A new class of versatile chiral-bridged atropisomeric diphosphine ligands: Remarkably efficient ligand syntheses and their applications in highly enantioselective hydrogenation reactions

Article abstract of DOI:10.1021/ja0602694

A series of chiral diphosphine ligands denoted as PQ-Phos was prepared by atropdiastereoselective Ullmann coupling and ring-closure reactions. The Ullmann coupling reaction of the biaryl diphosphine dioxides is featured by highly efficient central-to-axial chirality transfer with diastereomeric excess >99%. This substrate-directed diastereomeric biaryl coupling reaction is unprecedented for the preparation of chiral diphosphine dioxides, and our method precludes the tedious resolution procedures usually required for preparing enantiomerically pure diphosphine ligands. The effect of chiral recognition was also revealed in a relevant asymmetric ring-closure reaction. The chiral tether bridging the two aryl units creates a conformationally rigid scaffold essential for enantiofacial differentiation; fine-tuning of the ligand scaffold (e.g., dihedral angles) can be achieved by varying the chain length of the chiral tether. The enantiomerically pure Ru- and Ir-PQ-Phos complexes have been prepared and applied to the catalytic enantioselective hydrogenations of α- and β-ketoesters (C=O bond reduction), 2-(6′-methoxy- 2′-naphthyl)-propenoic acid, alkyl-substituted β-dehydroamino acids (C=C bond reduction), and N-heteroaromatic compounds (C=N bond reduction). An excellent level of enantioselection (up to 99.9% ee) has been attained for the catalytic reactions. In addition, the significant ligand dihedral angle effects on the Ir-catalyzed asymmetric hydrogenation of N-heteroaromatic compounds were also revealed.

Full text of DOI:10.1021/ja0602694

Published on Web 04/08/2006
A New Class of Versatile Chiral-Bridged Atropisomeric
Diphosphine Ligands: Remarkably Efficient Ligand
Syntheses and Their Applications in Highly Enantioselective
Hydrogenation Reactions
Liqin Qiu, Fuk Yee Kwong, Jing Wu, Wai Har Lam, Shusun Chan, Wing-Yiu Yu,
Yue-Ming Li, Rongwei Guo, Zhongyuan Zhou, and Albert S. C. Chan*
Contribution from the Open Laboratory of Chirotechnology of the Institute of Molecular
Technology for Drug DiscoVery and Synthesis and Department of Applied Biology and
Chemical Technology, The Hong Kong Polytechnic UniVersity,
Hung Hom, Kowloon, Hong Kong
Received January 13, 2006; E-mail: bcachan@polyu.edu.hk
Abstract: A series of chiral diphosphine ligands denoted as PQ-Phos was prepared by atropdiastereo-
selective Ullmann coupling and ring-closure reactions. The Ullmann coupling reaction of the biaryl
diphosphine dioxides is featured by highly efficient central-to-axial chirality transfer with diastereomeric
excess >99%. This substrate-directed diastereomeric biaryl coupling reaction is unprecedented for the
preparation of chiral diphosphine dioxides, and our method precludes the tedious resolution procedures
usually required for preparing enantiomerically pure diphosphine ligands. The effect of chiral recognition
was also revealed in a relevant asymmetric ring-closure reaction. The chiral tether bridging the two aryl
units creates a conformationally rigid scaffold essential for enantiofacial differentiation; fine-tuning of the
ligand scaffold (e.g., dihedral angles) can be achieved by varying the chain length of the chiral tether. The
enantiomerically pure Ru- and Ir-PQ-Phos complexes have been prepared and applied to the catalytic
enantioselective hydrogenations of R- and â-ketoesters (CdO bond reduction), 2-(6′-methoxy-2′-naphthyl)-
propenoic acid, alkyl-substituted â-dehydroamino acids (CdC bond reduction), and N-heteroaromatic
compounds (CdN bond reduction). An excellent level of enantioselection (up to 99.9% ee) has been attained
for the catalytic reactions. In addition, the significant ligand dihedral angle effects on the Ir-catalyzed
asymmetric hydrogenation of N-heteroaromatic compounds were also revealed.
Introduction
The design and development of new chiral ligands for
efficient chirality transfer has a pivotal role in transition metal-
catalyzed asymmetric reactions.1 In this regard, chelating
diphosphine ligands with an atropisomeric biaryl scaffold proved
to be highly efficient chiral inducers in many enantioselective
transformations.2-7
asymmetric hydrogenation of certain substrates (e.g., R- and
â-ketoesters3e,f,5b) using these diphosphine ligands remains
problematic due to the lack of ligand rigidity. Moreover, several
Among many successful ligand systems, axially chiral BI-
NAP, MeO-Biphep, and P-Phos, etc. are the prototypical
supporting ligands that have found widespread uses in many
metal-catalyzed asymmetric reactions. Notable examples include
enantioselective hydrogenations and hydrosilylations with re-
markable degree of enantioselectivities.2a-c,8-9 Notwithstanding,
(2) (a) Pai, C.-C.; Lin, C.-W.; Lin, C.-C.; Chen, C.-C.; Chan, A. S. C. J. Am.
Chem. Soc. 2000, 122, 11513. (b) Pai, C.-C.; Chan, A. S. C. U.S. Patent
5,886,182, 1999. (c) Wu, J.; Ji, J.-X.; Chan, A. S. C. Proc. Natl. Acad.
Sci. U.S.A. 2005, 102, 3570. (d) Wu, J.; Chen, H.; Zhou Z.-Y.; Yeung
C.-H.; Chan, A. S. C. Synlett 2001, 1050. (e) Wu, J.; Chen, H.; Kwok
W.-K.; Lam K.-H.; Zhou Z.-Y.; Yeung C.-H.; Chan, A. S. C. Tetrahedron
Lett. 2002, 43, 1539. (f) Kwong, F. Y.; Li, Y.-M.; Lam, W. H.; Qiu, L.;
Lee, H. W.; Yeung, C. H.; Chan, K. S.; Chan, A. S. C. Chem. Eur. J.
2005, 11, 3872.
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2002, 43, 2789. (b) Duprat de Paule, S.; Champion, N.; Ratovelomanana-
Vidal, V.; Geneˆt, J.-P. Fr. Patent 2,830,254, 2001. (c) Duprat de Paule, S.;
Jeulin, S.; Ratovelomanana-Vidal, V.; Geneˆt, J.-P.; Champion, N.; Dellis,
P. Eur. J. Org. Chem. 2003, 1931. (d) Duprat de Paule, S.; Jeulin, S.;
Ratovelomanana-Vidal, V.; Geneˆt, J.-P.; Champion, N.; Dellis, P. Tetra-
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manana-Vidal, V.; Geneˆt, J.-P.; Champion, N.; Dellis, P. Angew. Chem.,
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J. AM. CHEM. SOC. 2006, 128, 5955-5965
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A R T I C L E S
Qiu et al.
studies revealed the influence of the bite angles in the chiral
diphosphines on the reactivity and selectivity of some catalytic
reactions, and optimal dihedral angles are essential for attaining
high enantioselectivities in asymmetric catalysis.3c-e,5b,10 For
example, a family of Tunaphos ligands with adjustable dihedral
angles was shown to effect highly enantioselective Ru-catalyzed
hydrogenation of â-ketoesters and enol acetates.11
Chirality transfer from central to planar/axial asymmetry for
the syntheses of optically active biaryl-derived diols has been
successfully demonstrated.12 Compared to the classical coupling-
resolution approaches, realization of highly diastereomeric aryl-
aryl coupling reactions through central-to-axial chirality transfer
is conceptually appealing since it avoids the tedious resolution
procedures for acquiring enantiomerically pure diphosphine
Figure 1. Central-to-axial chirality transfer for chiral ligand synthesis.
ligands (Figure 1). To our knowledge, the concept of central-
to-axial chirality transfer remains unexplored for the develop-
ment of atropisomeric biarylphosphines.
Pertinent to this concept, we previously pursued the inter-
molecular Ullmann coupling of two chiral dioxolane-modified
phosphine oxides with 40% de, and the two diastereomeric
diphosphine dioxides were separated chromatographically to
afford optically pure diphosphine ligands.13 The presence of
additional chiral centers on the ligand backbones was found to
exert significant influences on the enantioselectivity and activity
of the catalysts in asymmetric hydrogenations.13 Recently, we
succeeded in achieving a highly atropdiastereoselective Ullmann
coupling for preparing a novel bridged C2-symmetric biphenyl-
based diphosphine ligand (R)-[6,6′-(2S,3S-butadioxy)]-(2,2′)-
bis(diphenylphosphino)-(1,1′)-biphenyl [(Rax,2S,3S)-7a],14 ab-
breviated as RSS-7a. The atropdiastereoselective Ullmann
coupling reaction produced a diastereomerically pure biaryl
diphosphine dioxide, and thus no subsequent resolution was
required for the preparation of the enantiomerically pure chiral
ligand. The ligand RSS-7a showed excellent enantioselectivities
in asymmetric hydrogenations. As part of our continuing effort
in designing new ligand scaffolds for asymmetric catalysis, we
herein present a full account of the atropdiastereomeric Ullmann
coupling reactions for the synthesis of a series of atropisomeric
PQ-Phos such as (R,2S,3S)-Bu-PQ-Phos, 7a, (S,2R,4R)-Pent-
PQ-Phos, 7b, and (S,2R,5R)-Hex-PQ-Phos, 7c. Moreover, we
also present a ring-closure synthetic route (Scheme 2) as an
alternative pathway for preparing the opposite isomers of the
PQ-Phos ligands, which are unobtainable via the intramolecular
Ullmann coupling reaction. It is also noted that introduction of
a chiral bridge provides additional handles for fine-tuning the
ligand rigidity and the dihedral angle (and bite angle). The
catalytic activities of the Ru(II)- or Ir(I)-PQ-Phos complexes
in asymmetric hydrogenation reactions of R- and â-ketoesters,
2-(6′-methoxy-2′-naphthyl)propenoic acid, â-dehydroamino ac-
ids, and nitrogen-containing heteroaromatic compounds are
presented.
