Phenol-derived chiral phosphine-phosphite ligands in the rhodium-catalyzed enantioselective hydrogenation of functionalized olefins

Article abstract of DOI:10.1016/j.tetasy.2010.10.026

A set of 15 chiral Taddol- and Binol-based phosphine-phosphite ligands were tested in the Rh-catalyzed asymmetric hydrogenation of three olefins, methyl 2-hydroxymethyl-acrylate, 1-phenylvinyl acetate, and α-methyl cinnamic acid. The best enantioselectivities (up to 92% ee) were observed in the hydrogenation of methyl 2-hydroxymethyl-acrylate using Binol-based ligands. As previously observed in other applications of this class of modular chiral ligand in enantioselective catalysis, the stereochemical outcome of the reactions greatly depended on the substituents at the ligand aryl backbone in the ortho-position to the chiral phosphite unit.

Full text of DOI:10.1016/j.tetasy.2010.10.026

Tetrahedron: Asymmetry 21 (2010) 2671–2674
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Phenol-derived chiral phosphine–phosphite ligands in the
rhodium-catalyzed enantioselective hydrogenation of functionalized olefins
Tobias Robert a, Zohar Abiri b, Albertus J. Sandee b, Hans-Günther Schmalz a, , Joost N. H. Reek b,
⇑
⇑
a Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Köln, Germany
b Van’t Hoff Institute for Molecular Sciences, University of Amsterdam, Nieuwe Achtergracht 166, 1018 WV Amsterdam, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
A set of 15 chiral Taddol- and Binol-based phosphine–phosphite ligands were tested in the Rh-catalyzed
asymmetric hydrogenation of three olefins, methyl 2-hydroxymethyl-acrylate, 1-phenylvinyl acetate,
and a-methyl cinnamic acid. The best enantioselectivities (up to 92% ee) were observed in the hydroge-
nation of methyl 2-hydroxymethyl-acrylate using Binol-based ligands. As previously observed in other
applications of this class of modular chiral ligand in enantioselective catalysis, the stereochemical out-
come of the reactions greatly depended on the substituents at the ligand aryl backbone in the ortho-
position to the chiral phosphite unit.
Received 15 September 2010
Accepted 28 October 2010
Available online 20 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
intermediate in the synthesis of dihydroxycalamenenes
(Scheme 1a).7 Furthermore, ligands 1d and 1e performed better
Chiral bifunctional ligands have become an indispensable tool in
the development of new powerful metal-catalytic asymmetric
transformations1 and a broad variety of bidentate ligands have been
described and optimized over the last few decades.2 Among those,
non-symmetrical architectures with two electronically different
co-ordinating functionalities have proven to be superior in certain
cases to C2-symmetric compounds, as they allow better adjustment
tospecificreactionsystems.3 Inthiscontext, chiralphosphine–phos-
phites and phosphine–phosphoramidites have attracted much
interest due to the different donor abilities of their phosphorus func-
tions. Ligands of this type were successfully applied in Rh-catalyzed
hydrogentions4 and hydroformylation5 reactions.
As a contribution to this field, we recently reported an efficient
modular synthesis of novel non-symmetrical bidentate chiral
phosphine–phosphite ligands of type 1–4 (Fig. 1).6 These ligands
are accessible within only four synthetic steps starting from inex-
pensive substituted phenols as the backbone building blocks. By
employing different phenols, chlorophosphines, and chiral diols,
a high degree of variation of the ligand structure can be achieved.
