Highly Diastereoselective Heterogeneously Catalyzed Hydrogenation of Enamines for the Synthesis of Chiral β-Amino Acid Derivatives

Article abstract of DOI:10.1021/ja038812t

Pure (Z)-enamines readily prepared from β-ketoesters and amides using (S)-phenylglycine amide were hydrogenated with very high diastereoselectivities (up to 200:1) using heterogeneous catalysis. Hydrogenolytic cleavage of the (S)-phenylglycine amide afforded the corresponding chiral β-aminoesters and amides. The high geometrical purity of the (Z)-enamine and a simple activation procedure for the PtO₂ catalyst are essential in achieving high selectivity. Copyright

Full text of DOI:10.1021/ja038812t

Published on Web 02/19/2004
Highly Diastereoselective Heterogeneously Catalyzed Hydrogenation of
Enamines for the Synthesis of Chiral â-Amino Acid Derivatives
Norihiro Ikemoto,* David M. Tellers,* Spencer D. Dreher, Jinchu Liu, Angie Huang, Nelo R. Rivera,*
Eugenia Njolito, Yi Hsiao, J. Christopher McWilliams, J. Michael Williams, Joseph D. Armstrong, III,
Yongkui Sun, David J. Mathre, Edward J. J. Grabowski, and Richard D. Tillyer
Department of Process Research and the Catalysis and Reaction DiscoVery and DeVelopment Lab,
Merck and Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065-0900
Received October 1, 2003; E-mail: norihiro_ikemoto@merck.com
Table 1. Diastereoselective Hydrogenation of (Z)-2
Enantiopure â-amino acids and their derivatives are components
of a variety of important natural products and targets for pharma-
ceutical research.1 A useful method for preparing compounds of
this class in high enantioselectivity involves enantioselective
hydrogenation of the corresponding N-acyl protected dehydro-â-
amino acid derivative (enamine) using a homogeneous chiral
catalyst.2 However, this method typically requires prior separation
of the (Z)- and (E)-enamine isomers from generally poorly selective
mixtures to obtain this high enantioselectivity.3 Also, removal of
the N-acyl protecting group to access free â-aminoesters and amides
after hydrogenation is difficult. An alternative route is the hetero-
geneous diastereoselective hydrogenation of chiral enamines pro-
duced from â-ketoesters and chiral benzylamines followed by
hydrogenolysis of the benzyl group. The limited examples of
auxiliary-based hydrogenation methods appearing in the literature
proceed with low to moderate selectivity (<80% de).4 Despite this,
c
PtO a
(mol %)
additiveb
(mol %)
yield
the heterogeneous approach offers numerous advantages: ease in
separation of product from catalyst, low catalyst cost, catalyst reuse/
recovery, and facile catalytic deprotection. Consequently, there is
still a great impetus to develop asymmetric processes which employ
heterogeneous catalysts. Toward this end, we have developed a
diastereoselective heterogeneous catalytic system that converts
enamines derived from â-ketoesters and amides and chiral phe-
nylglycine amide (PGA) to â-amino acid derivatives in up to 99%
de (200:1 selectivity). This approach has been applied to a variety
of PGA-enamines affording stereoselectivities that are the highest
ever reported for heterogeneous catalysts and are comparable to
those of the best homogeneous catalysts.
We chose to explore the utility of the new chiral amine, (S)-
phenylglycine amide (PGA) (Table 1), as a chiral auxiliary.5 We
anticipated that the carboxamide functionality on phenylglycine
amide would serve as an additional point of coordination with the
heterogeneous catalyst to give a more ordered hydrogenation
transition state leading to higher diastereoselectivity. The (S)-PGA-
enamine esters and amides (2a-k, Table 1) were prepared by
stirring the corresponding â-ketoesters and amides with (S)-PGA
in methanol or 2-propanol in the presence of catalytic amounts of
acetic acid.6 In all examples studied, only the (Z)-enamine isomer
crystallized allowing isolation of the enamine in high geometrical
purity. The ORTEP diagram of 2b confirms the (Z)-enamine
geometry (Figure 1). Of note is the hydrogen bond between the
â-enamine proton and the carbonyl functionalities of the carboxa-
mide and methyl ester, which helps to stabilize the Z-isomer in
preference to the E-isomer.
