Chiral bisphospholane ligands (Me-ketalphos): Synthesis of their Rh(I) complexes and applications in asymmetric hydrogenation

Article abstract of DOI:10.1016/j.tet.2005.10.047

Rhodium complexes of functionalized bisphospholane ligands (S,S,S,S-Me-ketalphos) 1 and (R,S,S,R-Me-ketalphos) 2 have been used as catalyst precursors for the asymmetric hydrogenation of several different types of functionalized olefins and have achieved

Full text of DOI:10.1016/j.tet.2005.10.047

Tetrahedron 62 (2006) 868–871
Chiral bisphospholane ligands (Me-ketalphos): synthesis of their
Rh(I) complexes and applications in asymmetric hydrogenation
*
Qian Dai, Chun-Jiang Wang and Xumu Zhang
Department of Chemistry, The Pennsylvania State University, University Park 16802, USA
Received 20 July 2005; revised 14 October 2005; accepted 19 October 2005
Available online 9 November 2005
Abstract—Rhodium complexes of functionalized bisphospholane ligands (S,S,S,S-Me-ketalphos) 1 and (R,S,S,R-Me-ketalphos) 2 have been
used as catalyst precursors for the asymmetric hydrogenation of several different types of functionalized olefins and have achieved high
enantioselectivities.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
comparison to the corresponding isolated complexes. A
possible reason is that the formation of the achiral rhodium
catalyst species competes with the chiral active catalyst. In
our previous attempts to prepare the complexes in situ, we
found that the catalysts were inactive in the asymmetric
hydrogenation possibly due to the short incubation time of
metal precursor and the ligands. Based on a more recent
report,9 we were able to obtain the active species by extending
the incubation time. However, the asymmetric hydrogenation
results through the in situ method of mixing metal precursors
with ligands 1 and 2 leads to relatively lower ee’s compared
with the ones achieved by the isolated complexes. Also, the
results of the in situ method were not easily reproducible. In
this paper, we reported our studies based on the preparation of
isolated metal complexes of Me-ketalphos ligands for
asymmetric hydrogenation. The advantage of using the
isolated complexes is high reproducibility, enantioselectivity
and ease of operation (Fig. 1).
Development of new chiral phosphine ligands has played
a significant role in the transition metal catalyzed
asymmetric reactions during the last several decades.1
Chiral C2-symmetric bisphospholane ligands such as
DuPhos2 and its analogues RoPhos,3a BASPhos3b,4 and
MalPhos5 have attracted much attention due to their
effectiveness for asymmetric hydrogenation of functiona-
lized olefins and ketones.6 Recently, our group7,8 and
RajanBabu9 reported a series of modified DuPhos ligands
with ketal (1 and 2, named as ketalphos, prepared from
inexpensive D-mannitol) or hydroxyl groups at the 3 and 4
positions of the phospholanes. In our previous reports, only
one enantiomer of the ligands was synthesized. Designing a
catalytic system that can obtain both enantiomers of the
hydrogenation products is desired. Since preparation of the
enantiomer of 1 may require the expensive L-mannitol, it is
more practical to use its diastereomer 2 as ligand candidate
to achieve opposite enantioselectivities in asymmetric
hydrogenation. Rhodium complexes prepared in situ with
ligand 1 and 2 gave good ee’s in asymmetric hydrogenation
reactions.10 However, only some preliminary results for the
asymmetric hydrogenation of a-dyhydroamino acid deriva-
tives were given. A systematic study of both diastereomers
of Me-ketalphos in the hydrogenation of different kinds of
unsaturated compounds is of significant importance.
Figure 1. Structure of both diastereomers of Me-ketalphos.
According to the literature,2c,11 the use of in situ metal–
ligand complexes generally leads to slightly less ee values in
2. Results and discussion
(S,S,S,S)-Me-ketalphos and its diasteromer were prepared
from commercially available D-mannitol.8,9 Since the Rh-
NBD complex precursor is more reactive than the Rh-COD
Keywords: Hydrogenation; Catalyst; Rhodium.
*
Corresponding author. Tel.: C1 8148654221; fax: C1 8148653292;
e-mail: xumu@chem.psu.edu
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.10.047

