Sugar-based phosphite and phosphoroamidite ligands for the Cu-catalyzed asymmetric 1,4-addition to enones

Article abstract of DOI:10.1016/j.tetasy.2009.09.002

A modular sugar-based phosphoroamidite L1-L5a-g and phosphite L6-L9a-g ligand library was tested in the asymmetric Cu-catalyzed 1,4-conjugate addition reactions of β-substituted (cyclic and linear) and β,β′-disubstituted (cyclic) enones. The selectivity d

Full text of DOI:10.1016/j.tetasy.2009.09.002

Tetrahedron: Asymmetry 20 (2009) 2167–2172
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Tetrahedron: Asymmetry
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Sugar-based phosphite and phosphoroamidite ligands for the Cu-catalyzed
asymmetric 1,4-addition to enones
a,
b
b,
Eva Raluy a, Oscar Pàmies a, , Montserrat Diéguez , Stephane Rosset , Alexander Alexakis
*
*
*
a Departament de Química Física i Inorgànica, Universitat Rovira i Virgili, C/Marcelꢀlí Domingo s/n, 43007 Tarragona, Spain
b University of Geneva, Department of Organic Chemistry, 30, Quai Ernest Ansermet, 1211 Genève 4, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 July 2009
Accepted 2 September 2009
Available online 30 September 2009
A modular sugar-based phosphoroamidite L1–L5a–g and phosphite L6–L9a–g ligand library was tested in
the asymmetric Cu-catalyzed 1,4-conjugate addition reactions of b-substituted (cyclic and linear) and
b,b0-disubstituted (cyclic) enones. The selectivity depended strongly on the configuration of carbon atom
C-3, the size of the sugar backbone ring, the flexibility of the ligand backbone, the substituents and con-
figurations in the biaryl phosphoroamidite moieties a–g, the type of functional group attached to the
ligand backbone and the substrate structure. Therefore, by carefully selecting the ligand parameters,
enantioselectivities of up to 60% for cyclic substrates and 72% for linear ones were achieved.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
based monophosphoroamidite ligand library (Fig. 1, L1–L5a–g) in
the Cu-catalyzed asymmetric 1,4-addition of organometallic re-
Nowadays, asymmetric copper-catalyzed conjugate addition is
a well-developed methodology for creating C–C bonds stereoselec-
tivity.1 The last decade has seen important breakthroughs in what
is possible in the area of catalytic asymmetric 1,4-addition of alkyl
organometallic nucleophiles to enones. Most of the successful
asymmetric versions of this chemistry have made use of diorgano-
zinc reagents, particularly ZnEt2, a trend started by Alexakis (Cu-
catalysis) and Soai (Ni-catalysis).2 Viable ligand classes are now
available that give >90% ee for the addition of diorganozinc to sev-
eral types of cyclic and chalcone substrates.1 Phosphites and
phosphoroamidites based on biaryl moieties are amongst the most
efficient ligands.1j,k,3 Despite all these advances, there have been
relatively few publications describing the highly enantioselective
addition of organometallics to linear aliphatic enones or the use
of trialkylaluminium reagents as an alternative to organozincs.4
Additionally, trialkylaluminium reagents allow Cu-catalyzed 1,4-
addition to very challenging substrates (i.e., b,b0-disubstituted
enones), which are inert to organozinc methodologies.1j,4h,k This
justifies expanding the range of ligands for the Cu-catalyzed addi-
tion of organoaluminium reagents to enones, in particularly to lin-
ear aliphatic and b,b0-disubstituted enones. Carbohydrates are
particularly useful for this purpose because they are inexpensive
and because their modular constructions are easy.5 In this context
and encouraged by the success of monophosphoroamidite ligands
in this process, we herein report the use of a highly modular sugar-
agents to cyclic and linear enones. We also compare the effective-
ness of this phosphoroamidite ligand library with the results
obtained using related monophosphite ligands (Fig. 1, L6–L9a–
g).6 To do so, we have also expanded our previous work on mono-
phosphite ligands L6–L9a–g to other challenging classes of sub-
strates (i.e., nitroolefins and b,b0-disubstituted enones). Using
these ligands, we fully investigated the effects of systematically
varying the configuration of the carbon atom C-3 (ligands L1, L2,
L6 and L7), the size of the sugar backbone ring (ligands L3 and
L8), the flexibility of the ligand backbone (ligands L4, L5 and L9),
the substituents and configurations in the biaryl phosphoroamidite
moieties a–g and the type of functional group attached to the li-
gand backbone (X = O or NH).
2. Results and discussion
2.1. Ligand synthesis
The new phosphoroamidite ligands L2b–e and L4–L5b–e were
synthesized very efficiently in one step from the corresponding su-
gar amines, which were prepared on a large scale from
D-glucose,
D-fructose and
D
-galactose, as previously described (Scheme 1).7
Therefore, the reaction of the corresponding amine with 1 equiv
of the desired in situ formed phosphorochloridite in the presence
of pyridine afforded the desired ligands.
The new ligands L2a–e and L4–L5d–e were purified on neutral
alumina under an atmosphere of argon and were isolated as white
solids or colourless viscous liquids. They were stable at room tem-
perature and very stable to hydrolysis. Elemental analyses agreed
* Corresponding authors.
E-mail addresses: oscar.pamies@urv.cat (O. Pàmies), montserrat.dieguez@urv.cat
(M. Diéguez), alexandre.alexakis@chiorg.unige.ch (A. Alexakis).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.09.002

2168
E. Raluy et al. / Tetrahedron: Asymmetry 20 (2009) 2167–2172
O
6
O
O
O
O
O
O
O
P
O
P
O
5
O
P
O
X
O
O
O
O
O
X
6
O
1
X
5
O
O
2
4
4
2
O
O
O
O
O
3
1
3
X
O
O
O
O
X
P
O
O
O
O
P
O
O
L1 X = NH
L6 X = O
L2 X = NH
L7 X = O
L3 X = NH
L8 X = O
L4 X = NH
L9 X = O
L5 X = NH
R1
R2
O
=
O
O
O
O
O
R1
R2
a R1 = R2 = tBu
f
(R)ax
(S)ax
b R1 = tBu; R2 = OMe
c R1 = SiMe3; R2 = H
d R1 = R2 = Me
g
e R1 = allyl; R2 = H
Figure 1. Phosphite and phosphoroamidite ligands L1–L9a–g.
