Extending the concept of mixtures of chiral monodentate P-ligands in asymmetric Rh-catalyzed olefin-hydrogenation: Use of oxazaphospholidines

Article abstract of DOI:10.3987/COM-05-S(T)74

The previously described combinatorial concept of using mixtures of monodentate BINOL-derived phosphites, phosphonites or phosphoramidites as superior ligand systems in Rh-catalyzed asymmetric olefin-hydrogenation has been extended to include chiral oxaza

Full text of DOI:10.3987/COM-05-S(T)74

HETEROCYCLES, Vol. 67, No. 2, 2006
567
HETEROCYCLES, Vol. 67, No. 2, 2006, pp. 567 - 574. © The Japan Institute of Heterocyclic Chemistry
Received, 18th August, 2005, Accepted, 10th November, 2005, Published online, 11th November, 2005. COM-05-S(T)74
EXTENDING THE CONCEPT OF MIXTURES OF CHIRAL
MONODENTATE P-LIGANDS IN ASYMMETRIC Rh-CATALYZED
OLEFIN-HYDROGENATION: USE OF OXAZAPHOSPHOLIDINES
Manfred T. Reetz* and Marek Surowiec
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1,
45470 Mülheim/Ruhr, Germany, e-mail reetz@mpi-muelheim.mpg.de
Dedicated to Professor B.M. Trost on the occasion of his 65th birthday.
Abstract – The previously described combinatorial concept of using mixtures of
monodentate BINOL-derived phosphites, phosphonites or phosphoramidites as
superior ligand systems in Rh-catalyzed asymmetric olefin-hydrogenation has
been extended to include chiral oxazaphospholidines. Specifically, the latter were
prepared from ephedrine and pseudo-ephedrine according to literature procedures.
Mixtures of these P-ligands among themselves or in combination with a
BINOL-derived phosphonite lead to enhanced enantioselectivity in the
Rh-catalyzed hydrogenation of itaconic acid dimethyl ester (ee up to 89%).
In 2000 three groups reported that certain chiral monodentate P-ligands are well suited in asymmetric
Rh-catalyzed olefin-hydrogenation (ee >90%), namely BINOL-derived phosphites (1),1 phosphonites (2)2
and phosphoramidites (3).3 This came as a surprise, because it had been accepted for decades that
chelating bidentate diphosphines are necessary for obtaining high enantioselectivity, presumably due to
restricted rotational freedom around the Rh-P bonds.4 A detailed mechanistic study focusing on
phosphites (1) was published recently.5 On the basis of kinetics, non-linear effects, NMR spectral data
and DFT calculations it was shown that in the transition state of the reaction two monodentate P-ligands
are bonded to the metal.

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O
O
O
O
O
P
R
P OR
P NR2
O
1
2
3
1, 2, 3, 5, 6
Parallel to synthetic1, 2, 6 and mechanistic efforts regarding ligands (1 - 3),
we proposed in
5
2002/2003 a new approach to combinatorial asymmetric transition metal catalysis, namely the use of
mixtures of chiral monodentate ligands.7 Such a process leads to a mixture of three catalysts, the two
traditional complexes MLaLa and MLbLb (termed homo-combinations) and a new complex MLaLb (termed
hetero-combination) which can be expected to be in equilibrium with one another:
MLaLb
MLaLa
MLbLb
+
homo-combinations
hetero-combination
The distribution between the three species is not statistical. Rather, it is dictated by thermodynamics,
which means that variation of the La/Lb ratio will influence the relative population of the three catalysts or
pre-catalysts. If the hetero-combination dominates rate-wise and if it is more enantioselective than the
homo-combinations, then enhanced enantioselectivity can be expected.
Although the concept may not appeal to those who strive for well-defined single catalysts, the potential
advantage of the concept of using mixtures of monodentate ligands relates to the fact that high catalyst
diversity is generated without the need to prepare new ligands. In other words, once a set of ligands
(library) has been placed on the shelf by commercial acquisition or synthesis, mixing them leads to high
numbers of new catalysts. Since rational predictions based on theoretical analyses are not possible
presently, an empirical approach is necessary. In our original study we used rather small libraries of
ligands (1) and (2) (less than a dozen) in asymmetric olefin-hydrogenation, yet we were able to find
numerous hetero-combinations as hits which exhibit dramatically enhanced enantioselectivity relative to
7
the respective homo-combinations. Following our study, Feringa, de Vries and co-workers reported that
mixtures of phosphoramidites (3) also lead to enhanced enantioselectivity.8
We have recently extended the concept of mixtures of monodentate ligands to include the control of
regioselectivity 9 and diastereoselectivity. 10 In the present study we show that enhancing
enantioselectivity is not restricted to the use of mixtures of BINOL-derived P-ligands. Specifically,
ephedrine- and pseudo-ephedrine-derived oxazaphospholidines, first prepared by Bernard and Burgada11
and used by Alexakis12 as ligands in Cu-mediated conjugate addition reactions, result in substantial

