Chiral 1,4-bis-diphosphine ligands from optically active (Z)-olefines

Article abstract of DOI:10.1016/j.tetasy.2007.04.018

The catalytic asymmetric hydrogenation of prochiral ketones was carried out with Ru(II) complexes prepared from new chiral diphosphine ligands, cis-(R,R)-2,5-bis[(diarylphosphino)]-3-hexenes. These new ligands were prepared from enantiomerically pure (R,R) or (S,S)-(Z)-3-hexene-2,5 diol and enantiomeric excesses up to 85% were obtained in the reduction of 2-benzamidomethyl-3-oxobutanoate, starting material for the synthesis of 4-acetoxy-2-azetidinone.

Full text of DOI:10.1016/j.tetasy.2007.04.018

Tetrahedron: Asymmetry 18 (2007) 1278–1283
Chiral 1,4-bis-diphosphine ligands from optically active (Z)-olefines
Edoardo Cesarotti,a,* Isabella Rimoldi,a Paola Spallutoa and Francesco Demartinb
a
`
`
Dipartimento di Chimica Inorganica, Facolta di Farmacia, Universita degli Studi di Milano, Metallorganica e Analitica
e Istituto CNR-ISTM. Via G. Venezian, 21. I-20133 Milano, Italy
b
`
`
Dipartimento di Chimica Strutturale e Sterochimica Inorganica, Facolta di Farmacia, Universita degli Studi di Milano,
Via G. Venezian, 21. I-20133 Milano, Italy
Received 21 March 2007; accepted 18 April 2007
Available online 20 June 2007
Abstract—The catalytic asymmetric hydrogenation of prochiral ketones was carried out with Ru(II) complexes prepared from new chiral
diphosphine ligands, cis-(R,R)-2,5-bis[(diarylphosphino)]-3-hexenes. These new ligands were prepared from enantiomerically pure (R,R)
or (S,S)-(Z)-3-hexene-2,5 diol and enantiomeric excesses up to 85% were obtained in the reduction of 2-benzamidomethyl-3-oxobutano-
ate, starting material for the synthesis of 4-acetoxy-2-azetidinone.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
BITIOP6 became available; these ligands gave the corre-
sponding Ru–phosphine complexes catalysts able to reduce
C@O and C@N double bonds often with ees higher than
99%; no doubt that while the family of chelating diphos-
phines based on sterogenic carbon atoms is very large,
diphosphines based on axial chirality are a rather more
limited class of ligands.
Transition metals, which are known to be excellent cata-
lysts for asymmetric synthesis, have optically active diphos-
phine ligands as source of chirality. Usually chirality is
based upon one or more stereogenic atoms such as those
in DIOP, the breakthrough in the field of chiral phospho-
rus ligands.1 DIOP has a C2-axis with two stereogenic sp3
carbons, whose chirality depends on starting material, the
tartaric acid.
R. Nojori, Nobel Prize for Chemistry in 2001, recently
wrote ‘‘. . .. . . Despite the tremendous effort made to discover
useful asymmetric hydrogenation catalyst, there still remains
much potential for the continued development of these reac-
tions, only a limited number of truly efficient catalysts have
been found. Furthermore, because of the structural and func-
tional diversity of unsaturated organic compounds, no univer-
DIPAMP, the first example of a successful industrial appli-
cation of metal-catalyzed asymmetric hydrogenation has
two asymmetric phosphorus atoms.2 Thousands of ligands
based on stereogenic sp3 atoms derived from the systematic
exploitation of the chiral pool are currently available and
some of the corresponding Rh–phosphine complexes have
smoothed the way to natural and unnatural amino acids
by asymmetric hydrogenation of the corresponding
enamides.3
7
sal catalysts exist. . .. . .’’
As is epitomized in these words, in the area of asymmetric
catalysis there is still much potential research with regards
to the development of new catalysts with satisfactory
enantioselectivity, productivity and process robustness to
find applications on an industrial scale which is closely con-
nected to the availability of new chiral ligands.
