DIOPHEP, a chiral diastereoisomeric bisphosphine ligand: synthesis and applications in asymmetric hydrogenations

Article abstract of DOI:10.1016/j.tetasy.2008.07.009

Novel optically active diphosphine ligands, known as DIOPHEP, have been designed and synthesized starting from a derivative of tartaric acid. The ligands conjugate the sp³ chirality of the precursor of DIOP with the atropisomeric chirality of a biaryl scaffold. The stereorecognition abilities of DIOPHEP-Ru complex catalysts have been investigated in the asymmetric catalytic hydrogenation of some standard substrates suggesting a close relationship between dihedral angles and enantioselectivity.

Full text of DOI:10.1016/j.tetasy.2008.07.009

Tetrahedron: Asymmetry 19 (2008) 1654–1659
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
DIOPHEP, a chiral diastereoisomeric bisphosphine ligand: synthesis
and applications in asymmetric hydrogenations
b
b
a
a
Edoardo Cesarotti a, , Giorgio Abbiati , Elisabetta Rossi , Paola Spalluto , Isabella Rimoldi
*
a Università degli Studi di Milano, Facoltà di Farmacia, Dipartimento di Chimica Inorganica, Metallorganica ed Analitica, Via G. Venezian 21, 20133 Milano, Italy
b Università degli Studi di Milano, Facoltà di Farmacia, Istituto di Chimica Organica ‘Alessandro Marchesini’, Via G. Venezian 21, 20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 April 2008
Accepted 4 July 2008
Novel optically active diphosphine ligands, known as DIOPHEP, have been designed and synthesized
starting from a derivative of tartaric acid. The ligands conjugate the sp3 chirality of the precursor of DIOP
with the atropisomeric chirality of a biaryl scaffold. The stereorecognition abilities of DIOPHEP-Ru com-
plex catalysts have been investigated in the asymmetric catalytic hydrogenation of some standard sub-
strates suggesting a close relationship between dihedral angles and enantioselectivity.
Ó 2008 Published by Elsevier Ltd.
1. Introduction
DBTA;10 when the ligands are not basic enough to react with the
resolving agent however, they cannot be resolved with this meth-
Metal complexes and chiral ligands have become leading auxil-
iaries in the field of organic synthesis: reactions such as catalytic
asymmetric hydrogenations, hydroformylations, hydrocyanations
and isomerizations are now recognized as effective alternatives
in strategies for the preparation of compounds, which were
believed to be impossible to carry out by conventional stereoselec-
tive organic transformations.1–3
The greater part of the transition metals known as excellent
catalysts for asymmetric synthesis has optically active diphosphine
ligands as a source of chirality but, in spite of the great variety of
chiral ligands available, the development of new chiral ligands still
plays a crucial role in the development of catalysts characterized
by high enantioselectivity, diastereoselectivity, productivity and
process robustness.4
Since the pioneering works of Kagan on DIOP, the first example
of chelating diphosphines based on sp3 stereogenic carbon atoms,5
over the past 20 years a large amount of success has been achieved
by the use of atropisomeric chiral diphosphine ligands derived
from di-aryl or di-heteroaryl frames; ligands such as BINAP,6 BIP-
HEMP,7 MeO-BIPHEP7 or BITIOP8 and Rh(I) or Ru(II) give catalysts
able to reduce C@C and C@O double bonds with an ee% higher than
99%.
Many other diphosphines showing a C2 axial chirality have been
developed up to now,9 but most of these ligands are only obtained
in an enantiomerically pure form after tedious and somewhat
difficult resolution steps, usually based on the separation of the
diastereoisomeric adducts between the phosphorus oxides and
od10a,11 drastically reducing the synthetic opportunities connected,
for instance, with the use of a large range of aromatic frames con-
taining nitrogen atoms.
