Application of pyranoside phosphite-pyridine ligands to enantioselective metal-catalyzed allylic substitutions and conjugate 1,4-additions

Article abstract of DOI:10.1016/j.tetasy.2013.06.011

A series of glucopyranoside phosphite-pyridine ligands have been applied in the metal-catalyzed allylic substitution and conjugate 1,4-addition reactions of several substrate types. We have been able to identify ligands that provided promising enantioselectivities in the Pd-catalyzed intermolecular allylic substitution of cyclic substrates (ee's up to 86%) and desymmetrization (ee's up to 94%) and in the Cu-catalyzed conjugate addition of challenging aliphatic enones (ee's up to 90%).

Full text of DOI:10.1016/j.tetasy.2013.06.011

Tetrahedron: Asymmetry 24 (2013) 995–1000
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Application of pyranoside phosphite-pyridine ligands
to enantioselective metal-catalyzed allylic substitutions and
conjugate 1,4-additions
c,
c,
Matteo Lega a,b, Jessica Margalef c, Francesco Ruffo a,b, , Oscar Pàmies , Montserrat Diéguez
⇑
⇑
⇑
a Dipartimento di Scienze Chimiche, Università degli Studi di Napoli ‘Federico II’, Complesso Universitario di Monte S. Angelo, Via Cintia, I-80126 Napoli, Italy
b Consorzio Interuniversitario di Reattività Chimica e Catalisi, via Celso Ulpiani 27, I-70126 Bari, Italy
c Departament de Química Física i Inorgànica. Universitat Rovira i Virgili. Campus Sescelades, C/ Marcelꢀlí Domingo, s/n. 43007 Tarragona, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of glucopyranoside phosphite–pyridine ligands have been applied in the metal-catalyzed allylic
substitution and conjugate 1,4-addition reactions of several substrate types. We have been able to iden-
tify ligands that provided promising enantioselectivities in the Pd-catalyzed intermolecular allylic substi-
tution of cyclic substrates (ee’s up to 86%) and desymmetrization (ee’s up to 94%) and in the Cu-catalyzed
conjugate addition of challenging aliphatic enones (ee’s up to 90%).
Received 6 June 2013
Accepted 26 June 2013
Available online 25 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
glucopyranose backbone have been poorly explored,4 and mostly
when the coordinating functions are provided by phosphite and
Nowadays the preparation of enantiomerically pure compounds
plays a vital role in important areas such as pharmaceuticals, agro-
chemicals, fine chemicals, and natural product chemistry. Asym-
metric catalysis has emerged as a powerful tool for producing
enantiopure compounds. In this respect the metal-catalyzed allylic
substitution1 and conjugate 1,4-addition2 are two of the most pow-
erful carbon–carbon bond forming reactions for the construction of
enantioriched synthons for both biologically active and natural
compounds. The significant advantage of these processes is their
high compatibility with many functional groups. In order to
achieve the highest levels of reactivity and selectivity in metal-cat-
alyzed asymmetric reactions, several reaction parameters must be
optimized, the most crucial of which is perhaps the design of the
chiral ligand.
Over the last few years, a variety of sugar-derived ligands have
been successfully employed in several asymmetric metal-catalyzed
processes.3 Interest toward this class of building blocks is justified
by numerous advantages: the availability of stereogenic centers at
low cost, access to different epimers, abundance of groups that can
be straightforwardly functionalized in order to modulate the coor-
dinating and the steric and electronic properties of the ligands. On
this basis, modular libraries of ligands are approachable by the
suitable choice of a sugar backbone and the coordinating motifs.
pyridine moieties. This is in contrast with the importance of heter-
odonor P,N-ligands, which have been successfully applied in many
useful processes.5 Their versatility is mainly due to the contempo-
raneous presence of a soft and a hard coordinating function.6 The
hard end weakly coordinates to soft metal centers, and easily dis-
sociates in solution. This provides a vacant site whenever de-
manded, but also has a chance of stabilizing the metal by
chelation in the absence of competing donors.
For these reasons, we recently decided to prepare and investi-
gate the performance of pseudo-enantiomeric classes of glucose-
based P,N-ligands (Fig. 1) in asymmetric reactions where
phosphite–pyridine systems are known to be effective,7 such as
the asymmetric allylic alkylations, asymmetric conjugate 1,4-addi-
tions, and alkene hydrogenations.8 In a previous paper,9 we de-
scribed the synthesis and the behavior of part of ligands 1 and 2
(Fig. 1) in the Ir-catalyzed hydrogenation of poorly functionalized
alkenes. Satisfactory results were attained, which also allowed a
reasonable rationalization of the factors which affect the enanti-
oselectivity of the reaction.
Herein we report an extension of the type 1 family,10 and use of
the two classes of ligands in asymmetric Pd-catalyzed allylic sub-
stitution and Cu-catalyzed conjugate 1,4-addition of benchmark
substrates. These ligands contemplate systematic variations of
the position of the phosphite group at both C-2 (ligands 1) and
C-3 (ligands 2) of the pyranoside backbone, as well as different
substituents and configurations in the biaryl phosphite moiety a–
f with the aim of maximizing the catalyst performance.
