Highly enantioselective hydrogenation of α-dehydroamino esters and itaconates with triphosphorous bidentate ligands and the unprecedented solvent effect thereof

Article abstract of DOI:10.1021/jo0622429

(Chemical Equation Presented) An X-ray diffraction experiment revealed an interesting triphosphorous bidentate coordination in a Pd(II) complex of a phosphine-phosphoramidite ligand 1, which showed excellent enantioselectivity (up to 99.4% ee) in Rh-catalyzed hydrogenation of α-dehydroamino esters in acetone. A dramatic solvent effect was found in the hydrogenation of itaconates, which induces opposite chiralities of the product with the same catalytic system by the use of different solvents (e.g., 99.6% ee (R) in TFE vs 71.2% ee (S) in methyl ethyl ketone).

Full text of DOI:10.1021/jo0622429

expanded synthesis of 1 for highly enantioselective hydrogena-
tion of R-dehydroamino esters and itaconates (up to 99.6% ee).
Interestingly, we have observed a strong solvent effect in the
present catalytic system, in that a change of solvent could result
in opposite chiralities of the product.
Highly Enantioselective Hydrogenation of
r-Dehydroamino Esters and Itaconates with
Triphosphorous Bidentate Ligands and the
Unprecedented Solvent Effect Thereof
Previously, we demonstrated that 1 are excellent ligands for
Rh-catalyzed hydrogenation of aryl enamides, especially the
challenging ortho-substituted phenyl enamides and 1-naphthyl
enamide.4 NMR spectroscopy analysis revealed a highly pref-
erential chelating of rhodium with only two phosphorus donors,
leaving a third uncoordinated phosphine. Although computa-
tional study provided an approximate description of such a
configuration, direct structural information is necessary to
establish the proposed “triphosphorous-bidentate” feature and
gain insight into the chiral coordination environment around
the metal center. Thus, a single crystal of the PdCl2‚1a complex
was grown from CH2Cl2/hexane and subject to an X-ray
diffraction experiment.6 Consistent with NMR and computa-
tional results, the solved structure (Figure 1) revealed a well-
defined chiral coordination environment around the square-
planar d8 palladium (Pd(1)), which incorporates two properly
oriented P donors (P(1) and P(2)) within a six-membered
chelation ring in the presence of a third spectator phosphine
(P(3)). Fused to the chelation ring is a neighboring seven-
membered ring (P(2)-O(2)-C(3)-C(12)-C(14)-C(13)-O(1))
that imposes the spatial arrangement of the two substituents
(O(2) and N(1)) on P(2). As a consequence, O(2) is pulled back
from the top right quadrant whereas the dimethylamino group
(Me2N(1)-) protrudes forward to block the bottom right
quadrant. On the other side, two phenyl groups on P(1)
accommodate quasiequatorial and quasiaxial conformations,
respectively, the former occupying the top left quadrant and
the latter leaving the bottom left quadrant accessible. According
to the quadrant diagram rule,7 such a chiral environment, albeit
with C1-symmetry, would lead to R selectivity in the hydrogena-
tion of dehydroamino acids. Moreover, given the substitutes on
the phosphoramidite site of more steric hindrance (such as the
diisopropylamino group compared with the dimethylamino
group) or restricted conformational mobility (such as the
piperidyl group compared with the diethylamino group), the
chiral environment could be modified. To testify this point, we
have prepared a series of 1 in two standard methods (Scheme
1). 31P NMR spectroscopy analysis confirmed that each ligand
forms a well-defined triphosphorous bidentate complex with an
equivalent amount of Rh(COD)2BF4 in various solvents, which
were then applied in Rh-catalyzed hydrogenation of R-dehy-
droamino esters and itaconates.
Weicheng Zhang and Xumu Zhang*
Department of Chemistry, 104 Chemistry Building,
The PennsylVania State UniVersity, UniVersity Park,
PennsylVania 16802
xumu@chem.psu.edu
ReceiVed October 30, 2006
An X-ray diffraction experiment revealed an interesting
triphosphorous bidentate coordination in a Pd(II) complex
of a phosphine-phosphoramidite ligand 1, which showed
excellent enantioselectivity (up to 99.4% ee) in Rh-catalyzed
hydrogenation of R-dehydroamino esters in acetone. A
dramatic solvent effect was found in the hydrogenation of
itaconates, which induces opposite chiralities of the product
with the same catalytic system by the use of different solvents
(e.g., 99.6% ee (R) in TFE vs 71.2% ee (S) in methyl ethyl
ketone).
