these ligands, the P,N ligands have been
extensively used for catalytic applications and great progress has
been made in the past decades in achieving high enantioselectivi-
ties.3 The success of these P,N ligands has encouraged the synthesis
and application of structurally novel ligands based on the paracyc-
lophanes,4 trans-cyclohexylenediamine-based Trost modular,5
binaphthyl-type ligands,6 and biphenyl systems.7 However, there
are only a few examples on the study of chiral P,N ligands based
on carbohydrates for asymmetric catalysis.8
ment for the enantioselective discrimination on
a prochiral
substrate. Furthermore, the phosphinite group attached at C-3
and the imino group attached at C-2 could significantly affect the
electronic and steric effects of the chiral ligand. Herein, we report
the first synthesis of carbohydrate-based iminophosphinite ligands
10a–g and their successful application in Pd-catalyzed enantiose-
lective allylation.
As is well known, carbohydrates, which have been widely used
in organic synthesis as inexpensive starting materials or as chiral
auxiliaries,9 have only recently shown their huge potential as a
source of highly effective chiral ligands. The design and fine-tuning
of carbohydrate-based ligands are facilitated by the multiple func-
tional groups within this class of compounds. In the last few years,
some different carbohydrate-based P,N ligands have been pub-
lished, for example, Kunz et al. reported that carbohydrate-based
phosphine–oxazolines were good ligands for the Pd-catalyzed
asymmetric allylic substitution.10 Uemura et al. showed that a ser-
2. Results and discussion
2.1. Synthesis of carbohydrate-based iminophosphinite ligands
10a–g
The synthesis of chiral ligands 10a–g was initiated from inex-
pensive N-acetylglucosamine using
shown in Scheme 1, C-1 is selectively benzylated at the
a
standard procedure. As
-position,
a
then positions C-4 and C-6 are protected with a benzylidene ring
and the protection at C-2 can be removed easily.14 Ligands 10a–g
are synthesized very efficiently from the corresponding carbohy-
drate-based Schiff base 9a–g, which can be obtained in high yield
by the condensation of 2-aminoglucose 8 and a variety of benzal-
dehydes. The peak corresponding to C-1-NH2 observed in 2-amino-
glucose 8 at 2.26 ppm disappears and a new peak appears at
around 8.30 ppm arising from –CH@N indicating that the –NH2
ies of chiral phosphinite–oxazoline ligands derived from D-glucosa-
mine were highly effective for asymmetric allylic substitutions.11
This work was followed by the design and application of phos-
* Corresponding authors. Tel./fax: +86 571 28862867 (P.Z.).
E-mail address: chxyzpf@hotmail.com (P. Zhang).
0957-4166/$ - see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.06.037

C. Shen et al. / Tetrahedron: Asymmetry 21 (2010) 1936–1941
1937
O
O
MeO
O
Ph
O
OBz
O
O
O
O
O
PPh2
O
O
HN
O
N
R
O
Ph2P
OPiv
PivO
N
PAr2
2 Uemura (2000)11,12
Figure 1. Development of carbohydrate-based ligands in allylic alkylation.
OPiv
R
3 Ruffo (2010)13
1 Kunz (1998)10
O
O
HO
HO
HO
HO
O
O
Ph
O
Ph
O
O
O
(i)
(ii)
(iii)
OBn
O
OH
O
OBn
O
OBn
NH2
HO
HN
HN
HO
HN
HO
HO
Me
Me
Me
7
8
5
6
10a: Ar = Ph
O
O
O
b: Ar = 4-Cl-C6H4
Ph
Ph
O
O
c: Ar = 4-OCH3-C6H4
d: Ar = 4-NO2-C6H4
e: Ar = 2-CF3-C6H4
f: Ar = 3-Cl-C6H4
(v)
OBn
Ar
O
OBn
Ar
(iv)
O
PPh2
N
HO
N
g: Ar = 3-NO2-C6H4
10
9
Scheme 1. Synthesis of carbohydrate-based ligands 10a–g. Reagents and conditions: (i) BnOH, H+; (ii) PhCHO, ZnCl2; (iii) KOH, EtOH; (iv) ArCHO, CH3ONa–CH3OH; (v) Ph2PCl,
THF–Et3N.
Table 1
group present in the former was converted to its Schiff base. The
aryl group on the imine is trans to the sugar ring on the nitrogen
Optimization of reaction conditions using ligand 10aa
site due to the steric effect and the configuration of the imine is
E-configuration.15 The reaction of 9a–g with 1.1 equiv of Ph2PCl
and a catalytic amount of 4-(dimethylamino)pyridine(DMAP) in
THF–Et3N at ꢀ20 °C provided the desired ligands as white solids.
MeO2C
Ph
CO2Me
Ph
OAc
Ph
CH2(COOMe)2/BSA/Base
[Pd (η3- C3H5)Cl]2/L10a
Ph
Solvent
11a
(S)-12a
Ligands 10a–g derived from N-acetyl-D-glucosamine have the
Entry
Solvent
Conditions
Base
Yieldb (%)
eec (%) (config.)d
same absolute configuration (1S,2R,3R,4S,5R). Ligands 10a–g are
stable under dry conditions and are soluble in common organic sol-
vents and their 31P NMR, 1H NMR, and 13C NMR spectral data are in
good agreement with the suggested structures (see Section 4).
