Development of practical rhodium phosphine catalysts for the hydrogenation of β-dehydroamino acid derivatives

Article abstract of DOI:10.1021/op0602270

The rhodium-catalyzed asymmetric hydrogenation of various β-dehydroamino acid derivatives to give optically active β-amino acids has been examined. Chiral monodentate 4,5-dihydro-3H-dinaphthophosphepines, which are easily tuned and accessible in a multi-10-g scale, have been used as ligands. The enantioselectivity is largely dependent on the nature of the substituent at the phosphorous atom and on the structure of the substrate. Applying optimized conditions up to 94% ee was achieved.

Full text of DOI:10.1021/op0602270

Organic Process Research & Development 2007, 11, 568−577
Development of Practical Rhodium Phosphine Catalysts for the Hydrogenation
of â-Dehydroamino Acid Derivatives
Stephan Enthaler,† Giulia Erre,† Kathrin Junge,† Jens Holz,† Armin Bo¨rner,†,‡ Elisabetta Alberico,§ Ilenia Nieddu,|
Serafino Gladiali,*,| and Matthias Beller*,†
Leibniz Institut fu¨r Katalyse an der UniVersita¨t Rostock e.V., Albert-Einstein Strasse 29a, 18059 Rostock, Germany,
Institut fu¨r Chemie der UniVersita¨t Rostock, Albert-Einstein Strasse 3a, 18059 Rostock, Germany, Istituto di Chimica
Biomolecolare - CNR, traV. La Crucca 3, 07040 Sassari, Italy, and Dipartimento di Chimica, UniVersita` di Sassari,
Via Vienna 2, 07100 Sassari, Italy
Abstract:
tioselectivities have been obtained in this reaction by
applying rhodium- or ruthenium-catalysts with chiral diphos-
phines such as MeDuPhos, catASium M, BINAP, BINAPO,
BICP, TunaPhos, FerroTane, JosiPhos, DIOP, BPPM, P-Phos
and others.3
The rhodium-catalyzed asymmetric hydrogenation of various
â-dehydroamino acid derivatives to give optically active â-amino
acids has been examined. Chiral monodentate 4,5-dihydro-3H-
dinaphthophosphepines, which are easily tuned and accessible
in a multi-10-g scale, have been used as ligands. The enantio-
selectivity is largely dependent on the nature of the substituent
at the phosphorous atom and on the structure of the substrate.
Applying optimized conditions up to 94% ee was achieved.
A current trend in asymmetric catalysis is to switch from
chiral bidentate to chiral monodentate phosphines because
the latter are more easily accessible and tuneable than the
bidentate counterparts.4,5 Seminal contributions in this field
have come from Feringa and de Vries et al.6 (phosphora-
midites), Reetz et al.7 (phosphites), and Pringle and Claver
et al.8 (phosphonites). Furthermore, excellent enantioselec-
tivities were reported by Zhou and co-workers applying
monodentate spiro phosphoramidites (SIPHOS).9,10
Following the first report by Gladiali11 and parallel to the
work of Zhang,12 we have focused in recent years on different
monodentate phosphines based on a 4,5-dihydro-3H-dinaph-
tho[2,1-c;1′,2′-e]phosphepine framework (5 and 6a-j)
Introduction
The discovery of new effective drugs is an important
challenge for industrial and academic research. During the
last decades an intense area of research in medicinal
chemistry was the development of peptide-based therapeutics,
mainly constructed by R-amino acids. More recently, sig-
nificant attention was also directed to non-natural â-amino
acids, which are interesting building blocks for the synthesis
of biologically active compounds such as â-lactam antibio-
tics, the taxol derivatives, and â-peptides (Scheme 1).1 In
view of the growing demand of chiral â-amino acids, an
increasing number of synthetic methods have been estab-
lished for their preparation such as homologation of R-amino
acids, conjugate addition of amines to carbonyl compounds,
Mannich reaction, hydrogenation etc.1c,2 Within these meth-
odologies, asymmetric catalytic hydrogenation constitutes the
most attractive and versatile technology as to industrial
applications due to the remarkable improvements achieved
in the past few years in the asymmetric hydrogenation of
â-dehydroamino acid derivatives. Good-to-excellent enan-
(3) (a) Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J.; Bachman, G. L.;
Weinkauff, D. J. J. Am. Chem. Soc. 1977, 99, 5947-5952. (b) Achiwa, K.;
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Zhu, G.; Chen, Z.; Zhang, X. J. Org. Chem. 1999, 64, 6907-6910. (e)
Heller, D.; Holz, J.; Drexler, H.-J.; Lang, J.; Drauz, K.; Krimmer, H.-P.;
Bo¨rner, A. J. Org. Chem. 2001, 66, 6816-6817. (f) Yasutake, M.; Gridnev,
I. D.; Higashi, N.; Imamoto, T. Org. Lett. 2001, 3, 1701-1704. (g) Heller,
D.; Drexler, H.-J.; You, J.; Baumann, W.; Drauz, K.; Krimmer, H.-P.;
Bo¨rner, A. Chem. Eur. J. 2002, 8, 5196-5203. (h) Zhou, Y.-G.; Tang, W.;
Wang, W.-B.; Li, W.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 4952-
4953. (i) Yang, W.; Wu, S.; Zhang, X. J. Am. Chem. Soc. 2003, 125, 9570-
9571. (j) Komarov, I. V.; Monsees, A.; Spannenberg, A.; Baumann, W.;
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2003, 115, 942-945. (l) Holz, J.; Monsees, A.; Jiao, H.; You, J.; Komarov,
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1707. (m) Wu, J.; Chen, X.; Guo, R.; Yeung, C.-h.; Chan, A. S. C. J. Org.
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* To whom correspondence should be addressed. E-mail: matthias.beller@
catalysis.de. Fax: 49 381 12815000. Telephone: 49 381 1281113.