Unlike the reduction of C@C double bonds, the successful
catalytic reduction of prochiral C@X bonds (X = O, N)
was achieved only when di-aryl or di-heteroaryl ligands
with a C2 axial chirality such as BINAP,4 BIPHEMP5 or
Herein, we report a new class of chiral chelating diphos-
phines that should combine the easiness of synthesis of
ligands based on stereogenic sp3 carbon atoms with a
tendency to chelate to the metal in an octahedral geometry,
typical of the aromatic di-aryl or di-heteroaryl diphos-
phines with C2 axial chirality.
*
Corresponding author. Tel.: +39 02 503 14390; fax: +39 02 503 14405;
e-mail: edoardo.cesarotti@unimi.it
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.04.018

E. Cesarotti et al. / Tetrahedron: Asymmetry 18 (2007) 1278–1283
1279
HO
OH
Ar
a
b
P
Ar
C2 C3
1
R
R
C4
C2
C3
PAr2
PAr2
R
M
C4
R
a
M
Ar
P
Ar
R
HO
OH
AcO
OAc
HO
OAc
Ar
P
Ar
C4
3
(2R,5R)-2
(2S,5S)-1
R1 R1
C3
C2
C2 C3
M
b
R
C4
PAr2
Ar
P
PAr2
Ar
HO
OH
M
Figure 1.
(2R,5R)-1
Figure 1a shows a top and side view (upper and lower,
respectively) of these new ligands in comparison with
the general formula of an atropisomeric diphosphine
(Fig. 1b). A general feature of these ligands is that the dou-
ble bond between C2 and C3 and, consequently the C1–C4
atoms, defines the molecular plane; upon coordination to a
metal if the R group on the backbone assume the typical
equatorial disposition, the phosphorus can lie over and be-
low this plane according to the chirality of the two stereo-
genic atoms C1 and C4; furthermore upon coordination,
the aryl groups on the phosphorus are forced into the
axial/equatorial disposition that generates the usual C2 chi-
ral environment of chelating diphosphines around a metal.8
Scheme 1. Resolution of diols. Reaction conditions: (a) 1 = 1.4 M in
vinylacetate, Lipase AK (24,600 unit/g, Amano) 77 mg/ml, temperature
32 ꢁC, reaction time 16 h; (b) flash chromatography hexane/ethylace-
tate = 1/1.
or LiP(3,5-CH3)2C6H3) to give the corresponding diphos-
phines (Z)-(2R,5R)-diarylphosphino-3-hexene-(R,R)-ZED-
PHOS-6a and -(R,R)-ZEDPHOS-6b (Scheme 2).
The Rh(I) and Ru(II) complexes of the ligands (R,R)-ZED-
PHOS-6a and (R,R)-ZEDPHOS-6b were prepared by fol-
lowing the literature procedures and applied to the
catalytic hydrogenation of b-ketoesters and prochiral ole-
fins described in Figure 2.
This is a scaffold similar to that generated by the coordina-
tion of an atropisomeric diphosphine, (Fig. 1b); now the
molecular plane is defined by the metal and carbon atoms
C2 and C3 while the phosphorus atoms lie over and below
this plane according to the axial chirality of the ligand.
The results are summarized in Tables 1 and 2.
Before discussing the catalytic activities of Rh(I) and
Ru(II) complexes with (R,R)-ZEDPHOS ligand, it is worth
mentioning that the double bond in the 3-hexene scaffold of
the ligand was not reduced even under the most severe con-
ditions described in Table 1. [Ru((R,R)-ZEDPHOS-
6a)Cl2(DMF)n] was dissolved in MeOH and stirred at
The great difference of this new class with respect to atrop-
isomeric diphosphines is that the R substituents on the ste-
reogenic carbons C1 and C4 (Fig. 1a) can be easily changed
depending only on the chiral cis diols used as starting
materials.
