Biphenol-based ligands for Cu-catalyzed asymmetric conjugate addition

Article abstract of DOI:10.1016/j.tetasy.2004.05.016

The synthesis and characterization of seven new phosphoramidite ligands are described, as well as their use in copper-catalyzed 1,4-addition of diethylzinc to a wide range of substrates. Enantioselectivities of up to >99.5% are obtained.

Full text of DOI:10.1016/j.tetasy.2004.05.016

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2199–2203
Biphenol-based ligands for Cu-catalyzed asymmetric
conjugate addition
a,
a
b
a
*
Alexandre Alexakis, Damien Polet, Cyril Benhaim and St ꢀe phane Rosset
a
Department of Organic Chemistry, University of Geneva, 30 Quai Ernest Ansermet, CH-1211 Geneva, Switzerland
Department of Chemistry and Biochemistry, University of Texas at Austin, 1 University Station A5300, Austin, TX 78712-0165, USA
b
Received 23 April 2004; accepted 10 May 2004
Abstract—The synthesis and characterization of seven new phosphoramidite ligands are described, as well as their use in copper-
catalyzed 1,4-addition of diethylzinc to a wide range of substrates. Enantioselectivities of up to >99.5% are obtained.
Ó 2004Elsevier Ltd. All rights reserved.
1
. Introduction
biphenol part. We report herein the modification of the
biphenol scaffold of L0, together with a new amine
moiety and the consequence of the enantioselectivity on
the transformation of each substrate, in the presence of
these new ligands.
The conjugate addition reaction has seen an impressive
1
amount of development over the past decade. Among
the whole variety of ligands used in this reaction,
phosphorus-based ones are by far the most widely used
1f
chiral source. The combination of such ligands with
the use of dialkylzinc reagents has made this enantio-
selective methodology extensive and successful. Any
kind of trivalent phosphorus ligands (phosphanes,
phosphites, phosphoramidites, phosphonites) strongly
2. Results and discussion
2
Using a bis-(S)-(1-naphthalen-2-yl-ethyl)-amine deriva-
5
tive, we modified the biphenol core by introducing
3
accelerates the reaction.
Table 1. Synthesis of phosphoramidite ligands L1–7
We have recently demonstrated that phosphoramidite
ligands based on the atropoisomerically flexible biphe-
4
nol unit (Scheme 1) are excellent ligands. Thus, the
R1
R2
induced atropoisomerism of ligand L0 allows high
enantioselectivity in the asymmetric conjugate addition
of dialkyl zincs to a variety of Michael acceptors.
1
) PCl3, NEt3, THF
0
°C to rt
O
O
HN
P
N
R1
R2
2)
R1
R2
Ph
Ph
OH
OH
O
O
O
O
P
N
P
N
R1
R2
Ph
Ph
B1-7
L0
Scheme 1. Conformational atropoisomerism of L0.
1
2
a
Entry
Ligand
R
R
Yield (%)
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
L7
H
H
50
55
37
27
26
53
44
Me
Cl
Me
Cl
The modularity of these phosphoramidite ligands allows
for easy variation of the amino part as well as the
Me
H
OMe
Allyl
H
Ph
Methallyl
Ph
*
Corresponding author. Tel.: +41-22-37-96522; fax: +41-22-37-93215;
e-mail: alexandre.alexakis@chiorg.unige.ch
a
Determined after alumina chromatography.
0
957-4166/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.05.016

2200
A. Alexakis et al. / Tetrahedron: Asymmetry 15 (2004) 2199–2203
0
different functional groups at the ortho, ortho -positions
2
The replacement of the usual bis-(S)-(1-phen-2-yl-ethyl)-
amine by the new amine bis-(S)-(1-naphthalen-2-yl-
ethyl)-amine brings a larger steric requirement, which
has some positive effects on the enantioselectivity.
However, in some other cases, the steric hindrance
causes negative effects. Associated with a simple biphe-
nol unit (ligand L1) there was no notable improvement.
Ligands L2 and L5 both have in common a small ortho-
substituent on the biphenol part (Me for L2 and allyl for
L5). The results with cyclohexenone and cycloheptenone
(representative of cyclic enones) were impressive; cy-
clohexenone afforded the highest reported ee (see Table
2 and Scheme 2). The results with other substrates were
(R , Table 1). For some biphenols, it was easier to
1
introduce an additional substitution at the R position,
although the latter does not play a significant role. All
ligands L1–7 were synthesized by reaction of the chiral
amine with PCl , followed by addition of the biphenol
3
6
B1–7. They were isolated either as white powders or
colorless oils in 26–55% yields.