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Results and Discussion
Diastereoselective Ullmann Coupling Reactions. Scheme
1 depicts the diastereoselective Ullmann coupling reactions
(reaction e) for the synthesis of the chiral diphosphines 7.14
Treatment of diol tosylates/mesylates [n ) 0 (2a); n ) 1 (2b);
n )2, (2c)] with 3-bromoanisole afforded chiral bis(bromoether)
3a-c in 53%, 57%, and 74% yield, respectively. Lithium/
bromine exchange of 3 with n-BuLi followed by the addition
(13) Qiu, L.; Qi, J.; Pai, C.-C.; Chan, S.; Zhou, Z.; Choi, M. C. K.; Chan, A. S.
C. Org. Lett. 2002, 4, 4599.
(14) Qiu, L.; Wu, J.; Chan, S.; Au-Yeung, T. T.-L.; Ji, J.-X.; Guo, R.; Pai,
C.-C.; Zhou, Z.; Li, X.; Fan, Q.-H.; Chan, A. S. C. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5815.
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Chiral-Bridged Atropisomeric Diphosphine Ligands
A R T I C L E S
Scheme 1. Intramolecular Diastereoselective Coupling Pathwaysa
a Reaction conditions: (a) K2CO3 or Cs2CO3, DMSO, rt; (b) i. n-BuLi, THF, -78 °C; ii. Ph2PCl, -78 °C - rt; iii. H2O2, acetone, 0 °C; (c) i. LDA, THF,
-78 °C; ii. I2, -78 °C - rt; (d) i. LDA, -15 °C; ii. FeCl3, rt. (e) Cu, DMF, 140 °C; (f) HSiCl3, Bu3N, toluene, reflux.
of chlorodiphenylphosphine furnished the corresponding chiral
bridged arylphosphines, which were subsequently converted to
diphosphine oxides using 30% H2O2: 85% (4a), 86% (4b), and
91% (4c) yield. Ortho-lithiation with lithium diisopropylamide
at -78 °C followed by I2 quenching gave diiodides in good
yields: (89%) 5a, (82%) 5b, and 84% (5c).9b During an
optimization study, we found that when an iodine solution in
THF was added to the lithiated 4 at -78 °C, the product diiodide
was formed in only 30-40% yield along with a complicated
mixture of products. However, reversing the order of addition,
i.e., adding the lithiated 4 in THF to the iodine solution at -78
°C, afforded the diiodide products in up to 89% yield.
By employing the copper-mediated Ullmann coupling pro-
tocol, the chiral bridged phosphine oxides 5a-c underwent
homocoupling with excellent central-to-axial chirality transfer,
and the corresponding diphosphine dioxides [(RSS)-6a, de >
99%; (SRR)-6b, de > 99%; (SRR)-6c, de ) 98%] were obtained
in 91%, 71%, and 61% yields, respectively (Scheme 1).
Reduction of 6 with HSiCl3/Bu3N afforded the desired optically
pure PQ-Phos ligand 7a-c in 96%, 93%, and 97% yields,
respectively.
Previously, we showed that direct oxidative coupling of 4a
(n ) 0) was also a viable route to (RSS)-6a, which was formed
in 61% yield with > 99% de.14 In this study, we also attempted
to synthesize the chiral bridged diphosphine dioxides (SRR)-
6b,c directly from 4b,c (n ) 1 and 2) by the oxidative coupling
reaction. Using a lithium diisopropylamide/anhydrous FeCl3
procedure,14,15 the reactions of 4b and 4c produced (SRR)-6b
and (SRR)-6c in only 10-20% yields.
As noted earlier, the intramolecular Ullmann coupling reaction
of 5a produced (RSS)-6a with >99% diastereoselectivity. In
this work, the intramolecular Ullmann coupling of diiodides 5b,c
containing C3 (n ) 1)- and C4 (n ) 2)-bridges were examined.
For example, intramolecular coupling of 5b was found to
produce (SRR)-6b with >99% de based on 1H NMR and HPLC
analyses of the crude reaction mixture and optical rotation
measure of its crystal. Similarly, the analogous reaction of 5c
afforded (SRR)-6c in 98% de according to HPLC analysis of
the crude product. However, the intramolecular Ullmann
coupling reactions of 5b and 5c containing C3- and C4-bridges
gave the corresponding diphosphine dioxides in lower yields
[71% for (SRR)-6b and 61% for (SRR)-6c]. Nevertheless,
optically pure diphosphine dioxides 6b,c were obtained (71%
and 61% yields, respectively) after simple column chromatog-
raphy without chiral resolution.
Diastereomeric Ring-Closure Reaction. As noted above,
the chiral tether-directed intramolecular Ullmann coupling
reactions proved to be highly successful. However, attainment
of such a high diastereoselectivity limited the access to the other
diastereomers (e.g., (SSS)-6a, (RRR)-6b, and 6c) of the PQ-
Phos family of ligands. Considering the importance of structural
diversity in designing new chiral ligands for asymmetric
catalysis, we developed a diastereomeric ring-closure route for
preparing the other diastereomeric forms of the diphosphine
dioxides using C2-symmetric chiral diols as reagents (Scheme
2).
At the outset, demethylation of (S)- or (R)-MeO-BiphepO 8
with BBr3 followed by hydrolysis furnished (S)- or (R)-HO-
BiphepO 9 in 75% and 78% yields, respectively.16 Subsequently,
(S)- or (R)-9 reacted with (2R,3R)-butanediol dimesylate (2a)
in the presence of Cs2CO3 afforded (SSS)-6a or its diastereomer
(RSS)-6a in 58% and 64% yields, respectively. Likewise,
treatment of (S)- or (R)-9 with (2S,5S)-hexanediol tosylate (2c)
and K2CO3 as base produced (SRR)-6c in 68% yield. (RRR)-6c
was also isolated in 55% yield after chromatographic purifica-
tion.
The reaction of (S)-9 with (2S,4S)-pentanediol di-p-tosylate
(2b) produced (SRR)-6b in 72% yield via the ring-closure
reaction. However, if (R)-9 was employed as the starting
material, the (Rax)-form diastereomer was not obtained from the
1
analogous reaction with (2S,4S)-pentanediol di-p-tosylate. H
NMR analysis of the reaction mixture containing (R)-9 and
(2S,4S)-pentanediol di-p-tosylate revealed a mixture of oligo-
mers. With racemate 9 as the starting material, the reaction with
(15) (a) Evans, D. A.; Dinsmore, C. J. Tetrahedron Lett. 1993, 34, 6029. (b)
Feldman, K. S., Ensel, S. M.; Minard, R. D. J. Am. Chem. Soc. 1994, 116,
1742. (c) Feldman, K. S.; Ensel, S. M. J. Am. Chem. Soc. 1994, 116, 3357.
(d) Maitra, U.; Bandyopadhyay, A. K. Tetrahedron Lett. 1995, 36, 3749.
(16) Qiu, L.; Qi, J.; Ji, J.-X. Acta Crystallogr. 2003, C59, o33.
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A R T I C L E S
Qiu et al.
Scheme 2. Ring Closure Pathwaysa
a Reaction conditions: (a) BBr3, CH2Cl2, -78 °C- rt; (b) DMF, 55-60 °C, Cs2CO3 for 6a, K2CO3 for 6b, 6c.
Figure 2. ORTEP structures of diphosphine dioxides 6.
(2S,4S)-pentanediol di-p-tosylate gave (SRR)-6b exclusively as
a single diastereomer. These results clearly revealed the precise
chiral recognition directed by the linking unit in this ring-closure
reaction. To our best knowledge, this is the first successful
example to obtain single diastereomeric diphosphine oxides by
substrate-directed asymmetric ring-closure reaction. The mo-
lecular structures of 6a, 6b, 6c prepared via the two synthetic
routes were all determined by single-crystal X-ray diffraction
(Figure 2).
reactivity and selectivity of some asymmetric reactions.5b,11 It
is conceivable that the bite angle should increase with an
increase in the dihedral angles of the chelating atropisomeric
diphosphines. In this work, we have estimated the dihedral
angles of the PQ-Phos ligands 7a-7c using Chem 3D MM2
modeling, and the values are given in Table 1.17 To validate
this method, we also computed the dihedral angle of BINAP
by the Chem 3D MM2 method, and comparable values (86°
and 87°) to the literature values were obtained.3f,11a As shown
in Table 1, the dihedral angles show significant dependence on
MM2 Calculations of the Dihedral Angle of the New
Diphosphine Ligands. Bite angles (P-M-P) of chelating
diphosphine ligands are known to exert influence on the
(17) Chem 3D Ultra, 7.0.0 Version; Cambridge Scientific Computing, Inc., 2001.
9
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Chiral-Bridged Atropisomeric Diphosphine Ligands
A R T I C L E S
Table 1. Dihedral Angles of Ligands 7a-d
tions. As expected, comparable results (91-92% ee) were
obtained for the asymmetric hydrogenation of methyl pyruvate
(entries 10-13). The PQ-Phos ligands are also effective for the
asymmetric hydrogenation of ethyl R-ketoesters bearing bulky
R1 groups such as i-Pr, Ph, Ph(CH2)2; enantioselectivities of
96-98% ee have been attained (entries 14-31). To our
knowledge, these results are among the best thus far reported
for the homogeneous asymmetric hydrogenation of R-ketoesters.
A notable example in the literature is the asymmetric hydro-
genation of methyl benzoylformate using [RuI(p-cymene)-
BICHEP]I as a catalyst, and the product lactate was formed in
99% ee.18a
Asymmetric Hydrogenation of â-Ketoesters. The PQ-Phos
ligands have been applied for the catalytic hydrogenation of
â-ketoesters, and the results are summarized in Table 3.11a,19
Excellent ee’s of â-hydroxyesters were obtained with ligands
7a-c. In most cases, the ee’s compared favorably with the
results obtained using the MeO-Biphep or BINAP ligands. For
the hydrogenation of ethyl 2-chlorobenzoyl acetate, the Ru-
(BINAP) system was found to achieve only 16 and 10% ee for
the anti and syn products (entry 6). However, when the PQ-
Phos ligands (RSS)-7a and (SRR)-7b were employed for the
Ru-catalyzed ethyl 2-chlorobenzoyl acetate hydrogenation, the
anti-â-hydroxyester was obtained in 93% ee and 95% ee,
respectively. For the syn-â-hydroxyester, enantioselectivities of
26% (for RSS-7a) and 37% (for SRR-7b) were observed.