The remarkable potential of this class of modular chiral ligand was
demonstrated in our laboratories in a range of transition metal-
catalyzed reactions. As a first example, ligand 1b proved to be
superior (also in comparison to Binap) in the Rh-catalyzed asym-
metric hydroboration of the substituted styrene derivative 5, an
in the Cu-catalyzed asymmetric 1,4-addition of Grignard reagents
to cyclohexenone (Scheme 1b).8 It is noteworthy that these ligands
allowed us for the first time to transfer aryl- and alkenyl magne-
sium halides with high enantioselectivity. A third successful appli-
cation is the Cu-catalyzed allylic substitution of cinnamic chlorides
with Grignard reagents. Ligand 1g was remarkable in giving the
products in excellent regioselectivity and enantioselectivities of
up to 99% ee (Scheme 1c).9
In the last example, the performance of our ligands was exam-
ined in the Rh-catalyzed asymmetric hydroformylation of styrene
(Scheme 1d).10 In this case, ligands 1d–f in combination with
Rh(acac)(CO)2 induced high regioselectivities (up to 99:1) and
good enantioselectivities (up to 85% ee). Taddol-based phos-
phine–phosphite ligands were found to perform particularly well
in this type of reaction, surpassing the corresponding Binol-based
ligands of type 2.
As Scheme 1 indicates, different ligands were identified as being
suitable for different (individual) reaction systems. In this context,
the modular nature of our ligands greatly facilitated both the syn-
thesis of ligand libraries (for screening) and the structural optimi-
zation of promising ligands. It is noteworthy that Taddol-based
ligands of type 1 proved superior to other ligands in the cases men-
tioned. It also turned out that the substituents (especially R1) on
the phenolic backbone had a particularly pronounced influence
on the performance of the ligands and even subtle changes of the
substitution pattern effected the stereochemical outcome of the
reactions. For example, in the Cu-catalyzed asymmetric 1,4-addi-
tion (Scheme 1b), the enantioselectivity dropped from 92% ee to
50% ee when ligand 1d (R1 = tBu) was replaced by ligand 1c
(R1 = iPr).
⇑
Corresponding authors. Tel.: +49 22 1470 3063 (H.G.S.); +31 20 5256437
(J.N.H.R.).
E-mail addresses: schmalz@uni-koein.de (H.-G. Schmalz), j.n.h.reek@uva.nl
(J.N.H. Reek).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.10.026

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T. Robert et al. / Tetrahedron: Asymmetry 21 (2010) 2671–2674
O
R1
R1
O
O
O
R2
R3
O
P
R2
R3
O
P
O
O
PPh2
PPh2
R4
R4
2a R1 = Me
2d R1 = i-Pr
2e R1 = Ph
1a R1 = Me
1e R1 = t-Bu
1f R1 + R3 = t-Bu
1g R1 = Ph
1b R1 = R2 = Me
1c R1 = i-Pr,
2b R1+ R2 = Me
2c R1/R2 = (CH)4
1d R1 = i-Pr, R4 = Me
O
O
O
O
R1
R1
O
O
R2
R3
O
P
R2
R3
O
P
O
O
PPh2
PPh2
R4
R4
3a R1 = i-Pr
3b R1 = t-Bu
4a R1 = i-Pr
4b R1 + R3 = t-Bu
3c R1 + R3 = t-Bu
Figure 1. Phenol-derived, chiral phosphine–phosphite ligands of type 1–4. R1–R4 = H unless indicated otherwise.
The remarkable success of our phenol-derived modular ligands
in various asymmetric transformations prompted us to test them
in the Rh-catalyzed asymmetric hydrogenation of olefins.11 More
specifically, we decided to investigate the asymmetric hydrogena-
tion of some relevant functionalized olefins. The three olefins
selected for this study (Fig. 2) were: (1) methyl 2-hydroxymethyl-
acrylate 13, a precursor of the so-called Roche ester, which is an
important intermediate for natural product syntheses;12 (2) 1-phe-
nylvinyl ethanoate 14, a 1-aryl-enol-ester, the hydrogenation of
which opens an alternative entry to chiral benzylic alcohols;13
O
B
O
O
O
O
O
CatBH
a)
2 mol% [Rh(COD)2]BF4
2.2 mol% 1b
5
6
(3)
a-methyl cinnamic acid 15, the hydrogenation product of
80% (93% ee)
O
which is a key intermediate in the synthesis of rennin-inhibitors,14
secretase-inhibitors15, and other biologically active compounds.16
Despite the progress in asymmetric catalysis, the hydrogenation
of these substrates still represents a major challenge and only
few examples with high enantioselectivities have so far been re-
ported in the literature.