In this context, however, bidentate P,N-ligands based on
a
⇑
Corresponding authors. Tel.: +34 977558780; fax: +34 977559563.
E-mail address: montserrat.dieguez@urv.cat (M. Diéguez).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.06.011

996
M. Lega et al. / Tetrahedron: Asymmetry 24 (2013) 995–1000
Ph
O
O
O
O
O
O
OMe
O
R1
R2
tBu
P
N
O
O
O
O
O
O
O
O
=
1
O
R1
R2
tBu
Ph
O
O
O
f (R)ax
a R1= R2 = tBu
d (R)ax
O
R1= SiMe3; R2= H
R1= tBu; R2= OMe
(S)ax
e
O
b
c
P
HN
OBn
O
O
N
2
Figure 1. Carbohydrate-based phosphite–pyridine ligands 1a–f and 2a,c,d.
substrate, with dimethyl malonate (Eq. 1). The catalysts were gen-
erated in situ from the
-allyl-palladium chloride dimer [PdCl(g3
C3H5)]2, the corresponding ligand and a catalytic amount of the
corresponding base. The nucleophile was generated from dimethyl
malonate in the presence of N,O-bis(trimethylsilyl)-acetamide
(BSA).
2. Results and discussion
2.1. Synthesis of the ligands
p
-
The structure of the two libraries was developed by the imme-
diate functionalization of easily available -glucose and -glucosa-
D
D
mine (Scheme 1), as described in a previous paper.9 The new
phosphite–pyridine ligands 1c and 1f were synthesized using the
procedure previously described for ligands 1a,b,d,e. They were sta-
ble during purification on neutral alumina under an atmosphere of
argon and isolated as white solids. They were stable at room tem-
perature and very stable to hydrolysis. The elemental analyses
were in agreement with the assigned structure. The 1H, 13C and
31P NMR spectra were as expected for these C1 ligands. Thus, rapid
ring inversions (tropoisomerization) in the biphenyl-phosphorus
moiety c occurred on the NMR timescale, since the expected dia-
stereoisomers were not detected by low-temperature phosphorus
NMR.11
OAc
CH(COOMe)2
Ph
CH2(COOMe)2 / BSA
Ph
Ph
Ph
[Pd(μ-Cl)(η3-C3H5)]2 / 1-2a-f
S1
ð1Þ
The effects of the solvent and ligand-to-palladium ratio were inves-
tigated using the catalyst precursor containing ligand 1a (Table 1).
Our results show that both solvent and ligand-to-palladium ratio
affected the catalytic performance. The optimum trade-off between
enantioselectivities and activities was obtained when dichloro-
methane (DCM) was used as a solvent and without excess of ligand
(entry 6). Toluene and THF provided the lowest activities and
enantioselectivities (entries 2 and 3). On the other hand, the activity
obtained with DMF was higher than in dichloromethane, but the
enantioselectivity was lower (entries 4 vs 1). It should be noted that
the sense of enantioselectivity achieved in DMF is opposite to that
of DCM, which suggests that the coordination of DMF plays a role
2.2. Asymmetric Pd-catalyzed allylic alkylation reactions
For the initial evaluation of phosphite–pyridine ligands 1–2a–f,
we chose the Pd-catalyzed allylic substitution of rac-1,3-diphenyl-
3-acetoxyprop-1-ene S1, which is widely used as
a model
O
Ph
O
O
O
Ph
(a)
P
Cl
O
O
O
O
O
D-glucose
O
O
O
O
HO
OMe
O
OMe
(d)
P
N
N
3
1
O
O
P
Cl
Ph
O
O
Ph
O
(b,c)
O
O
O
O
O
D-glucosamine
HO
O
P
(d)
HN
OBn
O
HN
OBn
O
O
2
4
N
N
Scheme 1. Synthesis of phosphite–pyridine ligands 1–2a–d. Reagents: (a) Ref. 12a; (b) Ref. 12b; (c) Ref. 9; (d) (RO)2PCl/Py/toluene.

M. Lega et al. / Tetrahedron: Asymmetry 24 (2013) 995–1000
997
Table 1
we can also conclude that although the fluxional biphenyl phos-
phite moieties in ligands 1a–c adopt mainly the (R)-configuration,
the tropoisomerism of the fluxional biphenyl moieties in ligands
1a–c is controlled by substituents at the ortho- and para-positions
of the biphenyl phosphite moiety. Thus, for example while the
presence of bulky trimethyl silyl groups at the ortho-positions con-
trols the tropoisomerization almost completely, the presence of
methoxy groups at the para-positions led to poor tropoisomerism
control.