Q. Dai et al. / Tetrahedron 62 (2006) 868–871
869
Scheme 1. Synthesis of rhodium bisphospholane complex 4 and 5.
Table 2. Asymmetric hydrogenation of enamides by 4 and 5a
complex in the initiation reaction,12 we selected
[Rh(NBD)2]BF4 as the complex precursor in our catalyst
precursor preparation (Scheme 1). To a solution of ligand
in methanol was added 1 equiv of the complex precursor
and stirred at rt for 15 min. After removal of the solvent, the
Rh-Me-ketalphos complex gave a clean phosphorus NMR
at 100 ppm. These Rh-Me-ketalphos complexes were
Entry Substrate
Complex ee (%)b Confign.c
1
characterized by H, 31P NMR and HRMS.
1
2
3
4
5
6
7
8
ArZPh, RZisopropyl 6a
ArZPh, RZH 6b
ArZp-CF3-Ph, RZH 6c
ArZp-OMe-Ph, RZCH3 6d
ArZp-CF3-Ph, RZCH3 6e
ArZPh, RZCH3 6f
6a
6b
6c
6d
6e
6f
4
4
4
4
4
4
5
5
5
5
5
5
96
92
96
97
97
98
93
94
93
94
95
93
S
S
S
S
S
S
R
R
R
R
R
R
Using an enamide 6a as the substrate, we have performed
the condition optimization. As shown in Table 1, almost all
the solvents gave good to excellent ee’s except for ethanol
(87% ee). In screening of solvents, we initially used
methanol and found out that the results were not very
consistent.13 Both methylene chloride and isopropanol were
found to be solvents of the choice.
9
10
11
12
Table 1. Rhodium catalyzed asymmetric hydrogenation of an enamide 6aa
a The reactions were carried out at rt under 10 atm of H2 pressure for 24 h
with 100% conversions.
b Enantiomeric excesses were determined by chiral GC using a Supelco
Chiral Select 1000 (0.25 mm!30 m) column.
c The absolute configurations were assigned by comparision of the sign of
optical rotation with reported data.
Entry
Solvent
ee (%)b
1
2
3
4
5
6
CH2Cl2
CH3OH
C2H5OH
i-PrOH
THF
97
92
87
97
94
92
Table 3. Asymmetric hydrogenation of dehydroamino acid derivates by 4
and 5a
Toluene
a The reactions were carried out at rt under 10 atm of H2 pressure for 24 h
with 100% conversions.
b Enantiomeric excesses were determined by chiral GC using a Supelco
Chiral Select 1000 (0.25 mm!30 m) column.
Under the optimized conditions, we have investigated
asymmetric hydrogenation of enamides with both 4 and 5
as catalysts (Table 2). Complete conversions and very high
enantioselectivities were observed with complex 4 (92–98%
ee’s). The reaction time was not optimized to ensure
the complete conversion. A more detailed study on substrate
6d showed that a TON of 1000 can be achieved without
any deterioration of the enantioselectivity and a TOF of
70 hK1 15
. Catalyst 5 also behaved in a similar fashion, even
though the enantioselectivities were slightly lower.
Entry Substrate
Complex
ee
(%)b
Confign.c
1
2
3
4
5
6
7
8
R1ZH, R2ZH 8a
5
5
5
5
5
5
5
5
4
4
4
4
4
4
4
99
99
98
99
99
99
99
92
74
59
89
76
81
96
69
R
R
R
R
R
R
R
R
S
S
S
S
S
R1ZPh, R2ZH 8b
R1Zo-Cl-Ph, R2ZH 8C
R1Zp-F-Ph, R2ZH 8d
R1Zm-Br-Ph, R2ZH 8e
R1Z2-Thienyl, R2ZH 8f
14
R1Z2-Napthyl, R2ZH 8g
R1ZCH3, R2ZCH3 8h
9
8a
8b
8c
8d
8e
8f
10
11
12
13
14
15
For hydrogenation of dehydroamino acid derivatives,
complex 5 was found to be an excellent complex and high
ee’s for the substrates in Table 3 have been achieved (entries
1–7). In asymmetric hydrogenation, tetra-substituted sub-
strates usually are more challenging in both reactivity and
selectivity compared with tri-substituted ones. In our case,
entry 8 showed high enantioselectivity (92%) under mild
reaction condition, which is comparable to the best results
S
S
8h
a The reactions were carried out at rt under 3 atm of H2 pressure for 12 h.
b Enantiomeric excesses were determined by chiral GC using a Chirasil-Val
lll column.
c The absolute configurations were assigned by comparing the sign of
optical rotation with reported data.