In this study, we did not observe significant variation of
enantioselectivities with the dihedral angles (64°-89°) of the
PQ-Phos ligands in the asymmetric hydrogenation of substrates
having small R1 and R2 groups (entries 1-4). This finding was
rather distinct from the earlier findings by Zhang and co-workers
involving TunaPhos as ligand.11a However, for â-ketoesters
having bulkier R1 or R2 groups such as ethyl benzoyl acetate
and ethyl 2-chlorobenzoyl acetate (R1 ) Ph, R2 ) Cl) (entries
5 and 6), the influence of the dihedral angles on the enantiose-
lectivities became more apparent. The best results (97% ee) for
ethyl benzoyl acetate were obtained using ligand (SRR)-7b with
a dihedral angle ) 80° (entry 5). This observation may be
attributed to the steric interaction between the substrates and
the PQ-Phos ligand.
ligand
(SSS)-7a (RSS)-7a (SRR)-7b (SRR)-7c MeO- BINAP
Biphep
83.2°
dihedral 64.8°
angle
-66.5°
80.0°
88.8°
86.6°
the length of the chiral tethers: 64.8° [(SSS)-7a], -66.5° [(RSS)-
7a], 80.0° [(SRR)-7b] and 88.8° [(SRR)-7c].
Asymmetric Hydrogenation of r-Ketoesters. The enanti-
oselective hydrogenation of R-ketoesters provides a direct
approach to optically pure R-hydroxyesters, which are important
blocks for organic syntheses. In contrast to the great success
achieved in the asymmetric hydrogenation of â-ketoesters, the
success in the homogeneous asymmetric hydrogenation of
R-ketoesters has been quite limited.3c-d,4e,5b,18 R-Ketoesters are
known to be sensitive substrates for asymmetric hydrogenation
and often require delicate optimization of reaction conditions.
Occasionally, acid additives may be necessary to increase both
the activity and selectivity of the ruthenium catalysts for the
hydrogenation of ketones.18b Recently, we reported some
preliminary results of the ruthenium-catalyzed enantioselective
hydrogenation of methyl benzoylformate.14 The reaction em-
ploying (RSS)-7a as ligand afforded much better enantioselec-
tivity (97% ee) than that when using BINAP (79% ee) as ligand.
Here we describe a comprehensive study on the scope and
limitations on the Ru-PQ-Phos-catalyzed asymmetric hydroge-
nation of R-ketoesters.
Treatment of ethyl pyruvate (R1 ) Me, R2 ) Et) with
[Ru(RSS-7a)(C6H5)Cl]Cl (0.167 mol %) in MeOH (1 mL) under
500 psig H2 at room temperature for 44 h furnished ethyl (R)-
lactate in 93% yield and 93% ee (Table 2, entry 1). The
formation of methyl (R)-lactate (7%) due to transesterification
was also detected by chiral GC analysis. The ruthenium catalyst
was prepared by heating [Ru(benzene)Cl2]2 and 7 in a solution
of EtOH and CH2Cl2, following a literature procedure. For the
asymmetric hydrogenation of pyruvate, the current Ru-catalyzed
system based on RSS-7a can be used with high efficiency under
relatively mild hydrogen pressure and room temperature without
the need of additives.
As shown in Table 2, methanol was the solvent of choice
for the Ru-PQ-Phos-mediated asymmetric hydrogenation. Poor
conversion and enantioselectivities were obtained in THF and
dichloromethane as solvent (entries 2 and 3). To avoid trans-
esterification of the ethyl esters, ethanol had been used as solvent
for the catalytic hydrogenation. The Ru-catalyzed hydrogenation
of ethyl pyruvate in ethanol showed 87% conversion after 48 h
with 84% ee (entry 4). Although higher reaction temperature
(50-90 °C) accelerated the reaction to complete substrate
consumption in 24 h, the enantioselectivities decreased to the
level of 76-79% ee (entries 5 and 6).
Asymmetric Hydrogenation of 2-(6′-Methoxy-2′-naphth-
yl)propenoic Acid. Asymmetric hydrogenation of 2-(6′-meth-
oxy-2′-naphthyl)propenoic acid is an economical method for
the preparation of naproxen, a nonsteroidal antiinflammatory
drug.2b,13,14,20 The PQ-Phos ligands have been tested in this
reaction. As shown in Table 4, the reactivities and enantiose-
lectivities of the Ru catalysts with 7a-c as ligands compared
favorably with the Ru(BINAP) and Ru(MeO-Biphep) systems.
Methanol was found to be the best solvent; better ee’s were
obatined at 0 °C and under 1000 psi H2 pressure. Little
dependence of the ee values upon the ligand dihedral angles
was observed.
The asymmetric hydrogenation of ethyl pyruvate using other
ligands SSS-7a, SRR-7b, and SRR-7c also gave excellent
enantioselectivity (89-90% ee) under similar reaction condi-
(19) For some reviews, see: (a) Ager, D. J.; Laneman S. A. Tetrahedron:
Asymmetry 1997, 8, 3327. (b) Kwong, F. Y.; Qiu, L.; Lam, W. H.; Chan,
A. S. C. In AdVances in Organic Synthesis; Jenner, G., Ed.; Bentham:
Pakistan, 2005; Vol. 1, pp 261-299. For some examples, see: (c) Hu, A.
Ngo, H. L.; Lin, W. Angew. Chem., Int. Ed. 2004, 43, 2501. (d) Kitamura,
M.; Tokunaga, M.; Ohkuma, T.; Noyori, R. Org. Synth., 1993, 71, 1.
(20) (a) Harrington, P. J.; Lodewijk, E. Org. Process Res. DeV., 1997, 1, 72.
(b) Chan, A. S. C. U.S. Patent 4,994,607, 1991. (c) Chan, A. S. C. U.S.
Patent 5,144,050, 1992. (d) Rieu, J.-P.; Boucherle, A.; Cousse, H.; Mouzin,
G. Tetrahedron 1986, 42, 4095. (e) Uemura, T.; Zhang, X.; Matsumura,
K.; Sayo, N.; Kumobayashi, H.; Ohta, T.; Nozaki, K.; Takaya, H. J. Org.
Chem. 1996, 61, 5510.
(18) (a) Chiba T.; Miyashita, A.; Nohira, H.; Takaya, H. Tetrahedron Lett. 1993,
34, 2351. (b) Mashima, K.; Kusano, K.-H.; Sato, N.; Matsumura, Y.-I.;
Nozaki, K.; Kumobayashi, H.; Sayo, N.; Hori, Y.; Ishizaki, T.; Akutagawa,
S.; Takaya, H. J. Org. Chem. 1994, 59, 3064. (c) Hapiot, F.; Agbossou,
F.; Mortreux, A. Tetrahedron: Asymmetry 1995, 6, 11. (d) Carpentier, J.-
F.; Mortreux, A. Tetrahedron: Asymmetry 1997, 8, 1083. (e) Burk, M. J.;
Pizzano, A.; Martin, J. A. Organometallics 2000, 19, 250. (f) Boaz, N.
W.; Debenham, S. D.; Mackenzie, E. B.; Large, S. E. Org. Lett. 2002, 4,
2421. (g) Boaz, N. W.; Mackenzie, E. B.; Debenham, S. D.; Large, S. E.;
Ponasik, J. A. J. Org. Chem. 2005, 70, 1872.
9
J. AM. CHEM. SOC. VOL. 128, NO. 17, 2006 5959

A R T I C L E S
Qiu et al.
Table 2. Asymmetric Hydrogenation of R-Ketoesters Catalyzed by [RuL(η6-C6H6)Cl]Cla
entry
R1
R2
ligand
solvent
T (°
C)
time (h)
conv (%)
10/(10
+11) %
ee of 10,b config
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
i-Pr
i-Pr
i-Pr
i-Pr
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
Et
Et
Et
Et
Et
Et
Et
(RSS)-7a
(RSS)-7a
(RSS)-7a
(RSS)-7a
(RSS)-7a
(RSS)-7a
(SSS)-7a
(SRR)-7b
(SRR)-7c
(SSS)-7a
(RSS)-7a
(SRR)-7b
(SRR)-7c
(SSS)-7a
(RSS)-7a
(SRR)-7b
(SRR)-7c
(SSS)-7a
(RSS)-7a
(SRR)-7b
(SRR)-7c
(SSS)-7a
(RSS)-7a
(RSS)-7a
(SRR)-7b
(SRR)-7c
(SSS)-7a
(RSS)-7a
(SRR)-7b
(SRR)-7c
(SRR)-7c
MeOH
THF
DCM
EtOH
EtOH
rt
rt
rt
rt
44
48
48
48
24
20
48
48
48
48
48
48
48
100
44
100
100
20
20
20
20
62
40
55
60
60
72
48
72
60
74
>99
16
0
87
93
-
93 (R)
-
-
-
100
100
100
92
96
97
-
84 (R)
79 (R)
76 (R)
90 (S)
90 (S)
89 (S)
91 (S)
92 (R)
91 (S)
91 (S)
96 (S)
98 (R)
97 (S)
96 (S)
97 (S)
98 (R)
98 (S)
97 (S)
96 (S)
97 (R)
98 (R)
96 (S)
95 (S)
97 (S)
98 (R)
96 (S)
97 (S)
97 (S)
50
90
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
96
EtOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
9
Et
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Me
Me
Me
Me
Et
Et
Et
Et
Me
Me
Me
Me
Et
Et
Et
Et
Et
-
-
-
97
99
97
96
-
-
-
-
88
93
89
88
89
92
94
84
89
79
>99
>99
99
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Et
Et
Et
Et
99
>99
>99
98
Et
>99
a Reaction conditions: substrate/catalyst ) 600:1 (mol/mol); substrate concentration ) 0.5 mmol/mL, P ) 500 psi H2. b The ee values were determined
by chiral GC with a J&W Scientific Cyclosil-B column.