R1
O
R2
Table 1
R2
R1
Selected results for the Cu-catalyzed asymmetric 1,4-addition to S1 using ligands L1–
L9a–ga
H
N
*
O
O
Cl
P
+
R
NH2
% Convb (h)
% Yieldb
% eec
P
Entry
L
O
*
R
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19d
20d
21d
22d
23e
24f
L1a
L1b
L1c
L1d
L1e
L1f
100 (18)
100 (18)
100 (18)
99 (18)
100 (18)
100 (18)
100 (18)
95 (18)
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
98 (2)
85
79
82
77
85
89
88
75
89
76
87
92
95
87
78
89
85
67
24
28
8
26 (R)
24 (S)
32 (S)
10 (R)
4 (S)
14 (R)
56 (S)
18 (S)
9 (S)
R* = Sugar backbone
R1
R2
R2
R1
L2b-e, L4b-e, L5b-e
Scheme 1. Synthesis of the new phosphoroamidite ligands L2b–e and L4–L5b–e.
L1g
L2a
L2b
L2c
L3c
L4a
L4b
L4d
L5a
L5b
L5d
L5e
L6g
L7a
L8a
L9a
L1g
L1g
with the assigned structures. The 1H and 13C NMR spectra were as
expected for these C1 ligands. Two signals for each compound were
observed in the 31P NMR spectrum (see Section 4). Rapid ring
inversions (atropoisomerization) in the biphenyl-phosphorus moi-
eties b–e occurred on the NMR time scale instead of the expected
diastereoisomers, which were not detected by low-temperature
phosphorus NMR.8
5 (S)
21 (S)
20 (R)
22 (R)
10 (R)
11 (S)
10 (S)
8 (R)
8 (S)
20 (S)
23 (S)
4 (S)
8 (S)
35 (S)
20 (S)
2.2. Asymmetric conjugate 1,4-addition to cyclic enones
99 (2)
94 (2)
99 (2)
100 (18)
100 (18)
2.2.1. Asymmetric conjugated 1,4-addition of ZnEt2 and AlEt3 to
cyclohexenone S1
18
69
74
In the first set of experiments, we tested the new phosphoro-
amidite ligands L1–L5a–g in the copper-catalyzed conjugate addi-
tion of diethylzinc to 2-cyclohexenone S1 (Eq. 1). The latter was
chosen as a substrate because this reaction has already been per-
formed with a wide range of ligands with several donor groups,
thus enabling the efficiency of the various ligands systems to be di-
rectly compared.1
a
Reaction conditions: CuTC (2 mol %), ligand (2 mol %), ZnEt2 (1.5 equiv,
0.62 mmol), S1 (0.415 mmol), Et2O (2.5 mL) at ꢁ30 °C.
b
Conversion and yields determined by GC using undecane as internal standard
after 18 h.
c
Enantiomeric excess measured by GC using Lipodex A column.
Reported in the literature, see Ref. 6.
Using AlEt3 (1.5 equiv, 0.62 mmol).
Using Cu(OTf)2 in CH2Cl2 at 0 °C.
d
e
f
O
O
[Cu] / L1-L5a-g
ð1Þ
ZnEt2 or AlEt3
*
Et
of carbon atom C-3, the size of the sugar backbone ring, the flexi-
bility of the ligand backbone and the substituents and configura-
tions in the biaryl phosphoroamidite moieties a–g. The best
enantioselectivities (ee’s up to 56%; Table 1, entry 7) were obtained
using ligand L1g, which has the appropriate combination of ligand
parameter.
S1
1
The catalytic system was generated in situ by adding the corre-
sponding ligand to a suspension of catalyst precursor under stan-
dard conditions.9 The results are shown in Table 1. They indicate
that the enantioselectivity is highly affected by the configuration

E. Raluy et al. / Tetrahedron: Asymmetry 20 (2009) 2167–2172
2169
Table 2
With ligands L1a–g we studied the effects of the biaryl phosp-
horoamidite moiety on enantioselectivity. We found that the pres-
ence of bulky substituents at the ortho positions of the biphenyl
phosphite moiety had a positive effect on the enantioselectivity
(Table 1, entries 1–3 vs entries 4 and 5). We also observed a coop-
erative effect between the configuration of the biaryl moieties and
the configuration of carbon atom C-3 in the sugar backbone (Table
1, entries 6 and 7). The results indicate that the matched combina-
tion is achieved with ligand L1g, which has an (S)-configuration at
both the carbon atom C-3 and in the binaphthyl phosphoroamidite
moiety (Table 1, entry 7).
With ligands L2, whose configuration at C-3 is the opposite of
that of ligands L1, we studied the effect of this configuration in
the product outcome. The results indicated that this configuration
influences the enantioselectivity (Table 1, entries 8–10 vs entries
1–3). Therefore, ligands L2 with an (R) configuration at C-3 pro-
vided lower enantioselectivities than ligands L1.
Selected results for the Cu-catalyzed asymmetric 1,4-addition to S2 using ligands L1–
L9a–ga
Entry
L
% Convb (h)
% Yieldb
% eec
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
L1a
L1b
L1c
L1d
L1e
L1g
L2a
L2d
L2e
L3c
L4a
L4d
L4e
L5a
L6a
L6f
40 (18)
23 (18)
12 (18)
48 (18)
22 (18)
32 (18)
25 (18)
25 (18)
18 (18)
15 (18)
8 (18)
31
19
8
9 (S)
5 (S)
4 (S)
15 (S)
25 (S)
41 (S)
49 (S)
23 (S)
6 (S)
32
14
22
19
18
11
13
7
2 (S)
43 (S)
15 (S)
4 (S)
35 (S)
50 (R)
8 (S)
30 (S)
60 (S)
20 (S)
42 (S)
5 (S)
20 (18)
5 (18)
11
3
9
12 (18)
12 (18)
12 (18)
18 (18)
51 (48)
18 (18)
40 (18)
10 (18)
12 (18)
9
10
13
49
12
33
7
Ligands L3, which have a pyranoside backbone, provided lower
enantioselectivitities than the related furanoside ligands L1 (Table
1, entry 3 vs entry 11).