2
f
entry
2
time
[conv]e
de (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
uw (10)
uw (10)
uw (10)
aw (10)
aw (10)
aw (10)
aw (10)
aw (10)
aw (10)
aw (2.5)
aw (2.5)
aw (50)
aw (50)
aw (50)
aw (10)
aw (10)
3 h
3 h
3 h
3 h
4 h
8 h
2 d
2 d
1 d
12 h
1 d
2 d
3 d
2 d
2 d
2 d
[12%]
92
95
90
97
99
A (100)
A (300)
[100%]
[100%]
[97%]
B (3)
[96%]
87 (66)d
94 (82)
96 (88)
97 (94)
99 (98)
96 (88)
[70%]
96 (3R)g
97 (3S)
98 (3R)
98 (3R, 2S)
99 (3R)
97 (3R)
70 (3S)h
88
85 (46)
[24%]
86 (80)
96 (92)
78
89
97
a aw ) acid washed, uw ) unwashed. b A ) acetic acid, B )
triethylamine. c % assay yield. d % isolated yield (unoptimized). e Reaction
conversion. f Determined by HPLC. g The absolute configuration determined
after debenzylation to the free amine by comparing the sign of optical
rotations. h Assigned from the X-ray structure.
hydrogenation.7 A practical hydrogen pressure of 90 psi was used
at 22 °C. Initially, the reaction was slow using 10 mol % PtO2
(entry 1, Table 1). Acetic acid is often used to accelerate
hydrogenations catalyzed by PtO2 either by activating the catalyst
by dissolving surface bound alkali metals8 or by preventing
deactivation of the catalyst by the product amine.9 Addition of
increasing amounts of acetic acid improved the rate (entries 2, 3)
but resulted in a progressive decline in selectivity. We discovered
that acetic acid in the reaction mixture was undesirable because it
catalyzes isomerization to the less selective (E)-enamine.10 To
circumvent this, we developed a simple procedure involving
washing the catalyst with acetic acid and thoroughly drying the
With a convenient method for preparing the PGA-derived
enamines, we next sought to identify a heterogeneous catalyst.
Preliminary screening indicated that platinum oxide (PtO2, Adam’s
catalyst) in THF was the most active and selective catalyst for this
9
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10.1021/ja038812t CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
significant deuterium incorporation at the carboxamide NH2
(∼60%). These results are consistent with direct reduction of the
CdC bond as the major hydrogenation pathway15 rather than via
an initial isomerization to the imine tautomer followed by reduction
of the CdN bond. Deuterium incorporation at the carboxamide NH2
is consistent with coordination of this group to the catalyst surface,
possibly via the π-orbitals in the conformation seen in the X-ray
structure (Figure 1). In this model, the carboxamide binding with
the bulky phenyl group of PGA disposed away from the metal
surface enhances the diastereoface selective binding of the conju-
gated enamine system.
Thus, a new set of conditions was identified for the preparation
of â-aminoesters and amides via heterogeneous catalysis with
unprecedented diastereoselectivities and good substrate generality.
This approach offers an alternative synthetic strategy to asymmetric
hydrogenation methods.
Figure 1. X-ray structure of 2b.
solid after filtration.11 Thus, not only is the washed catalyst more
active than the unwashed catalyst, but it also significantly improved
the diastereoselectivity in the hydrogenation (entry 1 vs 4). This
catalyst still contained a small amount of residual acetic acid that
led to some isomerization and loss in selectivity. Addition of a
small amount of triethylamine, however, neutralized this acid and
improved the selectivity to a very high 99% de with little impact
on reaction rate (entry 5).