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
CH3CN
Toluene
CH2Cl2
rt, 18 h
rt, 18 h
rt, 18 h
rt, 18 h
rt, 18 h
rt, 18 h
rt, 18 h
ꢀ25 °C, 24 h
KOAc
LiOAc
NaOAc
NaH
LiOAc
LiOAc
LiOAc
LiOAc
92
97
93
75
86
92
91
80
80 (S)
85 (S)
74 (S)
62 (S)
75 (S)
78 (S)
80 (S)
90 (S)
2.2. Pd-catalyzed asymmetric allylic alkylation
To begin the search for effective ligands for the Pd-catalyzed
asymmetric allylic alkylation, we employed 1,3-diphenyl-2-prope-
nyl acetate 11a as a model substrate and dimethyl malonate as the
nucleophile. Initially, the reaction was performed in the presence
a
Reaction conditions: 0.25 mmol of substrate, 0.75 mmol of base, 0.75 mmol of
dimethylmalonate,
0.025 mmol of [Pd(
0.75 mmol
of
N,O-bis(trimethylsilyl)acetamide(BSA),
g
3-C3H5)Cl]2, 0.050 mmol of L 10a. Reactions were conducted
under nitrogen. The catalysts were prepared by treating [Pd(g
3-C3H5)Cl]2 with
of [Pd(g
3-C3H5)Cl]2 (2.5 mol %), ligand 10a (5 mol %), N,O-bis(tri-
ligands at 25 °C for 1 h before use.
methylsilyl) acetamide (BSA, 3 equiv), and KOAc as an additive in
CH2Cl2; the reaction proceeded smoothly to give good enantiose-
lectivity (80% ee) (Table 1, entry 1). By using LiOAc instead of KOAc,
the enantioselectivity of 12a increased to 85% ee (entry 2). How-
ever, by the use of NaOAc instead of KOAc the enantioselectivity
of 12a was decreased to 74% ee (entry 3). Using NaH as a base in-
stead of KOAc also decreased both the enantioselectivity and yield
(entry 4). Thus the reaction using lithium as an alkali metal gave
the best result in the various metal acetates. Next, the effect of sol-
vents on this reaction was investigated. When the reaction was
carried out in CH2Cl2, the enantioselectivity was obtained higher
than that in THF, CH3CN, and PhMe (entry 1 vs entries 5, 6, and
7). Lowering the reaction temperature to ꢀ25 °C further improved
b
Isolated yields.
c
Determined by chiral HPLC using a Chiralpak OD column (eluent: hexane/2-
propanol = 99:1, 0.7 mL/min.)
d
The absolute configuration was determined by comparison of the specific
rotation with that of the literature.16
the enantioselectivity to 90% ee, but a longer time was required to
complete the reaction (entry 8).
With the optimized reaction conditions in hand (CH2Cl2 as sol-
vent, 11a as substrate, LiOAc as base, and completing the reaction
at rt), the asymmetric allylic alkylation of 11a with ligands 10a–g
was studied and the results are summarized in Table 2. Ligand 10b

1938
C. Shen et al. / Tetrahedron: Asymmetry 21 (2010) 1936–1941
Table 2
Table 3
Asymmetric allylic alkylation with ligands 10a–ga
Pd-catalyzed allylic alkylation studies using iminophosphinite ligand 10da
3
L10d/
Entry
Ligand
Yieldb (%)
eec (%)
Configd
[Pd (η - C3H5)Cl]2
Nu
OAc
R1
+ NuH
1
2
3
4
5
6
7
8e
10a
10b
10c
10d
10e
10f
92
93
90
95
73
84
92
80
82
83
75
90
57
86
89
92
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
R1
R1
R1
BSA/LiOAc/CH2Cl2
(S)-12
11
a:
R
1 = Ph
b: R1 = Me
10g
10d
Entry
Substrate
NuH
Yieldb (%)
eec (%) Configd
1
2
3
4
5
6
7
8
11a
11a
11a
11a
11a
11a
11b
11b
CH2(CO2 Me)2
CH2(CO2Et)2
95
93
90
91
86
84
62
38
90 (S)
92 (S)
88 (S)
85 (S)
77 (S)
82 (S)
51 (S)
36 (S)
a
Reaction conditions: room temperature, 0.25 mmol of substrate, 0.75 mmol of
LiOAc, 0.75 mmol of dimethylmalonate, 0.75 mmol of N,O-bis(trimethylsilyl)acet-
CH2(CO2Bn)2
MeCH(CO2Me)2
AcNH(CO2Me)2
C6H5CH2NH2
CH2(CO2Me)2
C6H5CH2NH2
amide(BSA), 0.025 mmol of Pd(g
3-C3H5)Cl]2, 0.05 mmol of ligands. Reactions were
conducted under nitrogen. The catalysts were prepared by treating [Pd(g3
C3H5)Cl]2 with ligands at 25 °C for 1 h before use.
-
b
Isolated yields.
c
Determined by chiral HPLC using a Chiralpak OD column (eluent: hexane/2-
propanol = 99:1, 0.7 mL/min.)
d
a
The absolute configuration was determined by comparison of the specific
Reaction conditions: room temperature, 0.25 mmol of substrate, 0.75 mmol of
LiOAc, 0.75 mmol of dimethylmalonate, 0.75 mmol of N,O-bis(trimethylsilyl)acet-
rotation with that of the literature.16
e
T = ꢀ25 °C.
amide(BSA), 0.025 mmol of Pd(g
3-C3H5)Cl]2, 0.05 mmol of ligand 10d. Reactions
were conducted under nitrogen. The catalysts were prepared by treating [Pd(g3
C3H5)Cl]2 with ligands at 25 °C for 1 h before use.