All the ligands were screened under previously reported
7
new experimental conditions with a variety of Michael
acceptors, such as cyclic and acyclic enones and nitro-
olefins (Table 2).
Table 2. Enantioselective copper-catalyzed 1,4-addition of diethylzinc on various substrates
Cu(I)
O
2
%CuTC , 4%L*
2
-
EWG
Et
EWG
S
Et O , -30°C , 12h
CuTC =
1
.2 Et Zn
+
2
R
R
O
a
Entry Substrate
Conversion%, ee%, (absolute stereochemistry)
L1
L2L3
L4
L5
L6
L7
O
b
c
c
1
>99, 89, (R) >99, 99.5, (R) >99, 95, (R) >99, 98, (R) >99, 99.3, (R) >99, 98, (R) 94, 90, (R)
O
b
c
2
>99, 95, (R) >99, 98, (R)
98, 72, (R)
>99, 98, (R) >99, 98, (R)
>99, 94, (R) >99, 92, (R)
O
b
c
3
>99, 47, (þ) >99, 54, (þ)
>99, 20, (À) 98, 34, (þ)
98, 26, (þ)
91, 17, (À)
>99, 10, (þ)
15
O
b
c
4
5
>99, 30, (S) >99, 39, (S)
>99, 9, (S)
24, 12, (S)
>99, 40, (S) 90, 71, (R)
88, 71, (R)
33, 72, (S)
>99, 47, (S)
Ph
Ph
Ph
O
b
c
>99, 60, (S) 99, 81, (S)
80, 60, (S)
95, 7, (R)
––
93, 50, (S)
O
b
6
7
>99, 32, (R) >99, 41, (R)
40, 15, (R)
>99, 80, (R)
>99, 42, (S)
99, 90, (R)
>99, 6, (R)
––
Me
O
b
c
97, 74, (S)
>99, 74, (S)
>99, 63, (S) 95, 72, (S)
>99, 35, (S)
n-C H
Me
5
11
NO2
NO2
8
9
––
––
>99, 72, (R)
>99, 40, (S) >99, 59, (S) >99, 86, (S)
>99, 73, (S) ––
>99, 74, (S) ––
Ph
––
––
––
>99, 54, (S) >99, 87, (S)
>99, 70, (S) >99, 90, (S)
p-Tol
NO2
10
––
––
>99, 51, (S) ––
O
NO
2
c
1
1
2
––
––
>99, 94, (S)
––
––
––
––
––
––
NO
2
c
1
90, 80, (+)
>99, 90, (þ) 95, 82, (þ)
>99, 81, (þ) ––
a
b
c
The best ee for each substrate is in bold.
Cu(OTf) , toluene.
Cu(OAc) ÆH O, Et
2
2
2
2
O.

A. Alexakis et al. / Tetrahedron: Asymmetry 15 (2004) 2199–2203
2201
larger groups (Ph) impede the coordination of the ligand
with Cu, resulting in lower enantioselectivities. In sum-
mary, some of the new phosphoramidite ligands, based
on the induced atropoisomerism of the biphenol unit,
are the best ligands for cyclohexenone and many nitro-
olefins, although no ligand showed general enantio-
selectivity on every substrate.
4
. Experimental
.1. General procedure for the ligand synthesis
To a stirred mixture of Et N (111 mmol) and PCl3
4
3
(
2
22.2 mmol) at 0 °C, a solution of bis-(S)-(1-naphthalen-
-yl-ethyl)-amine (22.2 mmol) in THF (10 mL) was
added and the reaction mixture stirred for 3 h at room
temperature. Biphenol (22.2 mmol) in a solution of THF
(5 mL) was slowly added to the reaction mixture at 0 °C
and then the suspension stirred at room temperature
overnight. The suspension was diluted in toluene (8 mL)
and filtered on neutral alumina and the solution then
concentrated and purified by flash chromatography
through neutral alumina using pure toluene as eluent, to
give the pure ligand as either a white solid or a colorless
oil.
Scheme 2. Chromatogram of ethylcyclohexanone, using L2.
4.2. (5,7-Dioxa-6-phospha-dibenzo[a,c]cyclohepten-6-yl)-
bis-(S)-(1-naphthalen-2-yl-ethyl)-amine, L1
2
0
also among the best: 81% ee for benzalacetone (entry 5),
Yield 50%; white foam; ½aŠ ¼ À404:9 (c 1.12, CHCl
3
);
D
1
9
4% for nitrocyclohexene (entry 11) with L2; 86% ee for
nitrostyrene (entry 8), 90% for p-methoxynitrostyrene
entry 10) with L5.
