Design and synthesis of new bidentate phosphoramidite ligands for enantioselective copper-catalyzed conjugate addition of diethylzinc to enones

Article abstract of DOI:10.1016/j.tetasy.2006.10.029

Several thioaryl- and phosphino-phosphoramidite ligands have been synthesized from commercially available β-aminoalcohols. This new family of bidentate ligands are highly active in the enantioselective copper-catalyzed conjugate addition of diethylzinc to

Full text of DOI:10.1016/j.tetasy.2006.10.029

Tetrahedron: Asymmetry 17 (2006) 2726–2729
Design and synthesis of new bidentate phosphoramidite ligands
for enantioselective copper-catalyzed conjugate addition of
diethylzinc to enones
*
*
´
´
Fabien Boeda, Diane Rix, Herve Clavier, Christophe Crevisy and Marc Mauduit
`
`
´
UMR CNRS 6226 ‘Sciences Chimiques de Rennes’, Equipe Synthese Organique et Systemes Organises, Ecole Nationale Superieure
´
de Chimie de Rennes, Av. du Ge´ne´ral Leclerc, 35700 Rennes, France
Received 2 October 2006; accepted 20 October 2006
Abstract—Several thioaryl- and phosphino-phosphoramidite ligands have been synthesized from commercially available b-aminoalco-
hols. This new family of bidentate ligands are highly active in the enantioselective copper-catalyzed conjugate addition of diethylzinc
to both cyclic and acyclic enones showing moderate to good enantiomeric excesses of up to 81%.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Me
R'
O
O
O
O
The 1,4-conjugate addition of nucleophilic reagents to a,b-
unsaturated compounds is one of the most powerful meth-
ods for the formation of carbon–carbon bonds in organic
synthesis.1 Most efforts have been realized through the
development of copper2 and rhodium3 asymmetric conju-
gate addition of various alkylmetal (organozinc reagents,4
organoaluminium reagents5 and Grignard reagents)6 and
arylboronic acids7 to cyclic and acyclic unsaturated carbo-
nyls. Phosphoramidites have proved to be particularly effi-
cient in a wide range of catalyzed reactions.8 Although
monodentate phosphoramidites are commonly used in
Cu-catalyzed asymmetric conjugate addition of diorgano-
zinc reagents,9 only one example of bidentate phospho-
ramidites10 has been reported for that reaction.10d
P
S
N
P N
R''
R'''
*
*
Ph2P
1
2
Figure 1. Easily available thioaryl- or phosphine-phosphoramidite 1 and
2.
2. Results and discussion
Various phosphoramidite ligands, bearing a BINOL moi-
ety along with various amine moieties, were synthesized
to study the influence of steric hindrance and rigidity to-
wards selectivity. Ligands 1a–f were synthesized following
the simple procedure described in Scheme 1. Mesylates
3a–c11 were treated with sodium thiocresolate to give thio-
ethers 4a–c. Then, reduction of the Boc group with LiAlH4
gave methyl amines 5a–c. Alternatively, 4b was deprotected
under classical conditions to afford amine 5d, which was
then converted under reductive amination conditions to 5d.
Herein, we report the design and the synthesis of new
bidentate phosphoramidite ligands 1 and 2 derived from
commercially available b-aminoalcohols (Fig. 1). These
ligands have been evaluated in the enantioselective
copper-catalyzed conjugate addition of diethylzinc to both
cyclic and acyclic enones.