-
b
Isolated yields.
c
with a para-substituted chloro afforded the same level of reactivity
and enantioselectivity as 10a (83% ee, entry 2). Replacing 10b with
10c, which had a methoxy nitro group at the para-position of the
aryl ring, led to slightly lower enantioselectivities (75% ee, entry
3). The para-substituted nitro-substituted 10g gave the best results
(90% ee). Further improvement to 92% ee was attained when the
reaction temperature was lowered to ꢀ25 °C (entry 8). However,
when the ortho-trifluoromethyl-substituted ligand 10e was em-
ployed, the ee was significantly decreased to 57% with a 73% yield
(entry 5).
Determined by chiral HPLC using a Chiralpak OD column (eluent: hexane/2-
propanol = 99:1, 0.7 mL/min.)
d
The absolute configuration was determined by comparison of the specific
rotation with that of the literature.16
O
O
O
O
Ph
Ph
O
O
OBn
OBn
Good results were also obtained when meta-methoxy-substi-
tuted ligand 10f and meta-chloro-substituted ligand 10g were ap-
plied in the asymmetric allylic alkylation (entry 6 and 7). It was
found that ligands with electron-withdrawing substituents tended
to give higher catalytic activities and enantioselectivities than
those electron-donating substituents and all of these ligands affor-
ded the same configuration in the end product, namely the (S)-
enantiomer.
Under the optimized reaction conditions, the asymmetric allylic
alkylation of 11a with different nucleophiles using ligand 10d was
studied and the results are summarized in Table 3. Good reactivi-
ties and enantioselectivities were achieved with both bulky and
substituted malonates. The corresponding alkylated products were
obtained in quantitative yields and 77–92% ee (entries 2–6). How-
ever, when 1,3-dimethylallyl acetate 11b was used instead of 11a,
the reaction with dimethyl malonate gave the product in a moder-
ate enantioselectivity of 51% (entry 7). The reactions with benzyl-
amine as a nucleophile gave the corresponding products in poor
yields and with low enantioselectivities (entry 8).
N
N
O
P
O
P
Ph
Ph
Ph
Ph
Ar
Ph
Ar
Pd
Pd
Ph
Ph
Ph
A
B
Nu-
Nu-
fast
slow
-
Nu- = CH(COOMe)2
O
O
Ph
Ph
O
O
O
OBn
O
OBn
N
N
O
P
O
P
Ph
Ph
Ph
Ph
Ar
Ar
Nu
Pd
Pd
Ph
Ph
Ph
Ph
Nu
2.3. The mechanism for the asymmetric induction with
iminophosphinite ligands
Generally, palladium complexes of mixed donor ligands with
six-membered rings deliver higher enantioselectivities than those
with five-membered rings. Upon coordination, chiral phosphine–
imine ligands would form six-membered ring complexes with
palladium, thus it was thought that they could induce high enanti-
oselectivity in the allylic alkylation reaction. As a result, the mech-
anism for the asymmetric induction with this type of ligand is
rationalized on the basis of the stereochemical results obtained
(Fig. 2). Since the alkylated product (S)-12 was obtained as a major
enantiomer in the reaction of 11 with the malonate, the reaction
probably proceeds through intermediate A rather than intermedi-
MeO2C
Ph
CO2Me
Ph
MeO2C
Ph
CO2Me
Ph
major
(S)-enantiomer
minor
(R)-enantiomer
Figure 2. Proposed reaction mechanisms for the asymmetric allylic alkylation.
ate B in the equilibrium as shown in Figure 2. The steric repulsion
in the intermediate A between a phenyl moiety on the phosphorus

C. Shen et al. / Tetrahedron: Asymmetry 21 (2010) 1936–1941
1939
atom and a phenyl group of the
p
-allyl moiety seems to be smaller
4.2.2. Benzyl-4,6-O-benzylidene-2-deoxy-2-(4-chlorobenzy-
than that in B.
lideneamino)-a-D-glucoside 9b
Yield (1 mmol, 0.437 g, 91%). ½a D20
ꢁ
¼ þ7:8 (c 0.58, CHCl3); 1H
NMR (400 MHz, CDCl3): d 8.29 (s, 1H), 7.74–7.72 (m, 2H), 7.52–
7.50 (m, 2H,), 7.21–740 (m, 10H), 5.58 (s, 1H), 4.83 (d, J = 3.6 Hz,
1H), 4.78 (d, J = 12.0 Hz, 1H), 4.64 (d, J = 12.8 Hz, 1H), 4.48 (m,
1H), 4.28 (m, 1H), 4.12 (m, 1H), 3.79 (t, J = 10.8 Hz, 1H), 3.64 (d,
J = 9.2 Hz, 1H), 3.50–3.47 (d, J = 9.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3): 137.2, 129.2, 128.5, 128.3, 128.1, 128.0, 126.3, 101.8,
99.2, 81.9, 77.3, 77.0, 76.7, 71.3, 69.9, 62.8, 56.1; Anal. Calcd for
3. Conclusion
In conclusion, we have described the first application of carbo-
hydrate-based phosphinite–imine ligands in asymmetric allylic
alkylation reactions. The advantage of these phosphinite–imine li-
gands is that they can be easily prepared in a few steps from com-
mercial N-acetylglucosamine, an inexpensive natural chiral
feedstock. Good enantioselectivities (up to 92% ee) and yields were
obtained with ligand 10d in the palladium-catalyzed asymmetric
allylic alkylation. Further investigations of other substrates with
these phosphinite–imine ligands are underway and work is cur-
rently in progress in order to obtain the monocrystal of the differ-
ent complexes for the X-ray structure.