† Leibniz Institut fu¨r Katalyse e.V an der Universita¨t Rostock.
‡ Institut fu¨r Chemie der Universita¨t Rostock.
§ Istituto di Chimica Biomolecolare - CNR.
| Dipartimento di Chimica, Universita` di Sassari.
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10.1021/op0602270 CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/30/2006

Scheme 1. Selection of biologically active compounds containing â-amino acid units
(Scheme 3).13 The first catalytic application of such a ligand
(Ph-BINEPINE; 6a) in the Rh-catalyzed asymmetric hydro-
formylation of styrene was reported by one of us (S.G.) in
the early 1990s.11a In the following years, the Rostock group
has expanded the structural diversity of the BINEPINE ligand
family 6 into a library of ligands which has been screened
with remarkable success (ee up to 95%) in the asymmetric
hydrogenation with Rh- and Ru-catalysts of R-amino acid
precursors, dimethyl itaconate, enamides and â-ketoesters.13
In the meantime, the utility of Ph-BINEPINE 6a has been
demonstrated in a range of asymmetric reactions catalyzed
by different transition metals such as the Pd-catalyzed
umpoled-allylation of aldehydes and the Pt-catalyzed alkoxy-
cyclization of 1,5-enynes. The ligand itself without any metal
is an efficient chiral catalyst for the enantioselective acylation
of diols, and for [3 + 2] cycloadditions and [4 + 2]
annulations (Scheme 2).11d,e,14 Quite recently excellent enan-
tioselectivities have been scored in the Rh-catalyzed transfer
hydrogenation of R-amino acid precursors and itaconic acid
derivatives using formic acid as H-donor. Under these
conditions â-dehydroamino acids derivatives have also been
successfully hydrogenated, albeit in modest stereoselectivity.11f
Pursuing our ongoing research in hydrogenation chem-
istry, we report herein on the Rh-catalyzed asymmetric
hydrogenation of â-dehydroamino acid derivatives. A multi-
10-g scale synthesis of binaphthophosphepines is described,
which allowed these ligands to be commercialized last year.15
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Scheme 2. Applications of ligand class 6 in asymmetric synthesis
Results and Discussion
reagents to give a broad selection of ligand 6. The limited
number of commercially available dichlorophosphines and
the large diversity of Grignard compounds make the access
through 4-chloro-4,5-dihydro-3H-dinaphtho[2,1-c;1′,2′-e]-
phosphepine the route of choice to a library of ligands 6.
The syntheses of â-acetamido acrylates 7-11 and 14 were
carried out according to literature protocols by reaction of
the corresponding â-ketoester with NH4OAc followed by
acylation of the â-amino acrylate intermediate.3c,d E/Z-
Isomers were separated by crystallization and column chro-
matography. Ethyl 3-acetamido-3-phenyl-2-propenoate (12)
and methyl 3-benzamido butenoate (13) were synthesized
by reaction of the corresponding â-amino acrylate with acyl
chloride or benzoyl chloride.3l
To compare the behaviour of the Z- and E-isomers, initial
catalytic runs were carried out separately on the (Z)- and
(E)-methyl 3-acetamido butenoates (Z-7 and E-7, respec-
tively) as substrates and 4-phenyl-4,5-dihydro-3H-dinaphtho-
[2,1-c;1′,2′-e]phosphepine (6a) as our standard ligand.13
Typically, we used an in situ precatalytic mixture of 1
mol % [Rh(cod)2]BF4 and 2.1 mol % of the corresponding
ligand. All hydrogenation reactions were carried out in an
8-fold parallel reactor array with a reactor volume of 3.0
mL.18
The synthesis of binaphthophosphepines starts with di-
esterification of enantiomerically pure 2,2′-binaphthol16 (98%
ee) with trifluoromethanesulfonic acid anhydride in the
presence of pyridine (Scheme 3). The corresponding diester
was obtained in 99% yield, and subsequent nickel-catalyzed
Kumada coupling with methyl magnesium bromide led to
2,2′-dimethylbinaphthyl in 95% yield.13,17 Two different
synthetic strategies were established to obtain 4,5-dihydro-
3H-dinaphtho[2,1-c;1′,2′-e]phosphepine ligands 6. On the one
hand, double metalation of 2,2′-dimethylbinaphthyl with
n-butyl lithium in the presence of TMEDA (N,N,N′,N′-
tetramethylethylenediamine) followed by quenching with
commercially available dichlorophosphines gives ligands 6a
(P-phenyl) and 6i (P-tert-butyl) in 60-83% yield. Both
ligands have been synthesized on >10-g scale. In the second
procedure the dilithiated dimethyl binaphthalene is quenched
with diethylaminodichlorophosphine, giving the phosphepine
5 which, upon treatment with gaseous HCl, is converted into
4-chloro-4,5-dihydro-3H-dinaphtho[2,1-c;1′,2′-e]phosphe-
pine in 80% yield. This enantiomerically pure chlorophos-
phine is easily coupled with various Grignard or lithium
(15) The ligands Ph-BINEPINE (6a) and t-Bu-BINEPINE (6i) are commercially
available by Degussa DHC (Degussa Homogeneous Catalysis, Rodenbacher
Chaussee 4, building 097, 63457 Haunau (Wolfgang), Germany, (ww-
w.creavis.com/site_dhc/de/default.cfm)) with the product names catASium
KPh (6a) and catASium KtB (6i).
(16) Optically pure 2,2′-binaphthol is available on large scale from RCA (Reuter
Chemische Apparatebau KG), Engesserstr. 4, 79108 Freiburg, Germany.
(17) The synthesis of 2,2′-bistriflate-1,1′-binaphthyl (1.2 mol, 615 g, 92%) and
2,2′-dimethyl-1,1′-binaphthyl (0.74 mol, 201 g, 96%) was carried out in
large scale by the group of Zhang (See ref 11b).