The exploration of new effective ligands is a continuous
challenge in transition-metal-mediated asymmetric hydrogena-
tion.1 Recent mechanistic investigation of monodentate ligands,2
in association with the successful application of combinatorial
strategy in catalyst screening,3 inspired us to develop a new
family of air-stable modular phosphine-phosphoramidite ligands
1.4,5 In this communication, we presented structural character-
ization of a Pd/1a complex by X-ray diffraction and the
(1) (a) Zhang, X. Enantiomer 1999, 4, 541. (b) Tang, W.; Zhang, X.
Chem. ReV. 2003, 103, 3029.
(4) Zhang, W.; Zhang, X. Angew. Chem., Int. Ed. 2006, 45, 5515.
(5) For other representative phosphine-phosphoramidite ligands in
hydrogenation, see: (a) Francio, G.; Faraone, F.; Leitner, W. Angew. Chem.,
Int. Ed. 2000, 39, 1428. (b) Hu, H.-P.; Zheng, Z. Org. Lett. 2004, 6, 3585.
(c) Hu, H.-P.; Zheng, Z. Org. Lett. 2005, 7, 419. (d) Huang, J.-D.; Hu,
X.-P.; Duan, Z.-C.; Zeng, Q.-H.; Yu, S.-B.; Deng, J.; Wang, D.-Y.; Zheng,
Z. Org. Lett. 2006, 8, 4367.
(6) So far, we have not been able to obtain a suitable single crystal of
Rh/1 for the X-ray diffraction experiment. However, the structure of an
isoelectronic Pd(II) complex may provide valuable coordination information
as well. See, for example: Bayer, A.; Murszat, P.; Thewalt, U.; Rieger, B.
Eur. J. Inorg. Chem. 2002, 2614.
(2) Reetz, M. T.; Meiswinkel, A.; Mehler, G.; Angermund, K.; Graf,
M.; Thiel, W.; Mynott, R.; Blackmond, D. G. J. Am. Chem. Soc. 2005,
127, 10305.
(3) (a) Reetz, M. T.; Sell, T.; Meiswinkel, A.; Mehler, G. Angew. Chem.,
Int. Ed. 2003, 42, 790. (b) Reetz, M. T.; Mehler, G. Tetrahedron Lett. 2003,
44, 4593. (c) Reetz, M. T.; Mehler, G.; Meiswinkel, A. Tetrahedron:
Asymmetry 2004, 15, 2165. (d) Reetz, M. T.; Li, X. Tetrahedron 2004, 60,
9709. (e) Reetz, M. T.; Ma, J.-A.; Goddard, R. Angew. Chem., Int. Ed.
2005, 44, 412. (f) Pena, D.; Minnaard, A. J.; Boogers, J. A. F.; de Vries,
A. H. M.; de Vries, J. G.; Feringa, B. L. Org. Biomol. Chem. 2003, 1,
1087. (g) Hoen, R.; Boogers, J. A. F.; Bernsmann, H.; Minnaard, A. J.;
Meetsma, A.; Tiemersma-Wegman, T. D.; de Vries, A. H. M.; de Vries,
J. G.; Feringa, B. L. Angew. Chem., Int. Ed. 2005, 44, 4209.
(7) (a) Knowles, W. S. Acc. Chem. Res. 1983, 16, 106. (b) Gridnev,
I. D.; Imamoto, T. Acc. Chem. Res. 2004, 37, 633.
10.1021/jo0622429 CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/29/2006
1020
J. Org. Chem. 2007, 72, 1020-1023

FIGURE 1. ORTEP representation of PdCl2‚1a at 50% probability for the drawing of thermal ellipsoids (solvents and hydrogen atoms are omitted
for clarity). Selected bond lengths (Å): Pd(1)-Cl(1) 2.319, Pd(1)-Cl(2) 2.355, Pd(1)-P(1) 2.281, Pd(1)-P(2) 2.212.