Asymmetric allylic alkylation of rac-S1 with dimethylmalonate using ligand 1a. Effect
of the solvent and ligand-to-palladium ratioa
Entry
Solvent
Ratio L/Pd
% Convb (h)
% eec
1
2
3
4
5
6
DCM
Toluene
THF
DMF
DCM
DCM
1.1/1
1.1/1
1.1/1
1.1/1
2/1
100 (8)
18 (20)
16 (8)
100 (2)
100 (8)
100 (8)
41 (R)
0
6 (R)
26 (S)
34 (R)
42 (R)
0.75/1
We next applied ligands 1–2a–f in the allylic alkylation of the
less sterically demanding linear substrate rac-1,3-dimethyl-3-acet-
oxyprop-1-ene S2 and cyclic substrates rac-3-acetoxycyclohexene
S3 (widely used as a model substrate), rac-3-acetoxycyclopentene
S4, and rac-3-acetoxycycloheptene S5 Eqs. 2a and 2b. For these
substrates, it is usually more difficult to control the enantioselec-
tivity, mainly because of the presence of less sterically hindering
substituents, which are thought to play a crucial role in the enan-
tioselection observed in the corresponding Pd-allyl intermediate
a
Reaction conditions: 2 mL of solvent, 0.005 mmol of [Pd(
l
-Cl)(
g
3-C3H5)]2,
0.5 mmol of substrate, 0.2 mL of dimethylmalonate, 0.4 mL of BSA, a small amount
of KOAc at rt.
b
Evaluated by NMR spectroscopy of the crude reaction mixture. Reaction time in
hours shown in parentheses.
c
Determined by HPLC on a Chiralcel-OJ column.
in the active species, probably replacing the pyridine moiety and
therefore forcing the ligand to coordinate in
a monodentate
manner.13
OAc
CH(COOMe)2
CH2(COOMe)2 / BSA
Varying the ligand-to-palladium ratio showed that an excess of
ligand was not needed (entries 1 vs 6). The enantioselectivity
diminished upon increasing the amount of ligand (entry 5), proba-
bly due to the formation of a less selective PdL2 species.13
Under the optimized reaction conditions (i.e., dichloromethane
as the solvent and an L/Pd ratio of 0.75) we tested the remaining
ligands. The results, which are summarized in Table 2, indicate that
enantioselectivities are affected by the position of the phosphite
moiety at either C-2 (ligands 1) or C-3 (ligands 2) of the pyranoside
backbone as well as the substituents/configuration of the biaryl
phosphite moiety.
[Pd(μ-Cl)(η3-C3H5)]2 / 1-2a-f
S2
ð2aÞ
CH2(COOMe)2 / BSA
n
n
OAc
CH(COOMe)2
[Pd(μ-Cl)(η3-C3H5)]2 / 1-2a-f
S3
S4
S5
n = 1
n = 0
n = 2
The use of ligands 2 with the phosphite group attached to the C-
3 of the pyranoside backbone showed much lower activities and
enantioselectivities than those obtained with the catalytic system
Pd/1 (i.e., entries 1 and 7).
ð2bÞ
Our preliminary investigations into the solvent effect using ligand
1a provided a different trend to that observed in the previously
tested hindered substrate S1 (Table 3). The optimum compromise
between enantioselectivities and reaction rates was therefore ob-
tained when DMF was used as a solvent (entry 4).
Under the optimized conditions, the results in Table 4 again
showed that ligands 1 provided better enantioselectivities than li-
gands 2 (entries 1, 4 and 5 vs 7–9). However, the effect of the sub-
stituents and the configuration at the biaryl phosphite moiety
depends on the substrate type and it is different from substrate
S1. Thus, for linear substrate S2 the best results were achieved
using ligand 1e (ee’s up to 33%; entry 5), for cyclic substrates,
enantioselectivities were obtained when using the Pd/1f catalytic
system (ee’s up to 86%; entries 6 and 10). For the linear substrate
S2, enantioselectivities were poor, while for the unhindered cyclic
substrate S3, enantioselectivities increased up to 86% (entry 10).
This latter result encouraged us to test other cyclic substrates
The effect of the substituents and configuration at the biaryl
phosphite moiety was studied using ligands 1a–f. With regard to
the effect of the substituents at the biphenyl phosphite moiety,
we found that the presence of bulky trimethylsilyl groups at the
ortho position had a positive effect on the enantioselectivity (en-
tries 2 vs 1 and 3), while the presence of methoxy groups at the
para-positions had a negative effect (entry 3). With ligands 1d
and 1e, which contain different, enantiomerically pure, and biphe-
nyl moieties we found that there was a cooperative effect between
the configuration of the biaryl moiety and the ligand backbone on
the enantioselectivity. This led to a matched combination for li-
gand 1d, which contains an (R)-biphenyl moiety (Table 2, entry
4). In addition, if we compare the results of using ligands 1a–e,
Table 2
Asymmetric allylic alkylation of rac-S1 with dimethylmalonate using ligands 1–2a–fa
Entry
Ligand
% Convb (h)
% eec
Table 3
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
2a
2d
2e
100 (8)
86 (8)
100 (8)
100 (8)
100 (8)
100 (8)
6 (8)
42 (R)
50 (R)
35 (R)
52 (R)
21 (S)
26 (S)
0
Asymmetric allylic alkylation of unhindered linear rac-S2 and cyclic rac-S3 substrates
with dimethylmalonate using ligand 1a. Effect of the solventa
Entry
Solvent
S2
% Convb (h)
S3
% Convb (h)
% eec
% eec
1
2
3
4
DCM
Toluene
THF
56 (8)
10 (8)
24 (8)
100 (8)
4 (S)
0
9 (S)
10 (R)
5 (18)
<5 (18)
15 (18)
25 (18)
19 (R)
nd
16 (R)
14 (R)
11 (8)
19 (8)
2 (S)
0
DMF
a
Reaction conditions: 2 mL of CH2Cl2, 0.005 mmol of [Pd(
0.0075 mmol of ligand, 0.5 mmol of substrate, 0.2 mL of dimethylmalonate, 0.4 mL
l
-Cl)(g
3-C3H5)]2,
a
Reaction conditions: 2 mL of solvent, 0.005 mmol of [Pd(
l-Cl)(
g
3-C3H5)]2,
of BSA, a small amount of KOAc at rt.