*
Corresponding authors. Tel.: +33 2 23 23 80 74; fax: +33 2 23 23 81 08
(C.C.); tel.: +33 2 23 23 81 12; fax: +33 2 23 23 81 08 (M.M.); e-mail
Ligands 1a–f were obtained from amines 5a–d and BINOL
following a classical procedure:12 PCl3 was reacted with
amines 5a–d in the presence of Et3N at 75 °C. Then, at
addresses:
ensc-rennes.fr
christophe.crevisy@ensc-rennes.fr;
marc.mauduit@
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.10.029

F. Boeda et al. / Tetrahedron: Asymmetry 17 (2006) 2726–2729
2727
NHBoc
NHBoc
OMs
SNa
SNa
R
R
NH STol
R
LiAlH4
THF
MsCl / Et3N
CH2Cl2
72%
OH
THF
BocHN
OMs
BocHN
STol
THF
60%
8
9
3a R = H
4a R = H
5a R = H
89%
85%
72%
62%
70%
60%
3b R = CH2Ph
3c R = tBu
4b R = CH2Ph
4c R = tBu
5b R = CH Ph
5c R = tBu2
NHBoc
S
HN
LiAlH4
THF
S
PhH2C
1. TFA, CH2Cl2
PhH2C
66%
BocHN
STol
PhH2C NH STol
11
10
2. PhCHO
NaBH(OAc)3
CH2Cl2
83%
4b
5d
1) PCl3 / Et3N / toluene
O
O
R'
O
O
P
S
N
P
S
N
2) (R)-BINOL / Et3N
R
1) PCl3 / Et3N / toluene
toluene / THF
5a-d
O
O
32%
2) (R)- or (S)-BINOL / Et3N
1g
toluène / THF
(R) or (S)-BINOL
1a (S)-BINOL, R = CH2Ph, R' = Me
1b (R)-BINOL, R = CH2Ph, R' = Me
1c (R)-BINOL, R = H, R' = Me
1d (R)-BINOL, R = tBu, R' = Me
1e (S)-BINOL, R = tBu, R' = Me
1f (S)-BINOL, R = R' = CH2Ph
51%
Scheme 3. Synthesis of ligand 1g.
62%
49%
49%
35%
46%
Table 1. Optimization of the reaction conditions with ligand 1a
O
O
Scheme 1. Synthesis of ligands 1a–f.
Et2Zn(1.5 equiv)
Et
2 mol% 1a, 2 mol% "Cu"
13
12
or
PhCH2
PhCH2
PhCH2
BocHN
Ph2PK
or
LiAlH4
THF
Solvent, T °C
O
Et
O
THF
69%
BocHN
OMs
PPh2
NH PPh2
61%
15
Solvent Temp Time Conv.a eeb
6
7
3b
14
Entry Enone Cu
complex
(°C)
(h)
(%)
(%)
Me
1) PCl3 / Et3N / toluene
O
O
1
2
3
4
5
6
7
8
12
12
12
12
12
14
14
14
Cu(OTf)2 Et2O
rt
12
3
3
6
3
8
3
3
>99
>99
>99
84
90
69
56 (S)
54 (S)
72 (S)
81 (S)
57 (S)
32 (R)
57 (R)
63 (R)
P
N
2) (S)-BINOL / Et3N
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
Et2O
rt
toluene / THF
Et2O
0
Ph2P
Et2O
Toluene
À30
44%
0
2
Toluene À30
Toluene
Et2O
0
0
90
93
Scheme 2. Synthesis of ligand 2.
a Determined by GC analysis.
b Determined by chiral GC analysis (Lipodex E).
À78 °C, a solution of BINOL and Et3N was added. Phos-
phoramidites were isolated in moderate yields after chro-
matography. Ligand 2 was obtained from mesylate 3b
following a similar procedure, except that Ph2PK was used
instead of sodium thiocresolate (Scheme 2). Ligand 1g was
obtained from protected (1R,2S)-1-amino-2-indanol 8 fol-
lowing a similar route (Scheme 3). Both phosphoramidites
were isolated in moderate yields after chromatography.
catalyst and 2 mol% of 1a, addition of diethylzinc to 2-
cyclohexenone 12 in diethylether at room temperature
yielded (R)-adduct 13 in complete conversion after 12 h
and 56% ee (entry 1).