a
Table 3. Asymmetric Hydrogenation of â-Ketoesters Catalyzed by RuLCl2(DMF)n
ee, config
entry
R1
R2
R3
(SSS)-7a
(RSS)-7a
(SRR)-7b
(SRR)-7c
(S)-MeO
−Biphep
(S)-BINAP
1b
2b
3b
4b
5c
6c
Me
Me
Me
ClCH2
Ph
H
H
H
H
H
Cl
Me
Et
CH2Ph
Et
Et
99.8 (S)
99.8 (S)
>99 (S)
97 (R)
89 (R)
71
>99 (R)
>99 (R)
>99 (R)
97 (S)
96 (S)
93
98 (S)
99 (S)
99 (S)
96 (R)
97 (R)
95
99 (S)
98 (S)
98 (S)
98 (S)
96 (R)
93 (R)
71
98 (S)
98 (S)
96 (S)
94 (R)
89 (R)
16
99 (S)
>99 (S)
96 (R)
95 (R)
73
Ph
Et
(13% anti)
(2S,3S)
9
(22% anti)
(2R,3R)
26
(2S,3S)
(28% anti)
37
(14% anti)
(2S,3S)
7
(16% anti)
(2S,3S)
5
(10% anti)
(2S,3S)
10
(87% syn)
(2R,3S)
(78% syn)
(2S,3R)
(72% syn)
(2R,3S)
(86% syn)
(2R,3S)
(84% syn)
(2R,3S)
(90% syn)
(2R,3S)
a Reaction conditions: solvents ) 12.5 µL CH2Cl2 + 987.5 µL MeOH or EtOH; reaction time ) 24 h, except for entry 6 (100 h); substrate/[Ru]) 667:1
(mol/mol), except for entry 6 (substrate/[Ru] ) 100/1); substrate concentration ) 0.5 mmol/mL; T ) 70 °C, except for entry 6 (room temperature) and entry
4 (optimum temperature, 70-100 °C); P ) 50 psi H2, except for entry 6 (1000 psi H2); complete conversions were obtained in all cases. b The ee values
were determined by chiral GC with a Varian CP Chirasil-DEX CB column (25 m × 0.25 mm) after converting the products to the corresponding acetyl
1
derivatives. c The ee values were determined by chiral HPLC with a Daicel Chiralcel OD column; the ratios of anti to syn products were determined by H
NMR.
Asymmetric Hydrogenation of (â-Acylamino)acrylates.
Enantiomerically pure â-amino acids and their derivatives are
important ingredients or intermediates for pharmaceutical
products.21 The asymmetric hydrogenation of dehydroamino
9
5960 J. AM. CHEM. SOC. VOL. 128, NO. 17, 2006

Chiral-Bridged Atropisomeric Diphosphine Ligands
A R T I C L E S
Table 4. Asymmetric Hydrogenation of 2-(6′-Methoxy-2′-naphthyl)propenoic Acid with [RuL(p-cymene)Cl]Cla,b
ee,conversionb
entry
P
H2 (psi)
T (°
C)
reaction time (h)
(SSS)-7a
(RSS)-7a
(SRR)-7b
(SRR)-7c
(S)-MeO
−Biphep
(S)-BINAP
1
2
3
4
5
1000
1500
1000
1000
1500
rt
rt
rt
0
4
4
0.5
24
24
91 (S)
93 (S)
91 (81%) (S)
96 (S)
97 (S)
90 (R)
91 (R)
89 (98%) (R)
95 (R)
96 (R)
89 (S)
90 (S)
89 (100%) (S)
95 (S)
95 (S)
88 (S)
90 (S)
88 (100%) (S)
95 (S)
95 (S)
89 (S)
90 (S)
89 (100%) (S)
94 (S)
89 (S)
90c (S)
89 (90%) (S)
94 (S)
0
94 (S)
-
a Reaction conditions: solvent ) MeOH (2.5 mL), substrate/catalyst ) 100:1 (mol/mol), substrate concentration ) 2.0 mg/mL. b The ee values were
determined by chiral HPLC with a Sumichiral OA-2500 column; complete conversions were obtained in all cases, except for entry 3. c P ) 1600 psi H2.
Table 5. Asymmetric Hydrogenation of â-(Acylamino)Acrylates
with [RuL(η6-C6H6)Cl]Cla
acteristic dependence of the enantioselectivity upon the dihedral
angles of the ligands was apparent. Substrates with a bulky alkyl
substituent gave the best ee (up to 99.9%, entry 11).
Asymmetric Hydrogenation of N-Heteroaromatic Com-
pounds. The asymmetric hydrogenation of CdN bonds is an
appealing protocol for the synthesis of chiral amines. The
enantioselective hydrogenation of quinolines and other N-
heteroaromatic compounds, which are easily available, provides
enantiomerically pure tetrahydroquinoxalines and heterocycloal-
kanes of great biological interest.24 Thus far, there are limited
successful literature examples concerning highly enantioselective
hydrogenation of CdN bond to chiral amines.25,26 Recently, the
asymmetric hydrogenation of quinolines using [Ir(COD)Cl]2/
MeO-Biphep/I2 catalyst was established and 83-95% yield and
>90% ee were reported.26a
In this regard, we undertook a study on the asymmetric
hydrogenation of N-heteroaromatic compounds using the PQ-
Phos ligands 7a-7c instead of MeO-Biphep. As shown in Table
6, this reaction was strongly solvent dependent. Toluene was
found to be the solvent of choice for the reaction of quinoline
12. For example, the best enantioselectivity (92% ee) was
obtained for the hydrogenation of 2,6-dimethylquinoline in
toluene (entry 3). Nevertheless, for the hydrogenation of
2-methylquinoxaline 13 and 2,3,3-trimethylindolenine 14, THF
and CH2Cl2 appeared to be the best solvents (entries 8 and 10).
Further studies are listed in Table 7.
ee,b config.
T
time
(h)
entry
R1
R2
(
°C)
(SSS)-7a
(RSS)-7a
(SRR)-7b
(SRR)-7c
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Et
Me rt
6
48
6
48
6
48
6
48
6
97 (R)
97 (R)
97 (R)
97 (R)
95 (R)
95 (R)
95 (R)
97 (R)
93 (R)
94 (R)
96 (S)
98 (S)
96 (S)
98 (S)
95 (S)
97 (S)
94 (S)
99 (S)
94 (S)
96 (S)
96 (R)
97 (R)
96 (R)
97 (R)
94 (R)
96 (R)
95 (R)
96 (R)
92 (R)
92 (R)
97 (R)
98 (R)
97 (R)
99 (R)
95 (R)
97 (R)
96 (R)
97 (R)
94 (R)
95 (R)
Me
Et
Et
0
rt
0
Me rt
Me
Et
0
i-Pr Me rt
i-Pr Me
n-Pr Et
0
rt
0
10 n-Pr Et
48
6
11 t-Bu Me rt
99.8 (R) 99.8 (S) 99.6 (R) >99.9 (R)
a
Reaction conditions: 1.7 mg substrate; substrate/catalyst ) 100 (mol/
mol); substrate concentration ) 0.05-0.09 M in MeOH, P ) 250 ps i H2;
the conversions were determined by NMR and GC analysis and were found
to be higher than 99.9% in all cases. b The ee values were determined by
chiral GC with a 25 m × 0.25 mm Chirasil-DEX CB column or 30 m ×
0.25 mm γ-DEX-225 column.
acids is one of the most efficient routes to the corresponding
optically active â-amino acids. Rh-catalyzed asymmetric hy-
drogenation of â-(acylamino)acrylates has recently been devel-
oped successufully.22 However, satisfactory examples with
ruthenium-catalyzed systems are limited.23
In this work, we found that the cationic Ru(II) complexes of
PQ-Phos showed a high level of asymmetric induction in the
asymmetric hydrogenation of â-alkyl-substituted â-(acylamino)-
acrylates (Table 5). Methanol was the best solvent for the
catalytic reaction. Generally, low reaction temperature (0 °C)
was essential to high enantioselectivity (>97% ee). No char-
(24) (a) Keay, J. D. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 8, pp 579-601. (b) Barton, D. H.
R.; Nakanishi, K.; Meth-Cohn, O., Eds. ComprehensiVe Natural Products
Chemistry; Elsevier: Oxford, 1999; Vol. 1-9.
(25) For early examples, see: (a) Spindler, F.; Pugin, B.; Blaser, H.-U. Angew.
Chem., Int. Ed. Engl. 1990, 29, 558. (b) Bakos, J.; Toth, I.; Heil, B.;
Szalontai, G.; Parkanyi, L.; Fulop, V. J. Organomet. Chem. 1989, 370,
263. (c) Kang, G.-J.; Cullen, W. R.; Fryzuk, M. D.; James, B. R.; Kutney,
J. P. J. Chem. Soc., Chem. Commun. 1988, 1466. (d) Vastag, S.; Bakos, J.;
Toros, S.; Takach, N. E.; King, R. B.; Heil, B.; Marko, L. J. Mol. Catal.
1984, 22, 283. (e) Ng Cheong Chan, Y.; Osborn, J. A. J. Am. Chem. Soc.
1990, 112, 9400. (f) Langlois, N.; Dang, T.-P.; Kagan, H. B. Tetrahedron
Lett. 1973, 4865. (g) Lensink, C.; de Vries, J. G. Tetrahedron: Asymmetry
1992, 3, 235. (h) Morimoto, T.; Nakajima, N.; Achiwa, K. Synlett 1995,
748. (i) Sablong, R.; Osborn, J. A. Tetrahedron Lett. 1996, 37, 4937. (j)
Schnider, P.; Koch, G.; Pre´toˆt, R.; Wang, G.; Bohnen, F. M.; Kru¨ger, C.;
Pfaltz, A. Chem. Eur. J. 1997, 3, 887. (k) Burk, M. J.; Feaster, J. E. J. Am.