C27H26ClNO5: C, 67.57; H, 5.46; N, 2.92. Found: C, 67.55; H, 5.47;
N, 2.93.
4.2.3. Benzyl-4,6-O-benzylidene-2-deoxy-2-(4-methoxybenzy-
lideneamino)-a-D-glucoside 9c
Yield (1 mmol, 0.404 g, 85%).
A
known product [16]:
½
a 2D0
ꢁ
¼ þ10:7 (c 0.12, CHCl3). 1H NMR (400 MHz, CDCl3): d 8.26(s,
4. Experimental
4.1. General
1H), 7.49–7.47 (m, 2H, Ph), 7.40–7.25 (m, 12H, Ph), 5.51 (s, 1H),
4.90 (d, J = 2.4 Hz, 1H), 4.74 (d, J = 12.0 Hz, 1H), 4.52 (d,
J = 12.0 Hz, 1H), 4.20–4.23 (m, 1H), 3.86 (m, 1H), 3.69–3.76 (m,
1H), 3.46 (t, J = 9.2 Hz, 1H), 2.82 (d, J = 8.0 Hz, 1H), 2.49 (s, 3H);
13C NMR (100 MHz, CDCl3): 137.17, 129.17, 128.49, 128.28,
128.04, 128.01, 126.28, 101.85, 99.18, 81.98, 77.33, 77.01, 76.68,
71.28, 69.88, 62.89, 56.06. Anal. Calcd for C27H27NO5: C, 72.78; H,
6.12; N, 3.15. Found: C, 72.79; H, 6.13; N, 3.14.
All syntheses were performed using standard Schlenk tech-
niques under an argon atmosphere. Solvents were commercially
obtained at the highest commercial quality and were used without
further purification. Column chromatography was performed on
silica gel grade 60 (230–400 mesh). Analytical TLC: Silica Gel 60,
F254 plates from Merck, which were visualized by UV and phos-
phomolybdic acid staining. Optical rotation values were measured
on a PerkinElmer P241 polarimeter. Enantiomeric excesses (% ee)
were determined by HPLC (Agilent 1100 series) analysis using Chi-
ralcel OD column. The 1H, 13C, and 31P NMR spectra were recorded
on a Bruker Avance DRX-400 spectrometer; chemical shifts (d) are
given in ppm and are referenced to residual solvent peaks (1H NMR
and 13C NMR) or to an 85% H3PO4 in D2O externally (31P NMR). Ele-
mental analyses were performed on Carlo-Erba 1106. Compounds
2-aminoglucose 8, 1,3-diphenyl-2-propenyl acetate 11a, and 1,3-
dimethylallyl acetate 11b were prepared by previously described
methods.14
4.2.4. Benzyl-4,6-O-benzylidene-2-deoxy-2-(4-nitrobenzylide-
neamino)-a-D-glucoside 9d
Yield (1 mmol, 0.461 g, 94%). ½a D20
ꢁ
¼ þ10:6 (c 0.37, CHCl3); 1H
NMR (400 MHz, CDCl3): d 8.26 (s, 1H), 7.86–7.89 (m, 2H, Ph),
7.40–7.80 (m, 12H, Ph), 5.53 (s, 1 H), 4.92 (d, J = 4.0 Hz, 1H), 4.76
(d, J = 12.8 Hz, 1H), 4.51 (d, J = 12.8 Hz, 1H), 4.26–4.29 (m, 1H),
3.88 (m, 1H), 3.65–3.68 (m, 1H), 3.50 (t, J = 8.0 Hz, 1H), 2.84 (d,
J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): 164.9, 122.8, 141.5,
137.2, 136.5, 134.5, 132.7, 130.6, 129.5, 129.3, 128.5, 128.3,
127.8, 127.4, 126.0, 101.2, 82.6, 77.7, 77.0, 65.3; Anal. Calcd for
C27H26N2O7: C, 66.11; H, 5.34; N, 5.71. Found: C, 66.13; H, 5.35;
5.73.
4.2. General procedure for the synthesis of carbohydrate-based
Schiff base 9
4.2.5. Benzyl-4,6-O-benzylidene-2-deoxy-2-(2-trifluorometh-
ylbenzylideneamino)-a-D-glucoside 9e
To
deoxy-
a
suspension of benzyl-4,6-O-benzylidene-2-amino-2-
-glucoside (0.355 g, 1.0 mmol) in MeOH (10 ml) was
Yield (1 mmol, 0.441 g, 86%). ½a D20
ꢁ
¼ þ12:75 (c 0.48, CHCl3); 1H
a
-
D
NMR (400 MHz, CDCl3): d 8.26 (s, 1H), 7.64–7.88 (m, 9H), 5.55 (s,
1H), 5.50 (s, 1H), 4.85 (d, J = 3.6 Hz, 1H), 4.82 (d, J = 8.0 Hz, 1H),
4.67 (d, J = 8.0 Hz, 1H), 4.27–4.32 (m, 1H), 3.84–3.90 (m, 2H),
3.62–3.66 (m, 1H), 3.45 (t, J = 8.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3): 160.2, 137.1, 133.4, 132.7, 130.6, 129.9, 128.6, 128.7,
128.5, 128.3, 128.2, 127.9, 127.8, 127.6, 127.6, 127.5, 126.3,
126.0, 125.1, 101.6, 99.5, 81.5, 79.8, 79.5, 77.2, 77.1, 77.0, 76.4,
75.2, 75.1, 69.3, 69.0, 63.2; Anal. Calcd for C28H26F3NO5: C, 65.49;
H, 5.10; N, 2.73. Found: C, 65.51; H, 5.11; 5. 2.75.
