Highly efficient synthesis of β-amino acid derivatives via asymmetric hydrogenation of unprotected enamines

Article abstract of DOI:10.1021/ja047901i

A direct asymmetric hydrogenation of unprotected enamino esters and amides is described. Catalyzed by Rh complexes with Josiphos-type chiral ligands, this method gives β-amino esters and amides in high yield and high ee (93-97% ee). No acyl protection/deprotection is required. Copyright

Full text of DOI:10.1021/ja047901i

Published on Web 07/21/2004
Highly Efficient Synthesis of â-Amino Acid Derivatives via Asymmetric
Hydrogenation of Unprotected Enamines
Yi Hsiao,*,† Nelo R. Rivera,*,† Thorsten Rosner,*,† Shane W. Krska,† Eugenia Njolito,† Fang Wang,‡
Yongkui Sun,† Joseph D. Armstrong, III,† Edward J. J. Grabowski,† Richard D. Tillyer,†
Felix Spindler,§ and Christophe Malan§
Departments of Process Research and Analytical Research, Merck Research Laboratories, Merck and Co., Inc.,
Rahway, New Jersey 07065, and SolVias AG, P.O. Box 4002, Basel, Switzerland
Received April 12, 2004; E-mail: yi_xiao@merck.com; nelo_rivera@merck.com; thorsten_rosner@merck.com
Scheme 1. Asymmetric Hydrogenation of Unprotected Enamines
â-Amino acids have found extensive application in the life
sciences as components of biologically active peptides and small-
molecule pharmaceuticals.1 Synthetic derivatives of biologically
relevant peptides incorporating â-amino acids often display interest-
ing pharmacological activity, with increased potency and enzymatic
stability relative to their native counterparts, and have played im-
portant roles in advancing the understanding of enzyme mecha-
nisms, protein conformations, and properties related to molecular
recognition.2 In organic synthesis, â-amino acids are commonly
used as chiral building blocks,3 and a great deal of research has
focused on facile, practical, and scalable methods for their prepara-
tion.4,5
Given its inherent efficiency and atom economy,6 catalytic
asymmetric hydrogenation would seem to be an ideal approach to
Table 1. Asymmetric Hydrogenation of 1aa
c
entry
ligand
yieldb % ee % configuration
preparing enantiopure â-amino acids. Indeed, such methods are
among the most studied and widely applied for the enantioselective
preparation of R-amino acids.7-9 Yet, despite significant advance-
ments in recent years,10 asymmetric hydrogenation has yet to find
application in the large-scale preparation of enantiopure â-amino
acids.11 Their practical preparation still relies on the resolution of
racemates12 or the use of chiral auxiliaries.13
One significant drawback to current approaches to asymmetric
hydrogenation of unsaturated â-amino acids is the requirement of
an acyl protecting group on the nitrogen: this group is considered
indispensable to satisfy the chelation requirement between the
substrate and the metal, leading to high reactivity and selectivity.14,15
Direct acylation of enamines is not a trivial chemical transformation,
and there are no other efficient methods for enamide synthesis.16
In addition, removal of the acyl group often requires heating in
strongly acidic or basic conditions, which may be incompatible with
other functional groups in the molecule. The difficulty and redun-
dancy of introduction and removal of the acetamide group has
seriously limited the use of this otherwise powerful synthetic
method.
We report here the first general method of high-yielding, highly
enantioselective hydrogenations of unprotected â-enamine esters
1 and amides 3 (Scheme 1).17 This transformation obviates the need
for N-protecting group chemistry, directly yielding the desired
â-amino acid derivative. The â-enamino esters (1) and amides (3)
are easily prepared in high yield by reaction of NH4OAc with the
corresponding readily available â-keto esters and amides.18,19 Both
are obtained exclusively as the (Z)-isomer via direct crystallization
from the reaction mixture.20
1
2
3
4
5
[((R,R)-DiPAMP)Rh(cod)]BF4
[((S,S)-Me-DuPHOS)Rh(cod)]BF4
(S)-BINAPHANE/[Rh(cod)]Cl]2
(S)-f-BINAPHANE/[Rh(cod)]Cl]2
(S)-C1-TUNEPHOS/[Rh(cod)]Cl]2
[((R,R)-Et-FerroTANE)Rh(cod)]BF4
(R)-(S)-I/[Rh(cod)]Cl]2
0.1
71.4
11.1
77.3
8.9
77.0
93.7
trace
57.6
15.0
0.9
9.3
10.8
9.8
2.4
88.0
96.1
S
R
S
S
R
S
6
7d
8e
9
(R)-(S)-I/[Rh(cod)]Cl]2
(R)-PHANEPHOS/[Rh(cod)]Cl]2
(+)-TMBTP/[Rh(cod)]Cl]2
((S)-BINAP)RuCl2
(R)-(S)-I/[Ir(cod)Cl]2
(R)-(S)-II/[Ir(cod)Cl]2
76.2
78.4
R
S
10
11
12
13
2.8
11.2
84.7
S
a Reaction conditions: in 2,2,2-trifluoroethanol (TFE), S/C ) 20, 1:1
ligand/metal, 90 psig H2, 50 °C, 18 h. For information on the ligands, see
Supporting Information. b Assayed by HPLC. c Assayed by chiral HPLC.
d With 1 mol % catalyst. e In MeOH.
Not surprisingly, a number of the metal-ligand complexes
screened gave poor results. The Rh-ferrocenophosphine (I)
complex, however, gave good conversion and enantiomeric excess.
Further examination of a number of other Josiphos-type ligands
with varying electronic and steric properties revealed that for ester
1a, ligand I gave the best results in terms of conversion and
enantioselectivity. With these encouraging results, we proceeded
to investigate the scope of this reaction on both enamine esters
and enamine amides.
Exploratory catalyst screening employed â-enamino ester 1a and
