Highly Selective Asymmetric Hydrogenation Using a Three Hindered Quadrant Bisphosphine Rhodium Catalyst

Article abstract of DOI:10.1021/ja048496y

A concise synthesis of both enantiomers of ligand 2 and rhodium complex 5 is presented. The crux of the synthesis is a chiral HPLC separation of the enantiomers of 4. Rhodium complex 5 possesses three hindered quadrants in the steric environment within which a substrate binds. Evidence is presented that this configuration leads to high enantioselectivity (>99% ee) for rhodium-catalyzed asymmetric hydrogenation of α-acetamido dehydroamino acids, 6a-e. High enantioselectivities are also reported for the hydrogenation of a substrate precursor, 8, of pharmaceutical candidate, pregabalin. Advantages for large-scale hydrogenation of 8 using catalyst 5a vs Rh-Me-DuPhos are discussed. Copyright

Full text of DOI:10.1021/ja048496y

Published on Web 04/24/2004
Highly Selective Asymmetric Hydrogenation Using a Three Hindered
Quadrant Bisphosphine Rhodium Catalyst
Garrett Hoge,* He-Ping Wu, William S. Kissel, Derek A. Pflum, Derek J. Greene, and Jian Bao
Pfizer Global Research and DeVelopment, 2800 Plymouth Road, Ann Arbor, Michigan 48105
Received March 15, 2004; E-mail: garrett.hoge@pfizer.com
An academic quest for new and unique chiral phosphine ligands
with properties superior to their predecessors is being driven by a
pharmaceutical industry that is demanding increasingly efficient
catalysts and better enantioselectivities for the manufacture of an
array of chiral products.1 However, many recent advances have
evolved by the manipulation of phosphine ligand structures whose
parent structures have been known for some time.2 Many historically
successful ligands are C2-symmetrical; therefore, C2-symmetry has
remained a popular design for contemporary ligands. One of the
better-known concepts of ligand design is the “quadrant diagram”
of ligand-metal complexes (Figure 1). It has become generally
accepted that chiral C2-symmetrical bisphosphine ligands whose
rhodium catalysts contain two nonadjacent hindered quadrants, such
as Bis-P*,3 1, is a “good” design for potentially high enantiose-
lectivity for the asymmetric hydrogenation of certain substrates.
This trend may have delayed the widespread development of useful
C1-symmetrical bisphosphine ligands and their corresponding
hydrogenation catalysts.4
Figure 1. Quadrant diagram of Rh-1 and Rh-2.
Scheme 1. Synthesis of Ligand 2 and Rhodium Complex 5a
We report the synthesis of ligand 2 and the three hindered
quadrant diagram of its rhodium complex (Figure 1).5,6 A rhodium
complex of 2 is reported to provide high enantioselectivity in
catalyzed asymmetric hydrogenation of R-acetamido dehydroamino
acids as well as a substrate precursor to the pharmaceutical candidate
pregabalin. Advantages are described for the use of the rhodium
complex to catalyze the large-scale hydrogenation of the pregabalin
substrate.
The facile synthesis of both enantiomers of 2 and their corre-
sponding rhodium complexes, 5, is highlighted in Scheme 1.
Synthesis of borane complex 4 was achieved in one step via the
treatment of 3 with s-BuLi to form the methyllithium anion followed
by the addition of di-tert-butylchlorophosphine. Coordination of
the intermediate with borane provided racemic 4 in 55% yield.
Separation via chiral preparatory HPLC produced each enantiomer
of ligand 4 in 90% mass recovery.7
After separation, either enantiomer of ligand 2 could be generated
from 4 via borane deprotection with DABCO in toluene at 80 °C.
However, ligand 2 is sensitive to oxidation via air exposure. Upon
formation, it was convenient to immediately synthesize its rhodium
complex, 5, by reaction with [Rh(COD)2]+ BF4-. Catalyst precursor
5 is stable in air for several hours. The absolute configuration of
5a was determined by X-ray crystallography.8
High enantioselectivities have been achieved using many dif-
ferent chiral ligands in the rhodium-catalyzed asymmetric hydro-
genation of R-acetamido dehydroamino acids. However, use of new
chiral catalysts for the hydrogenation of this class of substrates
provides the appropriate data for the comparison of catalyst
selectivity with established benchmarks. Hydrogenation of substrates
6a-e with 5a provided products 7a-e with near-perfect selectivity
(Table 1). Imamoto et al. previously reported the synthesis of a
similar ligand, 1-((1-adamantyl)methylphosphino)-2-(dicyclohexyl-
phosphino)ethane.4b However, the observed highest enantiomeric
a Reagents and Conditions: (a) (1) s-BuLi, THF, -78 °C; (2) di-tert-
butylchlorophosphine; (3) borane methyl sulfide complex (63% from 3);
(4) chiral preparatory HPLC separation (90% mass recovery); (b) DABCO,
80 °C, 4 h (81%); (c) [Rh(COD)2]+ BF4-, MeOH (64%).