OH
OH
OTs
HO
b
a
OH
OTs
2. Results and discussion
(2S,5S)-1
(2S,5S)-4
(2S,5S)-5
Scheme 1 depicts the reactions for the synthesis of the
chiral diphosphines hereafter defined as ZEDPHOS. Treat-
ment of a commercially available mixture of 50/50 meso
and racemic (2,5)-3-hexyne-diol 1 with Lypase AK in the
presence of vinylacetate9 led to the diacetylated stereoiso-
mer (2R,5R)-2 while the meso stereoisomer (2,5)-3-hex-
yne-diol 1 was selectively monoacylated. The unreacted
enantiomerically pure (2S,5S)-1 and the diacetylester
(2R,5R)-2 were easy isolated quantitatively by flash chro-
matography; the diol (2R,5R)-1 was obtained from
(2R,5R)-2 by acid hydrolysis.
c
PAr2
(2R,5R)-6a
(2R,5R)-6b
Ar = C6H5
PAr2
Ar = (3,5-(CH3)2)C6H3
Scheme 2. Synthesis of the (Z)-diarylphosphines. Reaction conditions: (a)
[sub] = 1.7 M, solvent: ethylacetate, Pd/CaCO3 (5 wt.%) 0.033 equiv,
quinoline 0.087 equiv, H2 pressure = 1 atm, temperature = 25 ꢁC; (b)
[sub] = 0.35 M, tosyl chloride = 1.25 equiv, NaOH = 4.5 equiv solvent:
anhydrous THF, temperature = ꢀ20 ꢁC, reaction time = 4 h; (c)
[sub] = 0.094 M, LiPAr2 = 0.26 M, solvent: anhydrous THF, tempera-
ture = ꢀ78 ꢁC, under inert atmosphere.
(2S,5S)-3-Hexyne-2,5-diol-1 was selectively reduced to (Z)-
(2S,5S)-3-hexene-2,5-diol-4 with Pd/CaCO3. (2S,5S)-3-
Hexene-2,5-diol di-p-tosylate-5 was reacted with LiPPh2

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E. Cesarotti et al. / Tetrahedron: Asymmetry 18 (2007) 1278–1283
O
OH
HN
O
O
O
O
OH
HN
O
OH
O
O
7a
O
8a
O
9a
11a
10a
OH
OH
O
*
*
OH
*
O
O
HN
O
*
OH
HN
O
OH
*
O
O
O
9b
11b
7b
10b
8b
Figure 2.
Table 1. Asymmetric hydrogenation of b-ketoesters catalyzed by RuL Cl2 (DMF)n or [RuL (p-cymene)I]Ia
*
*
Entry
Ligand
[Ru] catalyst
Substrate
Product
ee %
de %d
1
2
3
4
5
6
7
8
9
6a
6a
6b
6b
6a
6a
6a
6b
6b
[Ru(p-cymene)I]I
[Ru(p-cymene)I]I
[Ru(p-cymene)I]I
RuCl2(DMF)n
RuCl2(DMF)n
[Ru(p-cymene)I]I
RuCl2(DMF)n
RuCl2(DMF)n
[Ru(p-cymene)I]I
7a
7a
7a
7a
7a
8a
8a
8a
8a
(R)-7b
(R)-7b
(R)-7b
(R)-7b
4b
58b
63b
39b
66b
70c
71c
70c
85c
—
—
—
—
—
43
55
63
55
(R)-7b
(2S,3R)-8b
(2S,3R)-8b
(2S,3R)-8b
(2S,3R)-8b
a Reaction conditions: Solvent: CH2Cl2/MeOH = 7:3, except entry 1 (MeOH 100%); Reaction time 24 h; Conversion > 99%; Substrate/[Ru] = 50:1;
substrate concentration = 0.025 mmol/ml; T = 60 ꢁC; P = 50 atm H2.
b The ee values were determined by chiral GC DANI GC86.10 equipped with a capillary column with a chiral stationary phase MEGA DAcTButSilBETA
(25 m, internal diameter 0.35 mm).
c The ee values were determined by chiral HPLC with a Daicel Chiralcel OD colum or Chiralpak AD.
d The de values were determined by 1H NMR.
Table 2. Asymmetric hydrogenation of C@C double bonds catalyzed by RuCl2(DMF)n, [Ru(p-cymene)I]I or [Ru(COD)(g3-C3H5)2]a
Entry
Ligand
[Ru] catalyst
Substrate
Product
ee %h
1b
2d
3c,e
4d
5c,f
6b
7
6b
6b
6a
6a
6a
6a
6a
6a
6b
6b
RuCl2(DMF)n
RuCl2(DMF)n
[Ru(p-cymene)I]I
[Ru(p-cymene)I]I
[Ru(p-cymene)I]I
RuCl2(DMF)n
9a
10a
9a
(R)-9b
(R)-10b
9b
15
34
0
35
0
10
48
30
5
10a
9a
(R)-10b
9b
9a
(S)-9b
(R)-10b
(R)-10b
9b
RuCl2(DMF)n
10a
10a
9a
8d
9g
[Ru(COD)(g3-C3H5)2]
RuCl2(DMF)n
10g
RuCl2(DMF)n
10a
(R)-10b
10
a Reaction conditions: Solvent: MeOH; Reaction time 24 h; Conversion > 99%; Substrate/[Ru] = 100:1; substrate concentration = 0.025 mmol/ml;
T = 20ꢁC; P = 70 atm H2 if not otherwise stated.