H NMR (500 MHz, CDCl ) d 7.53–7.17 (m, 22H),
3
13
4
.82–4.78 (m, 2H), 1.90 (d, 6H, J ¼ 7:0 Hz); C NMR
(
(
125 MHz, CDCl ) d 151.9, 151.8, 151.0, 140.4, 132.9,
3
1
1
1
32.4, 131.2, 130.0, 129.8, 129.2, 129.0, 128.2, 127.9,
27.3, 127.0, 126.1, 125.7, 125.6, 125.3, 124.7, 124.1,
The presence of electron-withdrawing groups on the
biphenol unit (ligand L3) had a detrimental effect, par-
ticularly with acyclic enones and nitro-olefins. The po-
tential chelation with an ortho-methoxy group was
considered with ligand L4. The enantioselectivities with
the cyclic enones were excellent (both 98% ee), but much
less pronounced with acyclic enones. Surprisingly, this
ligand gave the best ee with cyclohexyl nitroethene: 90%
31
22.5, 122.1, 52.8, 52.7, 22.1. P NMR (203 MHz;
) d 146.3.
CDCl
3
4.3. Bis-(S)-(1-naphthalen-2-yl-ethyl)-(2,4,8,10-tetrameth-
yl-5,7-dioxa-6-phospha-dibenzo[a,c]cyclohepten-6-yl)-
amine, L2
(
entry 12).
20
Yield 55%; white foam; ½aŠ ¼ À435:0 (c 1.0, CHCl );
D
3
1
The ortho-methallyl group of ligand L6 brings a slightly
higher steric requirement than the allyl group of L5.
This subtle difference was enough to improve the ee to
H NMR (400 MHz, CDCl
3
) d 7.67 (d, 2H, J ¼ 6:8 Hz),
7
3
.52–7.02 (m, 16H), 4.89 (m, 2H), 2.55 (s, 3H), 2.38 (s,
H), 2.36 (s, 3H), 2.11 (s, 3H), 1.85 (d, 6H, J ¼ 4:0 Hz);
1
3
9
0% for methyl-hexenone (entry 6); however, in general,
C NMR (100 MHz, CDCl ) d 147.5, 141.2, 133.8,
3
the enantioselectivities were lower. An even larger ortho-
group, such as phenyl (ligand L7) clearly has a negative
effect.
1
1
5
1
33.3, 133.1, 132.7, 131.4, 130.6, 130.5, 129.7, 128.6,
28.2, 127.7, 127.6, 127.2, 126.6, 126.0, 125.8, 53.1,
31
3.0, 21.2, 17.8, 16.9; P NMR (162 MHz, CDCl ) d
3
42.0.
3. Conclusion
4.4. Bis-(S)-(1-naphthalen-2-yl-ethyl)-(2,4,8,10-tetrachloro-
5,7-dioxa-6-phospha-dibenzo[a,c]cyclohepten-6-yl)-amine,
L3
This series of new ligands shows that the steric
requirements, either on the biphenol part, or on the
amino part, of the phosphoramidite ligand has a strong
influence with small groups (Me, allyl) having a favor-
able influence on a wide range of substrates. In contrast,
2
D
0
Yield 37%; white foam; ½aŠ ¼ À417:0 (c 1.05, CHCl
3
);
1
H NMR (400 MHz, CDCl ), d 7.66–7.40 (m, 18H), 4.90
3

2202
A. Alexakis et al. / Tetrahedron: Asymmetry 15 (2004) 2199–2203
1
3
(
m, 2H), 1.93 (d, J ¼ 7:1 Hz, 6H); C NMR (100 MHz,
CDCl ) d 147.0, 146.9, 145.8, 139.7, 132.8, 132.4, 130.2,
30.0, 128.2, 127.9, 127.8, 127.7,127.4, 127.3, 126.3,
4.8. Bis-(S)-(1-naphthalen-2-yl-ethyl)-(2,4,8,10-tetraphen-
yl-5,7-dioxa-6-phospha-dibenzo[a,c]cyclohepten-6-yl)-
amine, L7
3
1
1
31
25.9, 125.7, 125.6, 125.4, 124.8, 55.2, 53.3, 24.9;
) d 148.1.
