Novel biphenol phosphoramidite ligands for the enantioselective copper-catalyzed conjugate addition of dialkyl zincs

Article abstract of DOI:10.1055/s-2001-16791

Phosphoramidite ligands, based on a chiral amine and atropoisomerically flexible biphenols, induce high enantioselectivities (ee's up to 98%) in the copper-catalyzed conjugate addition of dialkyl zinc reagents to a variety of Michael acceptors.

Full text of DOI:10.1055/s-2001-16791

LETTER
1375
Novel Biphenol Phosphoramidite Ligands for the Enantioselective Copper-
Catalyzed Conjugate Addition of Dialkyl zincs
Alexandre Alexakis, Stéphane Rosset, Janik Allamand, Sébastien March, Frédéric Guillen, Cyril Benhaim
Department of Organic Chemistry, University of Geneva, 30 quai Ernest Ansermet, Genève 4, Switzerland CH-1211
Fax (41 22) 328 73 96; E-mail: alexandre.alexakis@chiorg.unige.ch
Received 6 June 2001
matched
Ph
mismatched
Abstract: Phosphoramidite ligands, based on a chiral amine and at-
ropoisomerically flexible biphenols, induce high enantioselectivi-
ties (ee’s up to 98%) in the copper-catalyzed conjugate addition of
dialkyl zinc reagents to a variety of Michael acceptors.
Ph
Ph
Ph
O
Ph
Ph
P O
O
P O
O
O
Key words: asymmetric catalysis, copper, zinc, Michael additions,
phosphorus, atropoisomerism
O
O
O
Ph
O
Ph
Ph
Ph
L1
L1'
There have been many efforts in the field of asymmetric
conjugate addition through copper-catalysis.1 Among the
various ways to introduce the chiral information, we dem-
onstrated that trivalent phosphorous ligands were particu-
larly efficient.2 Later on, we introduced the use of
diorganozinc reagents as primary organometallics,3 and
since this first report, in 1993,3 this combination of a
chiral phosphorus ligand and dialkyl zincs has found
widespread use,4-8 although the reaction could be also pro-
moted by non-phosphorus ligands.9 Typically, cyclohex-
enone has served as representative Michael acceptor
(Scheme 1) with most often Cu(OTf)2 as copper source
(catalyst loading 0.5-2%), in toluene or CH2Cl2 as solvent.
Ph
Ph
O
O
O
P N
P N
Ph
O
Ph
L2
L2'
O
O
O
O
P O
P O
N
N
t-Bu
t-Bu
O
O
L3
L3'
Figure 1
O
O
0.5-2% CuOTf2
1-4% L*
the mismatched L3 ) for the same reaction. Both mis-
matched ligands afforded, however, the opposite enanti-
omer, showing that the binaphthol unit is imposing the
absolute stereochemistry of the conjugate adduct. Such
behavior of diastereomeric ligands is not unknown and
some examples have been reported.10
Et2Zn
+
Toluene
Et
*
–20 C°, 1.5 h
Scheme 1
Among the many ligands, which have been shown to be
efficient, the ones based on a modular concept are of
prime importance. Thus, a TADDOL or binaphthol moi-
ety forms a ring with the phosphorus atom, whereas a
chiral alcohol or amine is fixed on the exocyclic position
(Figure 1). This combination of two chiral moieties
around the phosphorus atom allows for the formation of
two diastereomeric ligands. The experimental results
show that only one diastereomeric combination affords
high enantioselectivities (the matched series) whereas the
other one (the mismatched series) does not.