excess (ee) for this ligand in rhodium-catalyzed asymmetric
hydrogenation of R-acetamido dehydroamino acids was 71%.
The practical application of 5a to the asymmetric hydrogenation
of 8 to form 9 is demonstrated in Table 2. Compound 9 can be
converted to pregabalin, a pharmaceutical used to treat epilepsy
and pain, as described previously.9 Using mild conditions (1 mol
% 5a, 45 psi H2), the transformation provided 9 as the sole product
of the hydrogenation in 99% ee (entry 1). Results have been reported
for the use of (R,R)-Rh-Me-DuPhos to catalyze this transforma-
tion.9,10 Entry 2 shows that (R,R)-Rh-Me-DuPhos is capable of
similarly high enantioselectivities under mild conditions.
Selectivity is an important factor that is considered in large-
scale asymmetric hydrogenation process research. However, many
other factors contribute to the final decision to apply a particular
catalyst in large-scale production. We examined two variables for
9
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J. AM. CHEM. SOC. 2004, 126, 5966-5967
10.1021/ja048496y CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Asymmetric Hydrogenation of R-Acetamido
Dehydroamino Acids Using 5a as Catalyst
study, our report may also have implications for the mechanistic
understanding of asymmetric hydrogenation selectivity. Applications
of 5 to the gamut of asymmetric hydrogenation substrate classes
are currently under investigation.
Acknowledgment. Pfizer, Inc. is acknowledged for continuing
support of this research. We thank Jon Bordner, Ivan Samardjiev,
and Brian Samas for assistance with X-ray crystallography.
1
2
3
entrya
substrate
R
R
R
eeb (%)
config.
1
2
3
4
5
6a
6b
6c
6d
6e
H
H
H
H
H
H
H
>99
>99
>99
>99
99
R
R
R
R
R
Supporting Information Available: Materials and methods, syn-
thetic procedures for 2-5, and the chiral preparatory HPLC separation
method for the enantiomers of 4. X-ray crystallographic data for 5a
(CIF). This material is available free of charge via the Internet at http://
pubs.acs.org.
Ph
H
Ph
Me
Me
Me
R2,R3 ) -C5H10-
a Reactions were performed on 1 mmol substrate at room temperature
with a substrate concentration of 0.2 M. Each was complete within 5 min.
b Enantiomeric excesses were determined via chiral HPLC or GC as
described in the Supporting Information.
References
(1) Reviews: (a) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029. (b)
Ohkuma, T.; Kitamura, M.; Noyori, R. In Catalytic Asymmetric Synthesis,
2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000; pp 1-110. (c)
Brown, J. M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.,
Pfalz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, 1999; Vol. I,
pp 121-182.
Table 2. Asymmetric Hydrogenation of 8: 5a vs
(R,R)-Rh-Me-DuPhos
(2) An excellent example is the development of an extraordinary number of
phospholane ligands, all of which are based on the DuPhos structure. For
a discussion on this topic, see: Hoge, G. J. Am. Chem. Soc. 2003, 125,
10219.
(3) Imamoto, T.; Watanabe, J.; Wada, Y.; Masuda, H.; Yamada, H.; Tsuruta,
H.; Matsukawa, S.; Yamaguchi, K. J. Am. Chem. Soc. 1998, 120, 1635.
(4) There have been reports of useful ligands that break the C2-symmetry
mold; however, cohesive models remain elusive for C1-symmetrical ligands
with respect to steric environments of the ligands and their corresponding
catalysts that translate to high enantioselectivity during hydrogenation.
See: (a) Blaser, H.; Brieden, W.; Pugin, B.; Spindler, F.; Studer, M.;
Togni, A. Top. Catal. 2002, 19, 3. (b) Ohashi, A.; Kikuchi, S.; Yasutake,
M.; Imamoto, T. Eur. J. Org. Chem. 2002, 15, 2535. (c) Matsumura, K.;
Shimizu, H.; Saito, T.; Kumobayashi, H. AdV. Synth. Catal. 2003, 345,
180.
