Amino acid based phosphoramidite ligands for the rhodium-catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1002/ejoc.200901044

Two sets of amino acid based phosphoramidite ligands with either a BINOL backbone (S_b-1a-e and R_b-1a) or a flexible biphenol backbone (2a-c and 2f) were synthesized and evaluated in the rhodium-catalyzed hydrogenation of different fu

Full text of DOI:10.1002/ejoc.200901044

FULL PAPER
DOI: 10.1002/ejoc.200901044
Amino Acid Based Phosphoramidite Ligands for the Rhodium-Catalyzed
Asymmetric Hydrogenation
Pierre-Alain R. Breuil[a] and Joost N. H. Reek*[a]
Keywords: Asymmetric catalysis / Hydrogenation / Homogeneous catalysis / Phosphoramidite / Rhodium
Two sets of amino acid based phosphoramidite ligands with
either a BINOL backbone (Sb-1a–e and Rb-1a) or a flexible
biphenol backbone (2a–c and 2f) were synthesized and
evaluated in the rhodium-catalyzed hydrogenation of dif-
ferent functionalized alkenes: dimethyl itaconate (3), methyl
2-acetamidoacrylate (4), methyl α-acetamidocinnamate (5)
and N-(3,4-dihydro-2-naphthalenyl)acetamide (6). The
amino acid fragment can be modified at three positions (R1–
R3) giving rise to modular ligands. Initial experiments vary-
ing the R1 position of the amino acid fragment, showed that
the valine-based phosphoramidite ligand Sb-1b forms the
most selective rhodium catalyst for three of the four sub-
strates of the current study. The modifications at the other
positions (R2 and R3) tweaked the ligand structure such that
enhanced selectivities were obtained; up to 97% ee is ob-
tained for the asymmetric hydrogenation of 4 with Sb-1e. For
ligands with two sources of chirality match/mismatch effects
are observed, the diastereoisomer Sb-1b giving higher selec-
tivity than the diastereoisomer Rb-1b for most of the sub-
strates. The set of phosphoramidite ligands having the flexi-
ble and cheap biphenol backbone is developed to study the
ability of the amino acid derivatives as the sole source of chi-
rality in the ligand to steer enantioselectivity in rhodium-
catalyzed hydrogenation. This study shows their capacity to
compete with their BINOL-based analogues and even to out-
class them depending on the substrate evaluated.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
finding the best catalyst is still based on trial-and-error and
sophisticated guesses, a combinatorial approach in which
chiral catalysts are prepared and screened in a parallel fash-
ion is a frequently applied strategy.[5] De Vries et al.[6] devel-
oped an instant library of phosphoramidite ligands in a
combinatorial approach, affording 96 ligands in one day by
varying the amine moiety. Among the amines commercially
available, the amino acids taken from the chiral pool are in
principle particularly attractive. They provide a versatile
and natural source of chiral building blocks with structural
diversity and are therefore especially suited for fine-tuning
of ligands. In addition, the functional groups can be utilized
for formation of supramolecular ligands[7] or for substrate
orientation via supramolecular interactions between sub-
strates and ligands.[8] Surprisingly, there has been no sys-
tematic investigation on the use of phosphoramidite ligands
derived from α-amino acids[9] and they have only been
scarcely used in catalysis.[10]
Herein, we report the straightforward synthesis of mono-
dentate phosphoramidite ligands derived from cheap and
readily available α-amino acid derivatives. A set of ligands
having a rigid enantiopure BINOL backbone (Sb-1 or Rb-
1) has been synthesized and their activity and selectivity
were evaluated in the rhodium-catalyzed hydrogenation of
functionalized alkenes. Thanks to the versatility of the
amino acid moieties we modified the R1, R2 and R3 posi-
tions (Figure 1) and studied their impact on the catalytic
outcome. In addition, we developed a set of ligands having
Introduction
The generally accepted dogma introduced in the 1970s
that bidentate ligands perform better than the monodentate
analogues in asymmetric transition-metal catalysis has been
overturned. Indeed the seminal reports of Reetz, Pringle,
Feringa and de Vries demonstrated that monodentate phos-
phite,[1a] phosphonite[1b] and phosphoramidite[1c] ligands
can be as active and selective as bidentate ligands in the
rhodium-catalyzed asymmetric hydrogenation reaction,
which is demonstrated for different substrates. The success-
ful applications of phosphoramidite ligands in various
asymmetric metal-catalyzed reactions[2] proved that they
form a new class of effective ligands. The so-called (S)-
MonoPhos[3] emerged as the archetypical phosphoramidite
ligand used in asymmetric catalysis. Despite the broad ap-
plicability, a single catalyst can address effectively the selec-
tive transformation of a limited number of substrates.[4]
Therefore, a time-consuming tweaking of the ligand struc-
ture by covalent modification is necessary to obtain accept-
able levels of enantioselectivities for a given substrate. As
[a] Van ’t Hoff Institute for Molecular Sciences, University of Am-
sterdam,
Nieuwe Achtergracht 166, 1018 WV Amsterdam, The Nether-
lands
Fax: +31-20-525-5604
E-mail: j.n.h.reek@uva.nl
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901044.