We first focused our attention on the influence of the
solvent and the hydrogen pressure. The first set of reactions
was run at constant concentration in toluene, dichlo-
romethane, methanol, ethanol,19 and 2-propanol at three
(18) Institute of Automation (IAT), Richard Wagner Str. 31/ H. 8, 18119 Rostock-
Warnemu¨nde, Germany.
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Scheme 3. Synthetic approach to 4,5-dihydro-3H-dinaphtho[2,1-c;1′,2′-e]phosphepine ligands 6
different pressures (2.5, 10.0, and 50.0 bar). Selected results
are presented in Figure 1.
results indicated ethanol and methanol as the best solvents
and 50.0 bar as the pressure of choice for the hydrogenation
of the Z-isomer (conversion: >99%; enantioselectivity:
92%).
In the case of hydrogenation of E-7 the best enantiose-
lectivity was consistently achieved at the lowest pressure (2.5
bar) and ranged between 42-79% ee, depending on the
solvent. After 24 h the reaction was complete only in
2-propanol, whereas lower conversions were observed in
ethanol, methanol, and toluene.20 No reaction at all took place
in dichloromethane. The stereoselectivity decreased upon
increasing the pressure of hydrogen to 10.0 bar or 50.0 bar.
From these results 2-propanol and 2.5 bar were selected as
solvent and pressure of choice, respectively, for the hydro-
genation of the E-isomer (conversion: >99%; enantioselec-
tivity: 79%). The hydrogenation of Z-7 resulted in higher
enantioselectivities in all the solvents (up to 92% ee).
Notably, compared to E-7 the configuration of the prevailing
enantiomer was always opposite. Furthermore, in ethanol and
in methanol the enantioselectivity/pressure trend was re-
versed, the top value (92% ee) having been reached at the
highest pressure (50.0 bar) compared to 86% ee at 2.5 bar.
Full conversions were obtained in all the experiments, except
in toluene (37%) and in dichloromethane (45%). These
No incorporation of deuterium in the product was noticed
upon running the reaction in methanol-d4. This is in line with
the absence in the reduction process of any interference of
transfer hydrogenation as well as of protonolysis of the
Rh-C bond of an alkyl rhodium intermediate.21 Two facets
deserving mention are (1) the Z-isomer gives higher ee’s than
the E-isomer, whereas in most cases the opposite behaviour
has been reported3 and (2) the configuration switches
depending on the different geometry of the double bond,
which has been scarcely reported.3c,22
Next, we investigated the influence of temperature on
enantioselectivity and conversion as shown in Figure 2.23
Applying our model ligand 6a we found a pronounced
negative effect on the enantioselectivity at higher tempera-
tures for both isomers. Interestingly, the loss of enantiose-
lectivity for the hydrogenation of E-7 is higher than for Z-7
(10 °C: E-7 79% ee (R) and Z-7 88% ee (S); 90 °C: E-7
rac and Z-7 60% ee (S)).
(19) The hydrogenation performed in ethanol and 2-propanol led exclusively to
product 7. No transesterification was observed.
(20) In the case of toluene we assume an inhibition of the catalyst by the solvent,
due to the formation of catalytical inactive rhodium-arene complexes.
Heller, D.; Drexler, H.-J.; Spannenberg, A.; Heller, B.; You, J.; Baumann,
W. Angew. Chem., Int. Ed. 2002, 41, 777-780.
(21) Tsukamoto, M.; Yoshimura, M.; Tsuda, K.; Kitamura, M. Tetrahedron 2006,
62, 5448-5453.
(22) Hu, X.-P.; Zheng, Z. Org. Lett. 2005, 7, 419-422.
(23) Jerphagnon, T.; Renaud, J.-L.; Demonchaux, P.; Ferreira, A.; Bruneau, C.
Tetrahedron: Asymmetry 2003, 14, 1973-1977.
Vol. 11, No. 3, 2007 / Organic Process Research & Development
•
571

Figure 2. Dependency of enantioselectivity versus temperature.
Reactions were carried out at corresponding temperature for
1-24 h with 0.0024 mmol [Rh(cod)2]BF4, 0.005 mmol ligand
6a and 0.24 mmol substrate in 2.0 mL of 2-propanol. Conver-
sions and ee’s were determined by GC (50 m Chiraldex â-PM,
130 °C, (S)-7a 15.1 min, (R)-7a 16.4 min).
Figure 1. Solvent and pressure variation. Reactions were
carried out at 10 °C for 24 h with 0.0024 mmol [Rh(cod)2]BF4,
0.005 mmol ligand 6a and 0.24 mmol substrate in 2.0 mL of
solvent. Conversions and ee’s were determined by GC (50 m
Chiraldex â-PM, 130 °C, (S)-7a 15.1 min, (R)-7a 16.4 min). The
absolute configuration was determined by comparison with
reported data.3l
Figure 3. Dependency of enantioselectivity versus E/Z ratio.
Reactions were carried out at 10 °C for 24 h with 0.0024 mmol
[Rh(cod)2]BF4, 0.005 mmol ligand 6a and 0.24 mmol substrate
in 2.0 mL of ethanol. Conversions and ee’s were determined
by GC (50 m Chiraldex â-PM, 130 °C, (S)-7a 15.1 min, (R)-7a
16.4 min).
For estimating the feasible enantioselectivity at lower
temperature we analysed the corresponding Eyring plot24 for
both isomers. As a consequence we considered 10 °C as
temperature of choice, because of good enantioselectivity
and also acceptable reaction times.