added substituted aldehyde (1.1 mmol), and the reaction mixture
was refluxed for 2.5 h to give a clear orange solution. The reaction
mixture was allowed to cool to room temperature and the solvent
was removed under reduced pressure. The residue was dissolved in
5 ml of CH2Cl2 and excess hexane was added to the solution while
stirring to afford a light yellow solid product, which was isolated
through filtration and dried under vacuum. The crude product
was recrystallised from ethanol to give a pure sample. The physical
and spectroscopic data of the compounds 9a–g are as follows.
4.2.6. Benzyl-4,6-O-benzylidene-2-deoxy-2-(3-Chlorobenzy-
4.2.1. Benzyl-4,6-O-benzylidene-2-deoxy-2-benzylideneamino-
lideneamino)-a-D-glucoside 9f
a-
D
-glucoside 9a
Yield (1 mmol, 0.442 g, 92%). ½a D20
ꢁ
¼ þ23:1 (c 0.68, CHCl3); 1H
Yield (1 mmol, 0.392 g, 88%). ½a D20
ꢁ
¼ þ16:9 (c 0.28, CHCl3); 1H
NMR (400 MHz, CDCl3): d 8.29 (s, 1H), 6.85–7.61 (m, 9H), 5.52 (s,
1H), 4.88 (d, J = 3.6 Hz, 1H), 4.84 (d, J = 8.4 Hz, 1H), 4.59 (d,
J = 8.4 Hz, 1H), 4.40–4.45 (m, 1H), 3.85–3.89 (m, 2H), 3.64–3.68
(m, 1H), 3.52 (t, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3):
162.3, 137.2, 133.6, 131.9, 130.7, 129.7, 128.4, 28.5, 128.0, 127.6,
127.7, 127.6, 127.7, 127.5, 126.4, 126.1, 125.3, 125.0, 101.7, 99.6,
81.8, 79.7, 79.4, 77.3, 77.2, 77.0, 76.8, 75.3, 75.3, 69.5, 69.1, 63.5;
Anal. Calcd for C27H26ClNO5: C, 67.57; H, 5.46; N, 2.92. Found: C,
67.55; H, 5.47; N, 2.93.
NMR (400 MHz, CDCl3): d 8.25 (s, 1H), 7.39–7.42 (m, 2H, Ph),
7.32–7.35 (m, 13H, Ph), 5.50 (s, 1H), 4.92 (d, J = 3.6 Hz, 1H), 4.67
(d, J = 12.4 Hz, 1H), 4.51 (d, J = 12.4 Hz, 1H), 4.20–4.24 (m, 1H),
3.83 (m, 1H), 3.67–3.74 (m, 1H), 3.43 (t, J = 8.0 Hz, 1H), 2.80 (d,
J = 7.6 Hz, 1H), 2.47 (s, 3H); 13C NMR (100 MHz, CDCl3): 141.2,
128.2, 128.5, 128.3, 128.0, 128.0, 127.0, 101.8, 98.7, 80.9, 77.34,
77.0, 76.6, 71.2, 68.9, 62.5, 56.0; Anal. Calcd for C27H27NO5: C,
72.79; H, 6.11; N, 3.14. Found: C, 72.80; H, 6.13; N, 3.15.

1940
C. Shen et al. / Tetrahedron: Asymmetry 21 (2010) 1936–1941
4.2.7. Benzyl-4,6-O-benzylidene-2-deoxy-2-(3-nitroben-
4.3.4. Benzyl-4,6-O-benzylidene-3-O-(diphenylphosphino)-2-
zylideneamino)-
a
-
D
-glucoside 9g
deoxy-2-(4-nitrobenzylideneamino)-a-D-glucoside 10d
Yield (1 mmol, 0.470 g, 96%). ½a D20
ꢁ
¼ þ5:3 (c 0.50, CHCl3); 1H
Yield (0.5 mmol, 310 g, 92%). ½a D20
ꢁ
¼ þ21:4 (c 0.39, CHCl3); 1H
NMR (400 MHz, CDCl3): d 8.31 (s, 1H), 7.70 (m, 2H), 7.52 (m, 2H),
7.42–7.35 (m, 5H), 7.19–7.26 (m, 5H), 5.59 (s, 1H), 4.88 (d,
J = 12.4 Hz, 1H), 4.83 (d, J = 3.2 Hz, 1H), 4.65 (d, J = 12.4 Hz, 1H),
4.43 (m, 1H), 4.08 (t, J = 9.2 Hz, 1H), 3.87 (t, J = 10.4 Hz, 1H), 3.69
(t, J = 9.2 Hz, 1H), 3.59 (m, 1H), 3.31(t, J = 8.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3): 164.1, 137.0, 137.0, 134.4, 129.3, 128.8, 128.4,
128.3, 127.8, 127.7, 126.3, 102.0, 100.9, 80.9, 77.4, 77.0, 76.7,
76.6, 71.9, 71.1, 68.8, 66.3; Anal. Calcd for C27H26N2O7: C, 66.11;
H, 5.34; N, 5.71. Found: C, 66.13; H, 5.35; 5.73.