Eur. J. Org. Chem. 2009, 6225–6230
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6225

P.-A. R. Breuil, J. N. H. Reek
FULL PAPER
a tropos biphenol backbone. We studied the ability of the on 3,3Ј-di-tert-butyl-2,2Ј-dihydroxy-5,5Ј-dimethoxy-1,1Ј-bi-
amino acids to steer enantioselectivity in the rhodium-cata- phenyl (tropos backbone 2) gave up to 92% yield using
lyzed hydrogenation using such ligands. Depending on the route a.
substrate studied, those ligands proved their capacity to
compete with the corresponding more expensive BINOL-
based analogues.
It should be noted that the phosphoramidite ligands de-
rived from BINOL (Sb-1a–d and Rb-1b) are rather sensitive
to hydrolysis and should be handled with care, while those
having the biphenol backbone (2a–c and 2f) and the N-
methylated phosphoramidite Sb-1e are only moderately sen-
sitive. All new ligands were fully characterized (see Experi-
mental Section) and then applied in the rhodium-catalyzed
hydrogenation of different functionalized alkenes.
The ligands Sb-1a–e, Rb-1b, 2a–c and 2f were evaluated
in the rhodium-catalyzed asymmetric hydrogenation of sub-
strates that varied electronically and sterically: dimethyl
itaconate (3), methyl 2-acetamidoacrylate (4), methyl α-
acetamidocinnamate (5) and N-(3,4-dihydro-2-naph-
thalenyl)acetamide (6) (see Figure 3 and Scheme 2). The re-
actions were carried out in CH2Cl2 at room temperature
under H2 pressure of 10 bar in the presence of 1 mol-% cat-
alysts, which were prepared in situ from Rh(nbd)2BF4 and
2.2 equiv. of the respective chiral ligand. The catalysis re-
sults are summarized in Tables 1, 2, and 3.
Figure 1. General structure of the amino acid based phosphor-
amidite ligands.
Results and Discussion
The ligands were synthesized in a two-step fashion start-
ing from commercially available hydrochloride salts of ester
derived amino acids (see Figure 2, a–f). Two synthetic
Full conversions and good enantioselectivities were ob-
routes (Scheme 1, Routes a and b) were used for the synthe- tained (up to 89% ee) for the hydrogenation of the dimethyl
sis of the phosphoramidite ligands starting from BINOL. itaconate (3). Increasing the steric bulk around the ad-
Yields up to 92% were obtained using route a, whereas ditional chiral center (R1 = iBu and R1 = iPr) leads to an
route b gave up to 76% yield, in both cases after purifica- increase of the selectivity, from 80% ee for Sb-1a to 89% ee
tion. The synthesis of the phosphoramidite ligands based for Sb-1b (Table 1, Entries 1 and 2). The ligand Sb-1c (R1 =
Figure 2. Scope of ligands synthesized and evaluated in asymmetric Rh-catalyzed hydrogenation.
Scheme 1. Two routes used for the synthesis of amino acid based phosphoramidite ligands.
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Eur. J. Org. Chem. 2009, 6225–6230

Rhodium-Catalyzed Asymmetric Hydrogenation
The catalyst based on phosphoramidite Sb-1b is the most
selective, up to 48% ee was reached for this difficult sub-
strate (Table 1, Entry 11).
Table 1. Evaluation of amino acid based phosphoramidite ligands
in the Rh-catalyzed hydrogenation of functionalized substrates.[a]
Entry Substrate
Ligand
R1
% Conversion % ee (config.)