0.0075 mmol of ligand, 0.5 mmol of substrate, 0.2 mL of dimethylmalonate, 0.4 mL
of BSA, a small amount of KOAc at rt.
b
Evaluated by NMR spectroscopy of the crude reaction mixture. Reaction time in
b
hours shown in parentheses.
Evaluated by GC. Reaction time in hours shown in parentheses.
c
c
Determined by HPLC on a Chiralcel-OJ column.
Determined by GC on a Chiralsil-Dex CB column.

998
M. Lega et al. / Tetrahedron: Asymmetry 24 (2013) 995–1000
Table 4
The results shown in Table 5 indicate that enantioselectivities were
affected by the position of the phosphite moiety at either C-2 (li-
gands 1) or C-3 (ligands 2) of the pyranoside backbone as well as
the substituents of the biaryl phosphite moiety, while there was
no effect on the configuration of the biaryl phosphite moiety. In
contrast to previously used substrates S1–S5, although the activities
achieved with ligands 2 were much lower than with ligands 1, the
enantioselectivities were higher with ligands 2 (Table 5, entries 4–5
vs 8–9). In general, the enantioselectivity seemed to be enhanced by
the significant overall steric hindrance of the phosphite moiety, as
found in 1f, which allowed us to obtain the chiral product in high
ee (94%, entry 6).
Asymmetric allylic alkylation of unhindered linear rac-S2 and cyclic rac-S3 substrates
with dimethylmalonate using ligands 1–2a–fa
Entry
Ligand
S2
% Convb (h)
S3
% Convb (h)
% eec
% eec
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
2a
2d
2e
1f
100 (8)
100 (6)
100 (6)
100 (6)
100 (6)
100 (6)
100 (6)
100 (6)
100 (6)
—
10 (R)
16 (R)
9 (R)
2 (R)
33 (R)
12 (R)
0
2 (R)
2 (R)
—
25 (18)
32 (20)
25 (20)
52 (20)
1 (20)
83 (20)
6 (20)
11 (20)
9 (20)
14 (R)
50 (S)
21 (S)
30 (R)
59 (S)
72 (S)d
30 (R)
16 (R)
22 (S)
86 (S)
9
10e
21 (120)
2.3. Asymmetric Cu-conjugate 1,4-addition
a
Reaction conditions: 2 mL of DMF, 0.005 mmol of [Pd(
l-Cl)(
g
3-C3H5)]2,
0.0075 mmol of ligand, 0.5 mmol of substrate, 0.2 mL of dimethylmalonate, 0.4 mL
of BSA, a small amount of KOAc at rt.
We next studied the application of pyranoside phosphite-pyri-
dine ligands 1–2a–f in the Cu-catalyzed conjugate addition of
diorganozinc reagents to two enones with different steric proper-
ties: 2-cyclohexenone S7, which is widely used as a model sub-
strate, and trans-3-nonen-2-one S8 Eqs. 4a and 4b. The latter
b
Evaluated by GC. Reaction time in hours shown in parentheses.
Determined by GC on a Chiralsil-Dex CB column.
The same reaction carried out in dichloromethane afforded 6% conversion in
c
d
64% ee (S).
e
Reaction carried out at 0 °C.
substrate, possessing only aliphatic substituents, is
a more
demanding substrate class for asymmetric conjugated additions
than cyclic S7 and other aromatic linear enones such as the chal-
cones. The high conformational mobility of this substrate, together
with the presence of only subtle substrate-catalyst steric interac-
tions makes designing effective enantioselective systems very
challenging21
[Pd(μ-Cl)(η3-C3H5)]2 / 1f
n
n
OAc
CH2(COOMe)2 / BSA
DMF / rt / 24 h
CH(COOMe)2
O
O
S4
S5
100% Conv. 45% (+)
100% Conv. 87% (S)
n = 0
n = 2
[Cu] / 1-2a-f
ð4aÞ
Scheme 2. Pd-catalyzed allylic alkylation of cyclic substrates S4 and S5.
ZnEt2
Et
S7
(Scheme 2). For the seven-membered cyclic substrate S5, enanti-
oselectivities of up to 87% were obtained.