b Substrate/[Ru] = 150:1.
c Substrate/[Ru] = 300:1.
d P = 10 atm H2.
e P = 50 atm H2.
f Solvent: CH2Cl2/MeOH = 7:3.
g Solvent: toluene.
h The ee values were determined by chiral GC DANI GC86.10 equipped with a capillary column with a chiral stationary phase MEGA DAcTButSilBETA
(25 m, internal diameter 0.35 mm).
60 ꢁC for 24 h under 70 atm H2; after evaporation of the
analysis of the brown residue were almost super imposable
to those of the complex before the treatment.
solvent the 1H, 31P NMR, MS-FAB+ spectra and elemental

E. Cesarotti et al. / Tetrahedron: Asymmetry 18 (2007) 1278–1283
1281
In a second test [Pd((R,R)-ZEDPHOS-6a)Cl2], (vide infra)
was dissolved in MeOH and stirred at 60 ꢁC for 72 h under
70 atm H2 in the presence of 5% [Ru((R,R)-ZEDPHOS-
6a)Cl2(DMF)n]. After the usual work-up, the Pd(II) com-
plex was recovered almost unchanged from the reaction
mixture.
ZEDPHOS-6a)]+ and [Rh(COD)((R,R)-ZEDPHOS-6b)]+
gave almost racemic N-acetyl-phenylalanine 11b; slightly
better results were obtained with RuCl2(DMF)n in the
reduction of tiglic acid (Table 2, entry 7). Again stereodif-
ferentiation was strongly dependent on the nature of the
catalyst precursor (Table 2, entries 4, 7 and 8) and on the
solvent (Table 2, entries 7 and 10).
Stereoselective reduction of b-ketosters provides a direct
approach to optically active b-hydroxyesters, which are
building blocks in the synthesis of bioactive products; par-
ticularly interesting is the reduction of substrate 2-benz-
amidomethyl-3-oxobutanoate 8a as 8b is the starting
material for the synthesis of 4-acetoxy-2-azetidinone 8c,
which is a key intermediate in the preparation of Carbape-
nem and other b-lactam antibiotics (Fig. 3).
Neither Ru(II) nor Rh(I) gave crystals suitable for an
X-ray investigation; a detailed structure of the ligand
(R,R)-ZEDPHOS-6a was possible by its palladium
dichloride complex.
[Pd((R,R)-ZEDPHOS-6a)Cl2] was prepared by exchange
from [Pd(C6H5CN)2Cl2] and (R,R)-ZEDPHOS-6a; crystals
for X-ray diffraction structural determination were ob-
tained by slow diffusion of diethyl ether in a CH2Cl2 solu-
tion. The molecular structure is reported in Figure 4a
(front view) and 4b (top view).
Stereodifferentiation appeared to be dependent on the sol-
vent and, to a lesser extent, on the catalyst precursor. The
highest enantiomeric excess (85%) was obtained in the
reduction of 8a with (R,R)-ZEDPHOS-6b and [Ru(p-cym-
ene)I]I (Table 1, entry 9). Methyl acetoacetate 7a was
reduced with 66% ee with RuCl2(DMF)n and (R,R)-
ZEDPHOS-6a (Table 1, entry 5). MeOH alone gave a dis-
appointing 4% ee but a 7:3 mixture CH2Cl2/MeOH raised
the ee to 58% (Table 1, compare entries 1 and 2). Both
ligands (R,R)-ZEDPHOS-6a and (R,R)-ZEDPHOS-6b
gave comparable results with [Ru(p-cymene)I]I in the
reduction of 7a (Table 1, compare entries 2 and 3) while
RuCl2(DMF)n gave comparable results in the reduction
of 8a (Table 1, compare entries 7 and 8) although different
enantioselectivities were obtained in the reduction of 7a
(Table 1, compare entries 4 and 5).