(5) Ligand 2 is referred to as “Trichickenfootphos” in Pfizer laboratories.
This name is derived from visual inspection of the ligand and the
association of tert-butyl groups with chicken feet.
(6) We have also succeeded in synthesizing 1-(tert-butylmethylphosphino)-
2-(di-tert-butylphosphino)ethane. This ligand produces enantioselectivities
similar to those of 2 in the rhodium-catalyzed asymmetric hydrogenation
of R-acetamido dehydroamino acids.
(7) Despite the stigma associated with chiral preparatory HPLC separations,
this type of separation is becoming increasingly important to the
pharmaceutical industry. That 4 contains one chiral center makes it ideal
for a chiral separation-based synthesis as well as a strong candidate for
production-scale separation via simulated moving bed (SMB) chroma-
tography. See: Welch, W. M.; Ewing, F. E.; Huang, J.; Menniti, F. S.;
Pagnozzi, M. J.; Kelly, K.; Seymour, P. A.; Guanowsky, V.; Guhan, S.;
Guinn, M. R.; Critchett, D.; Lazzaro, J.; Ganong, A. H.; DeVries, K. M.;
Staigers, T. L.; Chenard, B. L. Bioorg. Med. Chem. Lett. 2001, 11, 177.
(8) Interestingly, Imamoto’s methylene-bridged MiniPHOS ligand can only
be synthesized in bischelate form. No bischelate complex was observed
during the synthesis of 5. See: Yamanoi, Y.; Imamoto, T. J. Org. Chem.
1999, 64, 2988.
(9) Burk, M. J.; De Koning, P. D.; Grote, T. M.; Hoekstra, M. S.; Hoge, G.;
Jennings, R. A.; Kissel, W. S.; Le, T. V.; Lennon, I. C.; Mulhern, T. A.;
Ramsden, J. A.; Wade, R. A. J. Org. Chem. 2003, 68, 5731.
(10) (R,R)-Rh-Me-DuPhos ) (-)-1,2-bis((2R,5R)-2,5-dimethylphospholano)-
benzene(cyclooctadiene)rhodium (I) tetrafluoroborate.
(11) Concentration is an important factor in large-scale hydrogenation because
it determines the amount of product that can be produced in a finite reactor
volume.
substrate
psi
eee
(%)
c
entrya
catalyst
concb (%)
S/C
H
2
timed
1
2
3
4
5a
6
6
10
20
100 45 <15 min 99
100 90 <15 min 95
2700 45
(R,R)-Rh-Me-DuPhos
(R,R)-Rh-Me-DuPhos
5a
4 h
40 h
97
98
27000 50
a (R,R)-Rh-Me-DuPhos reactions were performed at 55 °C, while 5a
reactions were performed at room temperature. b Substrate concentration
in MeOH (w/w %). c Substrate:catalyst molar ratio. d Time at which gas
uptake had ceased. All entries afforded >98% conversions at this time.
e Enantiomeric excesses were determined via chiral GC as described in the
Supporting Information. All experiments afforded the S configuration.
the hydrogenation of 8 to contrast the properties of 5a and (R,R)-
Rh-Me-DuPhos: substrate concentration11 and catalyst loading. The
results utilizing catalyst precursor 5a were superior to those reported
for (R,R)-Rh-Me-DuPhos (entry 3)9 in both respects. Catalyst
precursor 5a is capable of producing 9 in 98% ee (100-g scale)
using two times more concentrated reaction solutions and one-tenth
of the reported catalyst loading (entry 4). Exploitation of these
factors could have a profound impact on the cost of goods for
producing a pharmaceutical on a scale that is appropriate for
worldwide consumption.
In conclusion, a facile synthetic route to both enantiomers of
ligand 2 and rhodium complex 5 was presented. Results reported
for the use of 5 in the asymmetric hydrogenation of R-acetamido
dehydroamino acids as well as a pregabalin substrate precursor
provide support for association of high enantiomeric excesses with
the three hindered quadrant motif exhibited by the catalyst.12
Although this communication does not contain a catalytic cycle
(12) No commentary on the mechanism of asymmetric hydrogenation using
this catalyst is being presented at this time; however, we feel that it is
prudent to associate the ligand and its design, the three hindered quadrant
motif, with high enantioselectivity for the demonstrated substrate classes.
JA048496Y
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