Recently different approaches based on the synthesis of biaryl
diphosphines as mixtures of diastereoisomers were explored. Enev
et al.12a obtained a bis-steroidal phosphine in a sequence of stereo-
selective reactions on diastereopure (R)- or (S)-4,40-bis(3-hydroxy-
estra-1,3,5(10),6,8-pentaene). Chan et al.12b prepared a biaryl
phosphine, known as PQ-Phos, in which the two aryl rings are teth-
ered by a chain bearing two stereogenic carbon atoms; the chirality
on the chain and the axial chirality give rise to a couple of diaste-
reoisomers that can more or less be easily separated by chromatog-
raphy, avoiding time consuming resolution procedures. By
increasing or decreasing the length of the chain, it is possible to ad-
just the dihedral angles of the diaryl scaffold with marked effects
on the enantioselectivity of asymmetric catalysis. Subtle changes
in the conformation of the ligands and the variation of the dihedral
angles of the diphosphine can modify the chiral array of the sub-
stituents on the phosphorus atoms, that is, the chirality transmit-
ters (usually aryl groups) increasing or decreasing the chiral
recognition of prochiral substrates; these effects can clearly be
seen with tunaphos,13 a family of ligands characterized by variable
dihedral angles and restricted rotations prepared by bridging the
aryl scaffold with carbon chains of variable length.
Herein, we report the synthesis and applications of chiral che-
lating diastereoisomeric diphosphines in which the bi-aryls are
bridged with a chiral chain derived from (S,S)-(ꢀ)-2,3-O-isopropi-
lidene-1,4-di-O-tosyl-D-threitol (Fig. 1), the same chiral starting
material of DIOP; in our aims these ligands should be the blending
of the two families of diphosphines, those based on stereogenic sp3
carbon atoms and those based on axial chirality.
* Corresponding author. Tel.: +39 02 503 14390; fax: +39 02 503 14405.
E-mail address: edoardo.cesarotti@unimi.it (E. Cesarotti).
0957-4166/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2008.07.009

E. Cesarotti et al. / Tetrahedron: Asymmetry 19 (2008) 1654–1659
1655
tion of the solutions at 296 nm, because in this way it is possible to
compare certain spectra of chiral compounds when very large
molar extinction coefficients are involved.
H
H
H
H
O
O
PPh2
PPh2
PPh2
PPh2
O
O
O
O
O
O
Despite the diphosphines, the oxides and the Rh(I) complexes
being couples of diastereoisomers, the CD spectra are almost mir-
ror images, quite similar to those reported for (R)- or (S)-BINAP15
and (R)- or (S)-MeO-BIPHEP14a which are really couples of enanti-
omers; this is not unexpected because the CD active electronic
transitions in 270–300 nm are essentially due to the biaryl chro-
mophores which, locally, can be considered in enantiomeric rela-
tionship. The small differences in the CD intensities probably
reflect the real diastereoisomeric nature of the ligands.
DIOPHEP (S,S,Sax)-1a
DIOPHEP (S,S,Rax)-1b
Figure 1.
2. Results and discussion
Unfortunately, in absence of suitable crystals for an X-ray struc-
tural determination, the absolute configuration of the biaryl scaf-
fold can be inferred only by the results of the catalytic activity;
comparing the absolute configuration of reduction products ob-
tained with the Ru(II) complexes of BITIOP, BINAP and BIPHEMP
with those reported herein (vide infra), it is possible to assign an
(S)-configuration to the (+)-DIOPHEP 1a and, obviously, an oppo-
site (R)-configuration to (ꢀ)-1b diastereoisomer.
The preparation of the ligands is shown in Scheme 1: racemic
HO-BIPHEP14 oxide reacts with S,S-2,3-O-isopropylidene-1,4-di-
O-tosyl-D-threitol in presence of K2CO3 to give an almost equimolar
mixture of diastereoisomers (+)-(S,S,Sax)-DIOPHEPO 2a and (ꢀ)-
(S,S,Rax)-DIOPHEPO 2b in 72% yield. Flash chromatography with
ethyl acetate/methanol/triethylamine = 9:1:0.1 on silica gel gives
2a (34%) and 2b (35%) in an almost enantiomerically pure form.
Reduction of the isolated oxides 2a and 2b with HSiCl3/Et3N in
toluene at 0 °C followed by treatment with aq NaOH 30% at 60 °C
affords the desired diastereoisomeric diphosphines (S,S,Sax)-DIOP-
HEP 1a and (S,S,Rax)-DIOPHEP 1b enantiomerically and chemically
pure.