NMR (400 MHz, CDCl3): d 8.30 (s, 1H), 6.90–7.44 (m, 24H), 5.45
(s, 1H), 4.80 (d, J = 3.6 Hz, 1H), 4.82 (d, J = 6.4 Hz, 1H), 4.58 (d,
J = 8.0 Hz, 1H), 4.35–4.40 (m, 1H), 3.84–3.87 (m, 2H), 3.61–3.62
(m, 1H), 3.45 (t, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3):
164.3, 144.9, 141.6, 137.1, 136.5, 134.4, 131.6, 130.7, 129.9,
129.2, 128.8, 128.4, 127.8, 127.6, 126.3, 101.5, 82.8, 77.4, 77.1,
65.5; 31P NMR (162 MHz, CDCl3): 114.9 ppm; Anal. Calcd for
C39H35N2O7P: C, 69.45; H, 5.22; N, 4.14. Found: C, 69.44; H, 5.20;
N, 4.15.
4.3. General procedure for the synthesis of carbohydrate-based
P,N ligands 10
4.3.5. Benzyl-4,6-O-benzylidene-3-O-(diphenylphosphino)-2-
deoxy-2-(2-trifluoromethylbenzylideneamino)-
10e
a-D-glucoside
To a solution of carbohydrate-based Schiff base 9 (0.5 mmol)
and a catalytic amount of 4-(dimethylamino)pyridine (10 mg) in
10 mL of degassed THF/Et3N (v/v, 4:1) was slowly added chlorodi-
phenylphosphine (0.1 mL, 0.6 mmol) at ꢀ20 °C, and the mixture
was stirred at this temperature. After 30 min, the mixture was con-
centrated to dryness and the residue was subjected to column
chromatography on Al2O3 with degassed hexane/AcOEt/Et3N (v/v,
10:1:0.1) as an eluent to give the product. The physical and spec-
troscopic data of the ligands 10a–g are as follows.
Yield (0.5 mmol, 0.280 g, 81%). ½a D20
ꢁ
¼ þ16:5 (c 0.50, CHCl3); 1H
NMR (400 MHz, CDCl3): d 8.29 (s, 1H), 6.87–7.63 (m, 24H), 5.54 (s,
1H), 4.86 (d, J = 2.4 Hz, 1H), 4.83 (d, J = 6.0 Hz, 1H), 4.66 (d,
J = 8.0 Hz, 1H), 4.28–4.32 (m, 1H), 3.84–3.90 (m, 2H), 3.62–
3.65(m, 1H), 3.46 (t, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3):
160.1, 137.1, 133.4, 131.7, 130.7, 129.9, 128.8, 128.7, 128.6,
128.3, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 126.2, 126.1,
125.1, 125.0, 101.6, 99.5, 81.9, 79.8, 79.6, 77.4, 77.1, 77.0, 76.7,
75.6, 75.5, 69.5, 69.1, 63.4; 31P NMR (162 MHz, CDCl3):
114.2 ppm; Anal. Calcd for C27H26NO5P: C, 68.88; H, 5.05; N,
2.02. Found: C, 68.86; H, 5.04; N, 2.04.
4.3.1. Benzyl-4,6-O-benzylidene-3-O-(diphenylphosphino)-2-
deoxy-2-benzylideneamino-a-D-glucoside 10a
Yield (0.5 mmol, 0.258 g, 82%). ½a D20
ꢁ
¼ þ15:9 (c 0.36, CHCl3); 1H
4.3.6. Benzyl-4,6-O-benzylidene-3-O-(diphenylphosphino)-2-
NMR (400 MHz, CDCl3): d 8.30 (s, 1H), 6.87–7.68 (m, 25H), 5.52 (s,
1H), 4.86 (d, J = 3.6 Hz, 1H), 4.80 (d, J = 8.0 Hz, 1H), 4.57 (d,
J = 8.0 Hz, 1H), 4.41–4.44 (m, 1H), 3.84–3.87 (m, 2H), 3.65–3.67
(m, 1H), 3.52 (t, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3):
162.6, 137.2, 133.4, 131.7, 131.6, 129.7, 128.6, 128.4, 128.3,
128.0, 127.7, 127.5, 127.4, 126.3, 126.5, 125.3, 125.0, 101.5, 99.9,
81.4, 79.7, 79.4, 77.2, 77.2, 77.2, 76.7, 75.3, 75.1, 69.8, 69.2, 63.0;
31P NMR (162 MHz, CDCl3): 114.5 ppm; Anal. Calcd for
deoxy-2-(3-chlorobenzylideneamino)-a-D-glucoside 10f
Yield (0.5 mmol, 0.279 g, 84%). ½a D20
ꢁ
¼ þ18:7 (c 0.56, CHCl3); 1H
NMR (400 MHz, CDCl3) d: 8.28 (s, 1H), 6.85–7.61 (m, 24H), 5.53 (s,
1H), 4.86 (d, J = 3.6 Hz, 1H), 4.84 (d, J = 8.0 Hz, 1H), 4.59 (d,
J = 8.4 Hz, 1H), 4.40–4.45 (m, 1H), 3.85–3.88 (m, 2H), 3.64–3.67
(m, 1H), 3.50 (t, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3):
162.3, 137.2, 133.5, 131.9, 130.7, 129.7, 128.9, 128.8, 128.4,
128.0, 127.6, 127.7, 127.6, 127.7, 127.5, 126.4, 126.1, 125.3,
125.0, 101.7, 99.6, 81.8, 79.8, 79.4, 77.2, 77.2, 77.1, 76.8, 75.4,
75.2, 69.6, 69.0, 63.6; 31P NMR (162 MHz, CDCl3): 114.5 ppm; Anal.