L6g
L7a
L7f
L7g
L8a
L9a
Using the most flexible ligands L4 and L5, which have the
phosphoroamidite moiety attached to a primary carbon, provided
lower enantioselectivities than ligands L1 (Table 1, entries 12–18).
Finally, after comparing these results with those from the re-
lated phosphite ligands L6–L9, we found that replacing the phos-
phite moiety with a phosphoroamidite group had a positive
effect on the enantioselectivity (Table 1, entries 7, 8, 11 and 12
vs entries 19–22).6
8
3 (S)
a
Reaction conditions: CuTC (4 mol %), ligand (4 mol %), AlEt3 (1.5 equiv,
0.62 mmol), S2 (0.415 mmol), Et2O (2.5 mL), T = ꢁ30 °C.
b
Conversion and yields determined by GC using undecane as internal standard
after 18 h.
c
Enantiomeric excess measured by GC using Lipodex E column.
We next used the ligand that provided the best results (ligand
L1g) to study the effect of several reaction parameters (i.e., catalyst
precursor, solvent, alkylating reagent and temperature) on the
enantioselectivity. However, enantioselectivities did not improve
(Table 1, entries 7, 23 and 24).
the phosphite moiety with a phosphoroamidite group (Table 2, en-
tries 15 and 18 vs entries 1 and 7). Also, in contrast to S1, the
enantioselectivity in phosphoroamidite ligands L1–L5a is hardly
affected by the flexibility of the ligand backbone (Table 2, entries
1, 7, 11 and 14), whereas for phosphite ligands L6–L9, increasing
the flexibility of the ligand negatively affected ee’s (Table 2, entries
15, 18, 21 and 22).
2.2.2. Asymmetric conjugate 1,4-addition of 3-methyl-
cyclohexenone S2
In summary, the best results (ee’s up to 60%) were obtained
with phosphite ligand L7a (Table 1, entry 18), which has bulky
tert-butyl groups at both the ortho- and para-positions of the
biphenyl moiety and a furanoside sugar-backbone.
To study further the potential of ligands L1–L9a–g, we tested
them in the copper-catalyzed conjugated addition of triethylalumi-
num to 3-methyl-cyclohexenone S2 (Eq. 2). The conjugate addition
of this type of substrate provides an efficient way to build stereo-
genic quaternary centres into a compound.1
2.3. Asymmetric conjugate 1,4-addition to linear enones
O
O
CuTC / L1-L9a-g
2.3.1. Asymmetric conjugated 1,4-addition of ZnEt2 and AlEt3 to
trans-3-nonen-2-one S3
ð2Þ
AlEt3
*
Et
We have also screened the new phosphoroamidite ligands L1–
L5a–g in the copper-catalyzed conjugated addition of several alkyl-
ating reagents to the linear substrate: trans-3-nonen-2-one S3
(Eq. 3). This enone, possessing only aliphatic substituents, is a more
demanding substrate class for asymmetric conjugated addition
than S1. The high conformational mobility of this substrate to-
gether with the presence of only subtle substrate-catalyst steric
interactions makes the design of effective enantioselective systems
a real challenge.4e,h,11
S2
2
For a long time, the 1,4-addition of b,b0-disubstituted enones
(such as S2) was unsuccessful because of the low reactivity of these
substrates with dialkylzinc reagents. Recently, Alexakis et al. have
disclosed that a combination of more reactive trialkylaluminum re-
agents and appropriately chosen reaction parameters would be
efficient in the 1,4-addition to this type of challenging substrate.10
The latter conditions were used for testing our ligand library in the
Cu-conjugated addition of substrate S2. The results are summa-
rized in Table 2. We found that enantioselectivity is highly affected
by the configuration of carbon atom C-3, the size of the sugar back-
bone ring, the flexibility of the ligand backbone, the substituents
and configurations in the biaryl phosphoroamidite moieties a–g
and the type of functional group attached to the ligand backbone.
However, the effect of these parameters on the conjugate addition
of substrate S2 was different from their effect on the conjugate
addition of substrate S1. As for substrate S1, the presence of bulky
substituents at the ortho position of the biphenyl moiety usually
had a positive effect on the enantioselectivity (Table 2, entries 7
vs 8 and 9); however, ee’s are negatively affected by replacing
O
O
[Cu] / L1-L5a-g
*
ð3Þ
ZnEt2 or AlR3
R
C5H11
C5H11
S3
3 R = Me
4 R = Et
The most representative results are shown in Table 3. In gen-
eral the ligand requirements were the same as those for the 1,4-
addition to S1 except for those regarding the substituents
and configurations in the biaryl phosphoroamidite moieties a–g.
Therefore, enantioselectivities were best (ee’s up to 49%) when

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E. Raluy et al. / Tetrahedron: Asymmetry 20 (2009) 2167–2172
Table 3
Selected results for the Cu-catalyzed asymmetric 1,4-addition to S3 using ligands L1–L9a–ga
Entry
L
Precursor
Alkylating reagent
% Convb (h)
% Yieldb
% eec
1
2
3
4
5
6
7
8
9
10
11d
12d
13
14
15
16
L1a
L1b
L1c
L1d
L1e
L1g
L2a
L3c
L4a
L5a
L6a
L7a
L1d
L1d
L1d
L1d
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
Cu(OTf)2
[Cu(CH3CN)4]BF4
CuTC
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
AlEt3
85 (18)
97 (18)
78 (18)
78 (18)
36 (18)
45 (18)
91 (18)
84 (18)
90 (18)
94 (18)
99 (2)
72
83
65
61
26
33
76
77
79
81
79
65
80
79
84
89
38 (R)
49 (R)
23 (R)
14 (R)
8 (R)
26 (S)
23 (S)
14 (S)
4 (S)
6 (S)
18 (R)
8 (S)
12 (R)
6 (R)
4 (R)
72 (2)
87 (18)
84 (18)
99 (18)
97 (18)
CuTC
ZnEt2
8 (R)
a
b
c
Reaction conditions: Cu-precursor (2 mol %), ligand (2 mol %), alkylating reagent (1.5 equiv, 0.62 mmol), S3 (0.415 mmol), Et2O (2.5 mL), T = ꢁ30 °C.