The original protocol used for the synthesis of methyl
3-acetamido butenoate (7) gives a mixture of E- and
Z-isomers whose composition depends on the reaction
conditions.1f Although separation of the isomers by fractional
crystallization is feasible, the selective hydrogenation of the
mixture is clearly advantageous. This prompted us to explore
the hydrogenation of different E/Z ratios including the
mixture obtained from the synthesis (Figure 3). The results
showed a linear decrease of enantioselectivity for all mixtures
and demostrated that the hydrogenation of the single isomers
led to highest enantioselectivity.
Recently, Heller and Bo¨rner have reported kinetics and
mechanistic investigations for the hydrogenation of E-7 and
Z-7 through the use of bidentate phosphine ligands. The
mentioned results modified the existent declaration that the
(24) Buschmann, H.; Scharf, H.-D.; Hoffmann, N.; Esser, P. Angew. Chem. 1991,
103, 480-518.
572
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Figure 5. Dependency of the optical purity of ligand 6a on
product selectivity. Reactions were carried out at 10 °C for 24 h
with 0.0024 mmol [Rh(cod)2]BF4, 0.005 mmol ligand 6a and
0.24 mmol substrate in 2.0 mL of methanol. Conversions and
ee’s were determined by GC (50 m Chiraldex â-PM, 130 °C,
(S)-7a 15.1 min, (R)-7a 16.4 min).
Figure 4. Dependency of hydrogen consumption versus reac-
tion time. Reactions were carried out under isobaric conditions
(1.0 bar) at 25 °C. [Rh(cod)2]BF4 (0.0072 mmol) and 0.015 mmol
ligand 6a were stirred for 10 min under hydrogen atmosphere
in 10.0 mL of methanol. Afterwards the substrate (0.72 mmol)
was added in 1.0 mL of methanol. The conversions and ee’s
were determined by GC (50 m Chiraldex â-PM, 130 °C, (S)-7a
15.1 min, (R)-7a 16.4 min).
ligand 6a of different enantiomeric purity, and the ee’s
observed have been plotted against the enantiomeric purity
of the ligand (Figure 5). For both Z-7 and E-7 a positive
nonlinear effect, which implies the bonding of at least two
ligands to the rhodium, is clearly apparent. Similar results
were reported by Reetz,7i Zhou,9b and Feringa6f for the
asymmetric hydrogenation of itaconic esters or R-amino acid
derivatives by the use of different monodentate P-donor
ligands. To verify the positive nonlinear effect we decreased
the amount of ligand to 1 equiv with respect to rhodium.
Here, we observed a diminished reaction rate compared to
the rate of hydrogenation with 2 equiv of ligand. In addition,
the amount of ligand was increased to 4 equiv with respect
to rhodium, but also in this case a reduced reaction rate was
monitored.
In previous studies we have shown the pronounced effect
that the substitution pattern at the P-centre of BINEPINE
ligands has on the stereoselectivity of the asymmetric
process.13 In order to evaluate this substituent effect the
asymmetric hydrogenation of E-7 and Z-7 was performed
in the optimized conditions previously devised with nine
different 4,5-dihydro-3H-dinaphtho[2,1-c;1′,2′-e]phosphep-
ines (6a-6i) (E-7: 2.5 bar hydrogen pressure, 2-propanol,
10 °C, 24 h; Z-7: 50.0 bar, ethanol, 10 °C, 24 h) (Table 1).
In the hydrogenation of E-7 the best enantioselectivities
up to 90, 88, and 87% ee, respectively, were achieved with
ligands 6g, 6d, and much to our surprise, with 6i (Table 1,
entries 7, 4, and 9). The last one has always given quite poor
results in the other benchmark tests where it has been
screened. The presence of electron-donating groups on the
P-aryl substituent has a positive effect on the stereoselectivity
(Table 1, entries 4, 6, and 7), whereas the opposite occurs
for electron-withdrawing groups (Table 1, entry 2). This trend
reaction rate for hydrogenation of E-isomers is higher than
that for the Z-isomers, because in some cases the opposite
behaviour was observed.3g
To classify ligand 6a we recorded the hydrogen uptake
in relation to the reaction time for the asymmetric hydro-
genation of E-7 and Z-7 with our catalyst in isobaric condi-
tions and under normal pressure of hydrogen (Figure 4).
To minimize the interfering effect of cyclooctadiene (cod),
the precatalyst was stirred for 10 min under hydrogen
atmosphere before adding the substrate E-7 or Z-7. We were
surprised to see that, unlike the case of most bidentate
ligands, in our case at 50% conversion it was the Z-isomer
which was hydrogenated faster (about 3.5 times the E-
isomer).
For gaining an insight into the structure of the catalyst,
the hydrogenation of Z-7 was perfomed using the preformed
complex [Rh(6a)2(nbd)]+CF3SO3 as the catalyst. This
-
cationic complex was prepared as previously reported by
us,11f and the reaction was run in MeOH at 5 bar at 25 °C.
Under these conditions, Z-7 was completely hydrogenated
in 12 h to give the (S)-enantiomer in 92% ee. This result is
quite close to the one obtained with the catalysts prepared
in situ by adding 2 equiv of the ligand 6a either to
[Rh(nbd)2]+BF4- (89% ee) or to [Rh(cod)2]+BF4- (88% ee).
From this it follows that the catalytically active species most
likely contain two monodentate P-ligands per Rh center and
that the ancillary diolefin ligand has a negligible effect, if
any, on the stereoselectivity, while the anion may exert some
influence. Further support to the presence of two ligands
around the metal comes from the search of nonlinear effect
(NLE) in the model reaction.25 A set of hydrogenations was
performed on both the isomers using various samples of
(25) (a) Girard, C.; Kagan, H. B.; Angew. Chem. 1998, 110, 3088-3127. (b)
Faller, J. W.; Parr, J. J. Am. Chem. Soc. 1993, 115, 804-805.