Chem. Soc. 1992, 114, 6266. (l) Zhu, G.; Zhang, X. Tetrahedron:
Asymmetry 1998, 9, 2415. (m) Bianchini, C.; Barbaro, P.; Scapacci, G.;
Farnetti, E.; Graziani, M. Organometallics 1998, 17, 3308.
(21) Juaristi, E., Ed. EnantioselectiVe Synthesis of â-Amino Acids; Wiley-
VCH: New York, 1997.
(22) (a) Pen˜a, D.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. J. Am. Chem.
Soc. 2002, 124, 14552. (b) Tang, W.; Zhang, X. Org. Lett. 2002, 4, 4159.
(c) Lee, S.-g.; Zhang, Y. J. Org. Lett. 2002, 4, 2429. (d) Yasutake, M.;
Gridnev, I. D.; Higashi, N.; Imamoto, T. Org. Lett. 2001, 3, 1701. (e) Heller,
D.; Holz, J.; Drexler, H.-J.; Lang, J.; Drauz, K.; Krimmer, H.-P.; Bo¨rner,
A. J. Org. Chem. 2001, 66, 6816. (f) Zhu, G.; Chen, Z.; Zhang, X. J. Org.
Chem. 1999, 64, 6907. (g) Furukawa, M.; Okawara, T.; Noguchi, Y.;
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Zhou, Q.-L. J. Org. Chem. 2004, 69, 4648.
(26) For recent examples, see: (a) Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han,
X.-W.; Zhou, Y.-G. J. Am. Chem. Soc. 2003, 125, 10536. (b) Lu, S.-M.;
Han, X.-W.; Zhou, Y.-G. AdV. Synth. Catal. 2004, 346, 909. (c) Cobley,
C. J.; Henschke, J. P. AdV. Synth. Catal. 2003, 345, 195. (d) Giernoth, R.;
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Lett. 2004, 6, 2213. (g) Blaser, H.-U.; Buser, H.-P.; Ha¨usel, R.; Jalett, H.-
P.; Spindler, F. J. Organomet. Chem. 2001, 621, 34.
(23) (a) Lubell, W. D.; Kitamura, M.; Noyori, R. Tetrahedron: Asymmetry 1991,
2, 543. (b) Zhou, Y.-G.; Tang, W.; Wang, W.-B.; Li, W.; Zhang, X. J.
Am. Chem. Soc. 2002, 124, 4952. (c) Tang, W.; Wu, S.; Zhang, X. Am.
Chem. Soc. 2003, 125, 9570. (d) Wu, J., Chen, X., Guo, R., Yeung, C.-H.;
Chan, A. S. C. J. Org. Chem. 2003, 68, 2490.
9
J. AM. CHEM. SOC. VOL. 128, NO. 17, 2006 5961

A R T I C L E S
Qiu et al.
Table 6. Asymmetric Hydrogenation of N-Heteroaromatic
Compounds with (SRR)-7ba
genation of substrates 13 and 14 (Table 7, entries 6 and 8).
Hence, (SRR)-7b is probably a more general ligand in asym-
metric hydrogenation of substituted quinoline compounds.
Conclusions
A practical protocol for the synthesis of enantiopure, axially
chiral diphosphine ligands has been developed. The chiral-
bridged diphosphine ligands were successfully prepared via two
synthetic routes: highly diastereoselective Ullmann coupling
and ring-closure processes. The introduction of a chiral bridge
with variable chain length offered a great potential in ligand
dihedral angle fine-tuning. Moreover, the chiral bridge provided
extra ligand rigidity and chiral control, which led to high
enantioslectivity in asymmetric hydrogenation. In particular,
highly efficient central-to-axial chirality transfer was realized
in the Ullmann coupling for atropdiastereoselective synthesis
of biaryl diphosphine dioxides. Thus, no resolution step was
required for the preparation of the enantiomerically pure chiral
ligands. In addition, it was not even necessary to separate the
diastereomers since essentially perfect diastereoselectivity has
been achieved. This pathway is also of high atom economy.
Besides, the effect of chiral recognition was also revealed in a
relevant asymmetric ring-closure reaction. These methodologies
are obviously useful for the development of new enantiomeri-
cally pure phosphine ligands. The Ru or Ir complexes with PQ-
Phos ligands exhibited versatile use in the hydrogenation of Cd
O, CdC, and CdN bonds and showed excellent asymmetric
induction abilities. The dihedral angle effect of the ligands in
the Ir-catalyzed asymmetric hydrogenation of N-heteroaromatic
compounds was also revealed. Further modifications and
explorations of these ligands to other asymmetric catalytic
reactions are in progress.
entry
substrate
solvent
eeb (%)
config
1
2
3
4
5
6
7
8
9
12a
12a
12a
12a
13
13
13
13
14
i-PrOH
CH2Cl2
toluene
THF
i-PrOH
CH2Cl2
toluene
THF
i-PrOH
CH2Cl2
toluene
THF
58
80
92
84
-
64
61
80
15
72
50
42
S
S
S
S
R
R
R
R
R
R
R
10
11
12
14
14
14
a Reaction conditions: 0.2 mmol substrate, substrate/catalyst ) 100 (mol/
mol), substrate concentration ) 0.2 mmol/mL, P ) 700 psi H2, reaction
time ) 20 h, the conversions were higher than 99% in all cases. b The ee
values were determined by chiral HPLC.
Table 7. Asymmetric Hydrogenation of N-Heteroaromatic
Compoundsa
ee,b config
entry substrate solvent (RSS)-7a (SSS)-7a (SRR)-7b (SRR)-7c (S)-MeO−Biphep
1
2
3
4
5
6
7
8
9
12a toluene 85 (R) 88 (S) 92 (S) 91 (S)
12b toluene 82 (R) 88 (S) 89 (S) 79 (S)
12c
90 (S)
83 (S)
88 (S)
94 (S)
72 (R)
28 (R)
65 (R)
50 (R)
55 (R)
Experimental Section
toluene 77 (R) 81 (S) 89 (S) 84 (S)
12d toluene 89 (R) 92 (S) 93 (S) 92 (S)
General Procedures. All reactions were carried out under an inert
atmosphere of dry nitrogen and were followed by TLC. Glassware was
flame dried before use. Standard syringe techniques were applied to
transfer dry solvents and reagents. The preparation of samples and the
setup of the high-pressure reactor were carried out either in a nitrogen-
filled continuously purged MBRAUN model lab master 230 glovebox
12e
13
13
14
14
toluene 53 (S) 61 (R) 70 (R) 64 (R)
toluene 39 (S) 39 (R) 61 (R) 21 (R)
THF
toluene 27 (S) 32 (R) 50 (R) 27 (R)
CH2Cl2 72 (R)
-
-
80 (R)
-
-
-
-
a Reaction conditions: 0.2 mmol substrate, substrate/catalyst ) 100 (mol/
mol), substrate concentration ) 0.2 mmol/mL, P ) 700 psi H2, reaction
time ) 20 h, the conversions were higher than 99.9% in all cases. b The ee
values were determined by chiral HPLC.
1
or by using standard Schlenk-type techniques. H, 31P, and 13C NMR
spectra were recorded on a Varian 500 spectrometer (500, 202, and
125 MHz, respectively) or on a Bruker DPX-400 spectrometer (400,
162, and 100 MHz respectively). Chemical shifts (δ) were given in
ppm and were referenced to residual solvent peaks (1H NMR, 13C NMR)
or to an external standard (85% H3PO4, 31P NMR). Mass spectra and
accurate mass measurements were carried out with a VG MICRO-
MASS, Fison VG platform, or a Finnigan model Mat 95 ST instrument.
Optical rotations were recorded on a Perkin-Elmer 341 polarimeter in
a 10-cm cell. HPLC analyses were performed using a Waters model
600 with a Waters 486 UV detector. Gas chromatography was
performed on an HP 4890A GC with an FID detector. THF and toluene
were freshly distilled from sodium/benzophenone ketyl, while DMSO,
DMF, CH2Cl2, and Bu3N were distilled from CaH2 under nitrogen
atmosphere. MeOH and EtOH were distilled from magnesium under
nitrogen atmosphere. All other chemicals were used as received from
Aldrich, Acros, or Strem without further purification. All substrates
used in moisture-sensitive reactions were predried twice with toluene
azeotrope prior to use.
Treatment of 12a with [Ir(COD)Cl]2/ SRR-7b (1 mol %) in
the presence of I2 (10 mol %) in toluene at room temperature
and 700 psi H2 afforded 2,6-dimethyl-1,2,3,4-tetrahydroquino-
line in 90% yield and 92% ee (entry 1). Full substrate conversion
was achieved in 20 h based on crude 1H NMR analysis.
Similarly, 7b was also found to produce comparable results for
other substrates under identical reaction conditions (entries 2-9).
Interestingly, the enantioselectivities were highly sensitive
to the dihedral angles of the ligands in the hydrogenation of all
studied N-heteroaromatic substrates. With (RSS)-7a as ligand
(dihedral angle ) -66.5°), the catalytic hydrogenation of 12c
gave 6-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline in 93%
yield and 77% ee (Table 7, entry 3). Likewise, 91% yield and
84% ee were obtained for the analogous reaction with (SRR)-
7c as ligand (dihedral angle ) 88.8°). The best results (89%
ee) were attained with ligand (SRR)-7b with dihedral angle )
80.0°, which was close to that of MeO-Biphep (83.2°). A more
pronounced dihedral angle effect was observed for the hydro-
Synthesis of (2R,4R)-2,4-Bis(3-bromophenoxy)pentane (3b). A
mixture of 3-bromophenol (0.746 g, 4.3 mmol) and K2CO3 (1.192 g,
8.6 mmol) in DMSO (5 mL) was stirred at room temperature for 1 h,
and then a solution of (2S,4S)-pentanediol di-p-tosylate (0.889 g, 2.2
9
5962 J. AM. CHEM. SOC. VOL. 128, NO. 17, 2006

Chiral-Bridged Atropisomeric Diphosphine Ligands
A R T I C L E S
mmol) in DMSO (10 mL) was added dropwise into this mixture over
a period of 4 h. The mixture was continuously stirred at room
temperature for 48 h before pouring into water (100 mL). The organic
phase was extracted with CH2Cl2. The extract was treated with 2 N
HCl solution (10 mL) and washed with water and brine again. The
organic layer was separated, dried over Na2SO4, and concentrated in
vacuo. The residue was purified through a silica gel column (eluent:
EtOAc/hexane ) 5/100) to give a colorless oil, 3 (0.505 g, 1.2 mmol,
2H), 7.35-7.39 (m, 8H), 7.43-7.47 (m, 4H), 7.58-7.63 (m, 8H); 31
P
NMR (CDCl3) 202 MHz: δ 30.34; 13C NMR (CDCl3) 125 MHz: δ
19.23, 31.68, 73.40, 118.45, 118.53, 119.40, 119.42, 123.84, 123.92,
128.19, 128.29, 129.48, 129.59, 131.70, 131.73, 131.81, 132.58, 133.13,
133.95, 157.69, 157.81; MS (ESI) calcd for C42H40P2O4 [M]+ 670.7,
found 671; HRMS (ESI): calcd for C42H41P2O4 [M + H]+ 671.2481,
found 671.2407; [R]20 ) -13.2 (c ) 1, CHCl3).