Using the acid washed catalyst, high selectivities were observed
with a wide range of (Z)-enamine esters and amides (Table 1). The
alkyl (R1) tri- and tetra-substituted enamines (2a-f) showed the
highest reactivity and selectivity (97-99% de). The relative
stereochemistry was the same in all of these examples as indicated.12
The aryl enamine esters (2g,i) were generally less reactive and
selective as compared to the electron-rich aryl enamine ester (2h)
and aryl enamine amides (2j,k) which displayed higher rates and
selectivities.
Hydrogenolysis of 3a-f (H2, Pd(OH)2/C, methanol, AcOH)
readily afforded the free alkyl â-aminoesters and amides with
2-phenylacetamide. Hydrogenolysis of the arylamines (3g-k) was
expected to be problematic under these conditions due to the
presence of competing benzylic sites, and, in fact, 3g afforded a
mixture of the desired â-aminoester and a deaminated ester
byproduct (56%).6 Finally, the diastereoselective hydrogenation and
debenzylation can be performed in one pot by simply adding Pd-
(OH)2/C after the enamine hydrogenation with platinum oxide.
The high diastereoselectivities reported here are remarkable
considering the structural complexity of Adam’s catalyst13 and the
reduced Pt. The important role that the PGA carboxamide group
plays is evident from the superior selectivities observed with PGA-
derived enamines as compared to the R-methylbenzylamine-derived
enamines4 and suggests a strong interaction of this group with the
catalyst surface. Invoking the classic Horiuti-Polanyi mechanism,14
selective binding of the back face of the (Z)-enamines 2 to the
catalyst surface, as directed by the coordinating PGA group,
followed by hydrogen transfer from the catalyst to the bound face
of 2 affords 3 with the observed stereochemistry. This diastereo-
facial discrimination is higher with the (Z)-enamines than with the
E-isomers and is enhanced when activated catalyst is used with
less alkali metal impurities present to inhibit hydrogen and substrate
binding.
Acknowledgment. We thank Dr. P. Dormer for NMR spec-
troscopic analysis, Dr. T. Novak for HRMS data, M. Biba and J.
DaSilva for chiral assays, Dr. T. Wang for elemental analysis, and
J. Chilenski for assistance with X-ray data.
Supporting Information Available: Experimental details and
crystallographic data (PDF and CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
References
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(5) PGA is a readily available and useful chiral amine source: Van der Sluis,
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Q. B. Org. Lett. 2001, 3, 3943.
(6) Experimental details are provided in the Supporting Information.
(7) Platinum oxide was found to be superior to all catalysts screened (Pt/C,
Pt/Al, Pd/C, and Pd/Al) in terms of both rate and selectivity.
(8) Keenan, C. W.; Giesemann, B. W.; Smith, H. A. J. Am. Chem. Soc. 1954,
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(10) Hydrogenation of 2a as an 82:18 (Z/E)-mixture afforded only 93% de
under the optimized conditions using acid washed PtO2.
(11) PtO2 (Engelhard, 15 g) was stirred 1 h in glacial acetic acid (50 mL) at
room temperature. The catalyst was filtered, rinsed with glacial acetic
acid (2 × 10 mL), and dried 1 day in a 50 °C vacuum oven. Analysis of
the acetic acid wash showed significant levels of Na and K (∼5 µg each/
mg of PtO2).
(12) Using the (R)-PGA will give the enantiomeric series.
(13) Mansour, A. N.; Sayers, D. E.; Cook, J. W., Jr.; Short, D. R.; Shannon,
R. D.; Katzer, J. R. J. Phys. Chem. 1984, 88, 1778.
To gain further insight into the mechanism of this hydrogenation,
a deuterium labeling study was performed. Reaction of 2a with
deuterium gas (90 psi D2 for 8 h, acid washed PtO2) afforded 3a
with deuterium incorporation at C2 (85%) and C3 (90%) and
(14) Horiuti, I.; Polanyi, M. Trans. Faraday Soc. 1934, 30, 1164.
(15) Syn-facial delivery of hydrogen is assumed and supported by the observed
cis-stereochemistry for 3d.
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