P
2
0
NMR (162 MHz, CDCl
3
Yield 44%; white foam; ½aŠ ¼ À263:0 (c 1.00, CHCl
3
);
D
1
H NMR (400 MHz, CDCl ), d (ppm): 7.82–7.23 (m,
3
13
3
8H), 4.30 (m, 2H), 1.11 (d, 6H, J ¼ 7:0 Hz); C NMR
(
100 MHz, CDCl ), d 147.6, 143.1, 140.3, 138.3, 137.6,
3
4.5. (4,8-Dimethoxy-2,10-dimethyl-5,7-dioxa-6-phospha-
dibenzo[a,c]cyclohepten-6-yl)-bis-(S)-(1-naphthalen-2-yl-
ethyl)-amine, L4
1
1
2
32.7, 128.9, 128.8, 128.2 (d), 128.1, 127.9, 127.8, 127.7,
27.6, 127.1 (d), 127.0, 126.9, 125.9, 125.4, 124.8, 55.2,
31
4.9; P NMR (162 MHz, CDCl ) d 145.7.
3
2
D
0
Yield 27%; white foam; ½aŠ ¼ À408:7 (c 1.05, CHCl
3
);
1
H NMR (400 MHz, CDCl ) d 7.66–7.19 (m, 14H), 6.92
3
(
d, 1H, J ¼ 1:2 Hz), 6.89 (d, 1H, J ¼ 1:0 Hz), 6.81 (d,
4.9. General procedure for the asymmetric conjugate
addition
1
2
1
1
1
1
5
1
H, J ¼ 1:8 Hz), 6.74(d, 1H, J ¼ 1:8 Hz), 4.87–4.79 (m,
H), 3.97 (s, 3H), 3.66 (s, 3H), 2.41 (s, 3H), 2.39 (s, 3H),
1
3
.90 (d, 6H, J ¼ 7:1 Hz); C NMR (100 MHz, CDCl ) d
To a solution of copper thiophenecarboxylate (CuTC)
(0.008 mmol) in Et O (1 mL) at room temperature under
nitrogen, was added the ligand (0.0166 mmol) and 1 mL
3
51.9, 151.3, 140.9, 133.8, 133.1, 133.0, 132.3, 131.8,
30.7, 129.1, 128.3, 127.9, 127.3, 127.2, 127.0, 126.1,
25.4, 125.3, 122.0, 121.8, 113.0, 112.4, 56.2, 55.7, 53.1,
2.9, 21.5, 21.4; P NMR (162 MHz, CDCl
46.1.
2
of Et O. The solution was stirred at 25 °C for 30 min and
2
31
3
) d (ppm):
then cooled to À30 °C. Et Zn (1 mL, 0.5 mmol 15% in
2
hexane) was added dropwise so that the temperature did
not rise over À30 °C. The solution was stirred for 5 min,
and the Michael acceptor (0.415 mmol) then added
dropwise, either neat or in solution in 0.5 mL of toluene.
The reaction mixture was stirred at À30 °C for 12 h
4.6. (4,8-Diallyl-5,7-dioxa-6-phosphadibenzo[a,c]cyclo-
hepten-6-yl)-bis-(S)-(1-naphthalen-2-yl-ethyl)-amine, L5
2
before being quenched by 2 M, HCl/Et O (aq satd
NH Cl in the case of nitroalkene compounds). The
4
enantiomeric excesses were determined by chiral GC or
6
SFC.
2
0
Yield 26%; colorless oil; ½aŠ ¼ À347:0 (c 1.04, CHCl );
D
H NMR (500 MHz, CDCl
3
1
3
), d (ppm): 7.69 (d, 2H,
J ¼ 7:4Hz), 7.56–7.16 (m, 18H), 6.09 (ddt, 1H,
J ¼ 16:9, 10.1, 6.6 Hz), 5.76 (ddt, 1H, J ¼ 16:9, 10.1,
6
.5 Hz), 5.23 (dq, 1H, J ¼ 16:9, 1.7 Hz), 5.17 (dd, 1H,
J ¼ 10:0, 1.8 Hz), 4.87 (m, 2H), 4.84 (dq, 1H, J ¼ 10:1,
.3 Hz), 4.70 (dq, 1H, J ¼ 17:0, 1.6 Hz), 3.94(dd, 1H,
Acknowledgements
1
J ¼ 15:2, 6.5 Hz), 3.61 (dd, 1H, J ¼ 15:3, 6.9 Hz), 3.15
13
The authors thank the BASF company for the generous
gift of chiral amines. The Swiss National Research
Foundation No 20-068095.02 and COST action D24/
(
d, 2H, J ¼ 6:5 Hz), 1.87 (d, 6H, J ¼ 6:8 Hz); C NMR
(
125 MHz, CDCl ), d 149.6, 149.5, 148.8 (d), 136.6,
3
1
1
1
1
36.4, 133.0, 132.7, 132.4, 131.9, 131.8 (d), 130.7 (d),
29.7, 129.6, 129.1, 128.6, 128.5, 128.2, 127.9 (d), 127.4,
27.3, 126.9, 126.3 (d), 125.7, 125.6, 125.3, 124.4, 123.9,
16.2, 115.7, 52.8, 52.7, 35.5, 34.4; P NMR (203 MHz,
) d 144.3.