SCHEME 1
of the benchmark substrate 3a with Rh(COD)2BF4/1a revealed
a distinct solvent effect. Both CH2Cl2 and TFE gave only poor
enantioselectivities (Table 1, entries 1 and 8 by 1a, 48.6% ee
and 54.6% ee, respectively), whereas remarkable improvement
was seen in toluene, THF, EtOAc, and MeOH (entries 2-4 and
7 by 1a). To our surprise, excellent enantioselectivities were
obtained in ketonic solvents such as acetone and methyl ethyl
ketone (MEK) (entries 5 and 6 by 1a, 97.4% ee and 98.2% ee,
respectively). Thus, acetone was chosen as the solvent for the
subsequent hydrogenation of 3b-k with 1a-d. As shown in
(8) (a) van den Berg, M.; Minnaard, A. J.; Schudde, E. P.; van Esch, J.;
de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2000,
122, 11539. (b) Berg, M. v. d.; Minnaard, A. J.; Haak, R. M.; Leeman, M.;
Schedde, E. P.; Meetsma, A.; Feringa, B. L.; de Vries, A. H. M.; Maljaars,
C. E. P.; Williams, C. E.; Hyett, D.; Boogers, J. A. F.; Henderickx,
H. J. W.; de Vries, J. G. AdV. Synth. Catal. 2003, 345, 308. (c) Bernsmann,
H.; Berg, M. v. d.; Hoen, R.; Minnaard, A. J.; Mehler, G.; Reetz, M. T.; de
Vries, J. G.; Feringa, B. L. J. Org. Chem. 2005, 70, 943. (d) Fu, Y.; Xie,
J.-H.; Hu, A.-G.; Zhou, H.; Wang, L.-X.; Zhou, Q.-L. Chem. Commun.
2002, 480. (e) Wu, S.; Zhang, W.; Zhang, Z.; Zhang, X. Org. Lett. 2004,
6, 3565. (f) Liu, Y.; Ding, K. J. Am. Chem. Soc. 2005, 127, 10488.
In Rh-catalyzed hydrogenation of R-dehydroamino esters and
itaconate derivatives, CH2Cl2 is the solvent of choice for most
bidentate5 and monodentate8 phosphoramidite ligands. For the
present catalytic system, desirable performance was also found
in the hydrogenation of enamides if CH2Cl2 or 2,2,2-trifluoro-
ethanol (TFE) is used as solvent.4 Interestingly, hydrogenation
J. Org. Chem, Vol. 72, No. 3, 2007 1021

TABLE 1. Rh-Catalyzed Asymmetric Hydrogenation of r-Dehydroamino Esters 3a
Rh-1 system/ee (%) (configuration)b
1b 1c
entry
substrate
R
solvent
1a
1d
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
CH2Cl2
toluene
THF
EtOAc
acetone
MEK
48.6 (R)
86.6 (R)
86.8 (R)
85.4 (R)
97.4 (R)
98.2 (R)
85.2 (R)
54.6 (R)
91.2 (R)
98.2 (R)
94.4 (R)
97.4 (R)
98.0 (R)
96.4 (R)
97.4 (R)
91.8 (R)
97.2 (R)
95.6 (R)
-
-
-
-
-
-
-
-
-
-
-
-
95.8 (R)
-
98.8 (R)
-
98.4 (R)
-
MeOH
TFE
-
-
-
-
-
-
9
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
96.8 (R)
97.4 (R)
97.0 (R)
97.4 (R)
98.0 (R)
98.2 (R)
97.2 (R)
95.6 (R)
98.4 (R)
96.2 (R)
98.6 (R)
98.4 (R)
95.6 (R)
98.0 (R)
98.4 (R)
99.4 (R)
97.2 (R)
96.6 (R)
99.0 (R)
92.6 (R)
99.2 (R)
97.0 (R)
96.6 (R)
98.2 (R)
97.2 (R)
98.6 (R)
96.6 (R)
96.8 (R)
99.2 (R)
96.8 (R)
10
11
12
13
14
15
16
17
18
4-F-Ph
2-Cl-Ph
4-Cl-Ph
3-Br-Ph
3g
3h
3i
3j
3k
4-MeO-Ph
4-CF3-Ph
thiophenyl
n-propyl
CH3OCH2
a All reactions were carried out under 1 bar of hydrogen pressure with an S/C ratio of 100:1 at room temperature for 18 h at 100% conversion. bDetermined
by chiral GC equipped with a Chirasil-L-Val column. The absolute configuration was assigned by comparing the observed optical rotation with the literature
data.