D
Synthesis of (2R,4R)-2,4-Bis[2-iodo-3-(diphenylphosphoryl)phe-
noxy]pentane (5b). To a solution of compound 4b (1.00 g, 1.5 mmol)
in THF (40 mL) was added dropwise lithium diisopropylamide (1.7
mL, 2.0 M) at -78 °C over a period of half an hour. After stirring for
an additional 3 h, the reaction mixture was cannulated into a flask
containing I2 (1.523 g, 6.0 mmol) and 40 mL of THF at -78 °C over
30 min. The mixture was warmed to ambient temperature over 2 h,
and the reaction was continued overnight. After the evaporation of the
solvent with a rotary evaporator, the residue was dissolved in CH2Cl2
(50 mL). The resulting solution was washed successively with saturated
aqueous ammonium chloride solution, water, and saturated sodium
thiosulfate solution, followed by drying over anhydrous Na2SO4.
Concentration in vacuo gave a crude product. Purification by silica
gel column chromatography afforded pure compound 5b (1.117 g, 1.23
mmol, 82.0% yield). 1H NMR (CDCl3) 500 MHz: δ 1.34 (d, J ) 6.0
Hz, 6H), 2.07 (dd, J ) 5.5 Hz, 7 Hz, 2H), 4.77-4.83 (m, 2H), 6.55-
6.60 (m, 2H), 6.80 (d, J ) 8.0 Hz, 2H), 7.08 (dt, J ) 3.2 Hz, 7.5 Hz,
1
56.5% yield). H NMR (CDCl3) 500 MHz: δ 1.30 (d, J ) 6.0 Hz,
6H), 1.95 (dd, J ) 5.5 Hz, 7.0 Hz, 2H), 4.55-4.61 (m, 2H), 6.72-
6.75 (m, 2H), 6.96-7.06 (m, 6H); 13C NMR (CDCl3) 125 MHz: δ
20.06, 44.76, 71.07, 114.74, 119.44, 122.82, 123.92, 130.51, 158.83;
MS (EI + VE + LMR): calcd for C17H18Br2O2 [M]+ 414.1, found
414.0; HRMS (EI + VE + LMR): calcd for C17H18Br2O2 [M]+
411.9674, found 411.9726; [R]20 ) -77.2 (c ) 1, hexane).
D
Synthesis of (2R,5R)-2,5-Bis(3-bromophenoxy)hexane (3c). 3c was
prepared from 1 and (2S,5S)-hexanediol-ditosylate (2c) by following
the same procedure described above for 3b as a colorless oil (74.4%
yield). 1H NMR (CDCl3) 500 MHz: δ 1.34 (d, J ) 6.5 Hz, 6H), 1.71-
1.77 (m, 2H), 1.88-1.92 (m, 2H), 4.37-4.41 (m, 2H), 6.83-6.86 (m,
2H), 7.09-7.17 (m, 6H); 13C NMR (CDCl3) 125 MHz: δ 19.43, 31.79,
73.59, 114.38, 118.88, 122.71, 123.47, 130.48, 158.69; HRMS (EI +
VE + LMR): calcd for C18H20Br2O2 [M]+ 425.9830, found 425.9896;
2H), 7.40-7.46 (m, 8H), 7.51-7.55 (m, 4H), 7.61-7.68 (m, 8H); 31
P
[R]20 ) -26.0 (c ) 1, CHCl3).
NMR (CDCl3) 202 MHz: δ 34.66; 13C NMR (CDCl3) 125 MHz: δ
20.03, 44.76, 72.82, 93.85, 93.91, 116.55, 116.57, 128.10, 128.19,
128.37, 128.41, 128.46, 128.51, 128.85, 128.96, 131.38, 131.68, 131.70,
131.72, 132.03, 132.11, 132.18, 132.23, 137.00, 137.84, 157.16, 157.26.
MS (ESI) calcd for C41H36I2P2O4 [M]+ 908.5, found 909; HRMS
(ESI): calcd for C41H37I2P2O4 [M + H]+ 909.0257, found 909.0283;
D
Synthesis of (2R,4R)-2,4-Bis[3-(diphenylphosphoryl)phenoxy]-
pentane (4b). Compound 3b (2.64 g, 6.4 mmol) was azeotropically
dried with dry toluene (15 mL × 2) and dissolved in dry THF (80
mL). n-BuLi (13.5 mmol, 1.6 M solution in hexane) was added
dropwise into the solution at -78 °C within 30 min under N2. After
stirring for an additional 1 h at this temperature, chlorodiphenylphos-
phine (2.5 mL, 13.5 mmol) in THF (5 mL) was added dropwise to the
resulting mixture. The reaction was continued at -78 °C for 1 h and
then at room temperature overnight. The resulting light-yellow solution
was extracted with CH2Cl2/water. The organic phase was separated,
washed with water and brine, and dried over Na2SO4. After evaporation
of the solvent, a light-yellow solid was obtained. The residue was
purified by silica gel column chromatography (eluent: EtOAc/hexane
) 5/100) to give a colorless oily solid. An aqueous H2O2 solution (30%,
8.5 mL) was added to a solution of this oily solid in acetone (30 mL)
at 0 °C. The reaction was monitored by thin-layer chromatography.
The product was extracted with dichloromethane twice. The combined
extract was washed successively with Na2S2O3 solution, water, and
brine, was dried over anhydrous Na2SO4, and was concentrated in vacuo
to give a crude product. Purification by silica gel column chromatog-
raphy (eluent: EtOAc/CHCl3/MeOH ) 200/200/20) afforded a pure
[R]20 ) -126.8 (c ) 1, CHCl3).
D
Synthesis of (2R,5R)-2,5-Bis[2-iodo-3-(diphenylphosphoryl)phe-
noxy]hexane (5c). 5c was prepared from 4c by following the same
1
procedure described above for 5b (84.0% yield). H NMR (CDCl3)
500 MHz: δ 1.34 (d, J ) 6.5 Hz, 6H), 1.82-1.86 (m, 2H), 1.94-1.98
(m, 2H), 4.35-4.50 (m, 2H), 6.63-6.69 (m, 2H), 6.88 (d, J ) 8.5 Hz,
2H), 7.17 (dt, J ) 7.6 Hz, 3.0 Hz, 2H), 7.42-7.48 (m, 8H), 7.51-
7.56 (m, 4H), 7.66-7.71 (m, 8H); 31P NMR (CDCl3) 202 MHz: δ
34.86; 13C NMR (CDCl3) 125 MHz: δ 19.26, 31.42, 75.38, 93.98,
94.03, 116.18, 127.87, 127.97, 128.19, 128.28, 128.29, 128.50, 128.61,
131.10, 131.50, 131.52, 131.82, 131.85, 131.89, 131.93, 137.01, 137.85,
157.01, 157.11; HRMS (ESI): calcd for C42H39I2P2O4 [M + H]+
923.0414, found 923.0385; [R]20 ) -62.0 (c ) 1, CHCl3).
D
Synthesis of (S)-[6,6′-(2S,3S-Butadioxy)]-(2,2′)-bis(diphenylphos-
phoryl)-(1,1′)-biphenyl [(SSS)-6a]. Synthetic Route II: Ring-Closure
Pathway. (S)-(6,6′-Dihydroxybiphenyl-2,2′-diyl)bis(diphenylphosphine
oxide) 9 (0.550 g, 0.938 mmol) was stirred at ambient temperature in
DMF (50 mL) in the presence of Cs2CO3 (2.445 g, 7.508 mmol) for
an hour. Into this mixture was added dropwise a DMF (25 mL) solution
of (2R,3R)-butanediol-dimesylate 2a (0.925 g, 3.755 mmol) for 3 h at
room temperature. The reaction continued at 60 °C for 48 h. The DMF
was distilled off under reduced pressure. The residue was dissolved in
CH2Cl2 and washed with water and brine successively. The organic
solution was dried over anhydrous Na2SO4 and was concentrated in
vacuo to give a crude product which could be purified by silica gel
column chromatography to obtain a pure white solid (SSS)-6a (0.346
1
colorless solid 4b (3.62 g, 5.5 mmol, 86.2% yield based on 3b). H
NMR (CDCl3) 500 MHz: δ 1.22 (d, J ) 6.0 Hz, 6H), 1.90 (t, J ) 6.3
Hz, 2H), 4.53-4.59 (m, 2H), 6.89-6.92 (m, 2H), 7.04 (dd, J ) 12.0
Hz, 7.5 Hz, 2H), 7.14-7.21 (m, 4H), 7.38-7.64 (m, 20H); 31P NMR
(CDCl3) 202 MHz: δ 32.13; 13C NMR (CDCl3) 125 MHz: δ 19.90,
44.36, 70.93, 119.22, 119.31, 119.59, 119.61, 124.23, 124.32, 128.39,
128.49, 129.62, 129.74, 131.92, 131.98, 132.06, 132.72, 133.23, 134.05,
157.87, 157.99; MS (ESI) calcd for C41H38P2O4 [M]+ 656.7, found 657;
HRMS (CI): calcd for C41H39P2O4 [M + H]+ 657.2324, found
1
g, 0.540 mmol, 57.6% yield based on (S)-9). H NMR (CDCl3): δ
657.1990; [R]20 ) -61.0 (c ) 1, CHCl3).