1
2
3
4
5
6
7
8
3
3
3
4
4
4
5
5
5
6
6
6
Sb-1a
Sb-1b
Sb-1c
Sb-1a
Sb-1b
Sb-1c
Sb-1a
Sb-1b
Sb-1c
Sb-1a
Sb-1b
Sb-1c
iBu
iPr
Bn
iBu
iPr
Bn
iBu
iPr
Bn
iBu
iPr
Bn
100
100
100
100
100
100
100
100
73
80 (S)
89 (S)
81 (S)
67 (R)
68 (R)
58 (R)
62 (R)
45 (R)
51 (R)
38 (R)
48 (R)
42 (R)
Figure 3. Substrates used to evaluate the hydrogenation properties
of rhodium complexes of 1 and 2.
9
10
11
12
50
51
10
[a] Ratio L/[Rh(nbd)2]BF4/substrate = 2.2:1:100; solvent: CH2Cl2.
Reaction performed at 10 bar H2 pressure at 298 K for 16 h. Con-
versions and enantioselectivities determined by chiral GC.
The influence of the amino acid moieties (i.e. R1) on the
catalytic results is significant and typically substrate-de-
pendent. Except for the hydrogenation of the methyl α-acet-
amidocinnamate (5), the best results were obtained using
ligand Sb-1b (Table 1, Entries 2, 5 and 11) having a valine
moiety. Further optimization was attempted by modifica-
tions to this ligand at the R2 and R3 position. We examined
the steric influence at the R2 position (ester group) by com-
paring the ligand Sb-1d (R2 = tBu) and the ligand Sb-1b (R2
= Me). The enantiomeric excess of the products is slightly
Scheme 2. Rh-catalyzed asymmetric hydrogenation of substrates 3,
4, 5 and 6.
Bn) provides similar selectivity to the iBu, up to 81% ee higher when the methyl group was used instead of the tBu,
(Table 1, Entry 3). Full conversions and moderate enantio- an effect that was observed for all substrates studied: 86%
selectivities were obtained in the hydrogenation of methyl ee vs. 89% for 3 (Table 2, Entries 1 and 2), 51% ee vs. 68%
2-acetamidoacrylate (4) (up to 68%). Modifying the alkyl for 4 (Table 2, Entries 5 and 6), 40% ee vs. 45% for 5
moiety R1 does not affect the catalytic outcome (Table 1, (Table 2, Entries 9 and 10) and 42% ee vs. 48% for 6
Entries 4 and 5) while a slight drop of selectivity is observed (Table 2, Entries 13 and 14). The steric hindrance brought
when the benzyl group is introduced. The catalyst based at the position R2 apparently results in lower selectivity, but
on the ligand Sb-1c affords 58% ee (Table 1, Entry 6). The also the activity is affected as is clear from the result ob-
hydrogenation of the more hindered alkene methyl α-acet- tained for the challenging substrate 6 that was converted to
amidocinnamate (5) showed that a better selectivity, but still 51% using the ligand Sb-1b and 29% using the ligand Sb-
moderate, was obtained with the phosphoramidite Sb-1a 1d (Table 2, Entries 13 and 14). Full conversion was ob-
(R1 = iBu, 62% ee, Table 1, Entry 7) compared to Sb-1b tained for the other substrates using both ligands, so differ-
(R1 = iPr, 45% ee, Table 1, Entry 8). The conversion clearly ences in activity could not be noticed. Importantly, the size
depends on the amino acid moiety for this more hindered of the R2 group, even if positioned relatively far from the
substrate, 73% of conversion was obtained with Sb-1c (R1 coordinated phosphorus atom at the metal center, influ-
= Bn), the enantioselectivity reaching 51% (Table 1, Entry ences the catalytic performance and provides a tool for li-
9), whereas Sb-1a and Sb-1b both lead to full conversion. A gand fine-tuning.
similar trend was observed in the hydrogenation of the rigid
We also studied the so-called match/mismatch effect by
N-(3,4-dihydro-2-naphthalenyl)acetamide (6), a notoriously comparing the selectivity induced by catalysts based on two
difficult substrate to hydrogenate. The conversion is most diasteroisomeric ligands with two sources of chirality. The
affected, as the rigidity of the substrate imposes severe con- corresponding diastereoisomer of Sb-1b was therefore syn-
straints on the catalyst. The phosphoramidite ligands with thesized using the same amino acid derivative in combina-
the leucine (Sb-1a) and the valine (Sb-1b) derivatives al- tion with (R)-BINOL backbone Rb-1 instead of (S)-BI-
lowed us to reach 50% and 51% conversion, respectively NOL. By comparing the results in the asymmetric hydro-
(Table 1, Entries 10 and 11) while using larger amino acid genation of various substrates we observed a mismatch ef-
such as phenylalanine (Sb-1c) derivative resulted in a con- fect with the ligand Rb-1b and a match effect with the li-
siderable drop of conversion to 10% (Table 1, Entry 12). gand Sb-1b on the selectivity of the hydrogenation reaction
Eur. J. Org. Chem. 2009, 6225–6230
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P.-A. R. Breuil, J. N. H. Reek
FULL PAPER
Table 2. Versatility of the valine-based phosphoramidite ligands in perform their rigid BINOL-based analogues,[12] and as a
Rh-catalyzed hydrogenation of functionalized substrates.[a]
bonus the building blocks are cheaper too. These types of
ligands therefore comprise interesting analogues to study.