It is well known that one of the main factors in determining
asymmetric control using chelating diphosphine ligands is the nat-
ural bite angle (bn)16 of metal complexes. In biaryl diphosphines,
the natural bite angle (bn) is strictly related to the dihedral angle
(h) of the biaryl backbone. In the asymmetric hydrogenation, in
particular the influence of h on the enantioselectivity has recently
been described by Zhang et al.,13 Saito et al.17 and Genêt et al.18 The
dihedral angles of biphenyl systems are expected to affect the ste-
ric bulk of the diphenyl-phosphino group. Clearly this hypothesis is
based on simple steric considerations and does not envisage the
electronic properties of complex or metal valence. A simple inspec-
tion of molecular models indicates that the dihedral angle (h) of
(S,S,Sax)-DIOPHEP 1a is higher than that of (S,S,Rax)-DIOPHEP 1b
when coordinated to a metal; a coarse measure gives about 70°
The CD spectra of the diastereoisomeric diphosphines (S,S,Sax)-
DIOPHEP 1a and (S,S,Rax)-DIOPHEP 1b, of (+)-(S,S,Sax)-DIOPHEPO
2a and (ꢀ)-(S,S,Rax)-DIOPHEPO 2b and of the corresponding rho-
dium complexes [((S,S,Sax)-DIOPHEP 1a)Rh(COD)]+ClO4 (+)-3a
ꢀ
and [(S,S,Rax)-DIOPHEP 1b)Rh(COD)]+ClO4
(ꢀ)-3b, prepared
ꢀ
according to standard procedure by ligand exchange from
[Rh(COD)2]+ClO4ꢀ, are reported in Figure 2; the CD spectra are re-
corded in CH2Cl2 and plotted as mDeg/A where A is the UV absorp-
H
O
O
OTs
OTs
H
POPh2
O
O
O
O
POPh2
POPh2
HO
HO
*
*
H
POPh2
H
K2CO3, n-butanol
reflux, 24 h
2a/2b
72%
flash chromatography
EtOAc: MeOH: TEA = 9:1:0.1
H
H
O
POPh2
POPh2
O
O
POPh2
POPh2
O
O
O
O
O
H
H
(S,S,S)-2a 35%
(S,S,R)-2b 36%
2: NaOH 30%
60 °C
1: HSiCl3, TEA
toluene, -78°C
2: NaOH 30%
60 °C
1: HSiCl3, TEA
toluene, -78°C
1a (90%)
Scheme 1. Synthesis of (S,S,Sax)-DIOPHEP 1a and (S,S,Rax)-DIOPHEP 1b.
1b (92%)

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E. Cesarotti et al. / Tetrahedron: Asymmetry 19 (2008) 1654–1659
Figure 2. CD spectra of 1a, 1b, 2a, 2b, (+)-3a and (ꢀ)-3b.
for 1a and 60° for 1b, enough to confirm that the bite angles bn
must be rather different, and as a consequence, the complexes
derived from the two diastereoisomers should show different
behaviours in asymmetric hydrogenations. These preliminary con-
siderations are supported by a more accurate computational inves-
tigation. We calculated the dihedral angles and the bite angles of
both diastereoisomeric metal complexes of DIOPHEP 1a and 1b.
Moreover, we refined our theoretical approach calculating the
‘flexibility range’ of the complexes.
All energy minimizations were carried out with a Polak-Ribiere
algorithm (RMS gradient 0.015 kcal molꢀ1 Åꢀ1), assuming the mol-
ecules in the gas phase.
As underlined by Van Leeuwen21 in evaluating these geometri-
cal parameters, it is more important to calculate a correct ‘trend’
rather than perfect geometries. Moreover, in order to correctly
compare the bite and dihedral angles of different metal-complexes,
all ligands in a series should be modelled under identical condi-
tions, using the same program, the same force field and the same
parameter set. As a consequence, with the double aim of validating
the calculation method and to compare the geometric features
amongst our phosphines and some well-known ligands, we opti-
mized the geometry and calculated the flexibility range of the me-
tal complexes of two diphosphines, BINAP and Hex-PQ-Phos
(Fig. 3).
According to reported methods, we performed calculations at
molecular mechanics level using the MM+ force field, (an imple-
mented version of Allinger MM219 force field included in the HYPER-
Ò
CHEM molecular modelling program),20 specifically developed for
small and middle sized organic molecules. Minimizations were
performed on the diphosphine–metal fragment without incorpora-
tion of other ligands at the metal centre. A ‘metal dummy atom’
(M) was used to direct the lone pairs of the phosphine ligands.