Conversion and yields determined by GC using undecane as internal standard after 18 h.
Enantiomeric excess measured by GC using 6-Me-2,3-pe-
Reported in the literature, see Ref. 6.
c-CD column.
d
Table 4
using ligand L1b, which has tert-butyl groups at the ortho posi-
tions and methoxy substituents at the para-positions of the
biphenyl moiety (Table 3, entry 2). We also studied the effect of
several reaction parameters (i.e., catalyst precursor, solvent, alkyl-
ating reagent and temperature) on the enantioselectivity. How-
ever, the enantioselectivities did not improve (Table 3, entry 2
vs entries 13–16).
Selected results for the Cu-catalyzed asymmetric 1,4-addition to S4 using ligands L1–
L9a–ga
Entry
L
Precursor Alkylating
reagent
% Convb
(h)
%
% eec
Yieldb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23d
24
L1a CuTC
L1b CuTC
L1c CuTC
L1d CuTC
L1e CuTC
L1g CuTC
L2a CuTC
L2d CuTC
L2e CuTC
L3c CuTC
L4d CuTC
L4e CuTC
L5a CuTC
L5d CuTC
L5e CuTC
L6a CuTC
L6f
L6g CuTC
L7g CuTC
L8f
L9f
L6g CuTC
L6g Cu(OTf)2
L6g CuTC
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
AlEt3
ZnEt2
ZnEt2
AlMe3
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
100 (18)
98 (18)
87
79
93
89
90
86
78
91
86
91
84
90
93
90
89
85
90
88
89
84
84
93
92
57
20 (S)
13 (S)
18 (S)
26 (S)
35 (S)
30 (S)
14 (R)
32 (R)
45 (R)
13 (S)
6 (R)
4 (R)
32 (R)
8 (R)
6 (R)
2 (S)
10 (R)
72 (R)
24 (S)
56 (R)
10 (S)
72 (R)
0
2.3.2. Asymmetric conjugated 1,4-addition of ZnEt2 and AlEt3 to
trans-nitrostyrene S4
Finally, we applied the ligand library L1–L9a–g in the copper-
catalyzed conjugated addition of several alkylating reagents to
the linear nitrolefin trans-nitrostyrene S4 (Eq. 4). The nitro group
is of particular synthetic importance, as it can be transformed into
a variety of valuable organic compounds such as aldehydes, car-
boxylic acids, nitriles, nitrooxides and amines.1j,12
Et
CuTC
NO2
NO2
[Cu] / L1-L9a-g
*
ð4Þ
ZnEt2 or AEt3
CuTC
CuTC
S4
5
The results are summarized in Table 4. We found that the pres-
ence of bulky substituents at the biaryl moiety had a negative ef-
fect on the enantioselectivity (Table 4, entries 1–6). However, for
the most flexible ligands L5, enantioselectivities were better with
bulky substituents at these positions (Table 4, entries 13–15). We
also found that phosphite ligands provided better enantioselectiv-
ities than their phosphoroamidite counterparts. Therefore the best
results (ee’s up to 72%) were obtained with ligand L6g (Table 4, en-
try 18). The reaction parameters (i.e., catalyst precursor, solvent,
alkylating reagent and temperature) also indicated that diethylzinc
can also be successfully used and that it provides the same enanti-
oselectivities as when triethylaluminum is used (Table 4, entries
18 and 22), whereas the use of trimethylaluminum reduces ee’s
(Table 4, entry 24).
56 (R)
a
Reaction conditions: Cu-precursor (2 mol %), ligand (2 mol %), alkylating
reagent (1.5 equiv, 0.62 mmol), S4 (0.415 mmol), Et2O (2.5 mL), T = ꢁ30 °C.
b
Conversion and yields determined by GC using undecane as internal standard
after 18 h.
c
Enantiomeric excess measured by GC using Lipodex E column.
T = 0 °C.
d
lyzed 1,4-conjugate addition reactions of cyclic and acyclic enon-
es. Our results indicated that the selectivity depended strongly
on the configuration of the carbon atom C-3, the size of the su-
gar backbone ring, the flexibility of the ligand backbone, the sub-
stituents and configurations in the biaryl phosphoroamidite
moieties a–g, the type of functional group attached to the ligand
backbone and the substrate structure. Therefore, by carefully
selecting the ligand parameters, we achieved enantioselectivities
of up to 60% for cyclic substrates and 72% for linear substrates.
3. Conclusions
A sugar-based phosphoroamidite L1–L5a–g and phosphite L6–
L9a–g ligand library has been tested in the asymmetric Cu-cata-

E. Raluy et al. / Tetrahedron: Asymmetry 20 (2009) 2167–2172
2171
(CH3), 55.8 (d, C-3, JC–P = 6.4 Hz), 63.9 (C-6), 74.7 (C-5), 79.7 (d,
C-4, JC–P = 3.2 Hz), 81.1 (C-2), 104.2 (C-1), 109.2 (CMe2), 112.2
(CMe2), 125.2 (CH@), 126.0 (CH@), 131.9 (C), 132.0 (C), 132.2
(CH@), 132.3 (C), 132.4 (C), 133.2 (CH@), 135.4 (CH@), 138.2 (C),
139.7 (C). Anal. Calcd for C28H36NO7P: C, 63.51; H, 6.85; N, 2.64.
Found: C, 63.48; H, 6.82; N, 2.65.