In the course of our studies to find new ligands, we pre-
pared an equimolecular mixture of ligands L2 and L2 ,
starting from racemic binaphthol. When the reaction was
performed using this mixture (Scheme 2), ethyl cyclohex-
anone was obtained in quantitative yield and with an ee of
66%, corresponding to the enantiomer given by L2! Thus,
although each ligand should afford an opposite enanti-
omer, the matched ligand L2 is largely more efficient and
overcomes the mismatched L2 .11
O
O
2% CuOTf2
For example, ligand L1 affords 96% ee for the conjugate
addition of diethylzinc onto cyclohexenone (Scheme 1),
whereas the mismatched ligand L1 affords a racemic
product.4d,4e Similarly, ligand L2 affords 98% ee5 (75%
for the mismatched L2 ) and ligand L3 52% ee6 (9% for
4% L2+L2' (1:1)
Et2Zn
+
Toluene
Et
–20 C°, 1.5 h
ee 66%
Scheme 2
Synlett 2001, No. 9, 1375–1378 ISSN 0936-5214 © Thieme Stuttgart · New York

1376
A. Alexakis et al.
LETTER
Table Asymmetric conjugate addition to various Michael accep-
tors in the presence of ligands L2-L6
Knowing that the atropoisomerism of the binaphthol unit
is of prime importance, we may wonder whether the chiral
amine alone could induce an atropoisomerism on a flexi-
ble biphenol unit. Using this principle of induced atropoi-
somerism, remarkable results were obtained by Mikami
and Noyori on Ru-catalyzed hydrogenations,12 by Bolm
on Zr-catalyzed Baeyer-Villiger oxidation,13 and by Reetz
on Rh-catalyzed hydrogenations with biphenol-based
phosphites.14 Some results on the Cu-catalyzed conjugate
addition were also reported by Pàmies.8
Ph
Ph
O
?
O
P N
P N
O
O
Ph
L4
Scheme 3
Ph
L4'
Accordingly, ligand L4/L4 was easily synthesized, and
shows a single set of signals by 1H, 13C and 31P NMR. This
ligand was tested with a variety of Michael acceptors un-
der the standard conditions described previously (2%
Cu(OTf)2, 4% ligand, toluene, -20 °C, 2 h). The results are
listed in the Table, with all reactions giving quantitative
conversion. In addition, two modified ligands (L5 and L6,
Figure 2) were also tested. It was known that, in the bi-
naphthol-based ligands (L2 and L3 for example), an ortho
subsituent provides improved results.5b,6b,13,14 Ligand L5,
bearing a methyl group in the ortho position, was de-
signed for that reason. Ligand L6, in contrast, increases
the steric bulk at the exocyclic amino moiety. The results
with these two new ligands are also shown in the Table.
Ph
Ph
O
O
P N
P N
O
O
Ph
Ph
L5
L6
Figure 2
aAll reactions gave a quantitative conversion. bAccording to ref 5. cU-
sing the same experimental conditions as for the other ligands.
dMe2Zn was used instead of Et2Zn. eAccording to ref 15. fAccording
to ref 18. gAccording to ref 16. hAccording to ref 17.
As can be seen in the Table, ligand L4 gave very good
enantioselectivity with cyclohexenone (ee 82%, entry 1)
and cycloheptenone (ee 77%, entry 3), but does not attain
the excellent level of the parent matched ligand L2.5 They
afford, however, higher enantioselectivity than the mis-
matched ligand L2 . Clear improvements were gained
with ligands L5 and L6 (ee’s 89% and 92%, respectively).
Of prime importance is the behavior of dimethyl zinc (en-
tries 2 and 4), which affords ee’s (98% and 97%, respec-
tively) equal to the more sophisticated ligand L2 !
generally gave inferior results than L2. However, it
should be noticed that 3-nonen-2-one (entry 7) gave better
enantioselectivities with our new ligands, particularly L5
16
(ee 77% instead of 66% with L2). With nitro-olefins
and alkylidene malonates,17 better results were also ob-
tained with the new ligands. With nitrostyrene (entry 11),
ligand L5 gave an ee of 66% (instead of 48% for L218),
and with nitrocyclohexene (entry 12) ligand L4 gave
an ee of 75% (instead of 67% with L2). With ethyl-
With the other tested Michael acceptors, mixed results
were obtained. In the case of acyclic enones, or the
macrocyclic one (entries 5, 6, 8, 9, 10),15 L4, L5 and L6
Synlett 2001, No. 9, 1375–1378 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Novel Biphenol Phosphoramidite Ligands
1377
(j) Huttenloch, O.; Spieler, J.; Waldmann, H. Chem. Eur. J.