The enantiomeric excesses of the products formed during
the hydrogenation of dimethyl itaconate (3) with these new
ligands varied from low (8%) to moderate (up to 70%,
Table 3, Entry 4). For this substrate the use of the enantio-
pure BINOL backbone affords higher selectivities. Also, the
activity of the catalysts is strongly affected by modifications
at the R1 position; only 2% conversion was obtained with
the phenylalanine-based phosphoramidite 2c (Table 3, En-
try 3) and 41% conversion with the tryptophan-based phos-
phoramidite 2f (Table 3, Entry 4). Both these amino acid
derivatives have an aromatic group. Application of the leu-
cine- and valine-based phosphoramidites 2a and 2b lead to
full conversion (Table 3, Entries 1 and 2), and these residues
are aliphatic. The hydrogenation of methyl 2-acetamidoac-
rylate (4) appeared less sensitive to changes at the amino
acid building block and the selectivities were comparable to
those obtained with the rigid BINOL derivatives (Table 3,
Entries 5–8). In general the enantioselectivities obtained
with the tropos phosphoramidite ligands are good (up to
Sub-
strate
% Conver-
sion
% ee
(config.)
Entry
Ligand
R2
R3
1
2
3
4
5
6
7
8
3
3
3
3
4
4
4
4
5
5
5
5
6
6
6
6
Sb-1b
Sb-1d
Rb-1b
Sb-1e
Sb-1b
Sb-1d
Rb-1b
Sb-1e
Sb-1b
Sb-1d
Rb-1b
Sb-1e
Sb-1b
Sb-1d
Rb-1b
Sb-1e
Me
tBu
Me
Me
Me
tBu
Me
Me
Me
tBu
Me
Me
Me
tBu
Me
Me
H
H
H
Me
H
H
H
Me
H
H
H
Me
H
H
H
Me
100
100
100
43
100
100
100
100
100
100
100
100
51
89 (S)
86 (S)
84 (R)
3 (S)
68 (R)
51 (R)
14 (S)
97 (R)
45 (R)
40 (R)
33 (S)
84 (R)
48 (R)
42 (R)
59 (S)
45 (R)
9
10
11
12
13
14
15
16
29
4
16
[a] Ratio L/[Rh(nbd)2]BF4/substrate = 2.2:1:100; solvent: CH2Cl2.
Reaction performed at 10 bar H2 pressure at 298 K for 16 h. Con-
versions and enantioselectivities determined by chiral GC.
of substrates 3, 4 and 5. The increase of selectivity is moder- 77%) and even slightly higher than the selectivities afforded
ate for the substrates 3 (from 84% ee to 89%, Table 2, En- by their BINOL analogues (68% ee obtained with Sb-1b).
tries 1 and 3) and 5 [from 33% ee to 45% (Table 2, Entries Ligand 2a is an exception as its rhodium catalyst resulted
9 and 11)] to large for the substrate 4 (from 14% to 68%, in a significant lower enantioselectivity of the product that
Table 2, Entries 5 and 7). For these substrates the conver- was formed (24% ee, Table 3, Entry 5). Similarly to the hy-
sion was 100%. The match/mismatch effect in the hydrogen- drogenation of the substrate 3, the activities obtained are
ation of the substrate 6 is opposite as the selectivity is lower with the amino acids having an aromatic group. In
higher when ligand Rb-1b is used compared to Sb-1b, with the hydrogenation of the substrate 5 low to moderate con-
59% and 48% enantioselectivity, respectively (Table 2, En- versions and selectivities were obtained (Table 3, Entries 9–
tries 13 and 15). In addition, a drop in conversion to 4% 12). In contrast, better conversion was obtained with the
for the ligand Rb-1b compared to 51% for the ligand Sb-1b flexible backbone and the valine moiety (64%, Table 3, En-
was obtained. The versatility of the amino acids allowed us try 14) in the asymmetric hydrogenation of 6 compared to
to modify the R3 position by using a N-methylated deriva- their BINOL analogues. Up to 51% ee was afforded
tive to synthesize the phosphoramidite Sb-1e. The effect of
that modification depends strongly on the substrate used.