Calcd for C39H35ClNO5P: C, 70.54; H, 5.30; N, 2.11. Found: C, 70.55;
H, 5.32; N, 2.10.
C39H36NO5P: C, 74.38; H, 5.75; N, 2.23; Found: C, 74.40; H, 5.76;
N, 2.22.
4.3.2. Benzyl-4,6-O-benzylidene-3-O-(diphenylphosphino)-2-
deoxy-2-(4-chlorobenzylideneamino)-a-D-glucoside 10b
Yield (0.5 mmol, 0.285 g, 86%). ½a D20
ꢁ
¼ þ20:3 (c 0.84, CHCl3); 1H
4.3.7. Benzyl-4,6-O-benzylidene-3-O-(diphenylphosphino)-2-
NMR (400 MHz, CDCl3): d 8.27 (s, 1H), 6.86–7.62 (m, 24H), 5.53 (s,
1H), 4.88 (d, J = 3.6 Hz, 1H), 4.82 (d, J = 8.0 Hz, 1H), 4.56 (d,
J = 8.0 Hz, 1H), 4.42–4.45 (m, 1H), 3.86–3.88 (m, 2H), 3.65–3.67
(m, 1H), 3.51 (t, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3):
162.2, 137.1, 133.4, 131.8, 130.6, 129.6, 128.9, 128.5, 128.3,
128.2, 127.9, 127.6, 127.5, 126.4, 126.6, 125.4, 125.2, 101.6, 99.8,
81.5, 79.7, 79.4, 77.2, 77.2, 77.1, 76.7, 75.3, 75.1, 69.7, 69.0, 63.5;
31P NMR (162 MHz, CDCl3): 114.6 ppm; Anal. Calcd for
deoxy-2-(3-nitrobenzylideneamino)-a-D-glucoside 10g
Yield (0.5 mmol, 0.303 g, 90%). ½a D20
ꢁ
¼ þ21:5 (c 0.37, CHCl3). 1H
NMR (400 MHz, CDCl3): d 8.26 (s, 1H), 6.91–7.46 (m, 24H), 5.48 (s,
1H), 4.83 (d, J = 3.6 Hz, 1H), 4.80 (d, J = 6.0 Hz, 1H), 4.58 (d,
J = 11.2 Hz, 1H), 4.38–4.41 (m, 1H), 3.83–3.88 (m, 2H), 3.60–3.62
(m, 1H), 3.44 (t, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) d:
164.2, 144.8, 141.6, 137.0, 136.6, 134.4, 131.7, 130.8, 129.8,
129.0, 128.7, 128.3, 127.9, 127.7, 126.2, 101.4, 82.9, 77.3, 77.0,
65.5; 31P NMR (162 MHz, CDCl3): 114.8 ppm; Anal. Calcd for
C39H35ClNO5P: C, 70.55; H, 5.30; N, 2.12. Found: C, 70.56; H,
5.30; N, 2.11.
C39H35N2O7P: C, 69.45; H, 5.22; N, 4.15. Found: C, 69.44; H, 5.20;
N, 4.16.
4.3.3. Benzyl-4,6-O-benzylidene-3-O-(diphenylphosphino)-2-
deoxy-2-(4-methoxybenzylideneamino)-
a
-
D
-glucoside 10c
4.4. General procedure for asymmetric allylic alkylations
Yield (0.5 mmol, 0.264 g, 80%). ½a D20
ꢁ
¼ þ13:5 (c 0.26, CHCl3); 1H
NMR (400 MHz, CDCl3): d 8.25 (s, 1H), 6.90–7.44 (m, 24H), 5.50 (s,
1 H), 4.90 (d, J = 2.4 Hz, 1H), 4.74 (d, J = 12.0 Hz, 1H), 4.51 (d,
J = 12.0 Hz, 1H), 4.21–4.23 (m, 1H), 3.88 (m, 1H), 3.69–3.78 (m,
1H), 3.45 (t, J = 8.4 Hz, 1H), 2.81 (d, J = 8.0 Hz, 1H), 2.48 (s, 3 H);
13C NMR (100 MHz, CDCl3): 161.3, 137.1, 137.17, 129.17, 128.49,
128.28, 128.04, 128.01, 126.28, 101.85, 99.18, 81.98, 77.33, 77.01,
76.68, 71.28, 69.88, 62.89, 56.06; 31P NMR (162 MHz, CDCl3):