[Pd((R,R)-ZEDPHOS)-6a)Cl2] is a slightly distorted square
planar complex; atoms Pd, Cl1, C1 and C2 lie in the mole-
˚
cular plane; only chlorine Cl2 is 0.061 A out of the least
square plane. The most relevant feature of the ligand in
the solid state is that the four phenyl rings are symmetri-
cally arranged above and below the molecular plane, as
shown in Figure 4a (front view) with the methyl group
close to the P2 atom in an almost perfect equatorial dispo-
sition in the molecular plane. In asymmetric hydrogena-
tion, the aryl groups on the phosphorus atoms are the
chirality transmitters assuming, upon the coordination, a
local C2 symmetry as determined by their axial/equatorial
disposition which in its turn is determined by the chirality
of the backbone. The X-ray structure of the square planar
Pd(II) complex shows that the phenyl groups assume a
disposition more close to Cs than C2 symmetry. This
arrangement should be typical of all the transition metals
in a square planar geometry, similar to those of Rh(I); if
such a disposition is maintained in solution, it should
explain why [Rh((2R,5R)-6a)(COD)]+ and [Rh((2R,
5R)-6b)(COD)]+ are very efficient catalysts in the hydro-
genation of N-acetyl-dehydrophenylalanine and N-ben-
zoyl-dehydrophenylalanine methyl ester but with very
Less satisfactory results were obtained in the reduction of
prochiral olefins. Cationic complexes [Rh(COD)((R,R)-
OTBS
OH
OCOCH3
HN
O
O
O
NH
8a
O
Figure 3.
Figure 4. (a) and (b) views of PdCl2(R,R)-ZEDPHOS-6a.

1282
E. Cesarotti et al. / Tetrahedron: Asymmetry 18 (2007) 1278–1283
poor enantioselectivities. The tendency of ligands 6a and 6b
to chelate to the metal in an octahedral geometry, typical of
Ru(II) complexes should keep away the metal from Cs
towards a more pronounced C2 symmetry. Whatever would
be the origin of the stereodifferentiation there is no doubt
that the Ru(II)-ZEDPHOS complexes are efficient enantio-
selective hydrogenation catalysts, at least for ketones. The
steric control of a catalytic hydrogenation is the result of
several factors amongst which geometric parameters and
bulkiness of the substituents on the ligand exert a central
role.
(S,S)-5 was obtained in 70% yield after crystallization from
diethyl ether and characterized with a melting point =
70 ꢁC with decomposition.
Elemental analysis calculated for C20H24O6S2: C, 56.59; H,
25
5.70; found: C, 56.94; H, 5.66. ½aꢁD ¼ þ35:4 (c
2.1 Æ 10ꢀ3 M; C3H6O) 1H NMR (300 MHz; CDCl3):
(ppm) 1.26 (6H; d), 2.48 (6H; s), 5.29–5.33 (2H; m), 5.41–
5.46 (2H; m), 7.34–7.36 (4H; d), 7.76–7.78 (4H; d).
3.3. Preparation of (R,R)-ZEDPHOS-6a
Efforts are currently being carried out in order to verify if
the introduction of bulkier groups on the C1 and/or C4
atoms will effect to a great extent the enantioselectivity of
the reaction.
A solution of LiPPh2 (0.98 mmol; 0.26 M in THF) was
dropped into a solution of (S,S)-5 in THF at ꢀ78 ꢁC, un-
der argon. After the addition the temperature was allowed
to rise to room temperature and stirred for an additional
30 min. The excess of LiPPh2 was neutralized by Na2-
SO4Æ10H2O and the mixture was filtered under argon.
Evaporation of the solvent followed by methanol afforded
the chiral diphosphine (R,R)-ZEDPHOS-6a enantiomeri-
cally and chemically pure.