Replacement of the precatalyst by a more soluble copper
We then evaluated their potential in the enantioselective
copper-conjugate addition of diethylzinc on 2-cyclohexe-
none 12 and 5-methyl-3-hexen-2-one 14 (Table 1). We be-
gan the study with the thiocresol-phophoramidite ligand
1a derived from (S)-phenylalaninol and (S)-BINOL. When
we used 2 mol% of copper(II) triflate (Cu(OTf)2) as the pre-
complex
such
as
copper(I)
thiophencarboxylate
(CuTC)9b,13 considerably accelerated the rate of the addi-
tion (3 h instead of 12 h) and increased the selectivity to
72% ee (entry 2). The choice of the solvent and the temper-
ature appeared to be important (entries 2–5). The selectiv-
ity proved to be dependant on the solvent and the

2728
F. Boeda et al. / Tetrahedron: Asymmetry 17 (2006) 2726–2729
substrate. For example, the best selectivity (81% ee) was
observed at À30 °C with 2-cyclohexenone (entry 4), while
in toluene the best result was obtained at 0 °C with enone
14. In the furthest studies, the reactions were carried out
at 0 °C, as the reaction was found to be sometimes very
slow at À30 °C in the presence of some substrates (e.g.,
12% conversion after 6 h with dimethylcyclohexenone,
Table 3, entry 1). The best results were obtained in Et2O
as the solvent (see for instance entries 3 and 5).
substitution of the N-methyl group in ligand 1a by a benzyl
group (ligand 1f, entry 6) did not allow to increase the
selectivity (66% ee), but led to a dramatic loss of activity
(only 54% of conversion after 4 h). In order to reduce the
flexibility of the chiral chelating side chain at the amine
moiety, we introduced the indane framework (ligand 1g).
Whereas ligands 1a and 1g were similar in activity, the
selectivity observed with 1g was much lower, reaching only
47% ee (entry 7). This had been confirmed by the use of
ligand 16 possessing a thiomethylether aryl group as chelat-
ing side chain. No selectivity was observed in this case (en-
try 8). Finally, ligand 2, to which the initial thioaryl
chelating group has been replaced by a diphenylphosphine
function, was evaluated. In this case, the activity remained
similar but the selectivity decreased to 53% ee (entry 9).
Concerning the addition of diethylzinc to the acyclic enone
14, a rapid screening of the ligands showed that 1a pro-
vided the best stereoselectivity (63% ee, entry 10) while
the diphosphine analogue 2 yielded poor results both in
activity and selectivity (entry 12).
Having identified these optimal reaction conditions, we
screened various chiral ligands to determine the most effi-
cient ones (Table 2). Firstly, because this bidentate ligand
possessed two chiral moieties,2a we evaluated ligand 1b de-
rived from (R)-BINOL and (S)-phenylalaninol. 56% enan-
tiomeric excess was obtained for the addition of diethylzinc
to 2-cyclohexenone (entry 2) instead of 72% obtained with
1a (entry 1). This clearly shows the mismatched effect
occurring in ligand 1b. Secondly, the absence of a stereo-
genic centre on the amine moiety of the phosphoramidite
ligand led to a slight decrease in selectivity (65% ee, entry
3). Moreover, when a more bulky group such as a tert-but-
yl was introduced (1e, entry 5), lower activity (72% of con-
version) and selectivity (56% ee) were observed. The
Having established the best ligand for the conjugate addi-
tion, we then evaluated the activity of ligand 1c towards
other cyclic enones (Table 3). In the case of more hindered
substrates, such as 4,4-dimethylcyclohexenone, a moderate
conversion was obtained after 6 h at 0 °C with 78% ee (en-
try 1). Addition of Et2Zn to 2-cycloheptenone (entry 2) was
achieved over 6 h with 64% ee. We next screened several
Table 2. Enantioselective copper-catalyzed conjugate addition of diethyl-
zinc to cyclic and acyclic enones with ligand 1a
O
O
Table 3. Enantioselective copper-catalyzed conjugate addition of diethyl-
zinc to cyclic and acyclic enones with ligand 1a
Et Zn
(1.5 equiv)
2
Et
2 mol% ligand, 2 mol% CuTC
Entry Substrate
Product
Time Conv.a eeb
12
13
or
(h)
(%)
(%)
or
Et2O, 0 °C
O
O
O
Et
O
6
6c
60
12
78
80
1
Et
14
15
O
Yielda (%)
ee (%)b
O
Entry
Enone
Ligand
Time (h)
2
6
1
1
96
>99
96
64
17
52
63
16
6
1
2
3
4
5
6
7
8
9
12
12
12
12
12
12
12
12
12
14
14
14
1a
1b
1c
1d
1e
1f
1g
16
2
3
4
3
2.5
6
4
3
3
3
>99
96
93
>99
72
54
>99
>99
97
93
80
72 (S)
56 (R)
65 (R)
30 (R)
56 (S)
66 (S)
47 (R)
0
53 (S)
63 (R)
33 (S)
5 (S)
Et
O
O
Et
3
4
5
6
7
Ph
Ph
O
Et
O
C5H11
C5H11
10
11
12c
1a
1c
2
3
5
4
O
Et
O
66
3.5
93
a Determined by GC analysis.