4. Experimental section
4.1. General considerations
All syntheses were performed by using standard Schlenk tech-
niques under an argon atmosphere. Solvents were purified using
standard procedures. Sugar amines were prepared from
L2e: Yield: 237 mg (42%). 31P NMR (C6D6), d: 146.9 (s, 1P). 1H
NMR (C6D6), d: 1.09 (s, 3H, CH3), 1.25 (s, 3H, CH3), 1.36 (s, 3H,
CH3), 1.52 (s, 3H, CH3), 3.37 (m, 2H, NH, H-3), 3.69 (m, 5H, H-2,
CH2 allyl), 3.82 (m, 2H, H-6, H-60), 3.91 (m, 1H, H-4), 4.34 (m, 1H,
D-glucose,
D
-fructose and
D
-galactose as described.7 Ligands L1a–g,7 L2a,7
L3c,7 L4–L5a7 and L6–L9a–g13 were prepared as previously de-
scribed. All other reagents were used in their commercially available
form. 1H, 13C{1H} and 31P{1H} NMR spectra were recorded on a Varian
Gemini 400 MHz spectrometer. The chemical shifts are referenced to
tetramethylsilane (1H and 13C) as the internal standard or to H3PO4
3
H-5), 5.13 (m, 4H, CH2@ allyl), 5.32 (d, 1H, H-1, J1–2 = 4.0 Hz),
6.07 (m, 2H, CH@ allyl), 6.9–7.2 (m, 6H, CH@). 13C NMR (C6D6), d:
25.5 (CH3), 26.6 (CH3), 26.9 (CH3), 27.0 (CH3), 35.7 (CH2 allyl),
58.6 (C-3), 68.0 (C-6), 78.0 (C-5), 80.9 (C-4), 81.6 (C-2), 104.8 (C-
1), 109.9 (CMe2), 112.6 (CMe2), 115.8 (CH2 allyl), 120.8 (CH@),
126.0 (C), 129.7 (C), 129.9 (CH@), 130.2 (CH@), 135.4 (C), 136.1
(C), 138.2 (CH@ allyl). Anal. Calcd for C30H36NO7P: C, 65.09; H,
6.55; N, 2.53. Found: C, 65.10; H, 6.53; N, 2.51.
(
31P) as the external standard. The 1H and 13C NMR spectral assign-
ments were determined by 1H–1H and 1H–13C correlation spectra.
4.2. General procedure for the preparation of ligands L1–L5a–g
L4b: Yield: 245 mg (38%). 31P NMR (C6D6), d: 147.8 (s, 1P). 1H
NMR (C6D6), d: 1.04 (s, 3H, CH3), 1.11 (s, 3H, CH3), 1.27 (s, 3H,
CH3), 1.44 (s, 3H, CH3), 1.49 (s, 9H, CH3, t-Bu), 1.51 (s, 9H, CH3, t-
Bu), 3.28 (s, 3H, CH3–O), 3.30 (s, 3H, CH3–O), 3.43 (m, 1H, H-6),
3.57 (m, 1H, H-60), 3.59 (m, 1H, H-1), 3.65 (m, 1H, H-10), 3.72 (m,
1H, NH), 3.75 (m, 1H, H-4), 4.40 (m, 1H, H-3), 4.42 (m, 1H, H-2),
7.0–7.2 (m, 4H, CH@). 13C NMR (C6D6), d: 24.4 (CH3), 25.7 (CH3),
26.5 (CH3), 26.8 (CH3), 31.6 (CH3, t-Bu), 31.7 (CH3, t-Bu), 35.0 (C,
t-Bu), 35.3 (C, t-Bu), 47.5 (d, C-6, JC–P = 12.1 Hz), 55.2 (CH3–O),
55.3 (CH3–O), 61.9 (C-1), 71.1 (C-3), 71.5 (C-4), 72.1 (C-2), 108.3
(CMe2), 109.3 (CMe2), 115.0 (CH@), 116.3 (CH@), 135.0 (C), 143.1
(C), 156.6 (C). Anal. Calcd for C34H48NO9P: C, 63.24; H, 7.49; N,
2.17. Found: C, 63.19; H, 7.50; N, 2.14.
Phosphorochloridite (2.2 mmol) produced in situ was dissolved
in toluene (5 mL) before pyridine (0.36 mL, 4.6 mmol) was added.
The amine (2 mmol) was azeotropically dried with toluene
(3 ꢂ 1 mL) and then dissolved in toluene (10 mL), to which pyri-
dine (0.36 mL, 4.6 mmol) was added. The amine solution was
transferred slowly at 0 °C to the solution of phosphorochloridite.
The reaction mixture was warmed to 80 °C and stirred overnight,
and the pyridine salts were removed by filtration. Evaporation of
the solvent gave a white foam, which was purified in a short path
of alumina (toluene/NEt3 = 100/1) to produce the corresponding li-
gand as a white powder or colourless liquid.
L2b: Yield: 284 mg (44%). 31P NMR (C6D6), d: 148.7 (s, 1P). 1H
NMR (C6D6), d: 1.02 (s, 3H, CH3), 1.23 (s, 3H, CH3), 1.35 (s, 3H,
CH3), 1.45 (s, 3H, CH3), 1.48 (s, 9H, CH3, t-Bu), 1.52 (s, 9H, CH3,
t-Bu), 3.04 (m, 1H, H-3), 3.24 (m, 1H, NH), 3.27 (s, 3H, CH3–O),
L4c: Yield: 228 mg (37%). 31P NMR (C6D6), d: 149.5 (s, 1P). 1H
NMR (C6D6), d: 0.40 (s, 9H, CH3–Si), 0.45 (s, 9H, CH3–Si), 1.06 (s,
3H, CH3), 1.09 (s, 3H, CH3), 1.29 (s, 3H, CH3), 1.39 (s, 3H, CH3),
3.27 (m, 1H, H-6), 3.38 (m, 1H, H-60), 3.60 (m, 1H, H-1), 3.67 (m,
1H, H-10), 3.73 (m, 1H, NH), 3.79 (m, 1H, H-4), 4.34 (m, 1H, H-3),
4.41 (m, 1H, H-2), 6.8–7.4 (m, 6H, CH@). 13C NMR (C6D6), d: 0.4
(CH3–Si), 0.5 (CH3–Si), 24.3 (CH3), 25.5 (CH3), 26.5 (CH3), 26.7
(CH3), 47.9 (d, C-6, JC–P = 8.2 Hz), 61.8 (C-1), 71.0 (C-3), 71.4 (C-
4), 72.2 (C-2), 108.3 (CMe2), 109.2 (CMe2), 124.9 (CH@), 126.0
(C), 129.6 (CH@), 131.9 (C), 132.0 (C), 135.8 (CH@), 135.9 (CH@),
136.5 (C), 138.2 (C), 155.7 (C). Anal. Calcd for C30H44NO7PSi2: C,
58.32; H, 7.18; N, 2.27. Found: C, 58.29; H, 7.16; N, 2.26.