3. Experimental
Catalytic reactions were performed in a 200 ml stainless
steel autoclave equipped with temperature control and
magnetic stirrer. Unless otherwise stated, materials were
obtained from commercial suppliers and used without fur-
ther purification. The rhodium and ruthenium catalysts
were prepared according to the well established literature
procedure.10
25
Yield % = 95%; ½aꢁD ¼ ꢀ50:3 (c 0.001 M; C3H6O); 31P
NMR (300 MHz; C3D6O): (ppm) ꢀ1.525 (s); 1H NMR
(300 MHz; C3D6O): (ppm) 0.54 (6H; d), 2.25–3.30 (2H;
m), 5.13–5.22 (2H; m), 7.32–7.64 (20H; m); 13C NMR
(300 MHz; C3D6O): (ppm) 17.75 (CH3), 29.63 (CH),
129.15 (@CH), 134.31 (C-aromatic).
31P NMR and 1H NMR spectra were recorded on a Bruker
DRX Avance 300 MHz equipped with a non-reverse probe
and also or on a Bruker DRX Avance 400 MHz. GC–MS
spectra were recorded on Thermo Finningan MD 800
equipped with GC Trace (SE 52 column: length 25 mt, /
int. 0.32 mm, film 0.4–0.45 lm). GC analysis: DANI
GC86.10 equipped with a capillary column with a chiral
stationary phase MEGA DAcTButSilBETA (25 m, inter-
nal diameter 0.35 mm). HPLC analysis: Merck–Hitachi
L-7100 equipped with Detector UV6000LP and Diacel
Chiralcel OD or Chiralpak AD.
3.4. Preparation of (R,R)-ZEDPHOS-6b
The ligand was prepared as (S,S)-ZEDPHOS-6a. Yield
% = 95%; 31P NMR (300 MHz) (C3D6O) (ppm): ꢀ2.703
1
(s); H NMR (300 MHz; C3D6O): (ppm) 0.46–0.53 (6H;
m), 2.28–2.32 (24H; d), 3.21 (2H; m), 5.08 (2H; m), 7.2–
7.67 (12H; m).
3.5. Preparation of PdCl2 (R,R)-ZEDPHOS-6a
3.1. Preparation of the diol (S,S)-4
A mixture of (R,R)-ZEDPHOS-6a (PM = 452.2; 0.21
mmol) and (C6H5CN)2PdCl2 (PM = 383.4; 0.21 mmol) in
argon-degassed acetone (5 ml) was stirred at rt for
30 min, under an argon atmosphere; the solvent was
removed by filtration to give a PdCl2(R,R)-ZEDPHOS-6a
complex as a yellow solid. Recrystallization of the crude
product by slow diffusion of ether into a CH2Cl2-saturated
solution afforded crystals suitable for X-ray structure
analysis.
The diol was prepared according to the literature.11
3.2. Preparation of (S,S)-bis-p-toluensulfonate (S,S)-5
A 10% solution of 3.50 g (18.30 mmol) tosyl chloride in
either THF or diethyl ether was added to a solution of
0.85 g (7.32 mmol) diol (S,S)-4 in THF, and the reaction
mixture cooled to ꢀ20 ꢁC. Thereafter a large excess of fi-
nely powdered sodium hydroxide was added in small por-
tions to the vigorously stirred solution. The temperature
was kept below ꢀ5 ꢁC during the sodium hydroxide addi-
tion. To complete the reaction, the solution was stirred
for another 3 h at 0 ꢁC and then poured into ice water.
The aqueous phase was extracted several times with dichlo-
romethane. After the collected organic extracts were dried
on sodium sulfate, the solvent was removed in vacuum and
the crude product recrystallized from diethyl ether. The
colourless crystals can be stored at ꢀ18 ꢁC for several
months without decomposition.
Yield % = 91%; Elemental analysis calculated for
C30H30P2PdCl2: C, 57.21; H, 4.80; found C, 56.26; H,
4.86. 31P NMR (300 MHz) (CDCl3) (ppm): 24.20 (s).
3.6. Preparation of [Ru(p-cymene)I(R,R)-ZEDPHOS-6a]+Iꢀ
This complex was prepared according to the literature pro-
cedure.10,12 31P NMR (300 MHz) (CDCl3) (ppm): 31.89 (d,
JPꢀP = 45.78 Hz), 27.14 (d, JPꢀP = 49.59 Hz), (JRuꢀP
576.02, JRuꢀP = 579.83).