Vol. 11, No. 3, 2007 / Organic Process Research & Development
•
573

Table 1. Hydrogenation of E-7 and Z-7 with different
4,5-dihydro-3H-dinaphtho[2,1-c;1′,2′-e]phosphepines (6a-6i)
Table 2. Influence of ester group on conversion and
enantioselectivity
entry ligand isomera conv. [%]b ee [%]b isomerc conv. [%]b ee [%]b
entry ligand isomera conv. [%]b ee [%]b isomerc conv. [%]b ee [%]b
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
6g
6h
6i
E
E
E
E
E
E
E
E
E
>99
91
80
>99
>99
91
>99
>99
>99
79 (R)
40 (R)
69 (R)
88 (R)
20 (R)
81 (R)
90 (R)
76 (R)
87 (R)
Z
Z
Z
Z
Z
Z
Z
Z
Z
>99
>99
>99
>99
>99
90
>99
5
3
92 (S)
32 (S)
80 (S)
86 (S)
rac
40 (S)
89 (S)
38 (S)
60 (S)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
6a
6b
6c
6d
6g
6h
6i
6a
6b
6c
6d
6g
6h
6i
E-8
E-8
E-8
E-8
E-8
E-8
E-8
E-9
E-9
E-9
E-9
E-9
E-9
E-9
98
79
65
98
97
>99
>99
>99
63
73
>99
92
>99
>99
83 (R)
46 (R)
20 (R)
84 (R)
84 (R)
66 (R)
80 (R)
70 (R)
40 (R)
20 (R)
76 (R)
72 (R)
66 (R)
76 (R)
Z-8
Z-8
Z-8
Z-8
Z-8
Z-8
Z-8
Z-9
Z-9
Z-9
Z-9
Z-9
Z-9
Z-9
>99
>99
>99
>99
>99
>99
>99
52
23
61
69
55
94 (S)
rac
36 (S)
83 (S)
85 (S)
rac
rac
78 (S)
46 (S)
24 (S)
91 (S)
73 (S)
rac
a All reactions were carried out at 10 °C under 2.5 bar pressure of hydrogen
for 24 h with 0.0024 mmol [Rh(cod)2]BF4, 0.005 mmol ligand and 0.24 mmol
substrate in 2-propanol (2.0 mL). b Conversions and ee’s were determined by
GC (50 m Chiraldex â-PM, 130 °C, (S)-7a 15.1 min, (R)-7a 16.4 min). The
absolute configuration was determined by comparing with reported data.3l c All
reactions were carried out at 10 °C under 50.0 bar pressure of hydrogen for 24
h with 0.0024 mmol [Rh(cod)2]BF4, 0.005 mmol ligand and 0.24 mmol substrate
in ethanol (2.0 mL).
34
32
6 (S)
a All reactions were carried out at 10 °C under 2.5 bar pressure of hydrogen
for 24 h with 0.0024 mmol [Rh(cod)2]BF4, 0.005 mmol ligand and 0.24 mmol
substrate in 2-propanol (2.0 mL). b Conversions and ee’s were determined by
GC (8 (25 m Lipodex E, 70/40-8-180, (R)-8a 33.2 min, (S)-8a 33.4 min), 9 (25
m Lipodex E, 70/25-10-180, (R)-9a 33.2 min, (S)-9a 33.4 min). The absolute
configurations were determined by comparing the sign of specific rotation with
reported data.3d c All reactions were carried out at 10 °C under 50.0 bar pressure
of hydrogen for 24 h with 0.0024 mmol [Rh(cod)2]BF4, 0.005 mmol ligand and
0.24 mmol substrate in ethanol (2.0 mL).
is similar to the one observed in the hydrogenation of Z-7
although in that case the best ee was scored with the plain
phenyl ligand 6a. Alkyl-substituted phosphepines 6h and 6i
produced catalysts of negligible activity in hydrogenation
of this substrate (Table 1, entries 8 and 9).
To explore scope and limitation of our ligand toolbox,
the asymmetric hydrogenation of a range of â-dehydroamino
acids derivatives was performed under optimized conditions
(Table 2). First the influence of the ester-group on the
hydrogenation of both Z- and E-isomers was investigated in
detail. For E-7 changing from methyl to isopropyl ester
resulted consistently in a slight decrease of stereoselectivity,
whereas in the case of the Z-isomer no reliable correlation
between ester functionality and enantioselectivity was de-
tected. Notably, a diminished yield for all hydrogenations
of Z-9 was attained (Table 2).
Scheme 4. Asymmetric hydrogenation of methyl
2-acetamidocylopent-1-enecarboxylate (14)a
a
All reactions were carried out at 10 °C under 50.0 bar pressure of hydrogen
for 24 h with 0.0024 mmol [Rh(cod)2]BF4, 0.005 mmol ligand and 0.24 mmol
substrate in ethanol (2.0 mL). Conversion, de’s and ee’s were determined by
GC (25 m Chirasil Val, 120 °C, 14a1 26.8 min, 14a2 27.6 min, 14a3 52.1 min,
14a4 53.0 min).
Finally, the influence of â3- and â2-substitution was
investigated on a set of seven different substrates (Scheme
4 and Table 3). While substitution of a methyl with an ethyl
group has negligible effects, an increase in the branching of
the alkyl group resulted in an improved selectivity with
ligands 6g and 6i. Furthermore, we also carried out a
substitution in the â3-position by an aromatic group (com-
pound Z-12). As a tendency, depletion of conversion and
enantioselectivity was observed in comparison to Z-8 (Table
1, entries 1-7 and Table 2, entries 15-21). A similar
negative effect was found after substitution of the acyl
protecting group by benzoyl and subjecting Z-13 in the
hydrogenation reaction (Table 3, entries 15-21).