870
Q. Dai et al. / Tetrahedron 62 (2006) 868–871
Table 4. Asymmetric hydrogenation of itaconic acid derivatives by complex 4 and 5a
Entry
Substrate
Complex
ee (%)b
Confign.c
1
2
3
4
R1ZH, R2ZCH3 10a
4
4
5
5
98
R
R
S
R1Zi-Pr, R2ZH 10b
10a
10b
99d
99
98d
S
a The reactions were carried out at rt under 10 atm of H2 pressure for 24 h with 100% conversions.
b Enantiomeric excesses were determined by chiral GC using a Gamma-DEX 225 column.
c The absolute configurations were assigned by comparing the sign of optical rotation with reported data.
d Enantiomeric excesses were determined on the corresponding methyl esters.
that have been reported.7,16 However, the complex 4 of
diastereomeric phospholane 1, only gave opposite selec-
tivities in much lower ee values. The detailed reason for
these results is still not clear. We have also explored
hydrogenation of itaconic acid derivatives with catalysts 4
and 5. Excellent results (up to O98% ee) were achieved
with 10a and 10b (Table 4).
(s, 2H), 1.55 (s, 6H), 1.54 (s, 6H), 1.30–1.37 (m, 6H),
0.73–0.79 (m, 6H). 31P NMR (CD3OD) d 100.1 (d, JRh-P
153.5 Hz); HRMS (cation) m/z calcd for C31H44O4P2Rh
645.1770, found 645.1737; HRMS (anion) m/z calcd for BF4
87.0029, found 87.0024.
Z
1
4.2.2. Rh(NBD)(2)]BF4. H NMR (360 MHz, CD3OD) d
8.04–8.28 (m, 2H), 7.86–7.88 (m, 2H), 6.14 (s, 2H), 4.40 (s,
2H), 4.28 (dd, JZ10.1, 18.9 Hz, 2H), 3.76 (dd, JZ8.9,
11.4 Hz, 4H), 2.81–2.92 (m, 2H), 2.62–2.79 (m, 2H), 2.06
(s, 2H), 1.64 (s, 6H), 1.62 (s, 6H), 1.30–1.60 (m, 6H),
3. Conclusion
In summary, rhodium complexes 4 and 5 of (S,S,S,S)-Me-
ketalphos and its diastereomer (R,S,S,R)-Me-ketalphos were
prepared and characterized by NMR spectroscopy. The
investigation of 4 and 5 in asymmetric hydrogenation of
several different types of functionalized alkenes showed that
catalyst 4 was highly enantioselective for the hydrogenation
of enamides, while catalyst 5 performed very well for both
enamides and dehydroamino acid derivatives.
0.87–0.93 (m, 6H). 31P NMR (CD3OD) d 100.8 (d, JRh-P
Z
158.0 Hz); HRMS (cation) m/z calcd for C31H44O4P2Rh
645.1770, found 645.1752; HRMS (anion) m/z calcd for BF4
87.0029, found 87.0021.
4.3. General hydrogenation procedure using 4 or 5
In a glove box, a solution of 0.005 mmol of catalyst in 1 mL
of CH2Cl2 was added 0.5 mmol of substrate. The resulting
mixture was transferred to an autoclave. The hydrogenation
was performed at rt under 3–10 atm of hydrogen for 12–24 h.
The hydrogen was carefully released and the reaction mixture
was passed through a short silica gel plug to remove the
catalyst. The ee were measured by GC with a chiral column
directly without any further purification. The absolute
configurations of the products were determined by comparing
the sign of optical rotation with the reported values.
4. Experimental
4.1. General methods
All reactions and manipulations were performed in a
nitrogen-filled glovebox or using standard schlenk tech-
niques. GC analysis was carried out using chiral capillary
columns: Chirasil-Val III FOST (Dimensions: 30 m!
0.25 mm) for dehydroamino acid derivatives; Chiral Select
1000 column (dimensions: 15 m!0.25 mm) for enamides;
g-225 (dimensions: 30 m!0.25 mm) for itaconic acid
derivatives. Chemical shifts were reported in ppm downfield
from tetramethylsilane with the solvent resonance as the
internal standard.
All the physical characterization data for substrates and
products can be found in Ref. 17 and the references therein.
Acknowledgements
4.2. General procedure for the synthesis of 4 and 5
This work was supported by the National Institutes of
Health. Thanks Dr. Duan Liu and Dr. Wenge Li for the all
the help and advice.
To a solution of Me-ketalphos 1 (135 mg, 0.3 mmol) in
20 mL of methanol was added [Rh(NBD)2]BF4 (112.2 mg,
0.3 mmol) [NBDZnorbornadiene], and the resulting bright
orange solution was stirred at rt for 15 min. Solvent was
removed under reduced pressure.
References and notes
1
4.2.1. Rh(NBD)(1)]BF4. H NMR (360 MHz, CD3OD) d
7.91–7.96 (m, 2H), 7.78–7.82 (m, 2H), 6.13 (s, 2H), 5.91 (s,
2H), 4.72 (dd, JZ8.04, 10.49 Hz, 2H), 4.29 (dd, JZ7.41,
10.31 Hz, 4H), 3.26–3.32 (m, 2H), 2.77–2.86 (m, 2H), 1.93
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Catalysis with Transition Metal Compounds, Vol. 2; VCH
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