The M–P distance was fixed at 2.315 Å, an average length of the
M–P bond in Rh and Ru complexes (force constant
100,000 kcal molꢀ1 Åꢀ1), whilst the force constant of P–M–P bond
angle was imposed to 0 kcal molꢀ1 degꢀ1 in order to eliminate
any contribution of the metal. Best conformations are obtained to-
wards an accurate conformational search. The flexibility range of
each complex was calculated towards a sequence of geometry opti-
mization, with the bite angle fixed at given values using restraints
(force constant 100,000 kcal molꢀ1 Åꢀ1) and energies were evalu-
ated by subsequent single point calculation without restraints.
We focused our attention on BINAP for its obvious pivotal and
reference role in asymmetric hydrogenation with Ru(II) complexes
and Hex-PQ-Phos diphosphines recently developed by Chan
et al.12b,22 These ligands are diastereoisomers in which the biaryl
scaffold is tethered by a chiral chain of 4 carbon atoms where
the diphosphines are more comparable to those reported in the
present paper because they fulfil contemporary to two conditions:
a chain and stereogenic atoms on it.
Calculated dihedral angles (h) and bite angles (bn) are summa-
rized in Table 1; from these results we can foresee some conse-
quences regarding the potential selectivity of ligands 1a and 1b:
(a) the activity of 1a, whose calculated metal complex display
PPh2
PPh2
PPh2
PPh2
O
O
PPh2
PPh2
O
O
(R,R,Sax)-Hex-PQ-Phos
(R,R,Rax)-Hex-PQ-Phos
(S)-BINAP
Figure 3.

E. Cesarotti et al. / Tetrahedron: Asymmetry 19 (2008) 1654–1659
1657
Table 1
The ligand (S,S,Sax)-DIOPHEP 1a gave the highest enantioselec-
tivities, always more than 94% either in the reduction of b-ketoest-
ers, (entries 1 and 3) or in the reduction of geraniol (entry 5),
whilst the diastereoisomer (S,S,Rax)-DIOPHEP 1b gave enantiose-
lectivities lower that 80% (entries 2, 4 and 6). These results could
be the result of the higher critical angles (bn and h) of (S,S,Sax)-
DIOPHEP 1a to the higher enantioselectivity making it rather sim-
ilar to BINAP and to (R,R,Sax)-Hex-PQ-Phos which have analogous
values of bn and h and an almost super-imposable flexibility range;
in our hands, the BINAP and [Ru(p-cymene)I]+Iꢀ catalyst precursor
gave enantioselectivities clustered around 95–97% ee in the reduc-
tion of substrates 6, 7 and 8 whilst (R,R,Sax)-Hex-PQ-Phos gives (S)-
6 in 99% ee.20
The confirmation of a strict relationship between the calculated
dihedral angle of the diphosphine when coordinated to a metal and
the enantioselectivity would come from the stereodifferentiating
ability of (R,R,Rax)-Hex-PQ-Phos. We have calculated for (R,R,Rax)-
Hex-PQ-Phos a h angle of 55.5° and a bn of 90.6° lower than that
of (R,R,Rax)-Hex-PQ-Phos and even that of (S,S,Rax)-DIOPHEP 1b;
unfortunately no data are available for this ligand which appar-
ently has not been synthetized. It is likely that the different stereo-
differentiating abilities of (S,S,Sax)-DIOPHEP 1a and (S,S,Rax)-
DIOPHEP 1b should be due also to the presence of the fused oxo-
lane ring which dictates a conformational rigidity of the biaryl
scaffold. The different dihedral angles in (+)-1a and (ꢀ)-1b impose
a more or less pronounced equatorial/axial disposition of the
phenyl groups of the diphosphine. It is worth mentioning that this
axial/equatorial disposition of the phenyl groups, giving them
the role of chirality transmitters, generates the C2 symmetry at
the metal which in turn determines the stereodifferentiation
on the incoming prochiral substrate.
Calculated dihedral and bite angle of diphosphine ligands
Ligand
E MM+ (kcal/mol)
h (°)
bn (°)
(S)-BINAP
44.6
78.3
83.1
81.2
82.8
71.5
73.0
55.5
72.7
61.4
98.6
101.1
90.6
100.7
93.0
(R,R,Sax)-Hex-PQ-Phos
(R,R,Rax)-Hex-PQ-Phos
(+)-(S,S,Sax)-1a
(ꢀ)-(S,S,Rax)-1b
the broader dihedral and bite angle, is similar to BINAP and to
(R,R,Sax)-Hex-PQ-Phos because they have comparable values of
critical angles and an almost super-imposable flexibility range
(Fig. 4); (b) on the other hand the metal complex of 1b shows
rather lower calculated geometrical parameters.