0003/01 (OFES contract No C02.0027) are also thanked
for financial support.
31
CDCl
3
References and notes
4
.7. [4,8-Bis-(2-methyl-allyl)-5,7-dioxa-6-phospha-di-
benzo[a,c]cyclohepten-6-yl]-bis-(S)-(1-naphthalen-2-yl-
1
. (a) Rossiter, B. E.; Swingle, N. M. Chem. Rev. 1992, 92,
71; (b) Alexakis, A. In Transition Metal Catalysed
7
ethyl)-amine, L6
Reactions; Murahashi, S.-I., Davies, S. G., Eds.; IUPAC
Blackwell Science: Oxford, 1999; p 303; (c) Tomioka, K.;
Nagaoka, Y. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer:
New York, 2000; p 1105; (d) Sibi, M. P.; Manyem, S.
Tetrahedron 2000, 56, 8033–8061; (e) Krause, N.; Hoff-
mann-R o€ der, A. Synthesis 2001, 171–196; (f) Alexakis,
A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221–
3236.
20
Yield 53%; colorless oil; ½aŠ ¼ À249:1 (c 1.06, CHCl
3
);
D
1
H NMR (500 MHz, CDCl ), d (ppm): 7.71 (d, 2H,
3
J ¼ 7:7 Hz), 7.52–7.17 (m, 18H), 4.90 (s, 1H), 4.86 (s,
2
H), 4.82 (s, 1H), 4.68 (s, 1H), 4.35 (s, 1H), 4.02 (d, 1H,
J ¼ 14:5 Hz), 3.49 (d, 1H, J ¼ 14:7 Hz), 3.16 (d of AB
system, 1H, J ¼ 16:7 Hz), 3.12 (d of AB system, 1H,
13
J ¼ 17:4Hz), 1.89–1.82 (m, 9H), 1.44(s, 3H);
C NMR
2
. (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346–353; (b)
Escher, I. H.; Pfaltz, A. Tetrahedron 2000, 56, 2879–2888;
(
125 MHz, CDCl
3
), d 149.9, 149.8, 149.0 (d), 144.7,
44.2, 132.9, 132.4, 132.1 (d), 131.9 (d), 131.4, 130.7,
1
1
1
5
(
1
c) Hu, X.; Chen, H.; Zhang, X. Angew. Chem., Int. Ed.
999, 38, 3518–3521; (d) Yan, M.; Zhou, Z.-Y.; Chan, A. S.
30.6, 130.6, 130.2, 130.1, 129.0, 128.6, 128.5, 128.2,
27.3 (d), 126.2, 125.5, 124.2, 123.6, 111.9, 111.6, 52.6,
C. Chem. Commun. 2000, 115–116; (e) Borner, C.; Dennis,
M. R.; Sinn, E.; Woodward, S. Eur. J. Org. Chem. 2001,
2435–2446.
31
2.5, 50.7, 39.4, 37.9, 22.9, 22.8, 22.6; P NMR
(
203 MHz, CDCl ) d 144.0.
3

A. Alexakis et al. / Tetrahedron: Asymmetry 15 (2004) 2199–2203
2203
3
4
5
. Alexakis, A.; Vastra, J.; Mangeney, P. Tetrahedron Lett.
1
Prian, F.; Rosset, S.; Ditrich, K. Tetrahedron Lett. 2004, 45,
1449–1451.
6. Alexakis, A.; Polet, D.; Rosset, S.; March, S. J. Org. Chem.
2004, in press.
7. Alexakis, A.; Benhaim, C.; Rosset, S.; Humam, M. J. Am.
Chem. Soc. 2002, 124, 5262–5263.
997, 38, 7745–7748.
. Alexakis, A.; Rosset, S.; Allamand, J.; March, S.; Guillen,
F.; Benhaim, C. Synlett 2001, 1375–1378.
. We have recently described a new practical synthesis of C2-
symmetrical secondary amines in: Alexakis, A.; Gille, S.;