Furanoside phosphite-phosphoroamidite and diphosphoroamidite ligands applied to asymmetric Cu-catalyzed allylic substitution reactions

Article abstract of DOI:10.1016/j.tetasy.2012.01.003

A phosphite-phosphoroamidite and diphosphoroamidite ligand library was applied in the Cu-catalyzed allylic substitution of a range of cinnamyl-type substrates using several organometallic nucleophiles. Results indicated that selectivity depended strongly on the ligand parameters (position of the phosphoroamidite group at either C-5 or C-3 of the furanoside backbone, as well as the configuration of C-3, the introduction of a second phosphoroamidite moiety, the substituents and configurations in the biaryl phosphite/ phosphoroamidite moieties), the nature of the leaving group of the substrate and the alkylating reagent. Good enantioselectivities (up to 76%) and activity combined with high regioselectivities were obtained.

Full text of DOI:10.1016/j.tetasy.2012.01.003

Tetrahedron: Asymmetry 23 (2012) 67–71
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Furanoside phosphite–phosphoroamidite and diphosphoroamidite ligands
applied to asymmetric Cu-catalyzed allylic substitution reactions
Marc Magre a, Javier Mazuela a, Montserrat Diéguez a, , Oscar Pàmies a, , Alexandre Alexakis b,
⇑
⇑
⇑
a Departament de Química Física i Inorgànica, Universitat Rovira i Virgili, Campus Sescelades, 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:
A phosphite–phosphoroamidite and diphosphoroamidite ligand library was applied in the Cu-catalyzed
allylic substitution of a range of cinnamyl-type substrates using several organometallic nucleophiles.
Results indicated that selectivity depended strongly on the ligand parameters (position of the phosphoro-
amidite group at either C-5 or C-3 of the furanoside backbone, as well as the configuration of C-3, the
introduction of a second phosphoroamidite moiety, the substituents and configurations in the biaryl
phosphite/phosphoroamidite moieties), the nature of the leaving group of the substrate and the alkylat-
ing reagent. Good enantioselectivities (up to 76%) and activity combined with high regioselectivities were
obtained.
Received 21 November 2011
Accepted 5 January 2012
Available online 8 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
duced for stereoselective allylic addition of organomagnesium
reagents, such as chiral diaminocarbenes (Fig. 1, ligands type 4)
Developing methods for enantioselective carbon–carbon bond
formation is one of the key issues in organic synthesis. A versatile
method for doing this is transition metal-catalyzed asymmetric
allylic substitution with carbon nucleophiles.1 Great effort has
been put into controlling the chemo-, regio-, and enantioselectivi-
ties of the reaction. Most asymmetric allylic substitutions have
been reported with soft nucleophiles (i.e., malonates and related
stabilized anions) and Pd as the metal source, although Mo, W,
Ru, Rh, and Ir catalysts have also proved to be effective for these
nucleophiles.1 In contrast, copper allows the use of hard, nonstabi-
lized nucleophiles, such as small alkyl groups in the form of orga-
nometallic species.2 Among the broad range of reagents available,
the use of Grignard reagents in the catalyzed asymmetric allylic
substitution reaction was first reported by Bäckvall and van Koten,
with chiral copper thiolate 1 (Fig. 1), yielding moderate enantio-
meric excesses.3 This pioneering work was soon followed by that
of Dübner and Knochel, who reported a highly enantioselective
version using a different system based on diorganozinc reagents
with ligand 2 (Fig. 1).4 Since then, most efforts have been directed
toward developing new efficient Cu catalysts for these organozinc
reagents.5 An important breakthrough in the use of Grignard
reagents was made by Alexakis et al. They reported highly regio-
and enantioselective Cu-phosphoroamidite catalyzed allylic
substitution of di- and tri-substituted cinnamyl chloride substrates
(Fig. 1, ligands type 3).6 Other successful ligands have been intro-
by Okamoto et al.7 and more recently ferrocenic bidentate phos-
phines (Fig. 1, ligand type 5) by Feringa et al.8
Apart from these latter bidentate phosphines, the most success-
ful ligands developed for this transformation are monodentate.