The ligands have been tested in the Ru-catalyzed hydrogena-
tions of some selected substrates, in particular in the reduction
of methyl 3-oxobutanoate 6, ethyl 2-(benzamidomethyl)-3-oxo-
butanoate 7 and geraniol 8; the complex [Ru(p-cymene)I]+Iꢀ has
been chosen as a catalyst precursor due to the good results ob-
tained in the reduction of 7, a valuable intermediate in the synthe-
sis of azetidinone which is in turn the precursor of Carbapenem;23
the asymmetric hydrogenations of ketones were carried out in
CH2Cl2/MeOH, (7:3 v/v) at 60 °C and at 50 atm H2; the reduction
of geraniol was carried out in MeOH at 20 °C and 100 atm H2;
the results are summarized in Table 2.
Table 2
Catalyzed reduction of b-ketoesters 6 and 7 and of geraniol 8
O
O
3. Experimental
O
O
O
HN
O
OH
O
All chemicals and solvents are commercially available and were
used after distillation or treatment with drying agents. Silica gel
F254 thin-layer plates were employed for thin-layer chromatogra-
Ph
8
6
7
phy (TLC). Silica gel 40–63 lm/60A was employed for flash column
Entry
Substrate
Ligand
de%
ee%
chromatography. Proton NMR spectra were recorded at room tem-
perature in CDCl3 at 500 MHz, with residual solvents as the inter-
nal reference. 13C NMR spectra were recorded at room temperature
in CDCl3 at 125.7 MHz, with residual solvents as the internal refer-
ence. The APT or DEPT sequences were used to distinguish the
methine and methyl carbon signals from those due to methylene
1
2
3
4
5
6
6
6
7
7
8
8
(+)-1a
(ꢀ)-1b
(+)-1a
(ꢀ)-1b
(+)-1a
(ꢀ)-1b
95.2 (S)
79.1 (R)
94.1(2R,3S)
73.7 (2S,3R)
97.0 (R)
56% (syn)
65% (syn)
65.2 (S)
Flexibility Range
11
10
9
S-BINAP
(R,R,R )-Hex-PQ-Phos
ax
(R,R,S )-Hex-PQ-Phos
ax
(S,S,S )- DIOPHEP 1a
ax
8
(S,S,R )-DIOPHEP 1b
ax
7
6
5
4
3
2
1
0
-1
75
80
85
90
95
100
105
110
115
120
125
bite angle
Figure 4. Flexibility range of different diphosphines.

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E. Cesarotti et al. / Tetrahedron: Asymmetry 19 (2008) 1654–1659
and quaternary carbons. Two-dimensional NMR experiments were
used, where appropriate, to aid in the assignment of structures.
HPLC analyses were performed with Merck-Hitachi 7100 pump,
ygenated 30% sodium hydroxide solution (10 mL) was added
carefully. The resulting mixture was then stirred at 60 °C until
the organic and aqueous layers became clear. The organic layer
was transferred via cannula to a Schlenk tube where, under nitro-
gen, was washed with degassed saturated NaCl solution (15 mL),
then with degassed water (15 mL), and finally dried over anhy-
drous Na2SO4 and concentrated under vacuum to give a crude
product. The crude product was washed with pentane (3 mL) to af-
ford 100.0 mg of pure (+)-(S,S,Sax)-DIOPHEP 1a as a white solid
(73% yield). (+)-(S,S,Sax)-DIOPHEP 1a: 1H NMR (500 MHz), CHCl3,
d (ppm) 1.28 (s, 3H, CH3), 1.37 (s, 3H, CH3), 3.56 (t, 1H, CH2,
J = 11.4), 4.08 (m, 1H, CH), 4.54 (dd, 1H, CH2, J = 3.7, 11.4), 6.74
(d, 1Harom, J = 7.64), 6.90 (d, 1Harom, J = 8.2), 7.12 (m, 2Harom),
7.17 (m, 3Harom), 7.29 (m, 4Harom), 7.46 (m, 2Harom); 31P
(500 MHz), CHCl3, d (ppm) ꢀ11.82; APCI(+)-MS m/z (relative inten-
loop 20 lL, detector HP 1050 DAD. Optical rotations were mea-
sured on a Perkin Elmer R241 polarimeter. The (RS)-(6,60-dihy-
droxybiphenyl-2,20-diyl)bis(diphenylphosphine oxide) was pre-
pared according to previously reported procedures.14
3.1. Synthesis of (S,S,Sax)-DIOPHEPO 2a and (S,S,Rax)-DIOPHEPO
2b
A well stirred suspension of (R,S)-(6,60-dihydroxybiphenyl-2,20-
diyl)bis(diphenylphosphine oxide) (0.6 g, 1.03 mmol), (S,S)-(ꢀ)-
2,3-O-isopropylidene-1,4-di-O-tosyl-threitol (0.48 g, 1.03 mmol)
and K2CO3 (0.35 g, 2.56 mmol) in dry butanol (18 mL) was heated
at 140 °C for 20 h. Then, the solvent was evaporated under reduced
pressure, and the crude mixture was taken up in ethyl acetate
(100 mL) and water (150 mL). The organic layer was separated
and the aqueous phase was extracted twice with ethyl acetate
(100 mL ꢁ 2). The combined organic phases were dried over anhy-
drous sodium sulphate, filtered and concentrated under vacuum.
