Expanding the family of phospholane-based ligands: 1,2-bis(2,5-diphenylphospholano)ethane

Article abstract of DOI:10.1021/ol0341952

(Matrix presented) 1,2-Bis(2,5-diphenylphospholano)ethane (Ph-BPE) has been synthesized for the first time through employment of an undemanding synthetic pathway. The new ligand exhibits enhanced activity and selectivity over the existing members of the B

Full text of DOI:10.1021/ol0341952

ORGANIC
LETTERS
2003
Vol. 5, No. 8
1273-1275
Expanding the Family of
Phospholane-Based Ligands:
1,2-Bis(2,5-diphenylphospholano)ethane
Christopher J. Pilkington* and Antonio Zanotti-Gerosa
Dowpharma, Chirotech Technology Ltd., a Subsidiary of The Dow Chemical Company,
Unit 321, Cambridge Science Park, Milton Road, Cambridge, CB4 0WG, UK
ilennon@dow.com
Received February 4, 2003
ABSTRACT
1,2-Bis(2,5-diphenylphospholano)ethane (Ph-BPE) has been synthesized for the first time through employment of an undemanding synthetic
pathway. The new ligand exhibits enhanced activity and selectivity over the existing members of the BPE ligand family in rhodium-catalyzed
asymmetric hydrogenation.
Asymmetric hydrogenation using transition metal complexes
represents one of the most effective methods for the synthesis
of optically active compounds.1 The complexes of the 1,2-
bis(2,5-dialkylphospholano)ethane (BPE) 1 and 1,2-bis(2,5-
dialkylphospholano)benzene (DuPHOS) 2 ligands (Figure 1),
first reported by Burk,2 have proven to be invaluable in this
field. These ligands, featuring a 2,5-disubstituted phospholane
structural motif, have essentially solved the problem of the
asymmetric hydrogenation of dehydroamino acids.3 Further-
more, the combination of robustness, high activity, and
excellent selectivity renders these ligands suitable for large-
scale industrial application.4 The practicality of phospholane
ligands is confirmed by the ever-growing number of struc-
tural analogues reported in the literature.5
(1) (a) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz,
A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vols. I-III. (b) Noyori,
R. Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New
York, 1993.
(2) (a) Burk, M. J.; Feaster, J. E.; Harlow, R. L. Organometallics 1990,
10, 2653. (b) Burk, M. J.; Feaster, J. E.; Harlow, R. L. Tetrahedron:
Asymmetry 1991, 2, 569. (c) Burk, M. J. J. Am. Chem. Soc. 1991, 113,
8518.
(3) Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am.
Chem. Soc. 1993, 115, 10125.
(4) Blaser, H. U.; Spindler, F.; Studer, M. Applied Catalysis A: General
2001, 221, 119.
(5) (a) Holz, J.; Quirmbach, M.; Schmidt, U.; Heller, D.; Stu¨rmer, R.;
Bo¨rner, A. J. Org. Chem. 1998, 63, 8031. (b) Yan, Y-. Y.; RajanBabu, T.
V. J. Org. Chem. 2000, 63, 900. (c) Li, W.; Zhang, Z.; Xiao, D.; Zhang, X.
J. Org. Chem. 2000, 63, 3489.
Figure 1. 2,5-Disubstituted phospholane ligands.
10.1021/ol0341952 CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/25/2003

