Improved catalytic asymmetric carbon-carbon bond formation using combinations of chiral and achiral monodentate ligands

Article abstract of DOI:10.1016/j.tetasy.2005.05.006

Mixtures of chiral and achiral monodentate phosphoramidite ligands lead to improved enantioselectivity in the rhodium-catalyzed boronic acid addition.

Full text of DOI:10.1016/j.tetasy.2005.05.006

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1901–1904
Improved catalytic asymmetric carbon–carbon bond formation
using combinations of chiral and achiral monodentate ligands
Ate Duursma, Diego Pen˜a, Adriaan J. Minnaard* and Ben L. Feringa*
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute, University of Groningen, Nijenborgh 4,
9747 AG Groningen, The Netherlands
Received 6 April 2005; accepted 5 May 2005
Abstract—Mixtures of chiral and achiral monodentate phosphoramidite ligands lead to improved enantioselectivity in the rhodium-
catalyzed boronic acid addition.
ꢀ 2005 Published by Elsevier Ltd.
1. Introduction
Herein, we report the first case of improved enantio-
selectivity in asymmetric C–C bond formation by the
use of a combination of a chiral and an achiral monod-
entate ligand compared to catalysts based solely on the
chiral ligand.
The monodentate ligand combination approach is a new
concept in asymmetric catalysis, in which a catalyst,
based on a combination of two different monodentate
ligands (hetero-complex), leads to improved results
compared to catalysts based on only one of the two li-
gands (homo-complexes) (Scheme 1).1 The hetero-com-
plexes are formed in situ by mixing the metal
precursor with the ligands. This means that the overall
activity and selectivity of the reaction depends on the ra-
tio of the complexes and their corresponding activities
and selectivities.
2. Results and discussion
A set of six monodentate ligands, consisting of three
achiral ligands L1–3 with different electronic properties
and three chiral phosphoramidite ligands L4–6, was
used as a basis for the ligand combinations (Fig. 1).5
The monodentate ligand combination approach was ap-
plied in the rhodium-catalyzed asymmetric conjugate
addition of phenylboronic acid.6 We have shown that
in addition to BINAP as the most commonly used li-
gand, also monodentate phosphoramidites are also very
effective ligands in this type of C–C bond formation.7
Lx Lx Ly Ly Lx Ly
M + Lx + Ly
M
M
+
M
+
chiral (a)chiral
homo-complexes
hetero-complex
Scheme 1. The monodentate ligand combination approach.
p-Methylnitrostyrene 1 was chosen as a substrate (Table
1).3a The product of this reaction, containing a benz-
hydrylic stereocentre, is important from a synthetic
point of view, in particular due to the presence of this
structural unit in a number of pharmaceutical intermedi-
ates. Nevertheless, nitrostyrenes are challenging sub-
strates for this reaction and high ees have not yet been
reported. The reaction conditions, in which phenyl-
boronic acid is formed in situ from phenyl boroxine 2
and 1 equiv of water per boron, results in this case in
higher conversions than the commonly used Hayashi–
Miyaura conditions with phenylboronic acid and water
as a cosolvent.
The success of this concept has been shown for asym-
metric carbon–hydrogen2 as well as carbon–carbon
bond formation3 employing a combination of two chiral
monodentate ligands, such as phosphoramidites, phos-
phites and phosphonites. In addition, the combination
of chiral and achiral monodentate ligands has been
shown by Reetz and Mehler to lead in some cases to a
reversal of enantioselectivity.4
*
Corresponding authors. Tel.: +31 50 3634258; fax: +31 50
3634296; e-mail addresses: a.j.minnaard@rug.nl; b.l.feringa@rug.nl
0957-4166/$ - see front matter ꢀ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2005.05.006