HETEROCYCLES, Vol. 67, No. 2, 2006
569
effects when used in combination with the BINOL-derived phosphonite (2) (R = C(CH3)3). The
oxazaphospholidines themselves as homo-combinations are not well suited as ligands in Rh-catalyzed
hydrogenation.
Following general literature methods,11, 12 several ligands were first prepared from ephedrine (4) and
pseudo-ephedrine (7):
OR
P
NEt2
P
HO
Ph
NHMe
Me
P(NEt2)3
ROH
O
NMe
O
NMe
90 °C / 6 h
toluene
60 °C / 4 h
toluene
Ph
Me
Ph
Me
4
5
6 a R = 2-naphthyl (de = 94%)
b R = t-butyl (de = 92%)
c R = 2,6-diiso-
propylphenyl (de = 96%)
OR
P
NEt2
P
HO
Ph
NHMe
Me
P(NEt2)3
ROH
O
NMe
O
NMe
90 °C / 36 h
toluene
60 °C / 4 h
toluene
Ph
Me
Ph
Me
7
8
9 a R = methyl (de = 88%)
b R = t-butyl (de = 94%)
c R = 2,6-diiso-
propylphenyl (de = 82%)
Upon treating 4 and 7 with P(NEt2)3 as shown, compound (5) was obtained as a single diastereomer and 8
was formed as a mixture of diastereomers (about 4:1). Since 5 and 8 are somewhat sensitive and require
careful handling, purification was not attempted. Rather, the crude forms were subjected to alcoholysis by
reaction with ROH in toluene for four hours. Under these conditions the thermodynamically more stable
oxazaphospholidines were formed with the configuration at phosphorus as shown in 6 and 9, respectively.
In order to obtain as diastereomerically pure as possible ligands for Rh-catalyzed olefin-hydrogenation,
chromatography (Al2O3/pentane) was performed resulting in nearly pure ligands (diastereomeric excess
(de) shown above).
Heterocycles (6) and (9) were then used as ligands in the Rh-catalyzed hydrogenation of itaconic acid
dimethyl ester (10). In doing so, the standard method1, 2, 3 of preparing the pre-catalyst was applied by
treating Rh(cod)2BF4 with two equivalents of a monodentate ligand (6) and (9), respectively, in
dichloromethane. This led to the formation of the pre-catalysts Rh(6)2(cod)BF4 and Rh(9)2(cod)BF4.

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CO2CH3
CO2CH3
10
CO2CH3
CO2CH3
11
Not surprisingly, these catalysts resulted in poor enantioselectivity, the ee-value not exceeding 43%
(Table 1, Entries 1-6), which does not even match up to the poor performance of the BINOL-derived
phosphonite (2) (R = C(CH3)3) having ee = 56% (Table 1, Entry 7). The combinatorial search was then
initiated by first using mixtures of 6a-c, of 9a-c and of 6a-c/9a-c (Table 1, Entries 8-22). The highest
enantioselectivity was reached with the hetero-combination 6b/9c showing ee = 59% (S) (Table 1, Entry
19). The individual components (6b) and (9c) in pure form are less selective (ee = 30% (S) and ee = 40%
(R), respectively) (Table 1, Entries 2 and 6). Thus, although the two homo-combinations induce opposite
enantioselectivity, their combination leads to clearly enhanced (S)-selectivity. Since in a mixture, all three
catalysts are present, these results are remarkable from a theoretical point of view. It strongly suggests
that a catalyst system composed of only 6b/9c, if ligand exchange were not to occur, would show
inherently high enantioselectivity, possibly higher than 90%. Theoretically, this might be achievable by
designing the proper covalent spacer between 6b and 9c with formation of an appropriate bidentate ligand.
Interestingly, a second combination 6c/9c also induces enhanced enantioselectivity (ee = 58% (R); Table
1, Entry 22). In this case both respective homo-combinations are (R)-selective (Table 1, Entries 3 and 6).
Moreover, the two least enantioselective ligands as homo-combinations, namely 6a (ee = 9% (R); Table 1,
Entry 1) and 9a (ee = 0%; Table 1, Entry 4), function in concert with one another in a hetero-combination
astonishingly well with ee = 38% (R) (Table 1, Entry 14). Of course, these observations have no
immediate practical value. Nevertheless, they are significant for theoretical reasons. Moreover, other
substrates may behave differently leading to high ees.
Table 1. Rh-catalyzed hydrogenation of itaconate (10) (Rh : substrate = 1 : 200, Rh : total ligand = 1 : 2;
1.3 bar H2; 22 °C; 12 h; dichloromethane). Conversion >95% in all cases.
Entry
Ligand
ee (%)
Homo-combinations
Configuration of 11
1
2
3
4
6a/6a
6b/6b
6c/6c
9a/9a
9
30
43
0
R
S
R
-