The crude product was purified by flash chromatography on silica
gel using ethyl acetate/2-propanol (9:1) as eluent to give 0.53 g of a
1:1 mixture of diastereoisomeric (S,S,Sax)-DIOPHEPO 2a and
(S,S,Rax)-DIOPHEPO 2b (combined yield 71%). Finally, the two dia-
stereoisomers were separated by flash chromatography performed
with a mixture of chloroform and 2-propanol (97:3) containing
0.5% of triethylamine, yields progressively (S,S,Sax)-DIOPHEPO 2a
(0.25 g) and (S,S,Rax)-DIOPHEPO 2b (0.26 g).
sity): 681 (M+, 100); [a]D = +54.5 (c 0.33 in CH2Cl2).
3.3. Reduction of (S,S,Rax)-DIOPHEPO 2b to (ꢀ)-(S,S,Rax)-
DIOPHEP 1b
Reduction of (S,S,Rax)-DIOPHEPO 2b (100 mg, 0.13 mmol) per-
formed as described above for the preparation of (+)-(S,S,Sax)-DIOP-
HEP 1a afforded (ꢀ)-(S,S,Rax)-DIOPHEP 1b as
a white solid
(88.1 mg, 92% yield).
(ꢀ)-(S,S,Rax)-DIOPHEP 1b: 1H NMR (500 MHz), CHCl3, d (ppm)
1.26 (s, 3H, CH3), 1.36 (s, 3H, CH3), 3.70 (m, 1H, CH), 4.06 (t, 1H,
CH2, J = 10.7), 4.28 (dd, 1H, CH2, J = 1.9, 10.7), 6.63 (d, 1Harom
,
J = 7.8), 6.86 (d, 1Harom, J = 8.2), 7.14 (m, 2Harom), 7.20 (m, 3Harom),
7.29 (m, 4Harom), 7.44 (m, 2Harom); 31P (500 MHz), CHCl3, d (ppm)
ꢀ9.50; APCI(+)-MS m/z (relative intensity): 681 (M+, 100);
(S,S,Sax)-DIOPHEPO 2a: 1H NMR (500 MHz), CHCl3, d (ppm) 1.35
(s, 6H, CH3), 3.58 (dd, 1H, CH2, J = 11.2, 11.7), 4.02 (m, 1H, CH), 4.53
(dd, 1H, CH2, J = 3.7, 11.7), 6.85 (dd, 1Harom, J = 7.7, 13.3), 7.06 (d,
1Harom, J = 8.3), 7.20 (tdd, 1Harom, J = 3.3, 7.7, 8.3), 7.32 (m, 4Harom),
7.39 (m, 2Harom), 7.49 (m, 2Harom), 7.74 (m, 2Harom); 13C NMR
(500 MHz), CHCl3, d (ppm) 27.2 (CH3), 69.8 (CH2), 76.6 (CH),
110.1 (C), 116.3, 126.4 (d), 127.4 (d), 127.8 (d), 128.1 (d), 130.8,
131.0, 132.3 (d), 132.8 (d) (Csp2 —H), 133.4, 133.6, 133.9, 134.2,
134.5, 134.8 (m, quaternary Csp2 , signals complicated by C–P cou-
pling), 154.7 (d, quaternary Csp2 ); 31P (500 MHz), CHCl3, d (ppm)
28.5; APCI(+)-MS m/z (relative intensity): 713 (M+, 100); HPLC
[a]
D = ꢀ45 (c 0.1 in CH2Cl2).