b Determined by chiral GC analysis (Lipodex E).
c Reaction performed in toluene.
NO2
Et
NO2
6
4
82
O
O
Et
P
S
N
NO2
>99
Ph
NO2
Ph
a Determined by GC analysis.
b Determined by chiral GC analysis (Lipodex E).
c Reaction performed at À30 °C.
16

F. Boeda et al. / Tetrahedron: Asymmetry 17 (2006) 2726–2729
2729
Clavier, H.; Coutable, L.; Guillemin, J. C.; Mauduit, M.
Tetrahedron: Asymmetry 2005, 16, 921–924.
other Michael acceptors with acyclic enones and nitroalk-
enes.14 These substrates, which are known to be problem-
atic, were tested under identical conditions at 0 °C.
Whereas the high reactivity of the catalytic system was
found to be good for all substrates, we have been disap-
pointed in the moderate stereoselectivity of the addition.
63% ee was observed in the best case with acyclic enones
(entry 5). Moreover, lower enantioselectivities were obs-
erved for the nitroalkene family, with which no value over
16% ee was obtained (entries 6 and 7). These last results
clearly show the scope of use of this bidentate phosphor-
amidite family in the copper-catalyzed conjugate addition.
´
5. For examples, see: (a) Diegez, S. M.; Deeremberg, O.; Claver,
C.; Van Leeuwen, P. W. N. M.; Kramer, P. Tetrahedron:
Asymmetry 2000, 11, 3161–3166; (b) Fraser, P. K.; Wood-
ward, S. Chem. Eur. J. 2003, 9, 776–783; (c) D’Augustin, M.;
Palais, L.; Alexakis, A. Angew. Chem., Int. Ed. 2005, 44,
1376–1378.
6. For examples, see: (a) Lopez, F.; Harutyunyan, S. R.;
Meetsma, A.; Minaard, A. J.; Feringa, B. L. Angew. Chem.,
Int. Ed. 2005, 44, 2752–2756; (b) Lee, K.-S.; Brown, M. K.;
Hird, A. W.; Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128,
7182–7184; (c) Martin, D.; Kehrli, S.; D’Augustin, M.;
Clavier, H.; Mauduit, M.; Alexakis, A. J. Am. Chem. Soc.
2006, 128, 8416–8417.
7. Takaya, Y.; Ogasawara, M.; Hayashi, T. J. Am. Chem. Soc.
1998, 120, 5579–5580.
3. Conclusion
8. See for instance: (a) Zhang, A.; Rajanbabu, T. V. J. Am.
Chem. Soc. 2006, 128, 5620–5621; (b) Bernsmann, H.; van der
Berg, M.; Hoen, R.; Minnaard, A. J.; Mehler, G.; Reetz, M.
T.; de Vries, J. G.; Feringa, B. L. J. Org. Chem. 2005, 70, 943–
951; (c) Graening, T.; Hartwig, J. F. J. Am. Chem. Soc. 2005,
127, 17192–17193; (d) Jensen, J. F.; Svendsen, B. Y.; la Cour,
T. V.; Pedersen, H. L.; Johannsen, M. J. Am. Chem. Soc.
2002, 124, 4558–4559, and references cited therein.