1.04 (d, J ) 5.0 Hz, 6H), 3.95-4.03 (m, 2H), 6.72 (d, J ) 8.0 Hz,
2H), 6.94 (dd, J ) 13.5 Hz, 7.0 Hz, 2H), 7.06 (dt, J ) 7.8 Hz, 3.3 Hz,
2H), 7.19-7.22 (m, 4H), 7.29-7.44 (m, 12H), 7.70-7.75 (m, 4H);
31P NMR: δ 28.69; 13C NMR: δ 19.43, 78.30, 125.37, 127.44, 127.53,
127.86, 127.89, 127.95, 127.98, 128.52, 128.64, 130.58, 130.60, 130.98,
131.00, 131.86, 131.93, 132.41, 132.49, 133.31, 134.15, 135.27, 136.10,
154.98, 155.08; HRMS (ESI): calcd for C40H35P2O4 [M + H]+
D
Synthesis of (2R,5R)-2,5-Bis[3-(diphenylphosphoryl)phenoxy]-
hexane (4c). 4c was prepared from 3c by following the same procedure
1
described above for 4b as a pure, colorless solid (91.2% yield). H
NMR (CDCl3) 500 MHz: δ 1.16 (d, J ) 6.0 Hz, 6H), 1.52-1.58 (m,
2H), 1.71-1.79 (m, 2H), 4.26-4.32 (m, 2H), 6.93-6.96 (m, 2H), 7.05
(dd, J ) 11.5 Hz, 6.5 Hz, 2H), 7.16-7.20 (m, 2H), 7.22-7.27 (m,
641.2011, found 641.1973. [R]20 ) +134.5 (c ) 1, CHCl3).
D
9
J. AM. CHEM. SOC. VOL. 128, NO. 17, 2006 5963

A R T I C L E S
Qiu et al.
Synthesis of (R)-[6,6′-(2S,3S-Butadioxy)]-(2,2′)-bis(diphenylphos-
phoryl)-(1,1′)-biphenyl [(RSS)-6a]. Synthetic Route II. (RSS)-6a was
prepared from (R)-9 and 2a by following the same procedure described
above for (SSS)-6a as a pure white solid (63.7% yield).
Synthesis of (S)-[6,6′-(2S,3S-Butadioxy)]-(2,2′)-bis(diphenylphos-
phino)-(1,1′)-biphenyl [(SSS)-7a]. A 100-mL, two-necked flask flitted
with a magnetic stirring bar and a reflux condenser was charged with
(SSS)-6a (515 mg, 0.804 mmol, 100% de) and the system was flushed
with nitrogen gas and azeotropically dried with dry toluene (10 mL ×
2). Under nitrogen atmosphere dry and degassed toluene (10 mL),
tributylamine (3.8 mL, 16.1 mmol), and trichlorosilane (1.7 mL, 16.1
mmol) were added to the flask by means of syringe. The mixture was
stirred at reflux overnight. After the solution was cooled to 0 °C, a
30% aqueous sodium hydroxide solution (24 mL) was carefully added.
The mixture was then stirred at 60 °C until the organic and aqueous
layers become clear. The organic product was extracted with toluene
(10 mL × 3, under nitrogen atmosphere), and the extract was washed
successively with water (10 mL × 2) and brine (10 mL × 2) and dried
over anhydrous Na2SO4. The organic layer was concentrated under
reduced pressure to give a crude product containing tributylamine. It
was washed with hexane (3 × 2 mL) to give a pure white, powdery
Synthesis of (S)-[6,6′-(2R,4R-Pentadioxy)]-(2,2′)-bis(diphenylphos-
phoryl)-(1,1′)-biphenyl [(SRR)-6b]. Synthetic Route I. Asymmetric
Ullmann Coupling. DMF (5 mL) was added into a flask containing
Cu powder (0.215 g, 3.36 mmol) and 5b (0.382 g, 0.42 mmol). The
resulting mixture was stirred at 140 °C for 12 h under a nitrogen
atmosphere. After the removal of the DMF solvent under reduced
pressure, the residue was boiled for 5 min with hot CHCl3 (10 mL ×
3). The insoluble solid was removed by filtration and was washed with
hot CHCl3 (5 mL × 3). The combined filtrate was washed successively
with saturated aqueous ammonium chloride and brine and was dried
over anhydrous Na2SO4. After the solvent was removed, the residue
was purified by silica gel column chromatography to give (SRR)-6b as
a white solid (194 mg, 0.296 mmol, 70.5% yield) and a recovered
compound 4c (50 mg, 0.076 mmol, 18.1% yield).1H NMR (CDCl3)
500 MHz: δ 1.19-1.21 (d, J ) 6 Hz, 6H), 1.64 (t, J ) 4.0 Hz, 2H),
4.31-4.36 (m, 2H), 6.82 (d, J ) 7.5 Hz, 2H), 6.86-6.90 (dd, J )
13.3 Hz, 7.8 Hz, 2H), 7.04-7.14 (m, 6H), 7.24 (t, J ) 7.3 Hz, 2H),
7.31-7.35 (m, 8H), 7.41 (t, J ) 7.5 Hz, 2H), 7.65-7.69 (dd, J ) 11.5
Hz, 7.0 Hz, 4H); 31P NMR (CDCl3) 202 MHz: δ 29.29; 13C NMR
(CDCl3) 125 MHz: δ 21.84, 40.57, 75.52, 120.52, 120.54, 126.77,
126.86, 127.19, 127.29, 127.80, 127.89, 128.44, 128.55, 130.43, 130.45,
131.00, 132.36, 132.44, 132.54, 133.01, 133.25, 133.69, 134.11, 134.51,
134.94, 156.99, 157.10; MS (ESI): calcd for C41H36P2O4 [M]+ 654.7,
found 655; HRMS (ESI): calcd for C41H37P2O4 [M + H]+ 655.2168,
1
product (SSS)-7a (489 mg, 95.0% yield). H NMR (CDCl3): δ 0.95
(d, J ) 6.5 Hz, 6H), 3.92-3.99 (m, 2H), 6.28 (d, J ) 8.5 Hz, 2H),
6.73-6.76 (m, 2H) 7.05-7.09 (m, 6H), 7.16-7.26 (m, 6H), 7.32-
7.37 (m, 6H), 7.49-7.53 (m, 4H); 31P NMR: δ -6.58; 13C NMR: δ
18.75, 76.93, 122.68, 127.74, 127.77, 127.80, 127.84, 128.10, 128.26,
128.29, 128.31, 128.36, 128.59, 133.07, 133.19, 133.31, 133.55, 133.63,
133.72, 134.17, 134.26, 134.35, 136.51, 136.54, 136.58, 138.17, 138.23,
138.30, 140.80, 140.82, 140.84, 154.80, 154.83, 154.86; MS (ESI):
calcd for C40H34P2O2 608.6, found 609; HRMS (ESI): calcd for
C40H35P2O2 [M + H]+ 609.2113, found 609.2087. [R]20D ) +351.5 (c
) 1, toluene).
found 655.2181; [R]20 ) +170.0 (c ) 1, CHCl3).
Synthesis of (S)-[6,6′-(2R,4R-Pentadioxy)]-(2,2′)-bis(diphenylphos-
phino)-(1,1′)-biphenyl [(SRR)-7b]. (SRR)-7b was prepared from (SRR)-
6b by following the same procedure described above for (SSS)-7a as
D
Synthetic Route II. (S)-(6,6′-Dihydroxybiphenyl-2,2′-diyl)bis(diphen-
ylphosphine oxide) 9 (0.403 g, 0.68 mmol), was stirred at ambient
temperature in DMF (50 mL) in the presence of K2CO3 (0.51 g, 3.70
mmol) for an hour. To this mixture was added dropwise a solution of
of (2S,4S)-pentanediol-di-p-tosylate (1.135 g, 2.75 mmol) in DMF (30
mL) over a period of 3 h at room temperature. The reaction continued
at room temperature for 12 h and then at 55 °C for 72 h. After the
removal of the DMF solvent under reduced pressure, the residue was
dissolved in CH2Cl2. The resulting solution was washed successively
with water and brine, followed by drying over anhydrous Na2SO4 and
concentration in vacuo to give a crude product. Purification was
performed by silica gel column chromatography as synthetic route I to
afford (SRR)-6b as a white solid (323 mg, 0.49 mmol, 71.7% yield
based on substrate 9). The acquired spectra and the optical rotation are
the same as those acquired via synthetic route I.
1
a white powder (93.1% yield). H NMR (CDCl3) 500 MHz: δ 1.23
(d, J ) 6.5 Hz, 6H), 1.72 (t, J ) 4.0 Hz, 2H), 4.36-4.42 (m, 2H),
6.68 (d, J ) 8.0 Hz, 2H), 6.83 (d, J ) 7.5 Hz, 2H), 7.05-7.20 (m,
12H), 7.30-7.40 (m, 6H), 7.56-7.60 (m, 4H); 31P NMR (CDCl3) 202
MHz: δ -9.88; 13C NMR (CDCl3) 125 MHz: δ 22.03, 40.72, 74.97,
118.03, 127.40, 127.56, 127.58, 128.16, 128.19, 128.22, 128.25, 128.63,
133.47, 133.55, 133.62, 133.81, 133.90, 133.98, 135.43, 135.56, 135.69,
137.38, 137.42, 137.45, 138.51, 138.57, 138.63, 138.70, 157.61, 157.65,
157.70; MS (ESI): calcd for C41H36P2O2 [M]+ 622.7, found 623; HRMS
(ESI): calcd for C41H37P2O2 [M + H]+ 623.2269, found 623.2250;
[R]20 ) +313.8 (c ) 1, toluene).