3.4. Preparation of [Ru(p-cymene) ((S,S,Sax)-DIOPHEP 1a)I]+Iꢀ
complex
To a Schlenk tube charged with (S,S,Sax)-DIOPHEP 1a (PM = 680;
13.6 mg; 0.02 mmol) and red brown diiodo(p-cymene)Ruthe-
nium(II) dimer (PM = 978.19; 8.8 mg; 0.009 mmol) was added
freshly distilled argon-degassed DMF (4 mL). The mixture was stir-
red at 100 °C for 2 h. The resulting brown solution was cooled to
50 °C and concentrated under reduced pressure to give [Ru(p-cym-
ene) ((S,S,Sax)-DIOPHEP 1a)I]+Iꢀ complex. The residue was left un-
der vacuum for 2 h; the ruthenium complex was utilized without
other purification in the enantioselective reduction reactions. 31P
NMR (300 MHz) CDCl3 d (ppm): 53.26–52.97 (d), 61.73–61.44
(d); FAB+ 908 (Mꢀ127 (ꢀI) = 781).
analysis was performed on
a LiChrospher RP-18E column
(125 ꢁ 4 mm), mobile phase methanol/water 70:30, flow rate
0.8 mL/min, T 30 °C, detection wavelength 210 nm.
(S,S,Rax)-DIOPHEPO 2b: 1H NMR (500 MHz), CHCl3, d (ppm) 1.33
(s, 6H, CH3), 3.73 (m, 1H, CH), 3.98 (dd, 1H, CH2, J = 11.0, 11.4), 4.24
(dd, 1H, CH2, J = 2.4, 11.0), 6.80 (dd, 1Harom, J = 7.7, 14.3), 7.10 (d,
1Harom, J = 8.1), 7.24 (tdd, 1Harom, J = 3.3, 7.7, 8.1), 7.30 (m, 4Harom),
7.38 (m, 2Harom), 7.45 (m, 2Harom), 7.72 (m, 2Harom); 13C NMR
(500 MHz), CHCl3, d (ppm) 27.0 (CH3), 73.8 (CH2), 80.2 (CH),
108.5 (C), 118.1, 126.3 (d), 127.4 (d), 127.8 (d), 128.5 (d), 130.7,
131.0, 132.3 (d), 132.7 (d) (Csp2 —H), 133.3, 133.8, 133.9, 134.2,
134.3, 134.8 (m, quaternary Csp2 , signals complicated by C–P cou-
pling), 157.5 (d, quaternary Csp2 ); 31P (500 MHz), CHCl3, d (ppm)
28.3; APCI(+)-MS m/z (relative intensity): 713 (M+, 100); HPLC
3.5. Preparation of [Ru(p-cymene)((S,S,Rax)-DIOPHEP 1b)I]+Iꢀ
complex
The complex was prepared as [Ru(p-cymene) ((S,S,Sax)-DIOPHEP
1a)I]+Iꢀ, described above.
31P NMR (300 MHz) CDCl3 d (ppm): 51.3–51.01 (d), 62.6–62.32
(d); FAB+ 908 (Mꢀ127 (ꢀI) = 781).
analysis was performed on
a LiChrospher RP-18E column
(125 ꢁ 4 mm), mobile phase methanol/water 70:30, flow rate
3.6. General procedure for the hydrogenation of methyl 3-oxo-
butanoate 6
0.8 mL/min, T 30 °C, detection wavelength 210 nm.