2001, 6, 671. (k) Degrado, S.J.; Mizutani, H.; Hoveyda, A.H.
J. Am. Chem. Soc. 2001, 123, 755.
idene malonate (entry 13) and pentylidene malonate (en-
try 14)17 all the new ligands afforded significantly higher
enantioselectivities, L5 being particularly efficient with
ethylidene malonate (ee 68% instead of 12% for L2) and
L6 with pentylidene malonate (ee 57% instead of 26% for
L2).
(8) (a) Pàmies, O.; Net, G.; Ruiz, A.; Claver, C. Tetrahedron:
Asymmetry 1999, 10, 2007. (b) Diéguez, Deerengerg, S.;
Pàmies, O.; Claver, C.; van Leeuwen, P.W.N.M., Kamer, P.
Tetrahedron: Asymmetry 2000, 11, 3161.
(9) (a) Wendisch, V.; Sewald, N Tetrahedron: Asymmetry 1997,
8, 1253. (b) Bennett, S.M.W.; Brown, S.M.; Muxworthy, J.P.;
Woodward, S. Tetrahedron Lett. 1999, 40, 1767.
(c) Chataigner, I.; Gennari, C.; Piarulli, U.; Ceccarelli, S.
Angew. Chem. Int. Ed. 2000, 39, 916.
(10) Zhang, S.Y.; Girard, C.; Kagan, B. Tetrahedron: Asymmetry
1995, 6, 2637. (b) for a review see : Muniz, K.; Bolm, C.
Chem. Eur. J. 2000, 6, 2309.
In summary, we have disclosed a series of simpler new
phosphorus ligands,19 based on the induced atropoisomer-
ism of the biphenol moiety. In many cases these new
ligands afforded as good and even better results than the
parent ligand based on chiral binaphthol. Theoretical stud-
ies are under way to get deeper insight on the atropoisom-
erism of biphenol systems under the influence of a
proximal chiral moiety.
(11) The addition of diethyl zinc to benzaldehyde has also been
described with a mixture of ligands : Bolm, C.; Muniz, K.
Hildebrand, J.P. Org. Lett. 1999, 1, 491.
(12) Mikami, K.; Korenaga, T.; Terada, M.; Ohkuma, T.; Pham, T.;
Noyori, R. Angew. Chem. Int. Ed. 1999, 38, 495. See also a
review : Mikami, K.; Terada, M.; Korenaga, T.; Matsumoto,
Y.; Matsukawa, S. Acc. Chem. Res. 2000, 33, 391.
(13) Bolm, C.; Beckmann, O. Chirality 2000, 12, 523.
(14) Reetz, M.T.; Neugebauer, T. Angew. Chem. Int. Ed. 1999, 38,
179.
(15) Alexakis A., Benhaïm C., Fournioux X., van den Heuvel A.,
J.-M. Levêque J.-M., March S., Rosset S. Synlett 1999, 1811.
(16) A. Alexakis, C. Benhaim Org. Lett. 2000, 2, 2579-2581.
(17) A. Alexakis, C. Benhaim Tetrahedron: Asymmetry 2001, 12,
1151.
Acknowledgement
The authors thank BASF for a generous gift of enantiopure amines,
the Swiss National Science Foundation No. 20-61891.00 and COST
action D12/0022/99 for financial support.
References and Notes
(1) (a) Rossiter, B.E.; Swingle, N.M. Chem. Rev. 1992, 92, 771.