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A. Duursma et al. / Tetrahedron: Asymmetry 16 (2005) 1901–1904
O
PPh3
P(OPh)3
P
N
O
L1
L2
L3
O
O
O
O
O
O
P
N
P
N
P
N
(R,R)-L6
(S,R,R)-L5
(S)-L4
Figure 1. Monodentate ligands used for the ligand combination approach.
Table 1. Rh-catalyzed asymmetric conjugate addition to p-methylnitrostyrene8
2% Rh(acac)(eth)2
2.5 % Lx + 2.5% Ly
NO2
NO2
+ (PhBO)3 + H2O
dioxane, 60oC, 3 h
1
2
3
Lx/Lx
Conv. (%)
ee (%)
Lx/Ly
Conv. (%)
ee (%)
L1/L1
L2/L2
L3/L3
L4/L4
L5/L5
L6/L6
8
83
100
11
4
0
0
L1/L5
L2/L4
L2/L5
L2/L6
L3/L4
L3/L5
12
97
73
78
94
83
5
0
0
0
23
28
—
0
7
0
À30
The use of triphenylphosphine L1 leads to catalysts with
a very low activity, in the homo- as well as the hetero-
combinations. The less basic triphenylphosphite L2 is
an efficient ligand for this reaction, but unfortunately
the hetero-combinations with chiral phosphoramidites
L4–6 resulted in racemic products. This indicates that
the homo-complex of L2 might be the most active cata-
lyst in the mixture. Achiral phosphoramidite L3 proved
to be the most suitable achiral ligand, resulting in com-
plete conversion to racemic 3 in the case of the homo-
combination. In contrast, the homo-combinations of
the relatively bulky chiral phosphoramidites L4–6 gave
rise to catalysts with a very low activity, a trend which
has been observed previously.3a The result of the hetero-
combination of L5 with L3 clearly demonstrates that the
hetero-complex is formed, since it leads to a drastic
improvement of conversion from 4% to 83%, a reversal
in absolute configuration and a slightly higher ee value
of À30% for product 3.
tioselective catalysts, although with a very low activity.
The hetero-combinations of L3 with L4–6 lead to cata-
lysts that possess both positive characteristics; they are
as active as the achiral catalyst based on L3 but at the
same time show enantioselectivities such as the ones
based on L4–6. For the hetero-combinations of L3 with
L4 and L5, a reversal of enantioselectivity is observed,
and in the case of the latter there is even an increase
in ee from 16% to 31%. The most striking results, how-
ever, were obtained with the combination of L3 with L6.
Whereas the homo-complex of L6 is inactive and the
homo-complex of L3 not enantioselective, the hetero-
complex of L3 with L6 is both an active and enantio-
selective catalyst.
Information about the relative amounts of the homo-
and hetero-complex formed when two different phos-
phoramidite ligands are added to the catalyst precursor
Rh(acac)(eth)2, was obtained by integration of their sig-
nals in the corresponding 31P NMR spectra. Whereas
This concept of using a small achiral ligand as an activa-
tor for a more bulky chiral ligand was subsequently
applied in the asymmetric conjugate addition of phenyl-
boroxine 2 to 2-cyclohexenone 4 (Table 2).
the homo-complexes appear as doublets (JRh–P
300 Hz), the hetero-complexes were observed as two
double doublets (JRh–P ꢀ 300 Hz, JP–P ꢀ 90 Hz) (Table 3).
ꢀ
These data demonstrate that the lack of enantioselectivity
obtained with mixtures of L2 and L4, L5 is not due to
the absence of a hetero-complex, but most likely due
to the fact that the homo-complex of L2 is a much more
active catalyst. This also shows that the most successful
As for p-methylnitrostyrene 1, the homo-combination of
the small achiral phosphoramidite L3 led to an active
catalyst for the addition to 4, whereas the homo-combi-
nations of the bulky phosphoramidites L4–6 gave enan-