=

E. Cesarotti et al. / Tetrahedron: Asymmetry 18 (2007) 1278–1283
1283
3.7. Preparation of [Rh(COD)(R,R)-ZEDPHOS-6a]
References
1. (a) Kagan, H. B.; Dang, T. J. Chem. Soc., Chem. Commun.
1971, 481; (b) Kagan, H. B.; Dang, T. J. Am. Chem. Soc. 1972,
94, 6429; (c) Kagan, H. B. Chiral Ligands for Asymmetric
Catalysis. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: New York, 1985; Vol. 5, Chapter 1.
2. (a) Vinegard, B. D.; Knowels, W. S.; Sabacky, M. J.;
Bachman, G. L.; Weinkauff, D. J. J. Am. Chem. Soc. 1972,
99, 5946; (b) Knowels, W. S. Angew. Chem., Int. Ed. 2002, 41,
1998–2007.
The complex was prepared according to the literature pro-
cedure.10,12 31P NMR (300 MHz) (CDCl3) (ppm): 24.56 (d,
JPꢀP = 144 Hz).
3.8. Preparation of [Ru(g3-C3H5)2(R,R)-ZEDPHOS-6a]
and of [RuCl2(DMF)n(R,R)-ZEDPHOS-6a]
The complexes were prepared according to the literature
procedure.10,12
3. (a) Halpern, J. Asymmetric Catalytic Hydrogenation: Mech-
anism and Origin of Enantioselection. In Asymmetric Syn-
thesis; Morrision, J. D., Ed.; Academic Press: New York,
1985; Vol. 5, (b) Brown, J. M.; Maddox, P. J. J. Chem. Soc.,
Chem. Commun. 1987, 1276; (c) Brown, J. M.; Chaloner, P.
A.; Morris, G. A. J. Chem. Soc., Chem. Commun. 1983, 664;
(d) Brown, J. M.; Chaloner, P. A. J. Chem. Soc., Chem.
Commun. 1980, 344; (e) Brown, J. M.; Parker, D. J. Chem.
Soc., Chem. Commun. 1980, 342; (f) Burk, M. J.; Allen, J. G.;
Kiesman, W. F. J. Am. Chem. Soc. 1998, 120, 657; (g) Dwars,
3.9. General procedure of the asymmetric hydrogenation
In a Schlenk tube sealed under argon, the substrate was
added to the precatalyst followed by 20 ml of a choice sol-
vent. The solution was stirred for 30 min and then trans-
ferred to an autoclave with a cannula.
`
T.; Schmidt, U.; Fischer, C.; Grassert, I.; Kempe, R.; FroE
hlich, R.; Drauz, K.; Oehme, G. Angew. Chem., Int. Ed. 1998,
37, 2851; (h) Imamoto, T.; Watanabe, J.; Wada, Y.; Masuda,
H.; Yamada, H.; Tsuruta, H.; Matsukawa, S.; Yamaguchi,
K. J. Am. Chem. Soc. 1998, 120, 1635.
The stainless steel autoclave (200 ml), equipped with tem-
perature control and magnetic stirrer, was purged 5 times
with hydrogen. After the transfer of the reaction mixture,
the autoclave was pressurized. At the end, the autoclave
was vented and the mixture was analyzed by GC–MS,
NMR spectra and HPLC.
4. (a) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008–2022;
(b) Noyori, R. Asymmetric Catalysis. In Organic Synthesis; J.
Wiley & Sons: New York, 1994; (c) Miyashita, A.; Yasuda,
H.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi, T.; Noyori, R.
J. Am. Chem. Soc. 1980, 102, 7932; (d) Noyori, R.; Takaya,
H. Acc. Chem. Res. 1990, 23, 345.
5. (a) Schmid, R.; Cereghetti, M.; Heiser, B.; Shonholzer, P.;
Hansen, H. Helv. Chim. Acta 1988, 71, 897; (b) Schmid, R.;
Broger, E.; Crameri, Y.; Foricher, J.; Lalonde, M.; Muller,
R.; Scalone, M.; Zutter, U.; Cereghetti, M.; Schoettel, G.
Pure Appl. Chem. 1996, 68, 131.