Table 1, 1c and 1d outperform 1a and 1b in most cases, which
tends to support the initial assumption that increasing steric
hindrance or conformational rigidity on the phosphoramidite
site could enhance enantioselectivity. However, no ligand gives
consistently superior results and occasionally 1a or 1b showed
the best selectivity among the whole series (entries 11 by 1b
and 15 by 1a). This phenomenon indicated that chiral induction
by 1 is still substrate-dependent. In other words, the ligand
structure has to match the steric requirements of the substrate
to achieve high enantioselectivity. Generally, excellent results
(96.8%∼99.4% ee) were attained for both aromatic (3a-i) and
aliphatic (3j,k) substrates, which is comparable to the results
given by other bidentate5 and monodentate8 phosphoramidite
ligands.
Hydrogenation of itaconate derivatives 5a-d with 1a revealed
a more dramatic solvent effect. In the case of dimethyl itaconate
5a, both CH2Cl2 and TFE gave excellent enantioselectivities
(Table 2, entries 1 and 8 of 6a, 96.6% and 99.2% ee,
respectively), whereas an abrupt drop in the ee value was seen
in toluene, THF, and MeOH. It is unexpected that reversed
enantioselectivities were observed by the use of EtOAc, acetone,
and MEK, leading to the opposite S configuration in the product
6a (entries 4-6 of 6a, 11.6%, 39.6%, and 30.4% ee, respec-
tively). A similar trend was found in the hydrogenation of 5b,
showing the reversed S selectivity with up to 71.2% ee by the
use of MEK (entry 6 of 6b). Such a strong S preference is in
sharp contrast to the nearly perfect R selectivity provided by
CH2Cl2 and TFE (entries 1 and 8 of 6b, 99.6% and 99.4% ee,
respectively). For the other two substrates 5c and 5d, opposite
enantioselectivities were also obtained. Not limited to 1a, the
other ligands 1b-d also gave reversed stereoselection in MEK,
though in a less remarkable degree.
TABLE 2. Rh-Catalyzed Asymmetric Hydrogenation of Itaconates
5a
product/ee (%) (configuration)b
entry ligand solvent 6a
6b
6c
6d
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1c
1d
1d
CH2Cl2 96.6 (R)
toluene 3.0 (R)c
99.6 (R)
96.8 (R) 97.0 (R)c
75.8 (R)c 92.8 (R) 92.2 (R)
THF
10.4 (R)
11.6 (S)c 43.4 (R)c 51.6 (R) 41.4 (R)
acetone 39.6 (S)
51.8 (S)c 17.0 (R) 25.4 (S)
25.4 (S)c 6.6 (R)
39.4 (R)
EtOAc
MEK
MeOH
TFE
TFE
MEK
TFE
MEK
TFE
MEK
30.4 (S)
71.2 (S)
30.8 (S) 32.6 (S)
86.6 (R) 12.8 (R)
98.8 (R) 99.4 (R)
88.6 (R) 94.2 (R)
19.4 (R) 17.4 (S)
97.4 (R) 99.4 (R)
32.0 (R)c 4.6 (S)
99.2 (R)
97.0 (R)
30.0 (R)
97.4 (R)
35.6 (R)
99.2 (R)
9.4 (R)
99.4 (R)
97.6 (R)
45.6 (S)
98.6 (R)
9
10
11
12
13
14
10.8 (S)c 90.6 (R) 84.6 (R)
99.6 (R)
28.0 (S)
97.4 (R) 99.6 (R)
19.8 (R) 13.2 (R)
a Unless mentioned otherwise, all reactions were carried out under 1 bar
of hydrogen pressure with an S/C ratio of 100:1 at room temperature for
18 h at 100% conversion. bDetermined by chiral GC equipped with a γ-dex
225 column. The absolute configuration was assigned by comparing the
observed optical rotation with the literature data. 6b-6d were converted
to the corresponding dimethyl ester 6a with TMSCHN2 or HCl in MeOH
before GC analysis. cIncomplete conversions (<100%) were observed. See
Supporting Information for details.