O
O
R
Finally, the ligands were examined in an intramolecular allylic
substitution (Table 5); namely the desymmetrisation of meso-
cyclopent-2-ene-1,4-diol S6 (Eq. 3), which affords a key precursor
of the mannostatines.14 In contrast to the intermolecular allylic
alkylation of S1–S5, the catalysts were generated in situ from
[Pd2(dba)3(CHCl3)], the corresponding ligand and using triethyl-
amine as a base, which are used as the standard conditions14
[Cu] / 1-2a-f
ZnR2
ð4bÞ
C5H11
C5H11
S8
For both substrates, the catalytic system was generated in situ by
adding the corresponding ligand to a suspension of the catalyst pre-
cursor. Since this reaction is very sensitive to the reaction condi-
tions (copper source, temperature, and solvent), we decided to
screen the ligands under the two conditions that were seen to be
best in combination with phosphite-based ligands (conditions
A15: Cu(OTf)2, toluene at rt and conditions B16: CuTC; Et2O at
ꢁ30 °C). The results shown in Table 6 indicate that the results are
highly substrate dependent. Thus, while for cyclic substrate S7 the
best results were obtained using ligands 1 under conditions B (en-
tries 1–2 vs 3–4), for linear substrate S8 the best results were ob-
tained when using ligands 2 under conditions A (entries 10–11 vs
14–15). Ligand 2a afforded high levels of enantioselectivity (ee’s
up to 90%; entries 11 and 16) in the conjugate addition of both
diethyl- and dimethyl zinc to the more challenging linear substrate
S8.
Finally and for the purpose of comparison with recently re-
ported glucopyranoside pyridine–phosphite ligands containing
enantiopure binaphthyl moieties,10 we also evaluated ligand 2a
in the conjugate addition to chalcone S9 using diethylzinc. The
reaction however proceeded with low enantiocontrol (ee’s up to
20%). This result is not unexpected because the steric requirements
needed to achieve high enantioselectivities in the conjugate addi-
tion of chalcone-type substrates are different to the ones required
for aliphatic enones such as S8.21
O
O
[Pd2(dba)3(CHCl3)] / 1-2a-f
O
O
O
O
N
NHTs
TsHN
Ts
NEt3 / THF
S6
ð3Þ
Table 5
Intramolecular asymmetric allylic substitution of meso-S6 using ligands 1–2a–fa
Entry
Ligand
% Convb (h)
% eec
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
2a
2d
2e
100 (0.5)
67 (0.5)
100 (0.5)
93 (0.5)
100 (0.5)
92 (0.5)
<10 (0.5)
26 (0.5)
55 (0.5)
76 (+)-(S,R)
80 (+)-(S,R)
62 (+)-(S,R)
19 (+)-(S,R)
17 (+)-(S,R)
94 (+)-(S,R)
nd
61 (+)-(S,R)
54 (+)-(S,R)
a
Reaction conditions: 1 mL of THF, 0.005 mmol of [Pd2(dba)3(CHCl3)],
0.015 mmol of ligand, 0.2 mmol of substrate, 0.3 mL of triethylamine at rt.
b
Evaluated by NMR spectroscopy of the crude reaction mixture. Reaction time in
hours shown in parentheses.
c
Determined by HPLC on a Chiralcel OD-H column.

M. Lega et al. / Tetrahedron: Asymmetry 24 (2013) 995–1000
999
Table 6
Asymmetric conjugate addition of substrates S7–S8 using ligands 1–2a–fa
Entry
Ligand
Substrate
Conditions
ZnR2
% Convb (h)
% Yieldb
% eec
1
2
3
4
5
6
7
8
1a
2a
1a
1b
1c
1d
1e
1f
2a
1a
2a
2d
2e
1a
2a
2a
S7
S7
S7
S7
S7
S7
S7
S7
S7
S8
S8
S8
S8
S8
S8
S8
A
A
B
B
B
B
B
B
B
A
A
A
A
B
B
A
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnEt2
ZnMe2
ZnMe2
ZnMe2
ZnMe2
ZnMe2
ZnMe2
ZnEt2
20 (3)
45 (3)
0
0
—
—
84 (18)
67 (18)
78 (18)
41 (18)
65 (18)
55 (18)
74 (18)
96 (18)
100 (18)
72 (18)
93 (18)
9 (18)
52
49
51
28
10
20
74
25
49
2
5 (R)
4 (R)
1 (R)
11 (R)
9 (R)
25 (R)
10 (S)
16 (S)
90 (R)
17 (R)
47 (R)
—
9
10
11
12
13
14
15
16
30
0
0
0 (18)
100 (18)
—
83 (R)
53
a
Reaction conditions: Conditions A: 2 mL of toluene, 0.003 mmol of Cu(OTf)2, 0.0075 mmol of ligand, 0.12 mmol of substrate, 0.24 mmol of ZnEt2. Conditions B: 4 mL of
diethyl ether, 0.0048 mmol of CuTC, 0.0096 mmol of ligand, 0.24 mmol of substrate, 0.36 mmol of ZnMe2.
b
Evaluated by GC using undecane as an internal standard. Reaction time in hours shown in parentheses.