The possibility of accessing phospholane units with
different substituents at the 2- and 5-positions has allowed
the steric fine-tuning necessary to obtain the best results over
a wide range of substrates.6 For example, Me-DuPHOS and
Et-DuPHOS (2a and 2b, respectively) usually provide the
best rhodium catalysts for the asymmetric hydrogenation of
dehydroamino acids3 and â-monosubstituted itaconates,7
while Me-BPE 1a is the ligand of choice for the rhodium-
catalyzed hydrogenation of â,â-disubstituted itaconates.7
An obvious modular extension to the 2,5-disubstituted
bisphospholane family of ligands are the aryl analogues.
However, these ligands have so far proved to be elusive.
The preferred method for the preparation of the dialkyl
phospholanes is the reaction of an appropriately substituted
cyclic sulfate, derived from the corresponding enantiomeri-
cally pure diol, with a lithiated phosphide.3 However, with
diaryl cyclic sulfates and dimesylates elimination or race-
mization is observed. The avoidance of such problems in
the formation of a 2,5-diphenyl phospholane unit has been
addressed in recent disclosures by Fiaud and co-workers on
the synthesis of 1-phenyl-2,5-diphenylphospholane 3.8 Using
these key publications as impetus, we endeavored to syn-
thesize the chiral phospholane ligand 1,2-bis(2,5-phenylphos-
pholano)ethane (Ph-BPE) 4 from phospholanic acid 5.
Herein, we report the synthesis of the Ph-BPE ligand and
its use in rhodium-catalyzed asymmetric hydrogenation.
The enantiomerically pure phospholanic acid 5 was
prepared and resolved according to the method reported by
Fiaud.8 Scheme 1 depicts the series of steps that led us from
framework was then accomplished by deprotonation of
adduct 6 with n-BuLi and reaction with 1,2-ethylene di-
tosylate to give bisphospholane 7. No formation of the
unwanted meso-compound was detected at this stage. The
formation of Ph-BPE 410 was finally realized by deprotection
of 7 with HBF4.11 The optical purity of Ph-BPE 4 was
confirmed by oxidation of a sample to the corresponding
phosphino-oxide and analysis by chiral HPLC.12
This pathway represents a reversal of the established
strategy for the synthesis of bidentate phospholane-based
ligands. The phospholane ring is constructed as a distinct
entity prior to attachment to the backbone rather than being
assembled at the end of the synthesis.
With the long sought after Ph-BPE ligand in hand, we
were able to test its performance in homogeneous asymmetric
hydrogenation and compare it with the other members of
the BPE ligand family. To this end, the rhodium complex
[(R,R)-Ph-BPE Rh COD]BF4 was prepared by reaction of
the free ligand with [Rh(COD)2]BF4 and tested against a
series of substrates.
Hydrogenation of methyl acetamidocinnamate 8 at a molar
substrate-to-catalyst ratio (S/C) of 3000 immediately indi-
cated that substantially improved activity and selectivity is
achieved with the Ph-BPE rhodium catalyst compared with
the other BPE rhodium catalysts (Table 1). The level of
Table 1. Asymmetric Hydrogenation of Methyl
Acetamido-cinnamate Using Rhodium BPE Catalystsa
Scheme 1. Preparation of the Ph-BPE Liganda
entry
ligand
time (min)
conversion (%)c
ee (%)c
1
2
3
4
(R,R)-1a
(R,R)-1b
(S,S)-1c
(R,R)-4
90
120
840
75
100
100
83
85 (R)d
88 (R)
94 (R)
99 (S)
100
a Reactions were performed simultaneously in an Argonaut Endeavor
reaction vessel with 1.5 M solutions of substrate in MeOH at 28 °C under
10 bar hydrogen pressure. b Molar substrate-to-catalyst ratio. c Conversion
and enantiomeric excess were determined by chiral GC. d Product stereo-
chemistry and enantioselectivity are consistent with that stated in ref 2b.
a Reagents and conditions: (a) (i) PhSiH3, toluene, 110 °C, 16
h; (ii) BH3‚SMe2, THF, from 0 °C to rt (95%). (b) n-BuLi, THF,
from -78 °C to rt, 30 min, then TsOCH2CH2OTs, THF, rt, 40 h
(69%). (c) HBF4‚OMe2, CH2Cl2, rt, 16 h (92%).
selectivity (99% ee) is comparable to that obtained with the
best DuPHOS ligands.13 Surprisingly, i-Pr-BPE gave much
lower activity than expected.
phospholanic acid 5 to Ph-BPE 4. Phospholanic acid 5 was
reduced using PhSiH3 and subsequently treated with BH3‚
SMe2 to afford borane adduct 6. Synthesis of the BPE
(10) 1H NMR (400 MHz, CDCl3) δ 0.57 (m, 2H), 0.96 (m, 2H), 1.76-
1.86 (m, 2H), 2.05-2.15 (m, 2H), 2.27 (m, 2H), 2.48 (m, 2H), 2.95 (m,
2H), 3.59 (m, 2H), 7.08 (m, 6H), 7.16 (m, 4H), 7.21 (m, 6H), 7.30 (m,
4H); 31P NMR (162 MHz, CDCl3) δ 16.01; 13C NMR (100.6 MHz, CDCl3)
δ 21.45 (dd, JCP ) 36.0 Hz, JCCP ) 27.1 Hz, bridge CH2), 31.92 (s, ring
CH2), 37.38 (s, ring CH2), 46.15 (m, ring CH), 50.57 (m, ring CH), 125.75
(s), 125.83 (s), 127.25 (s), 127.86 (m), 128.30 (s), 128.53 (s), 138.33 (m,
ipso-CAr), 144.65 (m, ipso-CAr); HRMS (EI) m/z calcd for C34H36P2
506.2292, found 506.2269; [R]D ) -174.9 (c ) 0.3, CH2Cl2).
(11) McKinstry, L.; Livinghouse, T. Tetrahedron 1995, 51, 7655.
(12) Chialpak AD-H (250 × 4.6 mm), heptane/EtOH 80/20, 1 mL/min,
25°C, detection by UV at 210 nm: 9.5 min (S,S), 15.2 min (R,R), 22.9 min
(meso); >98% ee.
9
(6) Burk, M. J. Acc. Chem. Res. 2000, 33, 363.
(7) Burk, M. J.; Bienewald, F.; Harris, M.; Zanotti-Gerosa, A. Angew.
Chem., Int. Ed. 1998, 37, 1931.
(8) (a) Guillen, F.; Fiaud, J-. C. Tetrahedron Lett. 1999, 40, 2939. (b)
Guillen, F.; Rivard, M.; Toffano, M.; Legros, J-. Y.; Daran, J-. C.; Fiaud,
J-. C. Tetrahedron 2002, 58, 5895.
(9) Soulier, E.; Cle´ment, J-. C.; Yaouanc, J-. J.; des Abbayes, H.
Tetrahedron Lett. 1998, 39, 4291.
1274
Org. Lett., Vol. 5, No. 8, 2003