O
RMgBr
b)
6 mol% 1e or 1f
*
4 mol% CuBr-SMe2
R
7
8
R = Alkyl, Alkenyl, Aryl
up to 92% ee
2. Results and discussion
The enantioselective hydrogenation of the three substrates
(Fig. 2) was investigated. All reactions were carried out under stan-
dard conditions using 1 mol % of [Rh(nbd)2]BF4 and 1.1 mol % of a
chiral ligand in CH2Cl2 for 12 h at room temperature with an H2
pressure of 40 bar. A first screening was carried out for compound
*
Cl
MeMgBr
3 mol% 1g
c)
2.5 mol% CuBr-SMe2
10
99% ee
9
*
H
H2/CO
O
O
O
d)
0.1 mol% Rh(acac)(CO)2
O
OH
0.4 mol% 1g
O
HO
O
11
12
13
14
15
up to 85% ee
iso / n: >98 : 2
Figure 2. Functionalized olefins were used in this study as substrates in the Rh-
Scheme 1. Selected applications for ligands of type 1.
catalyzed hydrogenation.

T. Robert et al. / Tetrahedron: Asymmetry 21 (2010) 2671–2674
2673
Table 1
Table 2
Results of the Rh-catalyzed asymmetric hydrogenation of 13a
Results of the Rh-catalyzed asymmetric hydrogenation of enol ester 14a
*
*
Entry
L
Conv.b (%)
eeb (%)
Config.b,c
Entry
L
Conv.b (%)
eeb (%)
Config.b,c
1
2
3
4
5
6
7
8
9
10
11
12
13
1b
1f
>99
>99
>99
>99
>99
>99
95
>99
>99
94
20
54
33
92
87
85
20
92
52
62
65
71
64
(S)
(S)
(S)
(R)
(R)
(R)
(R)
(R)
(S)
(S)
(S)
(S)
(S)
1
2
3
4
5
6
7
8
9
1a
1d
1e
1g
2c
2d
2e
3a
3c
4b
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
1
78
28
41
74
46
64
52
57
26
nd
(S)
(R)
(R)
(R)
(R)
(R)
(S)
(R)
(S)
1g
2a
2b
2c
2d
2e
3a
3b
3c
4a
4b
10
>99
>99
>99
a
Reaction conditions: 1 mol % of [Rh(nbd)2]BF4, 1.1 mol % of chiral ligand, CH2Cl2,
12 h, 40 bar H2.
b
Determined by chiral HPLC (ADH column).
Absolute configuration assigned by comparison with an authentic sample.
a
c
Reaction conditions: 1 mol % of [Rh(nbd)2]BF4, 1.1 mol % of chiral ligand, CH2Cl2,
12 h, 40 bar H2.
b
Determined by chiral GC (Supelco Beta-DEXÁcolumn) after esterification with
(CH3)SiCHN2.
Table 3
c
Absolute configuration assigned by comparison with an authentic sample.
Results of the Rh-catalyzed asymmetric hydrogenation of a
-methyl cinnamic acid 15a
*
#
L
Conv.b (%)
eeb (%)
Config.b,c
13 (Table 1). Conversion was excellent with all ligands (94–99%)
and the best enantioselectivities were obtained with the Binol-
based ligands 2a–e (up to 92% ee). Even though these Binol-based
ligands had proven less selective in previous applications
(Scheme 1), they surpassed the Taddol-based ligands in the hydro-
genation of 13. Again, the size of the substituent at the ortho-
position to the phosphite-moiety had a crucial effect on the
enantioselectivity. While ligands 2a (R1 = Me) and 2e (R1 = Ph)
yielded the product with high enantiomeric excess (92% ee) the
use of ligand 2d (R1 = iPr), for instance, afforded the product with
only 20% ee. It seems that only small substituents are tolerated
at the R1 position, and the phenyl group can reduce its steric de-
mand (i.e. make itself small) by twisting around the biphenyl bond
(Fig. 3).