114.5 ppm; Anal. Calcd for C40H38NO6P: C, 72.83; H, 5.80; N,
2.12. Found: C, 72.82; H, 5.81; N, 2.14.
Chiral ligand 10 (5 mol %) and [Pd(g
3-C3H5)Cl]2 (0.91 mg,
2.5 mol %) were dissolved in degassed CH2Cl2 (0.5 mL) under N2
and the solution was stirred at room temperature. After 30 min,
acetate 11 (0.25 g, 1.0 mmol) in toluene (1.5 mL) was added and
the mixture was stirred for 30 min. N,O-Bis-(trimethylsilyl)acetam-
ide (0.74 mL, 3 mmol), dimethyl malonate (0.35 mL, 3 mmol), and
KOAc (5 mg) were added to the above mixture in this order and
the mixture was stirred at this temperature. After 18 h the reaction
mixture was added to saturated NH4Cl (aq) and extracted with

C. Shen et al. / Tetrahedron: Asymmetry 21 (2010) 1936–1941
1941
3. (a) Seubert, C. K.; Sun, Y.; Thiel, W. R. Dalton Trans. 2009, 4971; (b) Mikhailine,
A.; Lough, A. J.; Morris, R. H. J. Am. Chem. Soc. 2009, 131, 1394; (c) Glegola, K.;
Johannesen, S. A.; Thim, L.; Goux-Henry, C.; Skrydstrup, T.; Framery, E.
Tetrahedron Lett. 2008, 49, 6635.
4. Jiang, B.; Lei, Y.; Zhao, X. J. Org. Chem. 2008, 73, 7833.
5. Butts, C. P.; Filali, E.; Lloyd-Jones, G. C.; Norrby, P.; Sale, D. A.; Schramm, Y. J. Am.
Chem. Soc. 2009, 131, 9945.
6. Feng, J.; Bohle, D. S.; Li, C. Tetrahedron: Asymmetry 2007, 18, 1043.
7. Lai, H.; Huang, Z.; Wu, Q.; Qin, Y. J. Org. Chem. 2009, 74, 283.
8. Benessere, V.; Litto, R. D.; Roma, A. D.; Ruffo, F. Coord. Chem. Rev. 2010, 254, 90.
9. (a) Diéguez, M.; Pàmies, O.; Claver, C. Chem. Rev. 2004, 104, 3189; (b) Diéguez,
M.; Claver, C.; Pàmies, O. Eur. J. Org. Chem. 2007, 4621; (c) Diéguez, M.; Pàmies,
O. Chem. Eur. J. 2008, 944; (d) Boysen, M. M. K. Chem. Eur. J. 2007, 13, 8648; (e)
Mao, J. G.; Zhang, P. F. Tetrahedron: Asymmetry 2009, 20, 566.
10. Gläser, B.; Kunz, H. Synlett 1998, 53.
Et2O (10 mL ꢂ 3), after which the extract was dried over MgSO4.
The solvent was removed under reduced pressure, and the residue
was subjected to column chromatography on silica gel with hex-
ane/AcOEt (v/v, 5:1) as an eluent to give compound 12. The enan-
tiomeric excess was determined by HPLC (Chiralcel OD column,
0.7 mL/min, hexane/2-propanol = 99:1). The configuration of allylic
alkylation product 12a from these reactions was proven to be (S)
by comparing the specific rotation with the literature values.16
Acknowledgments
11. Hashizume, T.; Yonehara, K.; Ohe, K.; Uemura, S. J. Org. Chem. 2000, 65, 5197.
12. (a) Mata, Y.; Diéguez, M.; Pàmies, O.; Claver, C. Adv. Synth. Catal. 2005, 347,
1943; (b) Dieguez, M.; Mazuela, J.; Pamies, O.; Verendel, J. J.; Andersson, P. G. J.
Am. Chem. Soc. 2008, 130, 7208.
This work was supported by the National Science and Technol-
ogy Ministry of China (No. 2007BAI34B05) and Zhejiang Provincial
Natural Science Foundation of China (No. Y4090052).
13. Benessere, V.; Ruffo, R. Tetrahedron: Asymmetry 2010, 21, 171.
14. (a) Benessere, V.; Del Litto, R.; Ruffo, F.; Moberg, C. Eur. J. Org. Chem. 2009,
1352; (b) De Roma, A.; Ruffo, F.; Woodward, S. Chem. Commun. 2008, 5384; (c)
Benessere, V.; De Roma, A.; Ruffo, F. ChemSusChem 2008, 1, 425.
15. (a) Mao, J. G.; Zhang, P. F. Tetrahedron: Asymmetry 2009, 20, 566; (b) Wang, D.;
Zhang, P. F.; Yu, B. Helv. Chim. Acta 2007, 90, 938; (c) Zhoua, G. B.; Zheng, W. X.;
Wang, D.; Zhang, P. F.; Pan, Y. J. Helv. Chim. Acta 2006, 89, 520; (d) Zhou, G. B.;
Zhang, P. F.; Pan, Y. J. Tetrahedron 2005, 61, 5671.
References
1. (a) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336; (b) Trost, B. M.;
Crawley, M. L. Chem. Rev. 2003, 103, 2921; (c) Lu, Z.; Ma, S. Angew. Chem., Int. Ed.
2008, 120, 258.
2. (a) Lai, H. S.; Huang, Z. Y.; Wu, Q.; Qin, Y. J. Org. Chem. 2008, 74, 283; (b) Jiang,
B.; Huang, Z. G. Tetrahedron Lett. 2007, 48, 1703; (c) Cheung, H. Y.; Yu, W. Y.;
Au-Yeung, T. T.-L.; Zhou, Z. Y.; Chan, A. S. C. Adv. Synth. Catal. 2009, 351, 1412.
16. Evans, D. A.; Michael, F. E.; Tedrow, J. S.; Campos, K. R. J. Am. Chem. Soc. 2003,
125, 3534.