´
3.29 (s, 3H, CH3–O), 3.76 (m, 1H, H-2), 3.89 (m, 1H, H-6), 3.92
(m, 1H, H-6), 4.00 (m, 1H, H-4), 4.52 (m, 1H, H-5), 5.33 (d, 1H, H-
3
1, J1–2 = 3.6 Hz), 6.62 (m, 1H, CH@), 6.70 (m, 1H, CH@), 7.11 (m,
2H, CH@). 13C NMR (C6D6), d: 26.2 (CH3), 26.4 (CH3), 28.8 (CH3),
28.9 (CH3), 31.4 (CH3, t-Bu), 31.6 (CH3, t-Bu), 35.7 (C, t-Bu), 35.8
(C, t-Bu), 55.2 (CH3–O), 55.4 (CH3–O), 55.8 (d, C-3, JC–P = 6.8 Hz),
64.0 (C-6), 75.7 (C-5), 79.8 (C-4), 80.3 (C-2), 104.3 (C-1), 109.6
(CMe2), 112.2 (CMe2), 112.5 (CH@), 113.8 (CH@), 114.9 (CH@),
115.0 (CH@), 134.8 (C), 134.9 (C), 143.0 (C), 143.2 (C), 156.4 (C),
156.7 (C). Anal. Calcd for C34H48NO9P: C, 63.24; H, 7.49; N, 2.17.
Found: C, 63.21; H, 7.52; N, 2.15.
L4d: Yield: 216 mg (41%). 31P NMR (C6D6), d: 144.4 (s, 1P). 1H
NMR (C6D6), d: 1.42 (s, 3H, CH3), 1.49 (s, 3H, CH3), 1.68 (s, 3H,
CH3), 1.73 (s, 3H, CH3), 2.49 (s, 6H, CH3), 2.73 (s, 6H, CH3), 3.74
(m, 1H, H-6), 3.94 (m, 1H, H-60), 4.03 (m, 1H, H-1), 4.05 (m, 1H,
H-10), 4.08 (m, 1H, NH), 4.13 (m, 1H, H-4), 4.76 (m, 1H, H-3),
4.80 (m, 1H, H-2), 7.3–7.5 (m, 4H, CH@). 13C NMR (C6D6), d: 17.1
(CH3), 21.1 (CH3), 24.3 (CH3), 25.6 (CH3), 26.4 (CH3), 26.8 (CH3),
46.7 (d, C-6, JC–P = 11.4 Hz), 61.9 (C-1), 71.1 (C-3), 71.4 (C-4), 71.8
(C-2), 108.4 (CMe2), 109.3 (CMe2), 128.3 (CH@), 128.6 (CH@),
131.6 (C), 131.7 (C), 133.6 (C). Anal. Calcd for C28H36NO7P: C,
63.51; H, 6.85; N, 2.64. Found: C, 63.46; H, 6.81; N, 2.63.
L2c: Yield: 315 mg (51%). 31P NMR (C6D6), d: 149.7 (s, 1P). 1HNMR
(C6D6), d: 0.35 (s, 3H, CH3–Si), 0.42 (s, 3H, CH3–Si), 1.04 (s, 3H, CH3),
1.26 (s, 3H, CH3), 1.36 (s, 3H, CH3), 1.43 (s, 3H, CH3), 2.87 (m, 1H, H-3),
3.12 (m, 1H, NH), 3.62 (m, 1H, H-2), 3.69 (m, 1H, H-6), 3.75 (m, 1H, H-
3
60), 3.97 (m, 1H, H-4), 4.65 (m, 1H, H-5), 5.26 (d, 1H, H-1, J1–
2 = 4.0 Hz), 6.7–7.4 (m, 6H, CH@). 13C NMR (C6D6), d: 0.5 (CH3–Si),
0.7 (CH3–Si), 26.5 (CH3), 26.7 (CH3), 26.9 (CH3), 27.0 (CH3), 55.4 (d,
C-3, JC–P = 1.6 Hz), 63.8 (C-6), 75.8 (C-5), 79.9 (d, C-4, JC–P = 1.6 Hz),
80.6 (C-2), 104.3 (C-1), 109.8 (CMe2), 112.4 (CMe2), 125.2 (CH@),
126.0 (CH@), 131.9 (C), 132.0 (C), 132.2 (CH@), 132.3 (C), 132.4 (C),
133.2 (CH@), 135.4 (CH@), 136.0 (CH@), 136.5 (C), 138.2 (C), 155.7
(C), 155.9 (C). Anal. Calcd for C30H44NO7PSi2: C, 58.32; H, 7.18; N,
2.27. Found: C, 58.36; H, 7.20; N, 2.24.
L4e: Yield: 265 mg (48%). 31P NMR (C6D6), d: 146.3 (s, 1P). 1H
NMR (C6D6), d: 1.06 (s, 3H, CH3), 1.09 (s, 3H, CH3), 1.32 (s, 3H,
CH3), 1.36 (s, 3H, CH3), 3.30 (m, 1H, H-6), 3.44 (m, 1H, H-60), 3.47
(m, 1H, H-1), 3.50 (m, 1H, H-10), 3.57 (m, 5H, NH, CH2 allyl), 4.41
(m, 2H, H-4, H-3), 5.07 (m, 5H, H-2, CH2@ allyl), 6.02 (m, 2H,
CH@ allyl), 6.9–7.4 (m, 6H, CH@). 13C NMR (C6D6), d: 24.3 (CH3),
25.6 (CH3), 26.5 (CH3), 26.8 (CH3), 35.2 (CH2 allyl), 35.4 (CH2 allyl),
47.0 (d, C-6, JC–P = 4.2 Hz), 61.8 (C-1), 71.0 (C-3), 71.4 (C-4), 71.9 (C-
2), 108.3 (CMe2), 109.2 (CMe2), 116.4 (CH2@ allyl), 116.6 (CH2@ al-
lyl), 124.9 (CH@), 125.0 (CH@), 126.3 (C), 128.8 (CH@), 130.3
(CH@), 133.1 (C), 133.2 (C), 137.3 (CH@ allyl), 137.5 (CH@ allyl).