9. See for instance: (a) Duursma, A.; Minnaard, A. J.; Feringa,
B. L. J. Am. Chem. Soc. 2003, 125, 3700–3701; (b) Alexakis,
A.; Benhaim, C.; Rosset, S.; Humam, M. J. Am. Chem. Soc.
2002, 124, 5262–5263.
In conclusion, a new family of chiral bidentate phosphor-
amidite ligands was designed and synthesized easily in a
five-step procedure. High reactivities and good enantiose-
lectivities were obtained in the copper-conjugate addition
of diethylzinc to cyclic and acyclic enones using the thio-
aryl-phosphoramidite ligand 1c (up to 81% ee). A study
in the use of ligands 1c and 2 in asymmetric hydrogenation
is currently under progress and will be reported in due
course.
10. (a) Huang, J. D.; Hu, X. P.; Duan, Z. C.; Zeng, Q.-H.; Yu, S.
B.; Deng, J.; Wang, D. Y.; Zheng, Z. Org. Lett. 2006, 8,
4367–4370; (b) Zeng, Q. H.; Hu, X. P.; Duan, Z. C.; Liang, X.
M.; Zheng, Z. Tetrahedron: Asymmetry 2005, 16, 1233–1238;
(c) Hu, X. P.; Zheng, Z. Org. Lett. 2005, 7, 419–422; (d)
Mandoli, A.; Arnold, L. A.; de Vries, A. H. M.; Salvadori, P.;
Feringa, B. L. Tetrahedron: Asymmetry 2001, 12, 1929–1937;
(e) Francio, G.; Faraone, F.; Leitner, W. Angew. Chem., Int.
Ed. 2000, 39, 1428–1430.
Acknowledgements
This work was supported by the CNRS, the Region
`
Bretagne and the Ministere de la Recherche et de la
Technologie (Grant to F.B., D.R. and H.C.).
11. (a) Rosenquist, A.; Thorstensson, F.; Johansson, P. O.;
Kvarnstroem, I.; Ayesa, S.; Classon, B.; Rakos, L.; Samu-
elsson, B. PCT Int. Appl. WO073216, 2005; (b) Spaltenstein,
A.; Carpino, P. A.; Miyake, F.; Hopkins, P. B. J. Org. Chem.
1987, 52, 3759–3766; (c) Shirude, P. S.; Kumar, V. A.;
Ganesh, K. N. Tetrahedron 2004, 60, 9485–9491.
References
1. (a) Perlmutter, P. Conjugate Addition Reaction in Organic
Synthesis. In Tetrahedron Organic Chemistry Series, No. 9;
Pergamon Press: Oxford, 1992; (b) Yamamoto, Y. Methods
Org. Chem. 1995, 4, 2041–2057.
12. (a) De Vries, A. H. M.; Meetsma, A.; Ferringa, B. L. Angew.
Chem., Int. Ed. 1996, 35, 2374–2376; (b) Rimkus, A.; Sewald,
N. Org. Lett. 2003, 1, 79–80.
13. Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2001, 3, 91–
93.
14. (a) Duncan, A. P.; Leighton, J. L. Org. Lett. 2004, 6, 4117; (b)
Polet, D.; Alexakis, A. Tetrahedron Lett. 2005, 46, 1529; (c)
Mampreian, D. M.; Hoveyda, A. H. Org. Lett. 2004, 6, 2829.
2. (a) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221–
3236; (b) Krause, N.; Hoffman-Ro¨der, A. Synthesis 2001,
171–196; (c) Ferringa, B. L. Acc. Chem. Res. 2000, 33, 346–
353.
3. Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829–2844.
4. For recent examples, see: (a) Mizutani, H.; Degrado, S. J.;
Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 779; (b)
Krauss, I. J.; Leighton, J. L. Org. Lett. 2003, 5, 3201; (c)