Determined by GC on a Lipodex A column for substrate S7 and a Beta-DEX column for substrate S8.
c
Ligand 1c. Yield: 131 mg (34%). 31P NMR (C6D6), d: 145.4. 1H
3. Conclusion
t
t
NMR (C6D6), d: 1.53 (s, 9H, CH3, Bu), 1.56 (s, 9H, CH3, Bu), 2.92
(s, 3H, CH3–O), 3.29 (s, 3H, CH3–O), 3.32 (s, 3H, CH3–O), 3.38 (m,
1H, H-6), 3.64 (m, 1H, H-4), 3.93 (m, 1H, H-5), 4.04 (dd, 1H, H-60,
A series of phosphite–pyridine ligands with the readily avail-
able glucopyranoside backbone have been applied in the metal-
catalyzed allylic substitution and conjugate 1,4-addition reactions
of several substrate types. By varying the position of the phosphite
moiety and the substituents/configuration at the biaryl phosphite
moiety we have been able to identify ligands that provide high
enantioselectivities in the Pd-catalyzed intermolecular allylic sub-
stitution of cyclic substrates S3–S5 (ee’s up to 86%) and desymmet-
rization of meso-cyclopent-2-ene-1,4-diol S6 (ee’s up to 94%) and
in the Cu-catalyzed conjugate 1,4-addition of dialkylzinc reagents
to a challenging aliphatic enone trans-3-nonen-2-one S8 (ee’s up
to 90%).
3
3
3
0
0
J6 –6 = 10.4 Hz, J6 –5 = = 5.2 Hz), 4.53 (d, 1H, H-1, J1–2 = 3.6 Hz),
4.94 (m, 1H, H-2), 5.10 (s, 1H, H-7), 6.38 (m, 1H, H-3), 6.5–8.4
t
t
(m, 13H, CH=). 13C NMR (C6D6), d: 30.8 (CH3, Bu), 30.9 (CH3, Bu),
t
35.2 (C, Bu), 54.6 (CH3–O), 54.7 (CH3–O), 54.8 (CH3–O), 62.5 (C-
5), 68.5 (C-6), 71.4 (d, C-3, JC–P = 3.8 Hz), 72.8 (C-2), 79.6 (C-4),
3
99.6 (C-1), 101.2 (C-7), 128–165 (aromatic carbons). Anal. Calcd
(%) for C42H48NO11P: C, 65.19; H, 6.25; N, 1.81. Found: C, 65.16;
H, 6.27; N, 1.80.
Ligand 1f. Yield: 144 mg (41%). 31P NMR (C6D6), d: 150.6. 1H
NMR (C6D6), d: 2.82 (s, 3H, CH3, CH3–O), 3.40 (m, 1H, H-6), 3.62
3
(m, 1H, H-4), 3.97 (m, 1H, CH, H-5), 4.03 (dd, 1H, H-60, J6 –
0
3
3
0
6 = 10.0 Hz, J6 –5 = 5.2 Hz), 4.38 (d, 1H, H-1, J1–2 = 4.0 Hz), 4.72
(m, 1H, H-2), 5.24 (s, 1H, H-7), 6.45 (m, 1H, CH@), 6.50 (m, 1H,
H-3), 6.8–8.4 (m, 20H, CH@). 13C NMR (C6D6), d: 54.8 (CH3-O),
4. Experimental
4.1. General
3
62.4 (C-5), 68.6 (C-6), 71.9 (C-3), 74.1 (d, C-2, JC–P = 13.7 Hz),
79.4 (C-4), 99.5 (d, C-1, JC–P = 4.6 Hz), 101.4 (C-7), 121–165 (aro-
3
All reactions were carried out using standard Schlenk tech-
niques under an atmosphere of argon or nitrogen. Solvents were
purified and dried by standard procedures. 1H, 13C{1H} NMR and
31P{1H} NMR spectra were recorded on a Varian Gemini 400 MHz
spectrometer. Chemical shifts are relative to TMS (1H and 13C) as
matic carbons). Anal. Calcd.(%) for C40H32NO9P: C, 68.47; H, 4.60;
N, 2.00. Found: C, 68.38; H, 4.57; N, 1.97.
4.3. Typical procedure for the allylic alkylation of substrates S1–
S5
internal standard or H3PO4 (
31P) as external standard. Ligands
1a,b,d,e and 2a–f were prepared as previously reported.9
A solution of [Pd(l-Cl)(g
3-C3H5)]2 (0.005 mmol) and ligand in
the desired solvent (1.0 mL) was stirred for 30 min. Next, a solution
of the corresponding substrate (0.5 mmol) in the same solvent
4.2. Typical procedure for the preparation of phosphite–pyridine
ligands 1c,f
(1.0 mL), dimethylmalonate
(0.200 mL),
N,O-bis(trimethyl-
silyl)acetamide (0.400 mL, 1.5 mmol), and a small amount of KOAc
were added. The reaction mixture was then stirred at room tem-
perature. After the desired reaction time, the reaction mixture
was diluted with Et2O (5 mL) and a saturated aqueous NH4Cl solu-
tion (25 mL) was added. The organic phase was extracted and dried
over MgSO4. For substrate S1, the solvent was removed and the
conversion was measured by 1H NMR. To determine the ee by HPLC
(Chiralcel OJ-H, 13% 2-propanol/hexane, flow 0.5 mL/min), a sam-
ple was filtered through basic alumina using dichloromethane as
the eluent.18 For substrates S2, S3, and S5, the conversion and
enantiomeric excess were determined by GC (Chiralsil-Dex CB col-
umn).19 For substrate S4, the conversion was measured by 1H NMR
and the ee was determined by 1H NMR using [Eu(hfc)3].20
The corresponding phosphorochloridite (0.55 mmol) produced
in situ17 was dissolved in toluene (2.5 mL) and pyridine (0.15 mL,
1.95 mmol) was added. The corresponding pyridine-hydroxyl com-
pound
3 (0.5 mmol) was azeotropically dried with toluene
(3 ꢂ 2 mL) and then dissolved in toluene (2.5 mL) to which pyri-
dine (0.15 mL, 1.95 mmol) was added. The alcohol solution was
then transferred slowly to a solution of phosphorochloridite. The
reaction mixture was stirred at 80 °C for 90 min, and the pyridine
salts were removed by filtration. Evaporation of the solvent gave a
white foam, which was purified by flash chromatography in alu-
mina (toluene/NEt3 = 100/1) to produce the corresponding ligand
as a white solid.