(b) Alexakis, A. in Transition Metal Catalysed Reactions;
Murahashi, S.-I.; Davies, S.G. Ed.; IUPAC Blackwell
Science, Oxford 1999; p 303. (c) Tomioka, K.; Nagaoka, Y. in
Comprehensive Asymmetric Catalysis, ed. Jacobsen, E. N.;
Pfaltz, A.; Yamamoto, H; Springer, New York 2000; p 1105.
(d) Sibi, M. P.; Manyem, S.; Tetrahedron 2000, 56, 8033.
(e) Krause, N.; Hoffmann-Röder, A. Synthesis 2001, 171.
(2) Alexakis, A.; Mutti, S.; Normant, J.F. J. Am. Chem. Soc. 1991,
113, 6332.
(18) Sewald, N.; Wendisch, V. Tetrahedron: Asymmetry 1998, 9,
1341.
(19) Typical Procedure for the Synthesis of the Ligands : To a
stirred mixture of Et3N (5 mmol) and PCl3 (1 mmol) at 0 C, a
solution of amine (1 mmol) in THF (2 mL) was added and the
reaction mixture was stirred for 3 h at r.t. Biphenol (neat or in
a solution of THF, 1.5 mL) was slowly added to the reaction
mixture at 0 C and then the suspension was stirred at r.t.
overnight. The suspension was diluted in toluene (8 mL) and
filtrated on Alox neutral, the solution was concentrated and
purified by flash chromatography on Alox neutral using pure
toluene as eluent, to give the pure ligand wich is very quickly
eluted in toluene.
(3) Alexakis, A.; Frutos, J.; Mangeney P. Tetrahedron:
Asymmetry 1993, 4, 2427.
(4) (a) Alexakis, A.; Vastra, J.; Mangeney, P. Tetrahedron Lett.
1997, 38, 7745. (b) Alexakis, A.; Vastra, J.; Burton, J.;
Mangeney, P. Tetrahedron: Asymmetry 1997, 8, 3193.
(c) Alexakis, A.; Burton, J.; Vastra, J.; Mangeney, P.
Tetrahedron: Asymmetry 1997, 8, 3987. (d) Alexakis, A.;
Vastra, J.; Burton, J.; Benhaim, C.; Mangeney, P.;
L4: - [ ]D = -236 (c = 3.0 in toluene). 1H NMR : = 1.73 (d,
J = 7 Hz, 6H, CH3-benzyl), 4.58 (q, J = 7 Hz, 1H, benzyl),
4.60 (q, J = 7 Hz, 1H, benzyl), 7.10 7.38 (m, 16H, ArH),
7.45 7.49 (m, 2H, ArH). 13C NMR : = 22.2, 52.6, 52.7,
122.0, 122.5, 124.0, 125.3, 126.6, 127.7, 127.9, 128.2, 128.9,
129.0, 129.1, 129.8, 130.0, 131.2, 143.0, 151.0, 151.1, 151.9,
152.0. 31P NMR : = 147.0.
Tetrahedron Lett. 1998, 39, 7869. (e) Alexakis, A.; Burton, J.;
Vastra, J.; Benhaim, C.; Fournioux, X.; van den Heuvel, A.;
Levêque, J.-M.; Mazé, F.; Rosset, S. Eur. J. Org. Chem. 2000,
4011.
(5) a) Feringa, B. L.; Pineschi, M; Arnold, L. A; Imbos, R; de
Vires, A. H. M. Angew. Chem. Int. Ed. Engl. 1997, 36, 2620.
(b) Arnold, L.A.; Imbos, R.; Mandoli, A.; de Vries, A.H.M.;
Naasz, R.; Feringa, B.L. Tetrahedron 2000, 56, 2865.
(c) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346.