However, Alexakis et al. found that the successfully MeO-substi-
tuted phosphoroamidite monodentate phosphorus ligands 3 can
act as bidentate P,O-ligands.6b On the basis of this finding we
decided to study a library of bidentate furanoside phosphite–
phosphoroamidite and diphosphoroamidite ligands L1–L5a–f in
the Cu-catalyzed allylic substitution reaction. These ligands have
the same advantages as carbohydrate and phosphite/phosphoro-
amidite ligands: that is, they are available at low cost, they have
high resistance to oxidation, and they have simple modular con-
structions.9 Therefore, with this library we fully investigated the
effects of systematically varying the position of the phosphoroami-
dite group at both C-5 (ligands L1 and L2) and C-3 (ligands L3 and
L4) of the furanoside backbone, as well as the effects of the config-
uration at C-3 of the furanoside backbone, the introduction of a
second phosphoroamidite moiety (ligands L5), and the substitu-
ents/configurations in the biaryl phosphite/phosphoroamidite
moieties (a–f). By carefully selecting the best of these elements
and using a range of Grignard reagents, we achieved good regio-
and enantioselectivities, and activities in different substrate types.
2. Results and discussion
Initially, we evaluated the phosphite–phosphoroamidite and
diphosphoroamidite ligand library L1–L5a–f (Fig. 2) in the cop-
per-catalyzed asymmetric allylic alkylation of cinnamyl chloride
⇑
Corresponding authors.
E-mail addresses: montserrat.dieguez@urv.cat (M. Diéguez), oscar.pamies@urv.
cat (O. Pàmies), alexandre.alexakis@chiorg.unige.ch (A. Alexakis).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2012.01.003

68
M. Magre et al. / Tetrahedron: Asymmetry 23 (2012) 67–71
H2N
OMe
OMe
NMe2
Cu
O
O
Fe
P
N
S
1
2
3
PPh2
NMe2
1-Naph
N
N
1-Naph
PPh2
Fe
CuCl
4
5
Figure 1. Ligands previously applied in asymmetric Cu-catalyzed allylic substitution reactions.
S1 using EtMgBr as the nucleophile (Eq. 1). The catalytic system
was generated in situ by adding the corresponding ligand to a
suspension of the catalyst precursor copper thiophene 2-carboxyl-
ate (CuTC).
observed a cooperative effect between the position of the phosp-
horoamidite group and the configuration of carbon atom C-3 of
the furanoside backbone. The results indicate that the best combi-
nation of these ligand parameters is achieved with ligands L2,
Et
Cl
EtMgBr
*
Et
ð1Þ
+
S1
CuTC
6
7
L1-L5a-f
The results are shown in Table 1. They indicate that regio- and
enantioselectivities are affected by the position of the phosphoro-
amidite group at either C-5 or C-3 of the furanoside backbone, and
by the configuration of C-3, the introduction of a second phosp-
horoamidite moiety, and the substituents and configurations in
the biaryl phosphite/phosphoroamidite moieties (a–f).
We first studied the effect of the position of the phosphoroami-
dite group at either C-5, ligands L1 and L2, or C-3, ligands L3 and
L4, of the furanoside backbone and the configuration of C-3. We
whose phosphoroamidite moiety is attached to C-5 and which
have an (R)-configuration of carbon atom C-3 on the tetrahydrofu-
ran ring (Table 1, entries 1–4).
We then used ligands L5 to study how catalytic performance
was affected by replacing the phosphite moiety with a phosp-
horoamidite group in preferred ligands L2. The results indicated
that the presence of a second phosphoroamidite moiety in the li-
gands had a negative effect on enantioselectivity (Table 1, entries
5 vs 2).
O
O
O
P
HN
O
O
P
O
O
O
O
O
O
O
O
P
HN
P
O
P
P
5
O
O
O
O
O
O
HN
1
4
2
O
O
O
O
3
O
O
X
O
NH
L4
O
P
O
P
L2
X= O
L1
L3
O
O
L5 X= NH
R1
R2
Me3Si
a
b
c
d
R1 = R2 = tBu
e
f
(S)ax
(R)ax
R1 = tBu; R2 = OMe
R1 = SiMe3; R2 = H
R1 = R2 = Me
O
O
O
O
O
=
O
R1
R2
Me3Si
Figure 2. Furanoside-based phosphite–phosphoroamidite and diphosphoroamidite ligand library L1–L5a–f.