1000
M. Lega et al. / Tetrahedron: Asymmetry 24 (2013) 995–1000
Claver, C. Coord. Chem. Rev. 2004, 248, 2165; (c) Diéguez, M.; Pàmies, O.; Claver,
C. Chem. Rev. 2004, 104, 3189; (d) Díaz, Y.; Castillón, S.; Claver, C. Chem. Soc. Rev.
2005, 34, 702; (e) Diéguez, M.; Claver, C.; Pàmies, O. Eur. J. Org. Chem. 2007,
4621; (f) Diéguez, M.; Pàmies, O. Chem. Eur. J. 2008, 944; (g) Boysen, M. M. K.
Chem. Eur. J. 2007, 13, 8648; (h) Benessere, V.; De Roma, A.; Del Litto, R.; Ruffo,
F. Coord. Chem. Rev. 2010, 254, 390; (i) Woodward, S.; Diéguez, M.; Pàmies, O.
Coord. Chem. Rev. 2007, 2010, 254.
4.4. Typical procedure for the desymmetrisation of S6
meso-2-Cyclopenten-1,4-diol-isocyanate (0.10 g, 0.20 mmol),
[Pd2(dba)3]ꢀCHCl3 (0.005 g, 0.005 mmol), and the ligand
(0.015 mmol) were dissolved in dry THF (1 mL) containing triethyl-
amine (0.030 g, 0.30 mmol). The mixture was then stirred at room
temperature, and, after the required reaction time, the solvent was
removed under vacuum. Column chromatography on silica gel (1:2
ethyl acetate/hexane) gave the desired product as a white solid in
80–85% yield. The conversion was measured by 1H NMR and the ee
was determined by HPLC on a Chiralcel OD-H column.
4. For representative examples, see: (a) Gläser, B.; Kunz, H. Synlett 1998, 53; (b)
Yonehara, K.; Hashizume, T.; Mori, K.; Ohe, K.; Uemura, S. Chem. Commun. 1999,
415; (c) Yonehara, K.; Jashizume, T.; Mori, K.; Ohe, K.; Uemura, S. J. Org. Chem.
1999, 64, 9374; (d) Yonehara, K.; Mori, K.; Hashizume, T.; Chung, K. G.; Ohe, K.;
Uemura, S. J. Organomet. Chem. 2000, 603, 40; (e) Borriello, C.; Cucciolito, M. E.;
Panunzi, A.; Ruffo, F. Inorg. Chim. Acta 2003, 353C, 238; (f) Mazuela, J.; Norrby,
P.-O.; Andersson, P. G.; Pàmies, O.; Diéguez, M. J. Am. Chem. Soc. 2011, 133,
13634; (g) Mata, Y.; Pàmies, Y.; Diéguez, M. Chem. Eur. J. 2007, 13, 3296; (h)
Mata, Y.; Pàmies, O.; Diéguez, M.; Claver, C. Adv. Synth. Catal. 1943, 2005, 347;
(i) Mata, Y.; Pàmies, O.; Diéguez, M. Adv. Synth. Catal. 2009, 351, 3217; (j) Mata,
Y.; Diéguez, M.; Pàmies, O.; Claver, C. Org. Lett. 2005, 7, 5597; (k) Diéguez, M.;
Mazuela, J.; Pàmies, O.; Verendel, J. J.; Andersson, P. G. J. Am. Chem. Soc. 2008,
130, 7208.
4.5. Typical procedure for the asymmetric conjugate 1,4-addition
Method A: A solution of the copper-catalyst precursor Cu(OTf)2
(1 mol %, 0.003 mmol) and the corresponding ligand (2.5 equiv,
0.0075 mmol) in 2 mL of dry toluene was stirred for 30 min at
room temperature. The alkylating organometallic reagent ZnR2
(2 equiv 1.2 M toluene or 1.0 M hexane solutions, 0.24 mmol)
was added dropwise and then the substrate (0.12 mmol). After
the desired time, the reaction was quenched with 2 M HCl
5. Börner, A. In Phosphorus Ligands in Asymmetric Catalysis: Synthesis and
Applications; Wiley-VCH, 2008; Vol. 2, and references therein.