L5: - [ ]D = -221 (c = 2.2 in toluene). 1H NMR : = 1.71 (d,
J = 7 Hz, 6H, CH3-benzyl), 2.09 (s, 3H, CH3-Ar), 2.33 (s, 3H,
CH3-Ar), 2.35 (s, 3H, CH3-Ar), 2.47 (s, 3H, CH3-Ar), 4.58
4.78 (m, 2H, benzyl), 6.98 7.30 (m, 14H, ArH). 13C NMR :
= 16.3, 17.3, 20.8, 52.5, 109.6, 125.3, 126.5, 127.65, 127.8,
127.9, 128.1, 128.2, 129.0, 129.3, 130.2, 130.9, 131.0, 132.6,
133.3, 137.5, 143.5, 147.1, 147.9, 148.0. 31P NMR : = 142.4.
L6: - [ ]D = +231 (c = 3.5 in toluene). 1H NMR : = 0.83 (t,
J = 7.3 Hz, 6H, CH3-ethyl), 2.10 2.17 (m, 2H, CH2-ethyl),
2.24 2.32 (m, 2H, CH2-ethyl), 4.27 (t, J = 10.3 Hz, 1H,
benzyl), 4.28 (t, J = 10.3 Hz, 1H, benzyl), 7.00 7.07 (m,
10H, ArH), 7.19 7.32 (m, 4H, ArH), 7.36 7.42 (m, 2H,
ArH), 7.51 7.54 (m, 2H, ArH). 13C NMR : = 11.6, 28.3,
29.6, 59.7, 59.8, 121.7, 122.5, 123.7, 124.6, 126.2, 127.5,
128.3, 129.0, 129.1, 129.7, 129.9, 131.4, 141.0, 150.9, 151.8,
151.9. 31P NMR : = 144.4.
(6) (a) Knöbel, A. K. H; Escher I. H.; Pfaltz, A. Synlett 1997,
1429. (b) Escher I. H.; Pfaltz, A. Tetrahedron 2000, 56, 2879.
(7) (a) Zhang, F.-Y.; Chan, A.S.C. Tetrahedron: Asymmetry
1998, 9, 1179. (b) Mori, T.; Kosaka, K.; Nakagawa, Y.;
Nagaoka, Y. Tomioka, K. Tetrahedron: Asymmetry 1998, 9,
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2988. (d) Hu, X.; Chen, H.; Zhang, X Angew. Chem. Int. Ed.
1999, 38, 3518. (e) Reetz, M.T. Pure Appl. Chem. 1999, 71,
1503. (f) Arena, C.G.; Calabro, G.P.; Francio, G.; Faraone, F.
Tetrahedron: Asymmetry 2000, 11, 2387. (g) Delapierre, G.;
Constantieux, T.; Brunel, J.M.; Buono, G. Eur. J. Org. Chem.
2000, 2507. (h) Müller, P.; Nury, P.; Bernardinelli Helv.
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LETTER
(or 0 °C) and the reaction mixture was stirred at this
temperature for 3-15 h depending to the enone, then quenched
by the careful addition of 1M HCl (ca. 2 mL). Diethyl ether
(ca. 8 mL) was added and the organic phases were combined,
dried (MgSO4) and purified by filtration on silicagel.
(20) Typical Procedure for the Conjugate Addition : A 50 mL
Schlenk tube was charged with Cu(OTf)2 (3 mg, 0.0083
mmol), toluene (3 mL), and the appropriate ligand (0.0166
mmol) as a solution in toluene (0.5 mL). The resulting mixture
was stirred for 30 min at r.t. and then cooled with an external
bath at –40 C (0 °C for nitro-olefins and alkylidene
malonates), whereupon the dialkylzinc reagent (0.58 mmol)
was added. After 10 min the appropriate Michael acceptor
(0.415 mmol) was added dropwise to the mixture at –40 C
Article Identifier:
1437-2096,E;2001,0,09,1375,1378,ftx,en;G10901ST.pdf
Synlett 2001, No. 9, 1375–1378 ISSN 0936-5214 © Thieme Stuttgart · New York