configuration. If both enantiomers of the product are to be
prepared, both enantiomers of the ligand have to be available.9
An alternative approach can be conceived if a catalytic system
Homogeneous asymmetric hydrogenation transfers the chiral-
ity of the catalyst into the reduced product, with one handedness
of the catalyst corresponding to one stereochemical configuration
of the product and the other handedness to the opposite
(9) Aware of this issue, our group recently developed DuanPhos as both
enantiomers compared with the previously reported TangPhos, which exists
as only one enantiomer. See: Liu, D.; Zhang, X. Eur. J. Org. Chem. 2005,
646.
1022 J. Org. Chem., Vol. 72, No. 3, 2007

used directly in the following step without purification. To a solution
of this intermediate (1 equiv) in THF (25 mL) was added freshly
prepared LDA or lithiated piperidine (2 equiv) in THF dropwise at
-78 °C over 10 min. Then the reaction mixture was stirred
overnight and warmed slowly to room temperature. The solvent
was then evaporated, and the mixture was subjected to flash column
chromatography on silica gel (EtOAc/hexane ) 1:15) to afford the
product as a white powder (78% yield for 1c, 72% yield for 1d).
(R)-O,O′-(3,3′-Bis(diphenylphosphino)-1,1′-dinaphthyl-2,2′-
is capable of generating opposite chiralities in the product.
Theoretically, reversal of enantioselectivity10 is not impossible
if the key enantiodifferentiating step is influenced significantly
by modified transition states or if an entirely different mecha-
nism is involved. In practice, both ammonium halides11 and
achiral monodentate ligands3b have been found to trigger such
an effect. Nevertheless, it is rare that the same metal/ligand
system induces opposite chiralities in the product simply due
to the use of different solvents.12 It can be reasoned that the
solvent may have participated in enantiodifferentiating steps that
are critical to the stereochemical outcome of the product, instead
of serving merely as spectator molecules. In addition, the
uncoordinated phosphine is situated close to the coordination
sphere.13 Whether it would have any effect during hydrogenation
is still unclear. The correct correlation between the quadrant
diagram of 1 and the observed R selectivity in the hydrogenation
of dehydroamino esters in ketonic solvents and itaconates in
CH2Cl2 and TFE suggests that hydrogenation under these
conditions may follow a mechanism7b that works for most C2-
symmetric ligands. Meanwhile, the discrepancy found in the
hydrogenation of itaconates in ketonic solvents may point to a
different mechanism. This result further demonstrates that
solvent screening is extremely important for a given catalytic
system and that catalyst optimization is critical for the develop-
ment of new ligands.
1
diyl)-N,N-diisopropylphosphorous Amidite (1c). H NMR (300
MHz, CD2Cl2): δ ) 0.91 (s, 6H), 1.29-1.42 (m, 6H), 3.25-3.37
(m, 2H), 7.16-7.61 (m, 30H). 13C NMR (75 MHz, CD2Cl2): δ )
23.38, 24.16, 24.85, 45.64, 45.82, 124.77, 128.71, 128.74, 128.81,
128.84, 129.00, 129.06, 129.09, 129.15, 129.40, 129.51, 133.65,
133.93, 133.98, 134.25, 134.98, 135.25, 151.91, 152.14, 152.48.
31P NMR (146 MHz, CD2Cl2): δ ) -14.38 (d, JP-P ) 29.7 Hz),
-12.65 (s), 151.70 (d, JP-P ) 30.9 Hz). HRMS (M + H+): calcd,
784.2663; found, 784.2680.