L2d: Yield: 280 mg (53%). 31P NMR (C6D6), d: 150.2 (s, 1P). 1H
NMR (C6D6), d: 1.05 (s, 3H, CH3), 1.24 (s, 3H, CH3), 1.36 (s, 3H,
CH3), 1.43 (s, 3H, CH3), 2.11 (s, 3H, CH3), 2.16 (s, 6H, CH3), 2.24
(s, 3H, CH3), 2.29 (s, 3H, CH3), 2.89 (m, 1H, H-3), 3.11 (m, 1H,
NH), 3.64 (m, 1H, H-2), 3.72 (m, 1H, H-6), 3.78 (m, 1H, H-60),
3
3.99 (m, 1H, H-4), 4.66 (m, 1H, H-5), 5.32 (d, 1H, H-1, J1–
2 = 4.0 Hz), 6.7–7.4 (m, 4H, CH@). 13C NMR (C6D6), d: 17.1 (CH3),
17.7 (CH3), 25.8 (CH3), 26.5 (CH3), 26.7 (CH3), 26.9 (CH3), 27.0

2172
E. Raluy et al. / Tetrahedron: Asymmetry 20 (2009) 2167–2172
Anal. Calcd for C30H36NO7P: C, 65.09; H, 6.55; N, 2.53. Found: C,
65.12; H, 6.58; N, 2.56.
temperature. The reaction was monitored by GC. The reaction
was quenched with HCl (2 M) and filtered twice through flash sil-
ica. Conversion, chemoselectivity and enantioselectivity were ob-
tained by GC.4i
L5b: Yield: 309 mg (48%). 31P NMR (C6D6), d: 147.6 (s, 1P). 1H
NMR (C6D6), d: 1.03 (s, 3H, CH3), 1.06 (s, 3H, CH3), 1.38 (s, 3H,
CH3), 1.44 (s, 3H, CH3), 1.54 (s, 9H, CH3, t-Bu), 1.56 (s, 18H, CH3,
t-Bu), 3.29 (m, 2H, H-6, H-60), 3.33 (s, 3H,CH3–O), 3.35 (s, 3H,
CH3–O), 3.49 (m, 1H, NH), 3.82 (m, 1H, H-1), 3.89 (m, 1H, H-5),
4.13 (m, 1H, H-3), 4.41 (m, 1H, H-2), 5.44 (m, 1H, H-4), 7.0–7.2
(m, 4H, CH@). 13C NMR (C6D6), d: 24.7 (CH3), 25.2 (CH3), 26.5
(CH3), 26.7 (CH3), 31,6 (CH3, t-Bu), 34.8 (C, t-Bu), 41.4 (d, C-2, JC–
P = 12.1 Hz), 55.4 (CH3–O), 69.5 (C-5), 71.3 (C-3), 71.5 (C-2), 71.8
(C-1), 97.0 (C-4), 108.7 (CMe2), 109.5 (CMe2), 115.2 (CH@), 115.5
(CH@), 129.6 (C), 135.0 (C), 135.1 (C), 142.9 (C), 156.4 (C). Anal.
Calcd for C34H48NO9P: C, 63.24; H, 7.49; N 2.17. Found: C, 63.26;
H, 7.50; N, 2.19.
Acknowledgements
We would like to thank the Spanish Government (Consolider
Ingenio CSD2006-0003, CTQ2007-62288/BQU, 2008PGIR/07 to O.P.
and 2008PGIR/08 to M.D.), the Catalan Government (2005SGR-
007777), the Swiss National Research Foundation (Grant No.
200020-113332) and COST action D40 (SER contract No. C07.0097)
for their financial support.
L5c: Yield: 234 mg (38%). 31P NMR (C6D6), d: 149.7 (s, 1P). 1H
NMR (C6D6), d: 0.31 (s, 3H, CH3–Si), 0.40 (s, 3H, CH3–Si), 1.05 (s,
3H, CH3), 1.23 (s, 3H, CH3), 1.36 (s, 3H, CH3), 1.42 (s, 3H, CH3),
3.28 (m, 1H, H-6), 3.31 (m, 1H, H-60), 3.42 (m, 1H, NH), 3.86 (m,
1H, H-1), 3.92 (m, 1H, H-5), 4.11 (m, 1H, H-3), 4.40 (m, 1H, H-2),
5.42 (m, 1H, H-4), 7.0–7.2 (m, 6H, CH@). 13C NMR (C6D6), d: 0.5
(CH3–Si), 0.7 (CH3–Si), 24.7 (CH3), 25.2 (CH3), 26.5 (CH3), 26.9
(CH3), 69.9 (C-5), 71.2 (C-3), 71.9 (C-2), 72.4 (C-1), 97.3 (C-4),
108.7 (CMe2), 109.9 (CMe2), 125.1 (CH@), 125.8 (CH@), 131.9 (C),
132.1 (C), 132.2 (CH@), 132.3 (C), 132.8 (C), 133.1 (CH@), 135.5
(CH@), 136.0 (CH@), 136.5 (C), 138.2 (C), 155.7 (C). Anal. Calcd
for C30H44NO7PSi2: C, 58.32; H, 7.18; N, 2.27. Found: C, 58.33; H,
7.22; N, 2.25.