A dramatic decrease of both activity and selectivity is ob-
served in the asymmetric hydrogenation of the dimethyl ita-
conate (3), only 3% enantioselectivity was obtained
Table 3. tropos phosphoramidite ligands in Rh-catalyzed hydrogen-
ation of functionalized substrates.[a]
Sub-
strate
% Con-
version
% ee
(config.)
Entry
Ligand R1
(Table 2, Entry 4) at a lower conversion of 43%. In con-
trast, in the asymmetric hydrogenation of 4 and 5 an impor-
tant increase in selectivity was obtained leading to excellent
ee, up to 97% and 84%, respectively (Table 2, Entries 8 and
12). Hydrogenation of 6 led to similar selectivity, 45% for
Sb-1e (Table 2, Entry 16) and 48% for Sb-1b (Table 2, Entry
13) while a noticeable difference in conversion (16% for Sb-
1e and 51% for Sb-1b) was obtained.
A new set of phosphoramidite ligands was also devel-
oped in which the stereogenic center brought by the amino
acid was the only source of chiral information. Instead of
the chiral BINOL backbone, the flexible biphenol back-
bone was used. It is known that this results in atropisomer-
ism rendering the two diastereomers in a fast equilibrium.
Gennari and co-workers demonstrated that in some par-
ticular cases these diastereoisomers are observable by 31P
NMR at low temperature.[11] Previously it also has been
1
2
3
4
5
6
7
8
3
3
3
3
4
4
4
4
5
5
5
5
6
6
6
6
2a
2b
2c
2f
2a
2b
2c
2f
2a
2b
2c
2f
2a
2b
2c
2f
iBu
iPr
Bn
100
100
2
8 (S)
16 (S)
26 (S)
70 (S)
24 (R)
70 (R)
77 (R)
70 (R)
16 (R)
7 (R)
21 (R)
19 (R)
34 (R)
40 (R)
51 (R)
41 (R)
3-Me-1H-indole
iBu
iPr
Bn
3-Me-1H-indole
iBu
iPr
Bn
3-Me-1H-indole
iBu
iPr
Bn
41
90
100
57
78
24
27
22
41
18
64
28
45
9
10
11
12
13
14
15
16
3-Me-1H-indole
[a] Ratio L/[Rh(nbd)2]BF4/substrate = 2.2:1:100; solvent: CH2Cl2.
Reaction performed at 10 bar H2 pressure at 298 K for 16 h. Con-
demonstrated that these types of flexible ligands can out- versions and enantioselectivities determined by chiral GC.
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Rhodium-Catalyzed Asymmetric Hydrogenation
(Table 3, Entry 15), competing with the best result obtained ligands with the amino acids as the sole source of chirality
with the BINOL-derived phosphoramidite ligands (59%, are able to steer enantioselectivity in the rhodium-catalyzed
Table 2, Entry 15).
hydrogenation. Although the current library is rather small,
In general, good conversions were obtained with the li- it is evident that the amino acid components in these li-
gands using amino acid building blocks with an alkyl resi- gands have added value, as these building blocks can be
due, whereas phosphoramidite 2c, having an aromatic varied tremendously and are very accessible. We anticipate
group at the R1 position (Table 3, Entries 3, 7, 11 and 15), that these new ligand structures will be widely used for the
gives rise to much lower conversions. The same phenome- screening of catalysts for asymmetric conversions, and rho-
non is observed when comparing the BINOL-based ligands dium-catalyzed asymmetric hydrogenation in particular.
Sb-1a, Sb-1b and Sb-1c. A plausible explanation for the low
activities is the effect of the tert-butyl groups attached to
Experimental Section
the biphenol ring that bring steric bulk close to the metal
center. Indeed the substitution of the 3,3Ј positions of the
BINOL or biphenol backbone is often used to enhance the
selectivity of a catalyst, but too bulky ligands are generally
less effective.[13] In the present case, the accessibility of the
substrate to the metal center can be hindered affording
lower activities.