6. (a) Espinet, P.; Soulantica, K. Coord. Chem. Rev. 1999, 193, 499; (b) Molina, P.;
Arques, A.; García, A.; Ramríez de Arellano, M. C. Eur. J. Inorg. Chem. 1988, 1359.
and references therein; (c) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem.
Soc. 1988, 120, 9722; (d) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.;
Sadighi, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1989, 121, 4369; (e) Amatore, C.;
Fuxa, A.; Jutand, A. Chem. Eur. J. 2000, 6, 1474.
7. For some exemple, see: (a) Chelucci, G.; Orrù, G.; Pinna, G. A. Tetrahedron 2003,
59, 9471; (b) van Leeuwen, P. W. N. M.; Kamer, P. C. J.; Claver, C.; Pàmies, O.;
Diéguez, M. Chem. Rev. 2011, 111, 2077.
8. For successful examples, see for instance: (a) Wan, H.; Hu, Y.; Liang, Y.; Gao, S.;
Wang, J.; Zheng, Z.; Hu, X. J. Org. Chem 2003, 68, 8277 (Cu-conjugate addition);
(b) Luo, X.; Hu, Y.; Hu, X. Tetrahedron: Asymmetry 2005, 16, 1227 (Cu-conjugate
addition); (c) Mazuela, J.; Pàmies, O.; Diéguez, M. Chem. Eur. J. 2013, 19, 2416
(Pd-allylic substituion); (d) Mazuela, J.; Pàmies, O.; Diéguez, M. Adv. Synth.
Catal. doi: http://dx.doi.org/10.1002/adsc.201201017 (Ir-hydrogenation).
9. Margalef, J.; Lega, M.; Ruffo, F.; Pàmies, O.; Diéguez, M. Tetrahedron: Asymmetry
2012, 23, 945.
(2 mL). Undecane (10 lL) was then added as an internal standard
and the organic layer filtered twice through a plug of silica.
Method B: A solution of CuTC (0.0048 mmol) and the ligand
(2.0 equiv) in diethyl ether (4 mL) was stirred for 30 min at room
temperature. After cooling to the desired temperature, the alkylat-
ing reagents (0.360 mmol) were added. The desired enone
(0.240 mmol) and undecane as the GC internal standard (20 lL)
were then added at the corresponding reaction temperature. The
reaction was monitored by GC. The reaction was quenched with
HCl (4 M) and filtered twice through flash silica.
10. A recent report described the synthesis of closely related ligands, see: Xia, H.;
Yan, H.; Shen, C.; Zhang, P. Catal. Commun. 2011, 16, 155.
For substrates S7 and S8, the conversion, chemoselectivity, and
enantioselectivity were determined by GC using Lipodex A and
beta-DEX columns, respectively.21
11. Pàmies, O.; Diéguez, M.; Net, G.; Ruiz, A.; Claver, C. Organometallics 2000, 19,
1488.
12. (a) Baek, J. Y.; Shin, Y.; Jeon, H. B.; Kim, K. S. Tetrahedron Lett. 2005, 46, 5143; (b)
Benessere, V.; De Roma, A.; Ruffo, F. ChemSusChem 2008, 1, 425.
13. Porte, A. M.; Reinbenspies, J.; Burgess, K. J. Am. Chem. Soc. 1998, 120, 9180.
14. (a) Trost, B. M.; Van Vranken, D. L. Angew. Chem., Int. Ed. 1992, 31, 228; (b)
Trost, B. M.; Van Vranken, D. L. J. Am. Chem. Soc. 1993, 115, 444; (c) Trost, B. M.;
Breit, B. Tetrahedron Lett. 1994, 35, 5817; (d) Trost, B. M.; Breit, B.; Peukert, S.;
Zambrano, J.; Ziller, J. W. Angew. Chem., Int. Ed. Engl. 1995, 34, 2386; (e) Trost, B.
M.; Patterson, D. E. J. Org. Chem. 1998, 63, 1339; (f) Lee, S.; Lim, C. W.; Song, C.
E.; Kim, K. M.; Jun, C. H. J. Org. Chem. 1999, 64, 4445; (g) Lim, C. W.; Lee, S.
Tetrahedron 2000, 56, 5135; (h) Trost, B. M.; Zambrano, J.; Ritcher, W. Synlett
2001, 907; (i) Buschmann, N.; Rueckert, A.; Blechert, S. J. Org. Chem. 2002, 67,
4325; (j) Song, C. E.; Yang, J. W.; Roh, E. J.; Lee, S. G.; Ahn, J. H.; Han, H. Angew.
Chem., Int. Ed. 2002, 41, 3852; (k) Trost, B. M.; Pan, Z.; Zambrano, J.; Kujat, G.
Angew. Chem., Int. Ed. 2002, 41, 4691; (l) Agarkov, A.; Uffman, E. W.; Gibeltson,
S. R. Org. Lett. 2003, 5, 2091; (m) Zhao, D.; Wang, Z.; Ding, K. Synlett 2005, 2067.
15. Pàmies, O.; Diéguez, M.; Net, G.; Ruiz, A.; Claver, C. Tetrahedron: Asymmetry
2000, 11, 4377.
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