a diverse array of commercially available catalysts and nonracemic
ligands. Representative results are summarized in Table 1.
As shown in Table 2, a wide variety of unprotected enamine
esters and amides all gave the corresponding â-amino acid
derivatives in high yield with good to excellent enantioselectivity
† Department of Process Research, Merck and Co., Inc.
‡ Department of Analytical Research, Merck and Co., Inc.
§ Solvias AG.
9
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J. AM. CHEM. SOC. 2004, 126, 9918-9919
10.1021/ja047901i CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Hydrogenation of Enamine Esters and
our hope that this discovery will provide a practical and efficient
method for the large-scale preparation of â-amino acids and their
derivatives.
Amidesa
time
h
yield
%
ee
%
b
entry
enamine
ligand
solvent
configuration
Acknowledgment. We thank Ms. Lisa DiMichele for assistance
with NMR spectra, Mr. Roy Helmy for LCMS data, and Dr.
Thomas J. Novak for HRMS data.
1
2
3
4
5
1a
1a
1b
1c
1d
1e
3a
3a
3b
3c
3d
I
I
I
I
I
I
II
II
II
II
II
TFE
MeOH
TFE
TFE
TFE
TFE
MeOH
TFE
MeOH
MeOH
MeOH
6
18
11
11
11
24
8
18
8
8
97.6
trace
87.5
85.4c
94.4
90.5
74.6
94.1
82.0
74.3
94.0
96.1
S
95.0
96.1
93.3
95.7
95.6
82.2
96.3
96.0
97.1
S
(-)
R
(-)
(-)
(-)
(+)
(+)
(-)
Supporting Information Available: General procedures for syn-
thesis of enamines and their hydrogenations; physical characterization
data for substrates and products (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
6
7
8d
9e
10
11
References
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G. C., Ed.; Chapman and Hall: New York, 1985; Chapter 3.
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8
a Reaction conditions: 0.15 mol % [(COD)RhCl]2, 0.3 mol % ligand,
50 °C, 90-100 psig H2. b Assay yield. c Isolated yield. d With 1 mol %
catalyst. e With 0.7 mol % catalyst.
(3) Cardillo, G.; Tomasini, C. Chem. Soc. ReV. 1996, 117-128.
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using only 0.3 mol % catalyst under relatively mild conditions (100
psig H2). Ligand I gave the best results in the hydrogenation of
enamine esters, while ligand II gave the highest rates and
enantioselectivities for the hydrogenation of enamine amides.
Interestingly, this catalytic system exhibited a high sensitivity to
solvent. For hydrogenation of enamine esters, TFE is preferred for
high reactivity and selectivity. In MeOH, however, the reaction
was almost totally inhibited (entry 2 in Table 2). On the other hand,
the hydrogenations of enamine amides gave much higher selectivity
in MeOH than in TFE (entry 8). It is believed that the solvent acidity
plays an important role in the reaction.21
The success of this hydrogenation method despite the lack of a
directing N-acyl group on the substrate begs the question of what
sort of mechanism is operative that gives high rates of reaction
and high enantiofacial selectivity in the Rh-H insertion step.
Mechanistic studies are ongoing and will be reported in due course.
However, preliminary results of deuterium labeling studies suggest
the intriguing possibility that the reaction proceeds through the imine
tautomer, making this reaction mechanistically analogous to â-ke-
toester and -amide hydrogenations.8,22
(5) For the latest review, see: Ma, J.-A. Angew. Chem., Int. Ed. 2003, 42,
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(9) For example, the classic L-DOPA synthesis: Knowles, W. S. Acc. Chem.
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Process Res. DeV. 2003, 7, 866.
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(16) Burk, M. J.; Casy, G.; Johnson, N. B. J. Org. Chem. 1998, 63, 6084.
(17) For previous examples of asymmetric hydrogenation of electron-rich
N-alkyl and N,N-dialkyl enamines, see: (a) Lee, N. E.; Buchwald, S. L.
J. Am. Chem. Soc. 1994, 116, 5985. (b) Tararov, V. I.; Kadyrov, R.;
Riermeier, T. H.; Holz, J.; Bo¨rner, A. Tetrahedron Lett. 2000, 41, 2351.
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Kumobayashi, H. U.S. Patent 5859249, 1999.
(18) Commercially unavailable â-keto esters were prepared via the Masamune
protocol: Brooks, D. W.; Lu, L. D.-L.; Masamune, S. Angew Chem., Int.
Ed. Engl. 1979, 18, 72.
(19) Simple amide exchange of the â-keto esters gives the corresponding
amides: Kibler, C. J.; Weissverger, A. Org. Synth. Collect. Vol. III, 108.
(20) It is postulated that the intramolecular hydrogen bond dictates this
phenomenon. The (Z)-conformation of the substrates is confirmed by NMR
(NOE).
In summary, we have discovered an unprecedented enantiose-
lective reduction of unprotected enamino esters and amides using
commercially available ligands under mild hydrogenation condi-
tions. This method gives high enantioselectivity, high reactivity,
and wide applicability and requires no protecting groups. Contrary
to accepted thinking, our results clearly show that the N-acyl group
is not a prerequisite for such transformations to be effected. It is
(21) The effect of TFE in enamine ester hydrogenations can be mimicked by
other acidic alcohols such as phenol derivatives.
(22) When amide 3a was reduced in MeOH with D2 using catalyst II/[(COD)-
RhCl]2, we observed D-incorporation only in the â-position.
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