D
Synthesis of (S)-[6,6′-(2R,5R-Hexadioxy)]-(2,2′)-bis(diphenylphos-
phino)-(1,1′)-biphenyl [(SRR)-7c). (SRR)-7c was prepared from (SRR)-
6c by following the same procedure described above for (SSS)-7a as a
light-yellow needle crystal (97% yield). 1H NMR (CDCl3): δ 1.00 (d,
J ) 6.5 Hz, 6H), 1.17-1.20 (m, 2H), 1.71-1.78 (m, 2H), 4.36-4.44
(m, 2H), 6.62 (d, J ) 7.5 Hz, 2H), 6.75 (d, 8.5 Hz, 2H), 7.08-7.17
Synthesis of (S)-[6,6′-(2R,5R-Hexadioxy)]-(2,2′)-bis(diphenylphos-
phoryl)-(1,1′)-biphenyl [(SRR)-6c]. Synthetic Route I. (SRR)-6c was
prepared from 5c by following the same procedure described above
for (SRR)-6b as a white solid (61.0% yield). At the same time,
(R)-[6,6′-(2R,5R-hexadioxy)]-(2,2′)-bis(diphenylphosphoryl)-(1,1′)-bi-
phenyl ((RRR)-6c) was produced as a trace part. The ratio of (SRR)-6c
to (RRR)-6c was 99:1 by HPLC analysis (HPLC conditions: AD-H
column, eluent: hexane/i-PrOH ) 85/15, λ ) 254 nm, flow rate )
0.5 mL/min); t1 ) 19.8 min for (SRR)-6c. t2 ) 41.2 min for (RRR)-
6c). A recovered compound 4c was also acquired in 20.5% yield.
Synthetic Route II. (SRR)-6c was prepared from (S)-9 and 2c by
following the same procedure described above for (SSS)-6a (68.4%
yield). 1H NMR (CDCl3): δ 0.97 (d, J ) 6 Hz, 6H), 1.16 (d, 10.0 Hz,
2H), 1.72 (d, J ) 9.0 Hz, 2H), 4.42-4.49 (m, 2H), 6.82 (dd, J ) 13.5
Hz, 7.5 Hz, 2H), 6.88 (d, J ) 8.0 Hz, 2H), 7.11-7.15 (m, 2H), 7.20-
7.23 (m, 4H), 7.32-7.38 (m, 6H), 7.41-7.45 (m, 6H), 7.74 (dd, J )
11.8 Hz, 7.2 Hz, 4H); 31P NMR: δ 30.03; 13C NMR: δ 18.65, 25.63,
75.61, 118.90, 125.88, 125.98, 127.31, 127.40, 127.80, 127.89, 128.05,
130.49, 130.51, 130.94, 132.27, 132.35, 132.55, 132.63, 132.78, 133.36,
133.65, 133.88, 134.19, 134.71, 155.82, 155.93; HRMS (ESI): calcd
for C42H39P2O4 [M + H]+ 669.2324, found 669.2251; [R]20D ) +76.0
(c ) 1, CHCl3).
(m, 12H), 7.24-7.26 (m, 6H), 7.38-7.41 (m, 4H); 31P NMR:
δ
-10.75; 13C NMR: δ 19.28, 27.17, 75.82, 115.75, 126.42, 127.50,
127.52, 127.55, 127.60, 127.92, 128.10, 128.12, 128.14, 128.45, 133.60,
133.69, 133.77, 133.82, 133.91, 133.99, 134.88, 135.02, 135.16, 137.46,
137.50, 137.55, 138.62, 138.67,138.74, 139.23, 139.25, 139.27, 156.41,
156.46, 156.50; HRMS (ESI): calcd for C42H39P2O2 [M + H]+
637.2425, found 637.2402; [R]20 ) +243.5 (c ) 1, Toluene).
D
Synthesis of (S)-(6,6′-Dihydroxybiphenyl-2,2′-diyl)bis(diphen-
ylphosphine oxide) ((S)-9). (S)-9 was prepared from (S)-8 by following
the same procedure reported in the literature as a white powder (83.0%
conversion, 90.9% selectivity).16 1H NMR (d-DMSO) 500 MHz: δ
6.53 (dd, J ) 13.8 Hz, 7.3 Hz, 2H), 6.72 (d, J ) 8.0 Hz, 2H), 6.97-
7.00 (m, 2H), 7.28-7.55 (m, 20H), 9.00 (s, 1H); 31P NMR (d-DMSO)
202 MHz: δ 29.2; 13C NMR (CD3OD + CD2Cl2) 100 MHz: δ 123.83,
129.71, 129.84, 132.50, 132.62, 132.69, 132.85, 135.15, 136.04, 136.19,
136.57, 136.67, 136.78, 136.88, 137.03, 137.13, 138.07, 138.17, 160.08,
160.22; HRMS (EI): calcd for C36H28P2O4 [M]+ 586.1463, found.
586.1439; [R]20 ) -80.6 (c ) 1, 1:1 CH2Cl2 + MeOH).
D
9
5964 J. AM. CHEM. SOC. VOL. 128, NO. 17, 2006

Chiral-Bridged Atropisomeric Diphosphine Ligands
A R T I C L E S
Synthesis of (R)-(6,6′-Dihydroxybiphenyl-2,2′-diyl)bis(diphen-
ylphosphine oxide) ((R)-9). (R)-9 was prepared from (R)-8 by following
the same procedure reported in the literature as a white powder (85.0%
conversion, 91.6% selectivity).16 1H NMR (d-DMSO) 500 MHz: δ
6.54 (dd, J ) 13.3 Hz, 8.3 Hz, 2H), 6.73 (d, J ) 8.0 Hz, 2H), 6.97-
7.01 (m, 2H), 7.28-7.56 (m, 20H), 9.01 (s, 1H); 31P NMR (d-DMSO)
202 MHz: δ 29.2; 13C NMR (CD3OD + CD2Cl2) 100 MHz: δ 123.99,
129.80, 129.92, 132.50, 132.53, 132.62, 132.66, 132.83, 135.07, 136.04,
136.55, 136.65, 136.78, 136.88, 137.00, 137.23, 138.04, 138.27, 160.12,
160.26; HRMS (ESI): calcd for C36H29P2O4 [M + H]+ 587.1541, found
R-ketoesters, â-ketoesters, 2-(6′-methoxy-2′-naphthyl)propenoic acid,
and â-dehydroamino acids were carried out by following the same
procedures described in the literature.14
General Procedures for the Asymmetric Hydrogenation of
N-Heteroaromatic Compounds. A mixture of [Ir(COD)Cl]2 (1 × 10-3
mmol) and ligand (2.2 × 10-3 mmol) in toluene (1 mL) was stirred at
room temperature for 30 min in a drybox, and the solution was
transferred to an autoclave into which I2 (1 × 10-2 mmol) and substrate
(0.2 mmol) had been placed beforehand. The hydrogenation reaction
was performed at room temperature under H2 (700 psi) for 20 h. After
releasing the hydrogenation, the reaction mixture was diluted with
dichloromethane (4 mL), and to this was added saturated Na2CO3
solution (1 mL), after which the mixture was then stirred for 15 min.
The aqueous layer was extracted with dichloromethane (5 mL × 3),
and the combined organic layers were dried over Na2SO4 and
concentrated to afford the crude product. Purification was performed
by a silica gel column eluted with hexane/EtOAc to give pure product.
The enantiomeric excesses were determined by chiral HPLC with chiral
columns (OJ-H for 12a-12c and 13, 14, OD-H for 12d, AS-H for
12e).
587.1530; [R]20 ) +80.2 (c ) 1, 1:1 CH2Cl2 + MeOH).
D
Preparation of Catalysts RuLCl2(DMF)n, [RuL(η6-C6H6)Cl]Cl
and [RuL(η6-C6H6)Cl]Cl. Catalysts RuLCl2(DMF)n, [RuL(η6-C6H6)-
Cl]Cl and [RuL(η6-C6H6)Cl]Cl were prepared by following the same
procedures reported in the literature.14
31P NMR (202 MHz, CD2Cl2) for [RuL(η6-C6H6)Cl]Cl:
[Ru(SSS-7a)(η6-C6H6)Cl]Cl: δ 31.53 (d, J ) 65.1 Hz), 38.37 (d, J )
65.1 Hz);
[Ru(SRR-7b)(η6-C6H6)Cl]Cl: δ 31.87 (d, J ) 65.4 Hz), 39.22 (d, J )
65.4 Hz);
[Ru(SRR-7c)(η6-C6H6)Cl]Cl: δ 31.60 (d, J ) 64.8 Hz), 38.62 (d, J )
64.8 Hz).
Acknowledgment. We thank the Hong Kong Research Grants
Council (Project # PolyU 5001/04 P), University Grants
Committee Areas of Excellence Scheme in Hong Kong (AoE
P/10-01) and the Hong Kong Polytechnic University Area of
Strategic Development Fund for financial support.
31P NMR (202 MHz, CDCl3) for [RuL(p-cymene)Cl]Cl:
[Ru(SSS-7a)(p-cymene)Cl]Cl: δ 29.40 (d, J ) 64.1 Hz), 43.10 (d, J
) 64.1 Hz);
[Ru(SRR-7b)(p-cymene)Cl]Cl: δ 28.90 (d, J ) 64.4 Hz), 43.00 (d, J
) 64.4 Hz);
[Ru(SRR-7c)(p-cymene)Cl]Cl: δ 28.74 (d, J ) 63.8 Hz), 42.63 (d, J
) 63.8 Hz);
[Ru(S)-MeO-Biphep(p-cymene)Cl]Cl: δ 27.04 (d, J ) 63.0 Hz), 41.49
(d, J ) 63.0 Hz).
General Procedures for the Asymmetric Hydrogenation of
r-Ketoesters, â-Ketoesters, 2-(6′-Methoxy-2′-naphthyl)propenoic
Acid and â-Dehydroamino Acids. Asymmetric hydrogenation of
Supporting Information Available: Spectroscopic charac-
terization for all new compounds; crystallographic data for
compounds (SSS)-6a, (SRR)-6b, and (SRR)-6c in CIF format.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JA0602694
9
J. AM. CHEM. SOC. VOL. 128, NO. 17, 2006 5965