As an example for tetra-substituted â-dehydroamino acid
precursor (â3- and â2-substitution) we tested methyl2-
acetamidocyclopent-1-enecarboxylate (14)26 under optimized
conditions for Z-isomers (Scheme 4). In the majority of cases
excellent diastereoselectivities up to >99% de were achieved,
accompanied by good to moderate conversions. Best enan-
tioselectivities up to 76% ee were obtained by utilizing
ligands 6a and 6b (Scheme 4).
An additional possibility offered by monodentate ligands
from which one can profit in asymmetric catalysis is the
possibility to introduce in the coordination sphere of the
(26) Tang, W.; Wu, S.; Zhang, X. J. Am. Chem. Soc. 2003, 125, 9570-9571.
574
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Vol. 11, No. 3, 2007 / Organic Process Research & Development

Table 3. Influence of â3-substitution on conversion and
enantioselectivity
Table 4. Application of ligand mixtures in the asymmetric
hydrogenation of Z-7 and E-7
entry
L1
L2
6a
PPh3
PCy3
6i
PPh3
PCy3
15d
isomer
conv. [%]c
ee [%]c
1
2
3
4
5
6
7
6a
6a
6a
6i
6i
6i
Za
Za
Za
Eb
Eb
Eb
Eb
>99
>99
>99
>99
>99
>99
21
92 (S)
76 (S)
78 (S)
87 (R)
34 (R)
88 (R)
12 (R)
entry ligand isomera conv. [%]b ee [%]b isomerc conv. [%]b ee [%]b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
6a
6b
6c
6d
6g
6h
6i
6a
6b
6c
6d
6g
6h
6i
6a
6b
6c
6d
6g
6h
6i
E-10
E-10
E-10
E-10
E-10
E-10
E-10
E-11
E-11
E-11
E-11
E-11
E-11
E-11
Z-12
Z-12
Z-12
Z-12
Z-12
Z-12
Z-12
>99
91
95
>99
>99
>99
>99
>99
39
88
50
>99
98
>99
99
46
90
95
91
25
33
78 (R)
44 (R)
60 (R)
78 (R)
75 (R)
72 (R)
84 (R)
26 (R)
42 (R)
70 (R)
60 (R)
88 (R)
34 (R)
90 (R)
70 (R)
26 (R)
47 (R)
52 (R)
38 (R)
54 (R)
36 (R)
Z-10
Z-10
Z-10
Z-10
Z-10
Z-10
Z-10
Z-11
Z-11
Z-11
Z-11
Z-11
Z-11
Z-11
Z-13
Z-13
Z-13
Z-13
Z-13
Z-13
Z-13
98
96
>99
97
93
97
47
>99
99
99
94
94
67
10
19
9
86 (S)
58 (S)
20 (S)
50 (S)
48 (S)
rac
24 (R)
78 (S)
68 (S)
28 (S)
26 (S)
68 (S)
rac
58 (R)
70 (-)
4 (-)
46 (+)
n.d.
48 (-)
n.d.
40 (-)
6i
a All reactions were carried out at 10 °C under 50.0 bar pressure of hydrogen
for 24 h with 0.0024 mmol [Rh(cod)2]BF4, 0.005 mmol ligand and 0.24 mmol
substrate in ethanol (2.0 mL). b All reactions were carried out at 10 °C under
2.5 bar pressure of hydrogen for 24 h with 0.0024 mmol [Rh(cod)2]BF4, 0.005
mmol ligand and 0.24 mmol substrate in 2-propanol (2.0 mL). c Conversions
and ee’s were determined by GC (50 m Chiraldex â-PM, 130 °C, (S)-7a 15.1
min, (R)-7a 16.4 min). The absolute configuration was determined by comparing
with reported data.3l d 15 ) tris(2,4-di-tert-butylphenyl)phosphite.
of 1.05 to 1.05 equiv of the two ligands with respect to 1.0
equiv of [Rh(cod)2]BF4, and the reactions were carried out
under the optimized conditions defined above. As a general
trend, the heterocombination of monodentate ligands was
always less stereoselective compared to the homocombina-
tion of the pivotal ligands (Table 4). There was just one
notable exception for the system 6i/tricyclohexylphosphine
(Table 4, entry 6) which gave the same ee as obtained when
6i was used alone. Even if these results do not permit to
draw any substantial conclusion, we may infer that in these
conditions the catalytic activity of the different complexes
which are formed in solution lies in the same range and that
they compete for the substrate.
7
<1
11
<1
10
a All reactions were carried out at 10 °C under 2.5 bar pressure of hydrogen
for 24 h with 0.0024 mmol [Rh(cod)2]BF4, 0.005 mmol ligand and 0.24 mmol
substrate in 2-propanol (2.0 mL). b Conversion was determined by GC or 1H
NMR. The enantiomeric excess was determined by GC or HPLC (10 (25 m
Lipodex E, 120/30, (R)-10a 31.8 min, (S)-10a 32.2 min), 11 (25 m Lipodex E,
130/20, (R)-11a 33.2 min, (S)-11a 33.4 min), 12 (OD-H, n-hexane/ethanol 98:
2, 1.3 mL/min, (S)-12a 27.8 min, (R)-12a 36.8 min), 13 (Chiralcel OB-H,
n-hexane/2-propanol 90:10, 1.0 mL/min, (+)-13a 15.9 min, (-)-13a 18.8 min)).
The absolute configuration was determined by comparing with reported data or
by reported sign of specific rotation.3d,l c All reactions were carried out at 10
°C under 50.0 bar pressure of hydrogen for 24 h with 0.0024 mmol [Rh(cod)2]BF4,
0.005 mmol ligand and 0.24 mmol substrate in ethanol (2.0 mL).
Summary
metal two different ligands and to play the game of
matching-mismatching combinations of chiral elements.