3.10. X-ray crystal structure determination of PdCl2 (R,R)-
ZEDPHOS-6a
Crystal data. C30H30P2PdCl2, M = 629.78, monoclinic, a =
˚
9.3915(10), b = 14.3912(15), c = 20.5625(22) A, b =
3
˚
97.86(1)ꢁ, U = 2753.0(5) A , T = 294(2) K, space group
P21/c (No. 14), Z = 4, l = (Mo Ka) 1.002 mmꢀ1. 24,080
reflections (5413 unique, Rint = 0.049) were collected at
room temperature in the range 2.00 6 2h 6 52.06 ꢁ,
employing a partly twinned 0.14 · 0.05 · 0.03 mm crystal
mounted on a Siemens SMART CCD area-detector dif-
fractometer. Graphite monochromatized Mo Ka radiation
`
6. (a) Antognazza, P.; Sannicolo, F.; Benincori, T.; Brenna, E.;
Trimarco, L.; Cesarotti, E. J. Chem. Soc., Chem Commun.
`
1995, 685; (b) Cesarotti, E.; Antognazza, P.; Sannicolo, F.;
Benincori, T.; Brenna, E.; Trimarco, L.; Demartin, F.; Pilati,
T. J. Org. Chem. 1996, 61, 6244; (c) Cesarotti, E.; Benincori,
`
T.; Araneo, S.; Sannicolo, F. J. Org. Chem. 2000, 65, 2043.
7. Noyori, Ryoji Chem. Asian J. 2006, 1–2, 102–110.
8. (a) Chan, A. S. C.; Pluth, J. J.; Halpern, J. J. Am. Chem. Soc.
1980, 102, 5952; (b) Amstrong, S. K.; Brown, J. M.; Burk, M.
J. Tetrahedron Lett. 1993, 34, 879.
˚
(k = 0.71073 A) was used with the generator working at
45 kV and 40 mA.
9. (a) Kim, M. J.; Lee, I. S. J. Org. Chem. 1993, 58, 6483; (b)
Amador, M.; Ariza, X.; Garcia, J.; Sevilla, S. Org. Lett. 2002,
4, 4511.
10. Genet, J. P. Acc. Chem. Res. 2003, 36, 908–918.
11. (a) Kim, M. J.; Lee, I. S. J. Org. Chem. 1993, 58, 6483; (b)
Amador, M.; Ariza, X.; Garcia, J.; Sevilla, S. Org. Lett. 2002,
4, 4511; (c) Herges, R.; Hoock, C. Angew. Chem., Int. Ed.
Engl. 1992, 31, 1611.
Intensities were corrected for Lorentz-polarization effects
and empirical absorption correction (SADABS.13 The
structure was solved by direct methods (SIR-9714) and re-
2
fined on F o with the SHELXL-9715 programme (WinGX
suite16). All non-hydrogen atoms were refined with aniso-
tropic thermal parameters, while hydrogen atoms, located
`
on the DF maps, were allowed to rıde on their carbon atom.
Final R1 [wR2] values of 0.0928 [0.1347] on 3607 reflections
with I > 2r(I) [all data] and 318 parameters. The maximum
and minimum residual electron density on the final DF map
are 1.59 and ꢀ1.58 e A , respectively.
12. Mashima, K.; Kusano, K.; Sato, N.; Matsumura, Y.; Nozaki,
K.; Kumobayashi, H.; Sayo, N.; Hori, Y.; Ishizaki, T.;
Akutagawa, S.; Takaya, H. J. Org. Chem. 1994, 59, 3064–
3076.
13. SADABS Area-Detector Absorption Correction Program,
Bruker AXS Inc. Madison, WI, U.S.A., 2000.
14. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori,
G.; Spagna, R. J. Appl. Cryst. 1999, 32, 115.
3
˚
Crystallographic data (excluding structure factors) have
been deposited with the Cambridge Crystallographic Data
Centre as Supplementary Publication No. CCDC-640071.
These data can be obtained free of charge via www.ccdc.
cam.ac.uk/conts/retrieving.html (or from CCDC, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223
336033; e-mail: deposit@ccdc.cam.ac.uk.
15. Sheldrick, G. M. SHELX97—Programs for Crystal Structure
Analysis (Release 97-2); University of Go¨ttingen: Germany,
1998.
16. Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837.