General Procedure for the Preparation of Ligands Sb-1a-e and Rb-
1b
Method A: PCl3 (2.5 mL) was added to a Schlenk containing (S)-
or (R)-2,2Ј-bisnaphthol (1.0 mmol). The solution was refluxed
overnight. The excess of PCl3 was removed in vacuo. Anhydrous
toluene (3ϫ3 mL) was added and co-evaporated to remove the re-
maining PCl3 to obtain the phosphochloridite as a white foam. The
phosphochloridite was dissolved in 5 mL of dry toluene and the
solution was cooled to 0 °C. The amino acid derivative (1.1 mmol)
and NEt3 (2.1 mmol) were added and the solution was stirred for
1 h at 0 °C. After allowing the solution to warm to room tempera-
ture, the medium was stirred for 3 additional hours. The solution
was then filtered to remove the salt and the solvent evaporated.
Purification by flash chromatography (hexane/ethyl acetate, 8:2) af-
forded the corresponding ligand as a white powder.
Conclusions
Two sets of phosphoramidite ligands were synthesized
and evaluated in the rhodium-catalyzed hydrogenation of
different functionalized alkenes. The new ligands are made
from simple amino acid building blocks, giving new handles
to fine tune catalyst performance. Modification of the
amino acid residue (R1 position) was effective and resulted
in better performance for the current substrate alkyl chains
than aromatic side chains. The ligand Sb-1b, based on the
amino acid valine, was identified as most efficient in the
series, leading to the conclusion that for the current asym-
metric hydrogenation reactions the bulkiness should be
close to the ligand donor atom. Modifications of the valine
derivative led us to observe a substrate-dependent match/
mismatch effect, the diastereoisomer (S,S)-Sb-1b being
more selective than (R,S)-Rb-1b for three out of four sub-
strates. This ligand was further tuned by varying the ester
moiety, positioning additional steric bulk remote from the
phosphorus donor. Nevertheless, this also affects the cata-
lytic outcome, although to a reduced extent. At this posi-
tion a small alkyl group (R2 = Me) is preferred, because it
results in higher selectivities than a large one (R2 = tBu).
The final position that was modified was the NH next to
the phosphorus donor atom (R3). Having a methyl group
instead of a proton strongly affects the catalytic results. The
N-methylated valine-based phosphoramidite Sb-1e outper-
formed all the others, achieving excellent enantioselectivity,
with up to 97% for the methyl 2-acetamidoacrylate (4) and
up to 84% for the methyl α-acetamidocinnamate (5).
Method B: (S)-(+)-(3,5-dioxa-4-phosphacyclohepta[2,1-a;3,4-aЈ]di-
naphthalen-4-yl)diethylamine (1.0 mmol) was dissolved in 5 mL of
dry toluene in a Schlenk. To this solution the amino acid derivative
(1.2 mmol) and 1H-tetrazole (2.0 mmol) were added. The solution
was refluxed for 3 h. After filtration of the salt, the solvent was
evaporated. Purification by flash chromatography (hexane/ethyl
acetate, 8:2) afforded the corresponding ligand as a white powder.
General Procedure for Rhodium-Catalyzed Hydrogenation Reac-
tions: The hydrogenation experiments were carried out in a stainless
steel autoclave (150 mL) charged with an insert suitable for 8 reac-
tion vessels (including Teflon® mini stirring bars) for conducting
parallel reactions. In a typical experiment, to a solution of Rh(nbd)2-
BF4 (1 µmol, 1 equiv.) in 0.4 mL of dry CH2Cl2 was added a solu-
tion of ligand (2.2 µmol, 2.2 equiv.) in 0.6 mL of dry CH2Cl2. The
solution was stirred for 30 min. The mixture was then added to the
reaction vessels charged with 0.10 mmol of alkene substrate. Before
starting the catalytic reactions, the charged autoclave was purged
three times with 5 bar of H2 and then pressurized at 10 bar H2.
The reaction mixtures were stirred at 25 °C for 16 h. After catalysis
the pressure was released. The conversion and enantiomeric purity
were determined by chiral GC.
Supporting Information (see also the footnote on the first page of
this article): Experimental procedures, spectroscopic and analytical
data of ligands, substrate synthesis and chiral GC separations.
We prepared and studied also a set of amino acid based
phosphoramidite ligands having a flexible biphenol back-
bone. These tropos phosphoramidite ligands proved to be
effective ligands in rhodium-catalyzed hydrogenation, and
in some cases they compete with the rigid BINOL-based
ligands. In the selective hydrogenation of the methyl 2-acet-
amidoacrylate (4) they even surpassed their BINOL-based
analogues (77% ee obtained relative to 68%), proving that
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Received: September 11, 2009
Published Online: October 27, 2009
6230
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