(R)-O,O′-(3,3′-Bis(diphenylphosphino)-1,1′-dinaphthyl-2,2′-
diyl)-N,N-piperidylphosphorous Amidite (1d). 1H NMR (300
MHz, CD2Cl2): δ ) 1.21 (s, br, 4H), 1.51 (s, br, 2H), 2.98 (m,
4H), 7.27-7.69 (m, 30H). 13C NMR (75 MHz, CD2Cl2): δ ) 25.14,
27.09, 27.14, 29.93, 45.27, 45.32, 45,60, 124.78, 126.48, 128.55,
128.60, 128.64, 128.70, 128.83, 128.88, 128.94, 128.96, 128.98,
129.03, 133.31, 133.58, 134.95, 135.23, 136.94, 151.35, 151.37,
152.06. 31P NMR (146 MHz, CD2Cl2): δ ) -14.43 (d, JP-P
24.5 Hz), -12.49 (d, JP-P ) 4.3 Hz), 145.17 (dd, J1P-P ) 22.7 Hz,
J2 ) 3.6 Hz). HRMS (M + H+): calcd, 768.2350; found,
)
P-P
768.2350.
General Procedure for Asymmetric Hydrogenation. The stock
Experimental Section
solution of the Rh/1 complex (2 × 10-3 mol/L) was made by stirring
Rh(COD)2BF4 and 1a-d at a 1:1 molar ratio in desired solvents at
room temperature for 1 h in a nitrogen-filled glovebox. Then, an
aliquot of catalyst solution (0.5 mL, 0.001 mmol) was added into
the vial charged with substrate (0.1 mmol) dissolved in the desired
solvent (2.5 mL). All the vials were then placed in a steel autoclave
into which hydrogen gas was charged at 1 bar of pressure after
three “charge-release” cycles. After stirring at room temperature
for 18 h, hydrogen gas was released carefully and the solution was
concentrated and subjected to a short silica gel column to remove
the metal complex. The purified sample was analyzed by chiral
GC to determine ee and conversion. The itaconates 6b-d were
first converted to dimethyl ester 6a before column purification and
GC analysis.
General Procedure for the Synthesis of Phosphine-phos-
phoramidite Ligands 1. Synthesis of 2, 1a, and 1b has been
reported in ref 4. To a 50 mL Schlenk flask equipped with a
condenser were charged 2 (1.71 g, 2.61 mmol) and 20 mL of PCl3.
The mixture was stirred at 80 °C overnight and then cooled to room
temperature. The excessive PCl3 was removed in a vacuum.
Azeotropic distillation with toluene (10 mL) three times afforded
the intermediate chlorophosphite as a white powder, which was
(10) (a) In heterogeneous hydrogenation, reversal of enantioselectivity
is under active study. See, for example: Bonalumi, N.; Vargas, A.; Ferri,
D.; Burgi, T.; Mallat, T.; Baiker, A. J. Am. Chem. Soc. 2005, 127, 8467.
(b) In asymmetric transfer hydrogenation, it was shown very recently that
a subtle change in ligand structure can result in a switch of the product’s
absolute configurations. See: Zaitsev, A. B.; Adolfsson, H. Org. Lett. 2006,
8, 5129.
(11) Buriak, J. M.; Osborn, J. A. Organometallics 1996, 15, 3161.
(12) (a) A Rh complex of an R-glucosidic bisphosphinite ligand gave
73% ee (S) in ethanol but 6% ee (R) in benzene during the hydrogenation
of dehydroamino esters. See: Selke, R. J. Prakt. Chem. 1987, 329, 717.
(b) A Rh/PipPhos system gave 90% ee (R) in CH2Cl2 but 26% ee (S) in
MeOH during the hydrogenation of an enol acetate. See: Panella, L.;
Feringa, B. L.; de Vires, J. G.; Minnaard, A. J. Org. Lett. 2005, 7, 4177.
(13) According to the crystal structure of PdCl2‚1a, the distance from
P(3) to P(2) is 3.906 Å, from P(3) to N(1) is 3.779 Å, and from P(3) to
Pd(1) is 5.499 Å.
Acknowledgment. Financial support from the National
Institutes of Health is appreciated (NIH-GM58832). We thank
Dr. Yennawar for assistance with X-ray diffraction experiments
(NSF CHE-0131112).
Supporting Information Available: 1H, 13C, and 31P NMR
spectra of compounds 1c and 1d and X-ray crystal structure files
(.cif) for the PdCl2‚1a complex. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO0622429
J. Org. Chem, Vol. 72, No. 3, 2007 1023