1
2
3
4
5
6
7
8
1d
1f
12
44
71
2
36
2
30
24
33
2
(R)
(S)
(S)
nd
nd
(S)
(R)
(S)
1g
2a
2d
2e
3c
4b
1
26
20
8
4
22
a
Reaction conditions: 1 mol % of [Rh(nbd)2]BF4, 1.1 mol % of chiral ligand, CH2Cl2,
12 h, 40 bar H2.
b
Determined by chiral GC chiral GC (Supelco Beta-DEX column).
Absolute configuration assigned by comparison with an authentic sample.
c
The hydrogenation of
a-methyl cinnamic acid 15 proved to be
most challenging. Under the indicated conditions, only moderate
conversions and enantioselectivities were obtained (Table 3). Li-
gand 1f performed best with an enantiomeric excess of only 33%
ee at a good conversion of 71%. For this substrate, the use of
Binol-based ligands of type 2 led to low conversions and enantiose-
lectivities (626% ee).
H
H
O
O
O
O
O
P
O P
A noteworthy phenomenon was observed in the hydrogenation
of enol ester 14 and a-methyl cinnamic acid 15 using Taddol-based
ligands (types 1, 3, and 4). Although all ligands had the same abso-
lute configuration [they were prepared from (R,R)-tartaric acid],
the absolute configuration of the hydrogenation products de-
pended on the substituents on the ligand backbone. Similar effects
were previously observed in the Cu-catalyzed 1,4-addition of Grig-
nard reagents to cyclohexenone (using ligands of type 1)8 and in
the hydroformylation of styrene using indole-derived, Taddol-
based phosphine–phosphoramidite ligands.17 Obviously, small
differences in the steric environment of the rather bulky Taddol-
phosphite moieties lead to significant differences in the relative
energy of diastereomeric transition states. Further experiments
and quantum chemical calculations are required to understand this
interesting phenomenon in detail.
PPh2
PPh2
torsion angle ~ 0º
torsion angle ~ 90º
decreased steric demand
increased steric demand
Figure 3. Variable steric demand of a phenyl substituent at the R1 position.
In contrast to ligands of type 2, the use of Taddol-based ligands
of type 1 in the hydrogenation of 13 resulted in only moderate
enantioselectivities (up to 54% ee), which, however, were slightly
improved (up to 71% ee) by increasing the steric demand of the aryl
groups of the Taddol moiety (ligands of type 3 and 4).
The Rh-catalyzed enantioselective hydrogenation of the enol
ester 14 was next investigated. Although full conversion was
observed with all ligands tested, enantioselectivities never
exceeded 80% ee (Table 2). Again, Binol-based ligands of type 2
gave rise to good enantioselectivities (up to 74% ee), however,
the best results (78% ee) were obtained for this substrate with
the Taddol-derived ligand 1c (R1 = iPr). The fact that the closely re-
lated ligands 1a and 1d only led to low asymmetric induction (1%
ee and 28% ee, respectively) once again demonstrates the subtle
(and yet unpredictable) dependency of the ligand performance
on seemingly minor structural variations.
3. Conclusion
Herein we have shown that our modular, phenol-derived phos-
phine–phosphite ligands, types 1–4, clearly possess potential in
asymmetric hydrogenation reactions. By screening a small ligand
collection, we succeeded in identifying Binol-based ligands of type
2 to perform well in the hydrogenation of methyl 2-hydroxymeth-
ylacrylate 13 with up to 92% ee. Although less satisfying results
were obtained for substrates 14 (up to 78% ee) and 15 (up to 33%

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ee), the strong influence of subtle structural variations of the li-
gands on their performance became apparent. Thus, we are
optimistic that efficient modular synthesis provides the best
preconditions for the (focused) extension of our ligand library
and the development of powerful ligands for individual transition
metal-catalyzed reactions including the Rh-catalyzed hydrogena-
tion of challenging olefins.
4. Experimental
5. (a) Sakai, N.; Mano, S.; Nozaki, K.; Takaya, K. J. Am. Chem. Soc. 1993, 115, 7033–
7034; (b) Deerenberg, S.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.