HETEROCYCLES, Vol. 67, No. 2, 2006
571
5
6
7
9b/9b
9c/9c
15
40
S
R
R
(R)-2 (R = C(CH3)3)/ (R)-2 (R = C(CH3)3)
56
Hetero-combinations
8
9
6a/6b
12
8
S
6a/6c
R
R
R
R
R
R
R
-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
6b/6c
15
23
26
36
38
24
0
9a/9b
9a/9c
9b/9c
6a/9a
6a/9b
6a/9c
6b/9a
7
S
6b/9b
35
59
24
33
58
47
66
44
30
89
52
72
17
S
6b/9c
S
6c/9a
R
R
R
R
S
6c/9b
6c/9c
(R)-2 (R = C(CH3)3)/6b
(S)-2 (R = C(CH3)3)/6b
(R)-2 (R = C(CH3)3)/6c
(S)-2 (R = C(CH3)3)/6c
(R)-2 (R = C(CH3)3)/9b
(S)-2 (R = C(CH3)3)/9b
(R)-2 (R = C(CH3)3)/9c
(S)-2 (R = C(CH3)3)/9c
R
S
R
S
R
R
It might be argued that some of the hetero-combinations are not optimal because they happen to constitute
the mismatched case regarding the absolute configuration of the components. These cases were not
checked in the present study. However, in the case of hetero-combinations involving mixtures of
oxazaphospholidines and the phosphonite (2) (R = C(CH3)3), we did in fact study such a potential

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phenomenon by using the (R)- and (S)-form of the BINOL-derived P-ligand. Indeed, the
hetero-combination (R)-2 (R = C(CH3)3)/9b led to the highest enantioselectivity in the whole study (ee =
89% (R); Table 1, Entry 27), whereas the diastereomeric hetero-combination (S)-2 (R = C(CH3)3)/9b
turned out to be considerably less effective (ee = 52% (S); Table 1, Entry 28). This contrasts with the
performance of pure (R)-2 (R = C(CH3)3) leading to ee = 56% (R) (Table 1, Entry 7).
Finally, it was of interest to test the present oxazaphospholidines in combination with phosphites derived
from chiral diols other than BINOL. For this purpose we prepared the C2-symmetric phosphites ((R,R)-
and (S,S)-13) using the standard procedure as before. Yields of (R,R)- and (S,S)-13 were >90%.
O
HO
Ph
OH
Ph
1. P(NEt2)3
2.
P
O
O
OH
Ph
Ph
(R,R)-12
(R,R)-13
O
P
HO
Ph
OH
Ph
1. P(NEt2)3
2.
O
O
OH
Ph
Ph
(S,S)-12
(S,S)-13
Not surprisingly, (S,S)-13 (or the enantiomer) itself is not an effective ligand in the Rh-catalyzed
hydrogenation of 10, resulting in only 43% ee (R). In contrast, upon using ligand (13) in combination
with the pseudo-ephedrine-derived oxazaphospholidine (9a) which itself results in ee = 0%, dramatic
effects were observed. The hetero-combination 9a/(S,S)-13 constitutes the matched case leading to ee =
82% (R) which is superior to the diastereomeric hetero-combination 9a/(R,R)-13 (ee = 34% (S)).
In conclusion, we have demonstrated for the first time that the original concept of using mixtures of chiral
monodentate P-ligands in asymmetric Rh-catalyzed olefin-hydrogenation is not restricted to
BINOL-derived ligand systems. The actual enantioselectivities (up to 89% ee) are of little practical utility.
However, the effects observed are substantial, which suggests that chiral monodentate P-ligands of the

HETEROCYCLES, Vol. 67, No. 2, 2006
573
type (6) and (9) as well as numerous other sorts of chiral monodentate P-ligands need to studied in
mixtures not only when performing olefin-hydrogenation, but also when studying other types of transition
metal catalyzed asymmetric reactions. It must also be remembered that such a combinatorial approach not
only leads to a dramatic increase in catalyst diversity as shown in Table 1, variation of the La:Lb ratio is
yet another easily controlled parameter which may generate superior catalyst profiles. Finally, a given
"hit" in the hetero-combinatorial library may provide a lead on how to "design" an even better catalyst by
joining the two components La and Lb covalently by an appropriate spacer with formation of a bidentate
ligand. This option would lead back to the traditional concept of single catalysts having chelating
bidentate ligands.
ACKNOWLEDGEMENT
Support by the Fonds der Chemischen Industrie is gratefully acknowledged. M.S. thanks the Alexander
von Humboldt Foundation for a fellowship.
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