This opens the way to a combinatorial approach as developed
by Reetz et al.7d-f,27 and Feringa et al.28 for different transition
metal-catalyzed reactions.29
To foster this possibility, we have selected 6a and 6i as
the pivotal ligands for the hydrogenation of Z-7 and E-7,
respectively, in combination with achiral phosphines and
phosphites. The catalysts were prepared in situ using a ratio
In conclusion, we have shown that monodentate chiral
4,5-dihydro-3H-dinaphtho[2,1-c;1′,2′-e]phosphepine ligands
can be synthesized on multi-10-g scale from 2,2′-binaphthol.
They can be tuned easily by variation of the substituent at
the P-atom. This class of ligands can be used for various
rhodium- and ruthenium-catalyzed hydrogenations. For the
first time their application towards the synthesis of â-amino
acid derivatives is shown, and enantioselectivities up to 94%
ee were achieved.
(27) (a) Reetz, M. T.; Li, X. Angew. Chem., Int. Ed. 2005, 44, 2959-2962. (b)
Reetz, M. T.; Li, X. Angew. Chem., Int. Ed. 2005, 44, 2962-2964.
(28) (a) Duursma, A.; Hoen, R.; Schuppan, J.; Hulst, R.; Minnaard, A. J.; Feringa,
B. L. Org. Lett. 2003, 5, 3111-3113. (b) Duursma, A.; Pen˜a, D.; Minnaard,
A. J.; Feringa, B. L. Tetrahedron: Asymmetry 2005, 16, 1901-1904. (c)
Pen˜a, D.; Minnaard, A. J.; Boogers, J. A. F.; de Vries, A. H. M.; Feringa,
B. L. Org. Biomol. Chem. 2003, 1, 1087-1089.
(29) (a) Monti, C.; Gennari, C.; Piarulli, U.; de Vries, J. G.; de Vries, A. H. M.;
Lefort, L. Chem. Eur. J. 2005, 11, 6701-6717. (b) Ding, K.; Du, H.; Yuan,
Y.; Long, J. Chem. Eur. J. 2004, 10, 2872-2884.
Experimental Section
All manipulations were performed under argon
atmosphere using standard Schlenk techniques. Toluene,
n-hexane, and diethyl ether were distilled from sodium
benzophenone ketyl under argon. Methanol was distilled
from magnesium under argon. Ethanol and 2-propanol were
Vol. 11, No. 3, 2007 / Organic Process Research & Development
•
575

distilled from sodium under argon. Methylene chloride was
distilled from CaH2 under argon. Ligands 6 were synthesized
according to our previously published protocols.13 [Rh(cod)2]-
BF4 (purchased from Fluka) was used without further
purification. The synthesis of (S)-2,2′-dimethyl-1,1′-binaph-
thyl in a 200-g scale has been described in the literature.12b
Synthesis of 4-Phenyl-4,5-dihydro-3H-dinaphtho[2,1-
c;1′,2′-e]phosphepine (6a) and 4-tert-Butyl-4,5-dihydro-
3H-dinaphtho[2,1-c;1′,2′-e]phosphepine (6i) on 10-g Scale.
Synthesis of the Dilithio Species. A solution of n-BuLi (0.19
mol, 120 mL, 1.6 M in n-hexane) was concentrated under
vacuum and the residual oil dissolved in diethyl ether (60
mL). After cooling the mixture to 0 °C a solution of (S)-
2,2′-dimethyl-1,1′-binaphthyl (74.5 mmol, 21 g) in diethyl
ether (140 mL) was added over a dropping funnel during 20
min to give a red solution. Afterwards TMEDA (192 mmol,
28.6 mL, distilled over CaH2) was added slowly, and the
resulting solution was kept for 24 h at room temperature,
yielding deep red crystals. The supernatant solution was
decanted via a tube. The crystals were washed two times
with dry n-hexane (30 mL, removed by a tube) and dried
under vacuum to give 60-80% yield (24.6-37.8 g).
Synthesis of the 4-Phenyl-4,5-dihydro-3H-dinaphtho[2,1-
c;1′,2′-e]phosphepine (6a). Starting with the dilithium salt of
(S)-2,2′-dimethyl-1,1′-binaphthyl(24.5g, 44.4mmol)inn-hex-
ane (130 mL) a solution of phenyl dichlorophosphine (6.8 mL,
50.3 mmol) in n-hexane (55 mL) was added at 0 °C. After
2 h refluxing, the reaction mixture was quenched with water/
toluene. The organic layer was separated and dried over
MgSO4. The ligand 6a was purified by column chromatogra-
phy in dry toluene and gave light-yellow foam (12.9 g; 75%).
Synthesis of the 4-tert-Butyl-4,5-dihydro-3H-dinaphtho-
[2,1-c;1′,2′-e]phosphepine (6i). Starting with the dilithium
salt of (S)-2,2′-dimethyl-1,1′-binaphthyl (24.5 g, 44.4 mmol)
in n-hexane (130 mL) a solution of tert-butyl dichlorophos-
phine (8 g, 50.3 mmol) in n-hexane (55 mL) was added at
0 °C. After 3 h refluxing, the reaction mixture was quenched
with water/toluene. The organic layer was separated and dried
over MgSO4. The ligand 6i was purified by crystallization
from toluene (13.2 g; 81%).
overnight at -20 °C yielded the E-isomers of â-dehy-
droamino acid derivatives 7-11, which were recrystallized
three times from ethylacetate/n-hexane (1:1) to give colorless
crystals [yield of the main fraction referred to â-ketoester:
E-7: 1.4 g (11%), E-8: 1.2 g (10%), E-9: 1.5 g (11%),
E-10: 1.4 g (12%), E-11: 1.8 g (14%)].