The same trend was observed in the hydrogenation of
dimethyl itaconate 9 (Table 2). The reaction was tested at
Table 2. Asymmetric Hydrogenation of Dimethyl Itaconate
Using Rhodium BPE Catalystsa
Figure 2. Further hydrogenation substrates screened against Ph-
BPE 4.17
entry
ligand
time (min)
conversion (%)c
ee (%)c
10 and N-(1-phenylvinyl)acetamide 11 gave 99% ee with
full conversion. The Candoxatril precursor 12 was chosen
as an example of a substrate where asymmetric hydrogena-
tion has proved to be industrially valid.14 The ee for this
hydrogenation represents an improvement over the selectivity
obtained previously with other rhodium BPE catalysts and
is comparable with DuPHOS-based catalysts.15
In summary, we have reported the first preparation of the
ligand Ph-BPE 4 that exploits a synthetic route that concep-
tually differs from the established BPE ligand synthesis. The
replacement with phenyl groups of the alkyl substituents at
positions 2 and 5 of the phospholane ring has produced in
all of the cases examined a substantial increase in both the
activity and the selectivity obtainable in rhodium-catalyzed
asymmetric hydrogenation. The synthesis of other phenyl-
phospholane-based bisphosphine ligands is under way and
will be reported in due course.
1
2
3
4
(R,R)-1a
(R,R)-1b
(R,R)-1c
(R,R)-4
(R,R)-4
30
30
840
25
100
100
61
100
100
91 (R)
95 (R)
50 (S)
99 (S)
99 (S)
5d
10
a Reactions were performed simultaneously in an Argonaut Endeavor
reaction vessel with 2.5 M solutions of substrate in MeOH at 28 °C under
10 bar hydrogen pressure. b Molar substrate-to-catalyst ratio. c Conversion
and enantiomeric excess were determined by chiral GC. d Reaction was run
at a S/C of 10 000 in an impeller-stirred 300 mL reaction vessel; more
efficient stirring provides increased mass-transfer.
S/C ) 5000, and again the Ph-BPE Rh catalyst was found
to be the most active and by far the most selective of the
BPE-based catalysts. Low selectivity and low activity were
attained using i-Pr-BPE as the ligand. The high activity of
the Ph-BPE rhodium catalyst was further demonstrated by
reaction with dimethyl itaconate 9 at S/C ) 100 000. The
hydrogenation of 50 g of substrate went to completion
overnight with an ee of 99% (Scheme 2).
Acknowledgment. We thank Catherine Rippe, Natasha
Cheeseman, Jonathan Hill, and Brendan Mullen of Chiro-
tech’s analytical team for their skilled technical assistance.
We also thank Dr. Steve Challenger and Pfizer Ltd., for their
supply of the Candoxatril precursor.
Scheme 2. Asymmetric Hydrogenation of Dimethyl Itaconate
with Rhodium Ph-BPE 416
Supporting Information Available: Detailed experi-
mental procedures and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0341952
(14) Burk, M. J.; Bienewald, F.; Challenger, S.; Derrick, A.; Ramsden,
J. A. J. Org. Chem. 1999, 64, 3290.
(15) [(S,S)-Me-BPE Rh COD]BF4 80% ee; [(S,S)-Et-BPE Rh COD]BF4
97% ee; [(S,S)-i-Pr-BPE Rh COD]BF4 92% ee; see ref 14 for further details.
(16) Reactions were performed in a thermostated 300 mL reaction vessel
with 50 g of substrate in MeOH at 25°C under 10 bar hydrogen pressure.
The substrate was used as bought from Acros, 97% purity. S/C denotes
molar substrate-to-catalyst ratio. Conversion and enantiomeric excess were
determined by chiral GC.
(17) Reactions were performed in a 50 mL reaction vessel with 0.8-1
M solutions of substrate in MeOH at 25°C under 10 bar hydrogen pressure.
S/C denotes molar substrate-to-catalyst ratio. Conversion and enantiomeric
excess were determined by chiral GC or chiral HPLC.
The scope of the Ph-BPE rhodium catalyst’s utility was
further probed by hydrogenation of other substrates (Figure
2). The hydrogenation of both methyl 2-acetamidoacrylate
(13) Under the same conditions Me-DuPHOS produced an ee of 98%,
while Et-DuPHOS gave an ee > 99%.
Org. Lett., Vol. 5, No. 8, 2003
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