References
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L5d: Yield: 269 mg (51%). 31P NMR (C6D6), d: 145.3 (s, 1P). 1H
NMR (C6D6), d: 0.99 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.37 (s, 3H,
CH3), 1.47 (s, 3H, CH3), 2.11 (s, 3H, CH3), 2.13 (s, 3H, CH3), 2.36
(s, 6H, CH3), 3.32 (m, 2H, H-6, H-60), 3.50 (m, 1H, NH), 3.61 (m,
1H, H-1), 3.88 (m, 1H, H-5), 4.12 (m, 1H, H-3), 4.34 (m, 1H, H-2),
5.44 (m, 1H, H-4), 7.0–7.2 (m, 4H, CH@). 13C NMR (C6D6), d: 17.2
(CH3), 17.3 (CH3), 21.2 (CH3), 24.5 (CH3), 25.3 (CH3), 26.5 (CH3),
26.6 (CH3), 40.9 (d, C-2, JC–P = 7.6 Hz), 69.7 (C-5), 71.4 (C-3), 71.5
(C-2), 71.7 (C-1), 97.0 (C-4), 108.8 (CMe2), 109.5 (CMe2), 128.3
(CH@), 128.7 (CH@), 129.2 (CH@), 131.6 (C), 131.7 (C), 133.6 (C).
Anal. Calcd for C28H36NO7P: C, 63.51; H, 6.85; N, 2.64. Found: C,
63.53; H, 6.87; N, 2.62.
3. See for instance: (a) Hu, X.; Chen, H.; Zhang, X. Angew. Chem., Int. Ed. 1999, 38,
3518; (b) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346; (c) Escher, I. H.; Pfaltz, A.
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H.; Iwata, C. Tetrahedron 1996, 52, 14177; (b) Diéguez, M.; Deerenberg, S.;
Pàmies, O.; Claver, C.; van Leeuwen, P. W. N. M.; Kamer, P. Tetrahedron:
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776; (f) Su, L.; Li, X.; Chan, W. L.; Jia, X.; Chan, A. S. C. Tetrahedron: Asymmetry
2003, 14, 1865; (g) Eilitz, U.; Leßmann, F.; Seidelmann, O.; Wendisch, V.
Tetrahedron: Asymmetry 2003, 14, 3095; (h) d’Augustin, M.; Palais, L.; Alexakis,
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Albrow, V. E.; Blake, A. J.; Fryatt, R.; Wilson, C.; Woodward, S. Eur. J. Org. Chem.
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M.; Pàmies, O.; Ruiz, A.; Díaz, Y.; Castillón, S.; Claver, C. Coord. Chem. Rev. 2004,
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Asymmetric Catalysis; Malhotra, S. V., Ed.; American Chemical Society:
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L5e: Yield: 260 mg (47%). 31P NMR (C6D6), d: 147.8 (s, 1P). 1H
NMR (C6D6), d: 0.98 (s, 3H, CH3), 0.99 (s, 3H, CH3), 1.33 (s, 3H,
CH3), 1.42 (s, 3H, CH3), 3.18 (m, 2H, H-6, H-60), 3.44 (m, 1H, NH),
3.48 (m, 1H, H-1), 3.57 (m, 4H, CH2 allyl), 3.76 (m, 1H, H-5), 4.07
(m, 1H, H-3), 4.32 (m, 1H, H-2), 5.01 (m, 4H, CH2@ allyl), 5.38
(m, 1H, H-4), 5.97 (m, 2H, CH@ allyl), 6.9–7.2 (m, 6H, CH@). 13C
NMR (C6D6), d: 24.6 (CH3), 25.3 (CH3), 26.5 (CH3), 26.7 (CH3),
35.2 (CH2 allyl), 35.3 (CH2 allyl), 41.1 (d, C-2, JC–P = 9.2 Hz), 69.6
(C-5), 71.3 (C-3), 71.5 (C-2), 71.8 (C-1), 97.0 (C-4), 108.8 (CMe2),
109.5 (CMe2), 116.5 (CH2@ allyl), 116.7 (CH2@ allyl), 124.8
(CH@), 125.0 (CH@), 126.0 (C), 129.6 (C), 130.2 (CH@), 132.5 (C),
133.0 (C), 137.4 (CH@ allyl). Anal. Calcd for C30H36NO7P: C,
65.09; H, 6.55; N, 2.53. Found: C, 65.12; H, 6.57; N, 2.54.
6. Mata, Y.; Diéguez, M.; Pàmies, O.; Woodward, S. J. Oganomet. Chem. 2007, 692,
4315.
7. Raluy, E.; Diéguez, M. Pàmies, O. Tetrahedron: Asymmetry 2009. doi:10.1016/
j.tetasy.2009.06.014.
8. Pàmies, O.; Diéguez, M.; Net, G.; Ruiz, A.; Claver, C. Organometallics 2000, 19,
1488.
9. Alexakis, A.; Benhaim, C.; Rosset, S.; Humam, M. J. Am. Chem. Soc. 2002, 124,
5262.
4.3. Typical procedure for the catalytic conjugate addition of
alkylating reagents to enones
10. See for example Refs. 4h and 4k.
In a typical procedure, a solution of copper-catalyst precursor
11. (a) Alexakis, A.; Benhaïm, C.; Fournioux, X.; van der Hwuvel, A.; Levéque, J. M.;
March, S.; Rosset, S. Synlett 1999, 1811; (b) Bennett, S. M. W.; Brown, S. M.;
Muxworthy, J. P.; Woodward, S. Tetrahedron Lett. 1999, 40, 1767; (c) Bennett, S.
M. W.; Brown, S. M.; Cunnigham, A.; Dennis, M. R.; Muxworthy, J. P.; Oakley, M.
A.; Woodward, S. Tetrahedron 2000, 56, 2847; (d) De Roma, A.; Ruffo, F.;
Woodward, S. Chem. Commun. 2008, 5384.
(8.3 lmol) and furanoside ligand (16.6 lmol) in the appropriate
solvent (2 mL) was stirred for 30 min at room temperature. After
cooling to the desired temperature, the alkylating reagents (0.62
mmol) were added. A solution of the desired enone (0.415 mmol)
and undecane as the GC internal standard (0.25 mL) in dichloro-
methane (0.5 mL) was then added at the corresponding reaction
12. Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877.
13. Mata, Y.; Pàmies, O.; Diéguez, M.; Woodward, S. J. Org. Chem. 2006, 71, 8159.