Organometallics 2000, 19, 2065–2072; (c) Pàmies, O.; Net, G.; Ruiz, A.; Claver,
C. Tetrahedron: Asymmetry 2001, 12, 3441–3445; (d) Rubio, M.; Suárez, A.;
Álvarez, E.; Bianchini, C.; Oberhauser, W.; Peruzzini, M.; Pizzano, A.
Organometallics 2007, 26, 6428–6436; (e) Yan, Y.; Zhang, X. J. Am. Chem. Soc.
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6. (a) Velder, J.; Robert, T.; Weidner, I.; Neudörfl, J.-M.; Lex, J.; Schmalz, H.-G. Adv.
Synth. Catal. 2008, 350, 1309–1315; for earlier modular approaches to this
ligand class see: (b) Blume, F.; Zemolka, S.; Fey, T.; Kranich, R.; Schmalz, H.-G.
Adv. Synth. Catal. 2002, 344, 868–883; (c) Kranich, R.; Eis, K.; Geis, O.; Mühle, S.;
Bats, J. W.; Schmalz, H.-G. Chem. Eur. J. 2000, 6, 2874–2894.
4.1. General comments
All experiments were carried out under inert conditions. Sol-
vents were dried using standard methods. Hydrogenation reac-
tions were carried out in a Chemspeed Accelerator synthesis
robot and monitored by chiral GC. Ligands of types 1–4 were pre-
pared as published.6a
4.2. Typical hydrogenation procedure
7. Werle, S.; Fey, T.; Neudörfl, J.-M.; Schmalz, H.-G. Org. Lett. 2007, 9, 3555–3558.
8. Robert, T.; Velder, J.; Schmalz, H.-G. Angew. Chem., Int. Ed. 2008, 47, 7718–7721.
9. Lölsberg, W.; Ye, S.; Schmalz, H.-G. Adv. Synth. Catal. 2010, 352, 2023–2031.
10. Robert, T.; Abiri, Z.; Wassenaar, J.; Sandee, A. J.; Romanski, S.; Neudörfl, J.-M.;
Schmalz, H.-G.; Reek, J. N. H. Organometallics 2010, 29, 478–483.
11. (a) Modern Reduction Methods; Andersson, P. G., Munslow, I. J., Eds.; Wiley-VCH:
New York, 2008; (b) Handbook of Homogeneous Hydrogenation; de Vries, J. G.,
Elsevier, C. J., Eds.; Wiley-VCH: New York, 2006; (c) van Leeuwen, P. W. N. M.
Homogeneous Catalysis: Understanding the Art; Kluwer Academic Publishers:
Dordrecht, 2004.
12. For selected articles see: (a) Shin, Y.; Fournier, J.-H.; Fukui, Y.; Brückner, A. M.;
Curren, D. P. Angew. Chem., Int. Ed. 2004, 43, 4634–4637; (b) Paterson, I.;
Delgado, O.; Florence, G. J.; Lyothier, I.; O’Brien, M.; Scott, J. P.; Sereinig, N. J.
Org. Chem. 2005, 70, 150–160; (c) Kirkham, J. E. D.; Lee, V.; Baldwin, J. E. Chem.
Commun. 2006, 2863–2865.
All reagents, solvents, and starting materials were placed in the
synthesis robot, which then generated stock solutions of all the
compounds under inert atmosphere. After transferring all solu-
tions, the reaction vessels were pressurized with 40 bar H2 and
shaken for 12 h at room temperature. Conversion, regioselectivity,
and enantioselectivity were monitored by gas chromatography on
a chiral stationary phase.
Acknowledgment
13. For selected reviews see: (a) Tang, W.; Zhang, X. Chem. Rev. 2003, 103, 3029–
3069; (b) Komarov, I. V.; Börner, A. Angew. Chem. 2001, 113, 1237–1240;
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Kagan, H. B. Chem. Pharm. Bull. 2000, 48, 315–324.
This work was carried out in the context of Cost D40 and sup-
ported by the European Commission (Ligbank).
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