M. Magre et al. / Tetrahedron: Asymmetry 23 (2012) 67–71
69
Table 1
gand design. Regio- and enantioselectivities can be improved by
controlling not only the structural but also the reaction parame-
ters. In this case, both regio- and enantioselectivities were further
improved (98% regioselectivity with 70% ee) with ligand L2a by
lowering the reaction temperature to ꢁ78 °C (Table 1, entry 11).
It has been shown that the catalytic performance for this trans-
formation is highly dependent on a subtle balance between the nat-
ure of the leaving group, the type of organometallic reagent, and
the copper source among other reaction parameters.2 So we next
investigated whether the performance of our CuTC/L2a catalytic
system can be improved by using other leaving groups in the sub-
strate and by using dialkylzincs instead of Grignard reagents. The
results are summarized in Table 2. Using EtMgBr, we found that
the replacement of the chloride leaving group by a bromide S2 or
phosphonate group S3 leads to lower regio- and enantioselectivi-
ties (Table 2, entries 2 and 3 vs 1). On the other hand, the use of
dialkylzincs instead of Grignard reagents for the allylic substitution
of cinnamyl halides S1 and S2 leads to significantly lower regio-
and enantioselectivities (Table 2, entries 4 and 5 vs 1 and 2, respec-
tively). However, for phosphonate S3, enantioselectivity and to a
lesser extent regioselectivity increased when ZnEt2 was used, but
at the cost of activity (Table 2, entry 6 vs 3). Finally, and on the basis
of our previous results on Cu-catalyzed conjugate addition which
show that for some substrates the combination of dialkylzincs with
CuOTf2 leads to higher enantioselectivities, we decided to assess
the use of CuOTf2 as a source of copper. Unfortunately, no improve-
ment in the catalytic performance was observed (Table 2, entries 7
and 8 vs 4 and 5, respectively).
Selected results for the Cu-allylic substitution of cinnamyl chloride with EtMgBr using
ligands L1–L5a–fa
Entry
L
% Convb
6/7c
% eed
1
2
3
4
5
6
7
8
9
L1a
L2a
L3a
L4a
L5a
L2b
L2c
L2d
L2e
L2f
100
99
94/6
97/3
88/12
92/8
96/4
95/5
96/4
97/3
95/5
96/4
98/2
39 (S)
60 (S)
3 (S)
38 (S)
12 (S)
48 (S)
32 (S)
6 (S)
100
100
100
100
100
100
90
43 (S)
16 (R)
70 (S)
10
96
99
11e
L2a
a
Reaction conditions: CuTC (1 mol %), ligand (1 mol %), EtMgBr (1.2 equiv,
1.2 mmol), S1 (1 mmol), CH2Cl2 (2 mL), T = ꢁ50 °C.
b
Conversion determined by GC after 1 h.
Regioselectivity determined by GC.
Enantiomeric excess determined by GC on a Supelco b-DEX 120 column.
Reaction carried out at ꢁ78 °C.
c
d
e
We next studied the effects of the biaryl phosphite/phosphoro-
amidite moieties using ligands L2a–f (Table 1). We found that these
moieties mainly affected enantioselectivity, while their effect on
regioselectivity was less important. Results indicated that bulky
substituents at both ortho and para positions of the biphenyl phos-
phite/phosphoroamidite moieties need to be present if enantiose-
lectivities are to be high (Table 1, entries 2 vs 6–8). This indicates
that bulky substituents are necessary to control the tropoisomer-
ization of the biaryl phosphite/phosphoroamidite moieties in the
catalytic active species. Similar behavior has been observed for
other phosphite/phosphoroamidite based ligands in other metal-
catalyzed asymmetric transformations.10 Moreover, the presence
of bulky enantiopure binaphthyl moieties (e–f) did not further im-
prove enantioselectivity (Table 1, entries 2 vs 9–10). This suggests
that in ligand L2a, the biphenyl moiety attached to the phosphoro-
amidite adopts a configuration that is different from that of the
configuration of the biphenyl phosphite moiety.