Procedure B (Z-isomer Enriched Residue). The pure
Z-isomer was obtained by column chromatography (eluent:
ethylacetate/n-hexane, 1:1 or 1:2) [yield referred to â-ke-
toester: Z-7: 4.3 g (39%), Z-8: 1.2 g (35%) (0.035 mmol
â-ketoester), Z-9: 6.0 g (46%), Z-10: 1.6 g (26%) (0.035
mmol â-ketoester), Z-11: 4.0 g (31%)]. In the case of methyl
2-acetamidocyclopent-1-enecarboxylate (14) purification was
carried out by crystallization (3×) from ethylacetate/n-hexane
(1:1), yielding brown crystals [yield of the main fraction:
4.1 g (32%)].
Synthesis of Ethyl 3-Acetamido-3-phenyl-2-propenoate
(Z-12).3l To a solution of NH4OAc (0.65 mol) in ethanol
(100 mL) was added the corresponding â-ketoester (0.13
mol). After stirring for 60 h at room temperature the solvent
was removed, and a mixture of CHCl3 and water was added.
The organic layer was washed with water (3 × 50 mL) and
brine (50 mL) and dried over Na2SO4. The solvent was
evaporated under reduced pressure, yielding the correspond-
ing 3-amino-2-alkenoate. To a stirred solution of the corre-
sponding 3-amino-2-alkenoate (0.026 mmol) and pyridine
(0.046 mol) in toluene (50 mL) was added dropwise a
solution of acetyl chloride (0.027 mol) in toluene (10 mL)
at 0 °C. The mixture was stirred for 48 h at 25 °C. A further
amount of acetylchloride (0.027 mol) in toluene (10 mL)
was added at 0 °C, and the resulting mixture was stirred for
48 h. After quenching with aqueous NH4H2PO4 solution the
mixture was extracted with ethylacetate (3 × 50 mL). The
organic layer was washed with water (2 × 50 mL) and dried
over Na2SO4. The solvents were removed in vacuo, and the
obtained yellow oil was purified by column chromatography
(eluent: ethylacetate/n-hexane, 1:1), yielding yellow crystals
[yield: Z-12: 0.59 g (10%)].
Synthesis of Methyl 3-Benzamido-2-butenoate (Z-13).3l
To a solution of NH4OAc (0.65 mol) in ethanol (100 mL)
was added the corresponding â-ketoester (0.13 mol). After
stirring for 60 h at room temperature the solvent was
removed, and a mixture of CHCl3 and water was added. The
organic layer was washed with water (3 × 50 mL) and brine
(50 mL) and was dried over Na2SO4. The solvent was
evaporated under reduced pressure, yielding the correspond-
ing 3-amino-2-alkenoate. To a stirred solution of the corre-
sponding 3-amino-2-alkenoate (0.026 mmol) and pyridine
(0.046 mol) in diethylether (70 mL) was added dropwise a
solution of benzoyl chloride (0.027 mol) in toluene (10 mL)
at -30 °C. The mixture was stirred for 12 h at -30 °C and
for 24 h at room temperature. After quenching with aqueous
water the mixture was extracted with ethylacetate (3 × 50
mL). The organic layer was washed with HCl (1 mol/L) and
brine and dried over Na2SO4. The solvents were removed in
vacuo, and the obtained yellow oil was purified by column
chromatography (eluent: ethylacetate/n-hexane, 1:1), yield-
ing crystals [yield: Z-13: 2.9 g (9%)].
General Synthesis of â-Dehydroamino Acid Deriva-
tives 7-11 and 14.3c To a solution of NH4OAc (0.36 mol)
in methanol, ethanol, or 2-propanol (depending on the ester-
functionality (100 mL)) was added the corresponding â-ke-
toester (0.07 mol). After stirring for 60 h at room temperature
the solvent was removed, and a mixture of CHCl3 and water
was added. The organic layer was washed with water (3 ×
50 mL) and brine (50 mL) and dried over Na2SO4. The
solvent was evaporated under reduced pressure, yielding the
corresponding 3-amino-2-alkenoate. The 3-amino-2-alk-
enoate (0.07 mol), pyridine (0.13 mol), and acetic anhydride
(0.32 mol) were dissolved in THF (50 mL) and stirred for
12 h at 70 °C (procedure A) or 95 °C (procedure B). The
solution was reduced to half of the volume and ethylacetate
was added. After washing with water, HCl, NaHCO3, brine
and drying over Na2SO4, the solvent was removed.
Procedure A (E-Isomer Enriched Residue). Dissolving the
residue in ethylacetate/n-hexane (1:1) and storing the solution
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General Procedure for the Catalytic Hydrogenation
of â-Dehydroamino Acid Derivatives. A solution of the
â-dehydroamino acid derivative (0.24 mmol) and 1.0 mL of
solvent was transferred via syringe into an autoclave charged
with argon. The catalyst was generated in situ by stirring
[Rh(cod)2]BF4 (0.0024 mmol) and the corresponding 4,5-
dihydro-3H-dinaphthophosphepine ligand (0.005 mmol) in
1.0 mL of solvent for a period of 10 min and afterwards
transferring via syringe into the autoclave. The autoclave was
then charged with hydrogen and stirred at the required
temperature. After the predetermined time the hydrogen was
released, and the reaction mixture passed through a short
plug of silica gel. The conversion was measured by GC or
1H NMR and the enantioselectivity by GC or HPLC.
Acknowledgment
We thank Mrs. M. Heyken, Mrs. C. Voss, Mrs. G.
Wenzel, Mrs. K. Schro¨der, Mrs. S. Buchholz, and Dr. C.
Fischer (all Leibniz Institut fu¨r Katalyse e.V. an der
Universita¨t Rostock) for excellent technical and analytical
assistance. Dr. B. Hagemann is gratefully thanked for the
syntheses of ligands 6e and (R)-6a. Generous financial
support from the state of Mecklenburg-Western Pomerania
and the BMBF as well as the Deutsche Forschungsgemein-
schaft (Leibniz-Price) is gratefully acknowledged.
Received for review October 30, 2006.
OP0602270
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