3.2. Reduction of (S,S,Sax)-DIOPHEPO 2a to (+)-(S,S,Sax)-DIOPHEP
1a
In a Schlenk tube sealed with a rubber septum under an argon
atmosphere, the substrate (1 equiv) was added to the [Ru(p-
cymene)I(DIOPHEP)]+Iꢀ 3 (0.01 equiv), followed by 20 mL of dis-
tilled methanol. The solution was stirred for 30 min and then
transferred to an autoclave with a cannula. The stainless steel auto-
clave (200 mL), equipped with temperature control and magnetic
stirrer, was purged five times with hydrogen before use. After
the transfer of the reaction mixture, the autoclave was pressurized
HSiCl3 (0.407 mL, 4.04 mmol) was carefully added under nitro-
gen at 0 °C to a mixture of (S,S,Sax)-DIOPHEPO 2a (0.144 g,
0.202 mmol) and dry triethylamine (0.558 mL, 4.04 mmol) in dry
and degassed toluene (12 mL). The mixture was stirred and re-
fluxed overnight. Then the solution was cooled to 0 °C and a deox-

E. Cesarotti et al. / Tetrahedron: Asymmetry 19 (2008) 1654–1659
1659
3. Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H. Comprehensive Asymmetric Catalysis I–
III; Springer: Berlin, Heidelberg, New York, 2000.
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5. The choice of a chiral chain derived from tartaric acid is a tribute (particularly
from one of us, E.C.) to H. B. Kagan, a Master and one of the founders of the
metal-mediated asymmetric catalysis together with R. Noyori.
6. (a) Miyashita, A.; Yasuda, H.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi, T.; Noyori,
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at 50 atm and then warmed at 60 °C. At the end of the reaction, the
autoclave was vented, the catalyst was removed by filtration on a
short pad of cellulose and the solvent was evaporated. The conver-
sion was determined by 1H NMR. The enantiomeric excess of the
product was determined by GC on a chiral stationary phase column
(MEGA DAcTButSilBETA (25 m, internal diameter 0.35 mm).
3.7. General procedure for hydrogenation of ethyl-2-
(benzamidomethyl)-3-oxobutanoate 7
7. (a) Schmid, R.; Cereghetti, M.; Heiser, B.; Shonholzer, P.; Hansen, H. Helv. Chim.
Acta 1988, 71, 897–929; (b) Schmid, R.; Broger, E.; Crameri, Y.; Foricher, J.;
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Cesarotti, E. J. Chem. Soc., Chem Commun. 1995, 6, 685–686; (b) Cesarotti, E.;
Antognazza, P.; Sannicolò, F.; Benincori, T.; Brenna, E.; Trimarco, L.; Demartin,
F.; Pilati, T. J. Org. Chem. 1996, 61, 6244–6251; (c) Cesarotti, E.; Benincori, T.;
Piccolo, O.; Sannicolò, F. J. Org. Chem. 2000, 65, 2043–2047.
In a Schlenk tube sealed with a rubber septum under an argon
atmosphere, the substrate (1 equiv) was added to the [Ru(p-
cymene)I(DIOPHEP)I]+Iꢀ 3 (0.01 equiv), followed by 20 mL of a
mixture of CH2Cl2 and methanol (7:3 v/v). The solution was stirred
for 30 min and then transferred to an autoclave with a cannula. The
stainless steel autoclave (200 mL), equipped with temperature
control and magnetic stirrer, was purged five times with hydrogen
before use. After the transfer of the reaction mixture, the autoclave
is pressurized at 50 atm and then warmed at 60 °C. At the end of
the reaction, the autoclave was vented, the catalyst was removed
by filtration on a short pad of cellulose and the solvent was evap-
orated. The conversion was determined by 1H NMR. The diastereo-
isomeric excess and enantiomeric excess of the product were
determined by HPLC on a chiral stationary phase column (Diacel
Chiralcel ODÒ, n-hexane/isopropanol = 9:1; flow rate 0.6 mL/min,
k = 230 nm).
9. Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008–2022.
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3.8. General procedure for hydrogenation of geraniol 8
In a Schlenk tube sealed with a rubber septum under an argon
atmosphere, the substrate (1 equiv) was added to the [Ru(p-
cymene)I(DIOPHEP)I]+Iꢀ
3 (0.01 equiv), followed by 20 mL of
methanol. The solution was stirred for 30 min and then transferred
to an autoclave with a cannula. The stainless steel autoclave
(200 mL), equipped with temperature control and magnetic stirrer,
was purged five times with hydrogen before use. After the transfer
of the reaction mixture, the autoclave was pressurized at 100 atm
and stirred at room temperature. At the end of the reaction, the
autoclave was vented, the catalyst was removed by filtration on
a short pad of cellulose and the solvent was evaporated. The con-
version was determined by 1H NMR. The enantiomeric excess of
the product was determined by GC on a chiral stationary phase col-
umn (MEGA DAcTButSilBETA (25 m, internal diameter 0.35 mm).
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