Finally, we investigated the allylic substitution of a range of cin-
namyl type chlorides with various Grignard reagents. Cinnamyl
chloride S1 reacts with methyl and n-propyl Grignard reagents as
EtMgBr does (Table 3, entries 2 and 3 vs 1). However, the use of
i
a secondary Grignard reagent, PrMgBr, decreases both regio- and
enantioselectivities (Table 3, entry 4 vs 1). Regarding the substrate
scope, Table 3 shows that electron-donating groups at the para
position of the phenyl group, substrate S4, slightly decrease both
regio- and enantioselectivities (Table 3, entries 5 and 6 vs 1 and
4, respectively), while electron-withdrawing groups, substrate
S5, slightly increase enantioselectivities (Table 3, entries 7 and 8
vs 1 and 4, respectively). Interestingly, the allylic substitution
of 2-(3-chloro-propenyl)-naphthalene S6 provided the highest
To sum up, the best result was obtained with ligand L2a, which
contains the optimal combination of ligand parameters. These re-
sults clearly show the efficiency of highly modular scaffolds in li-
Table 2
a
Selected results for Cu-catalyzed allylic alkylation of several cinnamyl halides S1–S2 and phosphonate S3 using EtMgBr and ZnEt2
Et
Cu source / L2a
LG
Et
*
+
EtMgBr or ZnEt2
6
7
S1
S2
S3
LG= Cl
LG= Br
LG= OP(OEt)2
O
Entry
Cu salt
Substrate
Organometallic reagent
% Convb
6/7c
% eed
1
2
3
4
5
6
7
8
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuOTf2
CuOTf2
S1
S2
S3
S1
S2
S3
S1
S2
EtMgBr
EtMgBr
EtMgBr
ZnEt2
ZnEt2
ZnEt2
99
100
85
100
100
40
97/3
92/8
60 (S)
53 (S)
42 (S)
39 (S)
44 (S)
55 (S)
36 (S)
46 (S)
70/30
84/16
78/22
75/25
82/18
70/30
ZnEt2
ZnEt2
92
85
a
b
c
Reaction conditions: CuTC (1 mol %), ligand (1 mol %), EtMgBr (1.2 equiv, 1.2 mmol), S1 (1 mmol), CH2Cl2 (2 mL), T = ꢁ50 °C.
Conversion determined by GC after 1 h.
Regioselectivity determined by GC.
d
Enantiomeric excess determined by GC on a Supelco b-DEX 120 column.

70
M. Magre et al. / Tetrahedron: Asymmetry 23 (2012) 67–71
Table 3
Selected results for the Cu-catalyzed asymmetric allylic substitution of a range of cinnamyl-type chlorides with various Grignard reagentsa
R
CuTC / L2a
Ar
Cl
Ar
+
Ar
R
*
RMgBr
S1 Ar= Ph
γ
α
S4 Ar= 4-Me-C6H4
S5 Ar= 4-MeO-C6H4
S6 Ar= 2-Naph
Entry
Substrate
R
% Convb
c
/
ac
% eed
1
2
3
4
5
6
7
8
9
10
11
12
13e
14e
S1
S1
S1
S1
S4
S4
S5
S5
S6
S6
S6
S6
S6
S6
Et
99 (95)
98 (94)
99 (96)
97/3
98/2
97/3
92/8
93/7
88/12
97/3
92/8
96/4
96/4
95/5
90/10
96/4
97/3
60 (S)
59 (S)
59 (S)
35 (S)
54 (S)
32 (S)
62 (S)
40 (S)
68 (S)
67 (S)
67 (S)
41 (S)
76 (S)
73 (S)
Me
nPr
iPr
Et
98 (92)
100 (93)
100 (91)
99 (94)
100 (90)
100 (92)
100 (94)
100 (96)
100 (92)
100 (91)
100 (95)
iPr
Et
iPr
Et
Me
nPr
iPr
Et
Me
a
b
c
Reaction conditions: CuTC (1 mol %), L2a (1 mol %), RMgBr (1.2 equiv, 1.2 mmol), substrate (1 mmol), CH2Cl2 (2 mL), T = ꢁ50 °C.
Conversion determined by GC after 1 h. In parentheses the isolated yield of the mixture of regioisomers.
Regioselectivity determined by GC.
Enantiomeric excess determined by GC on a Supelco b-DEX 120 column.