A. Duursma et al. / Tetrahedron: Asymmetry 16 (2005) 1901–1904
Table 2. Rh-catalyzed asymmetric conjugate addition to 2-cyclohexenone8
1903
O
O
2% Rh(acac)(eth)2
2.5 % Lx + 2.5% Ly
+ (PhBO)3 + H2O
dioxane, 60oC, 3 h
2
5
4
Lx/Lx
Conv. (%)
ee (%)
Lx/Ly
Conv. (%)
ee (%)
L3/L3
L4/L4
L5/L5
L6/L6
100
22
18
0
0
27
16
—
L3/L4
L3/L5
L3/L6
100
79
À5
À31
22
98
Table 3. Relative amounts of homo- and hetero-complexes based on
31P NMR
dynamic library, see: (e) Monti, C.; Gennari, C.; Piarulli,
U. Tetrahedron Lett. 2004, 45, 6859–6862.
3. (a) Duursma, A.; Hoen, R.; Schuppan, J.; Hulst, R.;
Minnaard, A. J.; Feringa, B. L. Org. Lett. 2003, 5, 3111–
3113; (b) Duursma, A.; Boiteau, J. G.; Lefort, L.; Boogers,
J. A. F.; de Vries, A. H. M.; de Vries, J. G.; Minnaard, A.
J.; Feringa, B. L. J. Org. Chem. 2004, 69, 8045–8052.
4. Ref. 2b.
Lx/Ly
Rh(Lx)2
Rh(Lx)(Ly)
Rh(Ly)2
L2/L4
L2/L5
L3/L4
L3/L5
L3/L6
13
14
13
5
49
61
69
92
86
38
25
18
3
8
6
5. Phosphoramidite ligand L3 was prepared as follows: To a
solution of 1.74 g (10 mmol) of 1,2-phenylene phosphoro-
chloridite in 10 mL of anhydrous THF at 0 ꢁC was added a
solution of 711 mg (10 mmol) of pyrrolidine and 1.01 g
(10 mmol) of triethylamine in 5 mL of anhydrous THF.
The resulting white turbid mixture was stirred at 0 ꢁC for
1 h. The solvent was removed under reduced pressure and
the product purified by column chromatography (pentanes–
diethyl ether 10/1, Rf 0.9) to give 82 mg (0.4 mmol, 4%
combinations of ligands, L3 with L5 and L6, correspond
with a high proportion of the hetero-complex.9
3. Conclusion
1
yield) of L3 as a colourless oil. H NMR d: 6.93 (m, 4H),
It has been shown for the first time that a catalyst based
on a combination of a chiral and an achiral monoden-
tate ligand leads to a higher enantioselectivity compared
to the corresponding homo-complexes in asymmetric
C–C bond formation. Reversal of enantioselectivity,
improved enantioselectivity and maintenance of activity
were observed when a relatively small achiral phospho-
ramidite ligand was combined with a bulky chiral
phosphoramidite ligand. 31P NMR spectra showed that
the hetero-complexes are formed as the major species.
3.06 (m, 4H), 1.73 (m, 4H); 13C NMR d: 144.7 (d,
J = 8 Hz), 120.1 (s), 109.5 (s), 43.5 (d, J = 15 Hz), 24.5 (d,
J = 3 Hz); 31P NMR d: 141.5. HRMS calcd for
C10H12NO2P 209.060. Found 209.060. Phosphoramidite
ligands L4 and L5 have been reported before, see: Arnold,
L. A.; Imbos, R.; Mandoli, A.; De Vries, A. H. M.; Naasz,
R.; Feringa, B. L. Tetrahedron 2000, 56, 2865–2878, and
were prepared according to a recently reported procedure:
Boiteau, J. G.; Minnaard, A. J.; Feringa, B. L. J. Org.
Chem. 2003, 68, 9481–9484; Ligand L6 has been reported
before, see: Alexakis, A.; Rosset, S.; Allamand, J.;
March, S.; Guillen, F.; Benhaim, C. Synlett 2001, 1375–
1378.
Acknowledgements
6. (a) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics
1997, 16, 4229–4231; (b) Takaya, Y.; Ogasawara, M.;
Hayashi, T.; Saskai, M.; Miyaura, N. J. Am. Chem. Soc.
1998, 120, 5579–5580; (c) Hayashi, T.; Senda, T.; Takaya,
Y.; Ogasawara, M. J. Am. Chem. Soc. 1999, 121, 11591–
11592; (d) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003,
103, 2829–2844.
This project was funded by the National Research
School Combination Catalysis (NRSCC).
References
7. (a) Boiteau, J. G.; Imbos, R.; Minnaard, A. J.; Feringa, B.
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For an early example using mixtures of bidentate ligands
see: Kaptein, B.; Elsenberg, H.; Minnaard, A. J.; Brox-
terman, Q. B.; Hulshof, L. A.; Koek, J.; Vries, T. R.
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9709–9714; For an extension of this concept using a
8. General procedure: In a Schlenk tube 2.58 mg (0.01 mmol,
2 mol %) of Rh(acac)(eth)2 and two 0.012 mmol (2.5 mol %)
portions of ligand were dissolved in 1 mL of anhydrous
dioxane and stirred at room temperature for 15 min. Then,
0.5 mmol of the Michael acceptor, 0.67 mmol of phenyl-
boroxine and 10 lL of n-tridecane (internal standard for GC)
were added and the resulting mixture stirred for 2 min. An
initial sample was taken before the addition of 0.1 mL of
water after which the mixture was degassed and stirred for
3 h at 60 ꢁC. During the reaction, samples of 0.1 mL were
taken from the reaction mixture with a glass pipette and
added to 1 mL of a stirred mixture of diethyl ether–saturated

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A. Duursma et al. / Tetrahedron: Asymmetry 16 (2005) 1901–1904
aqueous NaHCO3 (1/1). After a few minutes, the organic
by GC on a Chiraldex A-TA column, 30 m · 0.25 mm ·
0.12 lm, 120 ꢁC isothermic, 58.0/60.1 min. For spectro-
scopic data of 3 and 5 see Ref. 7a.
layer was decanted, filtered over Na2SO4, and subjected to
GC and HPLC analysis. For 3: enantiomer separation by
HPLC on a Chiralpak OD column, heptanes–isopropanol
99/1, 210 nm, 12.7/14.3 min. For 5: Enantiomer separation
9. Imbalance in homo-complex ratios is due to errors in
weighing.