Reaction performed at ꢁ78 °C.
d
e
enantioselectivities (ee’s up to 76%, Table 3, entries 9–14) while
maintaining excellent regioselectivity.
and the mixture was stirred at room temperature for 30 min. The
allylic chloride (1 mmol) was introduced dropwise and the reac-
tion mixture was stirred at room temperature for a further 5 min
before being cooled to ꢁ50 °C. Grignard reagent (2–3 M in diethyl
ether, 1.2 equiv) in dichloromethane (0.5 mL) was added for
40 min via syringe pump. Once the addition was complete the
reaction mixture was left at ꢁ50 °C for one hour. The reaction
was then quenched by the addition of aqueous hydrochloric acid
(1 N, 2 mL). Diethyl ether (10 mL) was added and the aqueous
phase was separated and extracted further with diethyl ether
(3 ꢂ 3 mL). The combined organic fractions were washed with
brine (5 mL), dried over anhydrous sodium sulfate, filtered, and re-
duced in vacuo. Conversion and regioselectivity were determined
by 1H NMR, and enantiomeric excess was determined by GC.6a
The absolute configuration of the alkylation products has been as-
signed by comparing the retention times with those obtained with
enantioenriched samples prepared according to the literature.6a
The oily residue was purified by flash column chromatography
3. Conclusion
A
library of furanoside phosphite–phosphoroamidite and
diphosphoroamidite was applied in the Cu-catalyzed allylic substi-
tution of a range of cinnamyl-type substrates using several organo-
metallic nucleophiles. Good enantioselectivities (up to 76%) and
activity combined with high regioselectivities were obtained. Sys-
tematically varying the position of the phosphoroamidite group, at
either C-5 or C-3 of the furanoside backbone, as well as the config-
uration of C-3 and several substituents and configurations in the
biaryl phosphite/phosphoroamidite moieties had a strong effect
on the rate and selectivity. Enantioselectivity was the best with
the catalyst precursor containing ligand L2a, which has the optimal
combination of ligand parameters.
Our results also showed that the nature of the leaving group of
the substrate and the alkylating reagent also plays an important
role in determining activity and regio- and enantioselectivities.
2
0
(eluent = pentane) to yield the product as a mixture of SN and
SN regioisomers.6a
2
Acknowledgements
4. Experimental
We thank Dr. Eva Raluy for her help on the preliminary catalyst
results. We would also like to thank the Spanish Government for
providing grants CTQ2010-15835, and 2008PGIR/07 to O. Pàmies
and 2008PGIR/08 to M. Diéguez, the Catalan Government for grant
2009SGR116, and the ICREA Foundation for providing M. Diéguez
and O. Pàmies with financial support through the ICREA Academia
awards.
4.1. General considerations
All syntheses were performed using standard Schlenk tech-
niques under argon atmosphere. Solvents were purified by stan-
dard procedures. Ligands L1–L5a–f11 and substrates S3–S612
were prepared by previously described methods. All other reagents
were used as commercially available.
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4.2. General procedure for the Cu-catalyzed enantioselective
allylic substitution
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5. More recently, triorganomaluminum reagents and organoboronates have also
been successfully applied to this process. See, for instance: (a) Bournaud, C.;
Falciola, C.; Lecourt, T.; Rosset, S.; Alexakis, A.; Micouin, L. Org. Lett. 2006, 8,
3581; (b) Lee, Y.; Akiyama, K.; Gillingham, D. G.; Brown, K.; Hoveyda, A. H. J.
Am. Chem. Soc. 2008, 130, 446; (c) Pineschi, M.; Del Moro, F.; Crotti, P.; Macchia,
F. Org. Lett. 2005, 7, 3605; (e) Ito, H.; Ito, S.; Sasaki, Y.; Matsuura, K.; Sawamura,
M. J. Am. Chem. Soc. 2007, 129, 14856.
6. (a) Alexakis, A.; Croset, K. Org. Lett. 2002, 4, 4147; (b) Tissot-Croset, K.; Polet, D.;
Alexakis, A. Angew. Chem., Int. Ed. 2004, 43, 2426; (c) Falciola, C. A.; Tissot-
Croset, K.; Alexakis, A. Angew. Chem., Int. Ed. 2006, 45, 5995; (d) Falciola, C. A.;
Alexakis, A. Angew. Chem., Int. Ed. 2007, 46, 2619.
12. Tissot-Croset, K. PhD Thesis, University of Geneva, 2005.